Pharmacology

General Pharmacological Principles

Definitions, Routes of Drug Administration

LONG ESSAYS

Describe the routes of drug administration. Their merits and demerits with suitable
examples.
Drugs can be administered by a variety of routes. The choice of an appropriate route depends both on the drug as well
as patient-related factors.
Routes of drug administration can be classified into two major categories as follows:
Systemic
Oral
Sublingual
Rectal
Cutaneous
Inhalation
Parenteral
Local
Topical
For deeper tissues
Arterial supply
SYSTEMIC ROUTES
Drugs intended to directly enter the bloodstream and distributed all over the body through circulation including the site of
action are administered systemically.
Various systemic routes of drug administration are as follows:
Oral Route
Drugs available in solid dosage forms like capsules, spansules, dragees, powders, tablets and liquid forms like elixirs, syrups,
emulsions can be given orally.
Merits
Safer More convenient Noninvasive and painless
Assistance not required
Cheap
May be destroyed by gastric juices, or amount is con-
siderably reduced in first-pass metabolism.
Demerits
Action is slower, not suitable for emergencies. Unpalatable drugs are difficult to administer.
Can cause nausea or vomiting, may stain the teeth, leave an unpleasant taste. Certain drugs may not be absorbed, e.g.
streptomycin.
361
Sublingual Route
Here the tablet or pellet is placed under the tongue. Drug is directly absorbed into the circulation. Example: Glyceryl trinitrate,
buprenorphine, desamino-oxytocin
Merits
First-pass metabolism is bypassed.
Once desired effect is achieved the drug can be spat out. Rapid rate of absorption
Demerits
 Only lipid-soluble nonirritating drugs can be used. Inconvenient to the patient.
Rectal Route
Certain irritant and unpleasant drugs can be put into the rectum as suppositories or retention enema for systemic effect. For
example: Aminophylline, indomethacin, diazepam and ergotamine are a few of them.
Merits
Used in patients having recurrent vomiting. Bypass first-pass metabolism.
Demerits
Highly inconvenient and embarrassing Absorption is slow and unpredictable. May cause rectal inflammation.
Cutaneous Route
Highly lipid-soluble drugs are applied over the skin for low and prolonged action. First-pass metabolism in the liver is also
bypassed. Drug can be incorporated in an ointment and applied over specific areas of the skin. For example: Betamethasone
(Betnovate-C)
Transdermal Patches
These are the recent devices in the form of adhesive patches of various shapes and sizes which deliver the drug at a constant
controlled rate into the systemic circulation.
The drug is held in between an occlusive backing film and a rate controlling micropore membrane whose undersurface is
smeared with adhesive impregnated with priming dose of drug that is protected by another film to be peeled off just before
application.
The drug is absorbed percutaneously.
Usual sites of application are chest, abdomen, upper arm, lower back, behind the ear, buttock and mastoid region. For example:
Glyceryl trinitrate, fentanyl, nicotine, and oestradiol
Merits
Rate of drug delivery is constant. Patient compliance is better. Interindividual variations are reduced. Provides
smooth plasma concentrations without fluctuation.
Demerits
Mild irritation and erythema is possible that can be
overcome by changing the site.
Inhalation
Volatile liquids and gases are given by this route for systemic effects. For example: General anaesthetic agents
Merits
Quick onset of action. Very less dose is required. We can regulate the amount of drug administered.
Demerits
Local irritation leading to increased respiratory secre-
tions and bronchospasm.
Parenteral Route
Refers to drugs injected directly into tissue fluid or blood without having to cross the intestinal mucosa.
Merits
Drug action is faster and surer.
Gastric irritation and vomiting is not provoked. Can be used in unconscious, uncooperative patients. First-
pass metabolism is bypassed in the liver.
Demerits
Chances of systemic toxicity are very high compared to
the other routes.
Invasive, painful procedure Preparations have to be sterilized and are costlier. Assistance of another individual
required in most cases.
Various routes of parenteral drug administration are as follows:
Subcutaneous Intramuscular Intravenous Intradermal
Subcutaneous
The drug is injected into the loose subcutaneous tissue that is rich in nerve supply but is less vascular.
Special forms of administration in this route are as follows:
Dermojet: Needle is not used. Essentially painless procedure. High velocity jet of drug solution is projected from microfine
orifice using gun-like implement and the solution passes through superficial layers and gets deposited in the subcutaneous
layer.
Pellet implantation: Solid pellet is introduced with a trochar and canula. It provides sustained release of drug over weeks, e.g.
DOCA, testosterone.
Silastic implants: Crystalline drugs packed in biodegradable or nondegradable tubes or capsules implanted under the skin for
slow uniform leaching of the drug, e.g. norplant for contraception.
Merits
Self-administration is possible.
Repository (depot) preparations can be inserted into subcutaneous tissue.
Demerits
Not suitable for emergency as absorption is slow.
Suitable only for nonirritant drugs.
II. Intramuscular
Drugs are injected into larger skeletal muscles like deltoid, triceps, gluteus, rectus femoris, etc.
A volume of 5–10 mL can be given at a time. For
example: Tetanus toxoid, procaine penicillin.
Merits
Absorption is more rapid as the muscles are more vascular. Depot preparations can be administered by this route.
Demerits
Aseptic conditions are needed.
Self-administration is impractical as deep penetration is necessary. They may cause injury to the nerves.
Intravenous
Drugs are injected directly into the bloodstream through a vein.
Drugs are injected as bolus or infused slowly over hours
into superficial veins.
Merits
This route of drug administration is of great value in emergencies as the drug directly enters blood stream and effects are
produced immediately. 100% bioavailability, dosage of drug required is lesser.
Demerits
Most risky route.
Vital organs like brain, heart, etc. get exposed to higher concentrations of the drug. Systemic toxicity is increased.
Once injected the action of the drug cannot be halted.
Intradermal
Injected into the skin raising a bleb or scarring or multiple puncture of the epidermis through a drop of the drug is done. For
example: BCG vaccine, sensitivity tests.
LOCAL ROUTES
They can be used only for localized lesions at accessible sites and for drugs whose systemic absorption from these sites is
minimal, slow or absent.
High concentration is attained at the desired site without exposing the rest of the body to the adverse effects or toxicity of the
drug.
1. Topical
Refers to external application of the drug to the surface of the localized lesion.
Can be used to deliver the drug to skin, oropharyngeal or nasal mucosa, eyes, ear canal, anal canal, vagina, etc.
Examples:
Inhalation for bronchial mucosa (cromolyn sodium)
Irrigating solution or jellies (povidone iodine, lignocaine)
Paints, toothpastes, mouthwashes, gargles, lozenges, antiseptics, astringents, haemostatics
2. Deeper Tissues
Can be approached with a syringe and needle.
Care should be taken to see that the systemic absorption is slow.
Examples: Injection of local anaesthetic around a nerve, intra-articular injection of hydrocortisone acetate
3. Arterial Supply
Close intra-arterial injections can be used for a contrast media in angiography and anticancer drugs used in the femoral or
brachial artery to localize the effect for limb malignancies.
Q. 2. Describethe various sources of drugs in pharmacology with suitable examples.
According to WHO a drug is any substance or product that is used or intended to be used to modify or explore physiological
systems or pathological states for the benefit of the recipient.
The various sources of drug are as discussed below.
The source of a drug can be natural or synthetic.
Natural Sources
Naturally some drugs can be obtained from the following:
Plants: Alkaloids like atropine, morphine, quinine, reserpine and glycosides like digoxin and digitoxin
Animals: Insulin, heparin, gonadotropins, antitoxic sera
Minerals: Magnesium sulphate, aluminium hydroxide, iron, sulphur, radioactive isotopes
Microorganisms: Penicillin, cephalosporins, tetracycline, and other antibiotics
Humans: Immunoglobulins from blood, growth hor-
mone from anterior pituitary, chorionic gonadotropins from urine of pregnant woman
Synthetic Sources
Most drugs used now are obtained from synthetic or semisynthetic sources, e.g. quinolones, omeprazole. Some drugs are
obtained by cell cultures, e.g. urokinase from cultured human kidney cells.
Some are produced by recombinant DNA technology,
SHORT ESSAYS
e.g. human insulin, tissue plasminogen activator.

Discuss merits and demerits of oral and intravenous routes of administration.

Drugs can be administered by a variety of routes. The choice of an appropriate route depends both on the drug as well
as patient-related factors.
Merits and demerits of oral and intravenous routes of administration are as discussed below.
Oral Route
Drugs available in solid dosage forms like capsules, spansules, dragees, powders, tablets and liquid forms like elixirs, syrups,
emulsions can be given orally.
Merits
Safer
More convenient
Noninvasive and painless
Assistance not required
Cheap
May be destroyed by gastric juices, or amount is considerably reduced in first-pass metabolism.
Demerits
Action is slower, not suitable for emergencies.
Unpalatable drugs are difficult to administer.
Can cause nausea or vomiting, may stain the teeth, leave an unpleasant taste.
Certain drugs may not be absorbed, e.g. streptomycin.
Intravenous Route
Intravenous route is a type of parenteral drug administration where
drugs are injected directly into the bloodstream through a vein.
drugs are injected as bolus or infused slowly over hours into superficial veins.
Merits
This route of drug administration is of great value in emergencies as the drug directly enters blood stream and effects are
produced immediately.
100% bioavailability, dosage of drug required is lesser.
Demerits
Most risky route
Vital organs like brain, heart, etc get exposed to higher concentrations of the drug.
Systemic toxicity is increased.
Once injected the action of the drug cannot be halted.
Q. 2. Describethe routes of administration of drugs with examples.

Routes of drug administration can be classified into two major categories as follows:
Local
For superficial application: Topical
For deeper tissues: Sublingual, arterial supply
Systemic: Oral, rectal, cutaneous, transdermal patches, parenteral
Various routes of parenteral drug administration are as follows: 1. Subcutaneous
Intramuscular
Intravenous
Intradermal
LOCAL
Topical
Inhalation for bronchial mucosa—cromolyn sodium
Irrigating solution/jellies—povidone iodine, lignocaine
Deeper Tissues
For example: Injection of local anaesthetic around a nerve, intra-articular injection of hydrocortisone acetate
Arterial Supply
For example: Contrast media in angiography and anticancer drugs used in the femoral or brachial artery to localize the effect
for limb malignancies
SYSTEMIC
Oral
For example: Drugs available in solid dosage forms like capsules, spansules, dragees, powders, tablets and liquid forms
(elixirs, syrups, emulsions)
Sublingual
For Example: Glyceryl trinitrate, buprenorphine, desaminooxytocin
Rectal
For example: Aminophylline, indomethacin, diazepam, ergotamine
Cutaneous
For example: Cyclovir 5% skin cream, betamethasone
(Betnovate-C)
Transdermal Patches
For example: Glyceryl trinitrate, fentanyl, nicotine, hyoscine
Parenteral
Subcutaneous, e.g. DOCA, testosterone, norplant contraceptives
Intramuscular, e.g. tetanus toxoid, procaine penicillin
Intravenous, e.g. ampicillin, ribavirin
Intradermal, e.g. BCG vaccine, sensitivity tests
Q. 3. Write briefly about sublingual route of administration.

Sublingual Route
The tablet or pellet is placed under the tongue. Drug is directly absorbed into the circulation.
Merits
First-pass metabolism is bypassed.
Once desired effect is achieved the drug can be spat out.
Rapid rate of absorption
Demerits
Only lipid-soluble nonirritating drugs can be used.
Inconvenient to the patient
Example: Glyceryl trinitrate, buprenorphine, desaminooxytocin
Q. 4. Intravenous route of drug administration
In the intravenous route drugs are injected directly into bloodsteam through a vein.
Drugs are injected as
bolus: single and relatively a large dose of drug injected rapidly or slowly as a single unit into a vein,
slow intravenous (IV) injection, e.g. morphine and
intravenous infusion, i.e. adding the drug to a bottle containing dextrose or saline, e.g. dopamine infusion in cardiogenic shock.
Advantages
Drug directly enters bloodstream and exhibits quick onset of action, great value in emergencies. For example: IV diazepam in
status epilepticus
100% bioavailability
Dosage of drug required is lesser.
Large volume of fluid can be administered. For example: IV fluids in severe dehydrated patients
Hypertonic solutions can be infused by IV route. For example: 20% mannitol in cerebral oedema
Disadvantages
Most risky route. Vital organs like brain, heart, etc. get exposed to higher concentrations of the drug.
Systemic toxicity is increased.
Action cannot be stopped once the drug is injected.
Local irritation may cause phlebitis.
SHORT NOTES
Extravasation of some drugs may cause injury, necrosis and sloughing of tissues.

New drug delivery systems

Special drug delivery systems are used to improve duration of action of drug and thereby improve patient compliance.
Some forms of newer drug delivery are as follows:
Ocusert: Thin epithelial units containing the drug in a reservoir. For example: Pilocarpine used in glaucoma
Progestasert: Inserted into the uterus for delivering progesterone
Transdermal patches: The drug is held in between an occlusive backing film and a micropore membrane whose undersurface is
smeared with adhesive. For example: Glyceryl trinitrate, fentanyl, nicotine, hyoscine.
Prodrug: Inactive form of the drug that gets metabolized to an active form. For example: Levodopa, esters of penicillin.
Computerized miniature pumps—programmed to release drugs at a definite rate. For example: Insulin
Q. 2. Parenteral administration of drugs
 Refers to drugs injected directly into tissue fluid or blood without having to cross the intestinal mucosa. Drug action is
faster and surer. Can be used in unconscious, uncooperative patients. First-pass metabolism is bypassed in the liver.
Chances of systemic toxicity is very high. Invasive, painful procedure. Assistance of another individual required in most
cases. Various routes of parenteral drug administration are as
follows:
Subcutaneous
Dermojet
Pellet implantation, e.g. DOCA, testosterone
Silastic implants, e.g. norplant contraceptives
Intramuscular, e.g. tetanus toxoid, procaine penicillin
Intravenous, e.g. ampicillin, ribavirin
Intradermal, e.g. BCG vaccine, sensitivity tests
Q. 3. Sublingual administration of drug
Here the tablet or pellet of the drug is placed under the tongue and the drug is directly absorbed into the circulation.
It has advantage of
bypassing first-pass metabolism.
can be spat out once desired effect is achieved.
rapid rate of absorption.
The disadvantages of this route are
only lipid-soluble nonirritating drugs can be used.
inconvenient to the patient. For example: Glyceryl trinitrate, buprenorphine, desamino-oxytocin
Q. 4. Enumerate various routes of drug administration.

Local Route
 Topical inhalation for bronchial mucosa (cromolyn so-
dium), irrigating solution or jellies (povidone iodine, lignocaine)
For deeper tissues through arterial supply, e.g. injection
of local anaesthetic around a nerve, intra-articular injection of hydrocortisone acetate
Systemic Route
Oral solid dosage forms (capsules, spansules, dragees, powders, tablets) and liquid forms (elixirs, syrups, emulsions)
Sublingual (glyceryl trinitrate, buprenorphine, desaminooxytocin)
Rectal (aminophylline, indomethacin, diazepam, ergotamine)
Cutaneous (cyclovir 5% skin cream, betamethasone (Betnovate-C))
Transdermal patches (glyceryl trinitrate, fentanyl, nicotine, hyoscine)
Parenteral: Various types of this route of administration are as follows:
Subcutaneous (DOCA, testosterone, norplantcontraceptives)
Intramuscular (tetanus toxoid, procaine penicillin)
Intravenous (ampicillin, ribavirin)
Intradermal (ampicillin, ribavirin)
Q. 5. Advantages and disadvantages of oral route
Advantages
Oral route is used for drugs available in solid dosage forms like capsules, spansules, dragees, powders, tablets and liquid forms
like elixirs, syrups, emulsions.
This route is safer, more convenient, noninvasive, painless and cost effective.
Disadvantages
Action is slower.
Not suitable for emergencies
Unpalatable drugs are difficult to administer.
Can cause nausea or vomiting.
May stain the teeth.
Leave an unpleasant taste.
Q. 6. Advantages and disadvantages of inhalation route
Volatile liquids and gases are given by inhalation, e.g. general anaesthetics, salbutamol.
Advantages
Instantaneous absorption
Serves as local route in pulmonary disorders, hence is more effective and less harmful.
First-pass metabolism is avoided.
Blood levels can be controlled by controlling absorption and excretion.
Disadvantages
1. Irritant gases enhance pulmonary secretions and cause bronchospasm.
Q. 7. Drug nomenclature
A drug nomenclature generally has three categories of names which are as follows:
Chemical name: Describes the substance chemically, e.g. 1-(isopropylamino)-3-(1-naphthyloxy) propan- 2- ol or propranolol
A code name may be used by the manufacturer instead of this long name, e.g. RO 15-1788 for flumazenil
Nonproprietary name: Name accepted by a competent scientific body, like the United States Adopted Name (USAN), British
Approved Name (BAN), recommended International Nonproprietary name (rINN), for example Aminoglycosides, tricyclic
antidepressants

Pharmacokinetics
LONG ESSAYS
Proprietary name: Name assigned by the manufacturer and his property or trademark. One drug may have several proprietary
names. For example: Altol, Atcardil, Atecor, Aten for atenolol.
 Describe the various methods to prolong the duration of action of a drug.
Prolonging the duration of action of drug is sometimes advantageous.
By prolonging the duration of action frequency of drug administration can be reduced, patient compliance can be
improved,
large fluctuations in plasma concentration are avoided and
drug effect could be maintained overnight without disturbing sleep.
Drugs with half-life (t1/2) less than 4 h are suitable for controlled release while the drugs with half-life more than 4 h do not
need controlled release formulations.
Methods utilized for prolonging drug action are as follows:
By prolonging the absorption of the drug from the site of administration
By increasing plasma protein binding
By retarding the rate of metabolism
By retarding renal excretion
A. By Prolonging the Absorption
a. Oral Route
Sustained release preparations, coating with resins, plastic materials or other substances which temporarily disperse release of
the active ingredient in the GIT. Another technique utilizes a semipermeable membrane to control the release of drug from
tablet or capsules, e.g. iron, deriphyllin.
b. Parenteral Route
The subcutaneous and intramuscular injections of drug in the following:
Insoluble form and reducing solubility. For example:
Procaine penicillin Oily suspensions. For example: Depot progestins Altering particle size. For example: Insulin
zinc suspension as large crystals that are slowly absorbed. Pellet implantation—silastic capsules. For example: DOCA
Reduction in vascularity of the absorbing surface. For
example: Adrenaline 1 lignocaine (addition of vasoconstrictor)
Combining with protein. For example: Protamine 1 zinc
1 insulin vii. Chemical alteration—esterification. For example: Oes-
trogen, testosterone
c. Transdermal Drug Delivery Systems
The drug impregnated in transdermal adhesive patches.
For example: Scopolamine Ointments. For example: Nitroglycerine.
Ocusert (transmucosal) used in eye. For example: Pilocarpine
By Increasing Plasma Protein Binding
Few drugs have been prepared which are highly bound to plasma protein and are slowly released in the free active form.
Choosing more protein bound member of the group also favours this mechanism. For example: Sulphonamides like
sulphamethoxypyridazine, sulphadoxine
By Retarding Rate of Metabolism
Small chemical modification markedly affects the rate of metabolism without affecting the biological action.
For example: Addition of ethinyl group to oestradiol makes
it longer acting and suitable to be used as oral contraceptive.
Inhibition of the specific metabolizing enzyme by one drug can prolong the action of another drug. For example:
Physostigmine prolongs the action of acetylcholine by inhibiting the enzyme cholinesterase.
By inhibiting the enzyme peptidase in the renal
tubules the cilastatin prolongs action of imipenem.
D. By Retarding Renal Excretion
Renal excretion of the drug can be prolonged by competing with the same transportation system for the renal tubular secretion.
For example: Probenecid prolongs the action of penicillin and ampicillin.
Q. 2. Explain the means of biotransformationof drugs in the body with
examples.

BIOTRANSFORMATION
Biotransformation is the process of biochemical alteration of the drug in the body. Body treats most drugs as foreign
substances and tries to inactivate and eliminate them by various biochemical reactions. These processes convert the drugs into
more polar, water-soluble compounds so that they are easily excreted through the kidneys. Some drugs may be excreted
largely unchanged in the urine. For example: Frusemide, atenolol
The most important site for biotransformation is the liver. But the drugs get metabolized even in the kidneys, gut mucosa,
lungs, blood and skin.
 Though biotransformation generally inactivates the drug, some drugs may be converted to active or more active metabolites.
Biotransformation of drug may lead to the following:
Inactivation: where active drug–inactive metabolite results. For example: Pentobarbitone, morphine, chloramphenicol,
propranolol
Active metabolite from an active drug: Where there will be active drug—active metabolite. For example: Primidone–
phenobarbitone, digitoxin–digoxin, diazepam–oxazepam
Activation of inactive drug: where inactive drug is converted to active metabolite. For example: Levodopa–dopamine,
prednisone–prednisolone, enalapril–enalaprilat
When the metabolite of the drug is active, the duration of action of the drug gets prolonged.
Prodrug is an inactive form of drug which gets converted into the active form in the body.
Enzymes in Biotransformation
The biotransformation of a drug can be brought about by specific enzymes located in liver microsomes called microsomal
enzymes.
cytoplasm and mitochondria, plasma and other tissues
called nonmicrosomal enzymes. Chemical Reactions of Biotransformation
They can be classified into two phases as follows:
Phase I reactions or nonsynthetic reactions: Convert the drug to a more polar metabolite by oxidation, reduction or hydrolysis.
Catalyzed by mono-oxygenase present in the liver. Here the metabolite may be active or inactive.
Phase II reactions or synthetic reactions or conjugation reactions: If the metabolite is not sufficiently polar to be excreted, they
undergo phase II reaction.
A. Phase I reactions or nonsynthetic reactions
Oxidation
 This reaction involves addition of oxygen or negatively charged radical or either removal of hydrogen or positively charged
radical. Oxidations are the most important drug metabolizing reactions, various oxidation reactions include hydroxylation,
oxygenation at C, N or S atoms, N or O dealkylation, oxidative deamination, etc.
Oxidative reactions are mostly carried out by a group of mono-oxygenases in the liver. For example: Barbiturates,
phenothiazines, paracetamol, steroids, phenytoin, benzodiazepines.
Reduction: This reaction is the converse of oxidation and involves cytochrome P450 enzymes working in the opposite
direction. For example: Chloramphenicol, halothane and warfarin
Hydrolysis: This reaction involves cleavage of drug molecule by taking up a molecule of water. Occurs in liver, intestines,
plasma and other tissues.
Ester 1 H2O → acid 1 alcohol
For example: Choline esters, procaine, lignocaine, procainamide, pethidine, oxytocin
Cyclization: Here there is formation of a ring structure from a straight chain compound. For example: Proguanil
Decyclization: Here there is opening up of ring structure of cyclic drug molecule. For example: Barbiturates, phenytoin
B. Phase II or synthetic reactions
Endogenous water-soluble substances like glucuronic acid, sulphuric acid, or an amino acid combine with the drug or its phase
I metabolite to form a highly polar conjugate which is inactive and gets readily excreted by the kidneys. Large molecules are
excreted through bile.
Various synthetic reactions are as follows:
Glucuronide conjugation: This is most important synthetic reaction. Compounds with a hydroxyl or a carboxylic group are
easily conjugated with glucuronic acid derived from glucose. For example: Aspirin, morphine, metronidazole
Acetylation: Compounds having amino acids or hydrazine residues are conjugated with the help of acetyl coenzyme-A. For
example: Sulphonamides, isoniazid,
PAS, hydralazine Methylation: The amines and phenols can be methylated, methionine and cystine acting as methyl
donors. For example: Adrenaline, histamine and nicotinic acid
Sulphate conjugation: Phenolic compounds and steroids
are sulphated by sulphokinases. For example: Chloramphenicol, adrenal and sex steroids
Glycine conjugation: Salicylates and other drugs having carboxylic acid group are conjugated with glycine, but this is not a
major pathway of metabolism.
Glutathione conjugation: Serves to inactive highly reactive
quinone or epoxide intermediates formed during metabolism. For example: Paracetamol
SHORT ESSAYS
Drug metabolism
Biotransformation or drug metabolism is the process of biochemical alteration of the drug in the body.
 Body treats most drugs as foreign substances and tries to inactivate and eliminate them by various biochemical reactions.
These processes convert the drugs into more polar, water-soluble compounds so that they are easily excreted through the
kidneys. Some drugs may be
excreted largely unchanged in the urine. For example: Frusemide, atenolol
The most important site for biotransformation is the liver. But the drugs get metabolized even in the kidneys, gut mucosa,
lungs, blood and skin.
The biotransformation of a drug can be brought about by specific enzymes located in the following: 1. Liver
microsomes called microsomal enzymes
2. Cytoplasm and mitochondria, plasma and other tissues called nonmicrosomal enzymes

Ribonucleoside/nucleotide synthesis: It is important for activation of many purine and pyrimidine antimetabolites used in
cancer chemotherapy.
 The chemical reactions of biotransformation can take
place in two phases as follows:
Phase I: includes nonsynthetic reactions like
oxidation, e.g. barbiturates, phenothiazines,
paracetamol, steroids, phenytoin and benzodiazepines
reduction, e.g. chloramphenicol, halothane and warfarin
hydrolysis, e.g. choline esters, procaine, ligno-
caine, procainamide, pethidine and oxytocin
Phase II: includes synthetic reactions like
glucuronide conjugation, e.g. glucuronic acid, sulphuric acid or an amino acid
acetylation, e.g. sulphonamides, isoniazid, PAS, hydralazine
methylation, e.g. adrenaline, histamine and nicotinic acid
sulphonate conjugation, e.g. chloramphenicol, adre-
nal and sex steroids
glycine conjugation
glutathione conjugation, e.g. paracetamol
ribonucleoside or nucleotide synthesis, e.g. purine and pyrimidine antimetabolites used in cancer chemotherapy
Q. 2. Channels of drug excretion
Drug excretion takes place mainly through five main channels as follows:
Urine
Faeces
Exhaled air
Saliva and sweat
Milk
Renal excretion (urine) is the most important channel of excretion for most of the drugs. It takes place in three steps as
follows:
Glomerular filtration: All nonprotein drugs, whether lipid soluble or not, they are presented to the glomerulus are filtered. The
filtration depends on the plasma protein binding and the filtration rate. Normal filtration rate is 120 mL/min and reduces after
50 years of age.
Tubular reabsorption: Depends on lipid solubility and ionization of the drug at the existing urinary pH. About 99% of lipid-
soluble drugs are reabsorbed, but drugs like aminoglycoside, quaternary ammonium compounds that are lipid insoluble are not
reabsorbed.
Tubular secretion involves active transfer of organic acids and bases by two separate nonspecific mechanisms which operate in
the proximal tubules.
Faeces: Apart from the unabsorbed fraction, most of the drug present in the faeces is obtained from bile. Organic acids, bases
and steroids are actively transported into the bile by the nonspecific active transport mechanism.
Certain drugs like anthracene purgatives and heavy metals are excreted directly in the colon.
Exhaled air: Gases and volatile liquids (general anaesthetics, alcohols) are eliminated by lungs irrespective of the lipid
solubility.
Saliva and sweat: Drugs like lithium, potassium iodine, rifampicin are excreted by these routes.
Milk: The excretion of drug in milk is not important for the mother, but the suckling infant receives the drug. Milk has a lower
pH than plasma, hence basic drugs are somewhat more concentrated in it. However the total amount of drug reaching the
mother is generally small.
Q. 3. Define the term prodrug giving an example.

Prodrug is an inactive form of the drug that gets metabolized to the active derivative in the body. A prodrug may overcome
some of the disadvantages of the conventional forms of the drug administration. For example: Levodopa crosses blood-brain
barrier and then gets converted to dopamine. Prodrugs also help to prolong the duration of action of the drug. For example:
Esters of penicillin
Various examples of prodrugs and their active forms are listed in Table 2.1.
TABLE 2.1 Examples of Prodrugs and Their Active Forms
Prodrugs Active Forms
Levodopa Dopamine
Enalapril Enalaprilat
Dipivefrine Epinephrine
Acyclovir Acyclovir triphosphate
Bacampicillin Ampicillin
Q. 4. First-pass metabolism
 First-pass metabolism is the metabolism of the drug during its first passage from the site of absorption into systemic
circulation. Orally administered drugs have to pass via gut wall, portal vein and liver to enter the systemic circulation.
Certain drugs during this process of passage get metabolized and are removed or inactivated before they reach the systemic
circulation, this process is known as first-pass effect.
It results in decreased bioavailability and therapeutic effect of the drug. For example: Propranalol and nitroglycerine
Extent of metabolism depends on the individual and the drug. Bioavailability is increased in patients with liver disorders due
to reduction in hepatic metabolism.

Section | IV
Consequences of first-pass metabolism:
The dose has to be increased for some drugs, e.g. propranolol.
Route of administration has to be changed for drugs that undergo extensive first-pass metabolism, e.g. lignocaine, isoprenaline,
testosterone.
Q. 5. Bioavailability. Factors influencing it by oral route with examples.

Bioavailability is the fraction of the drug that reaches the systemic circulation following administration by any route.
Thus for a drug given intravenously, the bioavailability is 100%. For IM/SC injection, drugs are almost completely
absorbed while by oral route the bioavailability is low due to reduced absorption and high first-pass metabolism.
Factors influencing bioavailability of drugs are as follows:
Disintegration and dissolution time: Oral drugs have to disintegrated to be absorbed and then dissolved in gastrointestinal
fluids. Liquids are absorbed faster than solids.
Water-soluble drugs like aspirin reduce bioavailability.
Formulation: Inert substances used with drugs as diluents like starch slow absorption and reduce bioavailability.
Particle size: Small particles are easily absorbed than bigger particles and there is better bioavailability.
Lipid solubility: Lipid-soluble drugs are absorbed faster and they are more bioavailable.
pH and ionization: Ionized drugs are poorly absorbed compared to unionized drugs. Acidic drugs remain unionized in acidic
medium and are rapidly absorbed, e.g. aspirin, barbiturates.
Area and vascularity of the absorbing surface: The larger the surfaces are for absorption and more vascularity, there will be
more absorption and more bioavailability.
Gastrointestinal motility: Faster gastric emptying time ensures passage of drug to intestine is fast and more absorption.
Intestinal motility as in diarrhoea reduces absorption and the amount of drug available is reduced.
Presence of food: Delays gastric emptying and delays absorption.
Metabolism: Some drugs are degraded in the GI tract and bioavailability becomes zero.
SHORT NOTES
Diseases: Bioavailability is increased in patients with liver disorders due to reduction in hepatic metabolism.
 Bioavailability
Bioavailability is the fraction of the drug that reaches the systemic circulation following administration by any route. For a
drug given intravenously, the bioavailability is 100%. For IM/SC injection, drugs are almost completely absorbed while by oral
route the bioavailability is low due to reduced absorption and high firstpass metabolism.
Q. 2. Mention the factors which affect bioavailability.

The factors influencing bioavailability are as follows:

Disintegration and dissolution of time
Formulation
Particle size
Lipid solubility
pH and ionization
Area and vascularity of the absorbing surface
Gastrointestinal motility
Presence of food
Metabolism
Diseases
Q. 3. Biotransformation or drug metabolism

Biotransformation is the process of biochemical alteration of the drug in the body. Body treats most drugs as foreign
substances and tries to inactivate and eliminate them by various biochemical reactions. These processes convert the drugs into
more polar, water-soluble compounds so that they are easily excreted through the kidneys. Some drugs may be excreted
largely unchanged in the urine. For example: Frusemide, atenolol
 The most important site for biotransformation is the liver. But the drugs get metabolized even in the kidneys, gut mucosa,
lungs, blood and skin. The biotransformation of a drug can be brought about by specific enzymes located in liver
microsomes called microsomal enzymes and those located in cytoplasm, mitochondria, plasma and other tissues called
nonmicrosomal enzymes.
Q. 4. Define prodrug and give examples.

Prodrug is an inactive form of the drug that gets metabolized to the active derivative in the body.
A prodrug may overcome some of the disadvantages of the conventional forms of the drug administration. For example:
Levodopa crosses blood-brain barrier and then gets converted to dopamine.
Prodrugs also help to prolong the duration of action of the drug. For example: Esters of penicillin.
Various examples of prodrugs and their active forms are as given in Table 2.2.
drugs during this process of passage get metabolized and are removed or inactivated before they reach the systemic circulation,
this process is known as first-pass effect. It results in decreased bioavailability and therapeutic

TABLE 2.2 Examples of Prodrugs and Their Active Forms

Prodrugs Active Forms
Levodopa Dopamine
Enalapril Enalaprilat
Dipivefrine Epinephrine
Q. 5. Methods of prolonging the effects of a drug
The duration of action of a drug can be prolonged by interfering with the pharmacokinetic process by one of the following
methods:
Prolonging the absorption of the drug from the site of administration
Increasing plasma protein binding
Retarding the rate of metabolism
Delaying renal excretion
Advantages of prolonging the duration of action of a drug are as follows:
It helps to reduce the frequency of drug administration.
Improves patient compliance.
Large fluctuations in plasma concentrations are avoided.
Side effects related to high peak plasma concentrations can be avoided.
Drug affect can be maintained overnight without disturbing sleep.
Q. 6. First-pass metabolism with suitable examples.
 Orally administered drugs have to pass via gut wall, portal vein and liver to enter the systemic circulation. Certain effect of
the drug. For example: Propranolol and nitroglycerine
Consequences of first-pass metabolism are that the dose has to be increased for some drugs. For example: Propranolol or the
route of administration has to be changed for some drugs like lignocaine, isoprenaline, etc.
Q. 7. Pharmacokinetics
Pharmacokinetics is the study of the absorption, distribution, metabolism and excretion of drugs, i.e. movement of the drugs
into within and out of the body.
Once the drug is administered, it is absorbed and enters the blood and is distributed to different parts of the body, reaches the
site of action and is metabolized and is excreted out of the body. Pharmacokinetics examines the movement of a drug over
time through the body.
Q. 8. What is plasma half-life?
 Plasma half-life (t1/2) of a drug is the time taken for its plasma concentration to be reduced to half its original value.
It takes place in two phases as follows:
Initial rapid phase due to distribution
Later less declined phase due to elimination Plasma half-life t1/2 5 ln2/k where ln2 is the natural logarithm of 2 and k is the
elimination rate constant of the drug.
During
first t1/2: 50% of the drug is eliminated,
second t1/2: 75% (50 1 25) is eliminated and

Pharmacodynamics
LONG ESSAYS
Describe the various factors that modify the dos-
age and action of drugs.
The same dose of a drug can produce different degrees of
Or, response in different patients and even in the same patient
Discuss factors modifying drug action with examples. under different situations.
third t1/2: 87.5% (50 1 25 1 12.5) is eliminated.
Section | IV
Various factors that modify the effects of drugs are as follows:
Drug factors
Route of administration Presence of other drugs
Cumulation Dose
Placebo
Patient factors
Age
Body weight Sex
Species and race Environment Genetic factors vii. Emotional factors viii. Pathological state
ix. Tolerance
x. Drug dependence
DRUG FACTORS
Route of Administration
Route of administration governs the speed and intensity of drug response, e.g. magnesium sulphate given orally acts as a
purgative. But given IV causes CNS depression and has anticonvulsant effects. When topically applied reduces local oedema.
Hypertonic magnesium sulphate used as retention enema reduces intracranial tension.
Presence of Other Drugs
Drugs may modify the response to each other by pharmacokinetic or pharmacodynamic interaction between them. The
concurrent use of two or more drugs can influence the response of each other.
For example:
A combination of drugs is used in hypertension— hydralazine 1 propranolol for their beneficial interaction.
Penicillin and gentamicin should never be mixed in the same syringe.
Succinylcholine is prone to induce arrhythmias in digi-
talized patients.
Cumulation
When the rate of elimination of the drug is slower than the rate of administration, the drug may accumulate in the body causing
cumulative toxicity. For example: Drugs like digoxin, emetine, chloroquine are slowly eliminated, so they cumulate and result
in toxicity.
Prolonged use of chloroquine causes retinal damage.
Dose
The response to drug may be modified by the dose administered, as the dose is increased magnitude of the response also
increases proportionately till the maximum is reached. Further increase in doses produces adverse effects. For example: The
drugs used in myasthenia enhance muscle power in therapeutic doses, but in high doses it causes muscle paralysis.
Placebo
Placebo is the Latin word which means 'I will please'. It is a dummy medicine having no pharmacological effect.
Substances such as starch, lactose, etc. are used as placebos.
Uses
They are used for relief of subjective symptoms like anxiety, headache, tremors, pain and insomnia. They are used in
clinical trials to minimize bias.
PATIENT FACTORS i. Age
The pharmacokinetics of many drugs change with age.
 In neonates, the metabolizing function of the liver and the excretory function of kidney are not fully developed to handle
drugs. For example: Chloramphenicol can produce grey baby syndrome.
Calculation of the appropriate dose is important to avoid
toxicity. Formula for calculation of dose for children:
Young’s formula
Child's dose = Age (years) × Adult dose Age +12
In elderly people the capacity of the liver and kidney to handle the drug is reduced. Hence lower doses are recommended. ii.
Body Weight
The recommended dose is usually calculated for medium built persons whereas for the obese and underweight persons, the
dose has to be calculated individually.
Formula for calculation of dose according to body
weight is as follows:
Dose = Body weight (kg) × Average adult dose 70 iii. Sex
Sex can also influence the drug effect. The hormonal effects and smaller body size may influence drug response in
women. For example: Drugs like morphine and barbiturates can cause paradoxical response like excitement in females.
iv. Species and Race
Response to drugs may vary with species and race. For example: Rabbits are resistant to atropine.
Blacks need higher doses of atropine to produce
mydriasis.
v. Diet and Environment
Food interferes with the absorption of many drugs. For example: Tetracyclines form complexes with calcium in the food are
poorly absorbed. Certain environmental pollutants like DDT, cigarette smoke, insecticides and alcohol consumption are
known to induce hepatic microsomal enzymes and increase metabolism of drugs like oral contraceptives, theophylline, etc. So
the dose of these drugs administered may be inadequate.
vi. Genetic Factors
Variations in an individual’s response to drugs could genetically be mediated. Difference in response is due to variations in
the amount of drug metabolizing enzymes. For example: Acetylation of drugs
The rate of drug acetylation differs among individuals who may be fast or slow acetylators. For example: INH
sulphonamides and hydralazine are acetylated.
Slow acetylators treated with hydralazine are more likely to develop lupus erythematosus.
In G6PD deficiency—use of primaquine, sulfones and
quinolones can cause hemolysis.
vii. Psychological Factors
The doctor–patient relationship influences the response to a drug often to a large extent by acting on the patient’s
psychology. The patients confidence in the doctor may itself be sufficient to relieve a suffering, particularly the
psychosomatic disorders. This can be substantiated by the fact that large number of patients response to placebo.
viii. Diseases (Pathological States)
a. Presence of certain diseases can also influence the drug responses. For example:
In malabsorption syndrome, drugs are poorly absorbed.
In liver diseases, rate of drug metabolism is reduced. In renal dysfunction, drugs mainly excreted through kidneys are likely
to accumulate and cause toxicity.
ix. Tolerance
Repeated administration of certain drugs can result in a decrease in their pharmacological effect. Hence, higher doses of such
drugs are needed to produce a given response. Tolerance may be of two types as follows:
Natural tolerance: Some species or races show less sensitivity to certain drugs, e.g. black race is tolerant to mydriatics.
Acquired tolerance: Develops on repeated administration of a drug, e.g. barbiturates, opioids, nitrites.
Tolerance may develop to some actions of the drug and not to others. For example:
Morphine—tolerance develops to analgesic euphoric effects of morphine but not to its constipating and miotic effects.
Barbiturates—tolerance develops to sedative but not antiepileptic effects of barbiturates. Tachyphylaxis is the rapid
development of tolerance. When drugs are administered repeatedly at short intervals, tolerance develops and is known as
tachyphylaxis or acute tolerance. For example: Ephedrine, amphetamine, tyramine
x. Drug Dependence
Drug dependence can be defined as 'a state, psychic and sometimes also physical, resulting from the interaction between a
living organism and a drug characterized by behavioural and other response that always include a compulsion to take the drug
on a continuous or periodic basis in order to experience its psychic effects and sometimes to avoid the discomfort of its
absence'. For example: Alcohols, opioids, barbiturates, amphetamine
Dependence may be psychological or physical.
Q. 2. Describethe principles and mechanism of action of drugs with
examples. Add a note on enzyme induction.
PRINCIPLES OF DRUG ACTION
Drugs produce their effects by interacting with the physiological systems of the organisms. By such interaction, drugs can only
modify the rate of functions of the various systems but they cannot bring about qualitative changes, i.e. they cannot change the
basic functions of any physiological systems.
The basic types of drug action can be broadly classified as follows:
Stimulation Depression
Section | IV
Irritation
Replacement
Cytotoxic action Modification of the immune status
Stimulation is the selective enhancement of the level of activity of the specialized cells. For example: Adrenaline stimulates the
heart.
Depression is the selective diminution of activity of the specialized cells. For example: Quinidine depresses the heart.
Barbiturates depress the central nervous system.
Some drugs stimulate one system but may depress the other, e.g. morphine depresses the CNS but stimulates the vagus.
Irritation This is a nonselective, often noxious effect and is particularly applied to less specialized cells like epithelium,
connective tissue, etc.
Mild irritation may stimulate associated function, e.g. bitters increase salivary and gastric secretion, counterirritants increase
blood flow to the site.
Strong irritation results in inflammation, corrosion, necrosis and morphological damage. This may result in diminution or
loss of function. Replacement: Drugs may act by replacement specifically when there is deficiency of natural substances like
hormones, metabolites or nutrients. For example: Insulin in diabetes mellitus, iron in anaemia, vitamin C in scurvy.
Cytotoxic action Selective cytotoxic action for invading parasites or cancer cells, attenuating them without significantly
affecting the host cells is utilized for cure or palliation of infections and neoplasms.
 Drugs may act by specifically destroying infective organisms, e.g. penicillin or by cytotoxic effect on cancer cells, e.g.
anticancer drugs.
Modification of the immune status: Vaccines act by improving our immunity while immunosuppressants act by depressing
immunity, e.g. glucocorticoids.
MECHANISM OF DRUG ACTION
Most drugs act by binding to specific target proteins like receptors, enzymes and ion channels. They may act on the cell
membrane, inside or outside the cell to produce their effects.
Fundamental mechanisms of drug action may be distin-
guished into four categories:
Physical action Chemical action Through enzymes Through receptors
I. Physical Action
The action of a drug results from its physical properties like the following: Adsorption—activated charcoal in poisoning,
kaolin Mass of the drug—bulk laxatives like psyllium, bran and protectives like dimethicone
Osmotic property—osmotic diuretics, mannitol and magnesium sulphate
Radioactivity—radioiodine 131I and other radioisotopes Radio opacity—contrast media like barium sulphate,
urografin
II. Chemical Action
Drugs interact according to simple chemical reactions.
Examples:
Antacids like AlOH3 and others neutralize gastric HCl.
Oxidizing agents—potassium permanganate, I2 are germicidal and inactivate ingested alkaloids.
Chelating agents—bind heavy metals making them nontoxic, e.g. calcium disodium edentate, BAL, penicillamine.
III. Through Enzymes
 Enzymes are a very important target of drug action. Drugs can either increase or decrease the rate of enzymatically mediated
reactions.
Stimulation: Enzyme stimulation is relevant to endogenous mediators and modulators.
For example:
Adrenaline stimulates adenylyl cyclase.
Pyridoxine acts as a cofactor and increases.
Inhibition: Drugs may act by inhibition of various enzymes, thus altering the enzyme-mediated reactions.
For example:
Allopurinol inhibits the enzyme xanthine oxidase which converts xanthine to uric acid. Allopurinol is used to reduce synthesis
of the uric acid in treatment of chronic gout cases.
Xanthine Hypoxanthine Uric acid
Xanthine oxidase
↑ (−)
Allopurinol
Disulphiram inhibits aldehyde dehydrogenase enzyme and is used in treatment of chronic alcoholism.
IV. Through Receptors
Drugs may act by interacting with receptors in the body. Receptors are macromolecules present either on cell surface,
cytoplasm or in the nucleus where drug binds and interacts to bring about cellular change.
Drug 1 Receptor I Drug receptor complex n Response Receptors are specific proteins and have specificity and selectivity.
Drugs may have relatively selective action on one type of receptors like adrenergic receptors (a and b), cholinergic receptors
(muscarinic and nicotinic receptors), opioid receptors, etc. Affinity is the ability of the drug to bind to the receptor.
Intrinsic activity or efficacy is the ability of the drug to elicit a response after binding to the receptor.
 Agonist: An agonist is a substance that binds to the receptor and produces a response. It has affinity and intrinsic activity.
Antagonist: It is a substance that binds to the receptor and prevents action of agonist on the receptor. It has affinity but no
intrinsic activity.
Partial agonist binds to the receptor but has low intrin-
sic activity. It has affinity and less intrinsic activity. For example: Pindolol, buprenorphine
Inverse agonist: After binding to the receptors, some drugs act opposite to the agonist. They are called inverse agonists. It
has affinity and intrinsic activity (0–1).
For example: b-carbolines Ligand is a molecule which binds selectively to a specific receptor.
Site: The receptors may be present in the cell mem-
brane, in the cytoplasm, or in the nucleus.
Through Ion Channels
Drugs may interfere with the movement of ions across specific channels, e.g. calcium channel blockers, potassium channel
openers.
By Altering Metabolic Processes
SHORT ESSAYS
Drugs like antimicrobials alter the metabolic pathway in the microorganisms resulting in the destruction of the microorganisms,
e.g. sulphonamides interfere with bacterial folic acid synthesis.

Pharmacodynamics
Pharmacodynamics is the study of actions of the drugs on the body and their mechanisms of action.
Drugs produce their effects by interacting with the physiological systems of the organisms. By such interaction, drugs can
merely modify the rate of functions of the various systems. But they cannot bring about qualitative changes, i.e. they cannot
change the basic functions of any physiological systems. Thus drugs act by the following:
Stimulation is the increase in activity of the specialized cells, e.g. adrenaline stimulates the heart.
Depression is the decrease in activity of the specialized cells, e.g. quinidine depresses the heart, barbiturates depress the central
nervous system.
Some drugs stimulate one system but may depress the other, e.g. morphine depresses the CNS but stimulates the vagus.
Irritation: this can occur on all types of tissues in the body and result in inflammation, corrosion and necrosis.
Replacement: Drugs may act specifically when there is deficiency of natural substances like hormones, metabolites or
nutrients. For example: Insulin in diabetes mellitus, iron in anaemia, vitamin C in scurvy
Anti-infective or cytotoxic action: Drugs may act by specifically destroying infective organisms, e.g. penicillin or by cytotoxic
effect on cancer cells, e.g. anticancer drugs.
Modification of the immune status vaccines act by improving our immunity while immunosuppressants act by depressing
immunity, e.g. glucocorticoids.
Q. 2. Mention factors modifying drug action.
The same dose of a drug can produce different degrees of response in different patients and even in the same patient under
different situations. Various factors modify the dosage and action of the drug.
Factors that modify the effects of drugs are broadly classified as follows:
Drug factors
Route of administration
Presence of other drugs
Cumulation
Dose
Placebo
Patient factors
Age
Body weight
Sex
Species and race
Environment
Genetic factors
Section | IV
Emotional factor
Pathological state
Tolerance
Drug dependence
Q. 3. Placebo
Placebo is the Latin word for the term 'I will please'. It is a dummy medicine having no pharmacological effect. Substances
such as starch, lactose are used as placebos.
Uses of placebo are as follows:
1. They are used for relief of subjective symptoms like anxiety, headache, tremors, pain, insomnia. 2. Are used
in clinical trials to minimize bias.
Factors affecting placebo effect are as follows:
Patient factors: Patients with neurotic symptoms respond to placebos.
Drug factors: The placebo response can be affected by the presentation or route of administration of the drug. For example:
Colourful tablets such as red, blue, green and injectable preparations give better placebo preparation.
Doctor factors: Personality of the doctor, motivation, process of instruction, doctor–patient relationship are important factors
that affect the response to a placebo.
Q. 4. Drug antagonism
One drug inhibiting or opposing the action of another is antagonism. Based on the mechanisms, antagonism can be of
following types:
Chemical antagonism—Two drugs interact chemically to result in inactivation of the effect. For example: Chelating agents
inactivate heavy metals like lead and mercury to form inactive complexes.
Physiological antagonism: Two drugs act at different sites to produce opposing effects. For example: Histamine action on H2
receptors to produce bronchospasm and hypotension while adrenaline reverses these effects by acting on adrenergic receptors.
Antagonism at receptor level: The antagonists inhibit the binding of the agonist to the receptor. It may be
reversible/competitive antagonism: The agonist and antagonist compete for the same receptor. By increasing the concentration
of the agonist, the antagonism can be overcome. It is thus reversible antagonism. Acetylcholine and atropine compete at
muscarinic receptors.
irreversible antagonism: The antagonist binds so firmly by covalent bonds to the receptor that it dissociates very slowly or not
at all. Thus it blocks the action of the agonists and the blockade cannot be overcome by increasing the dose of the agonist and
hence it is irreversible. For example: Adrenaline and phenoxybenzamine at the a-adrenergic receptors
Noncompetitive inhibition: Here the antagonists block at the level of receptor–effector linkage.
Q. 5. Explain three types of drug antagonism with examples.

Antagonism is the condition where one drug opposes or inhibits the action of another drug. Based on the mechanisms,
antagonism can be of following types:
Chemical antagonism
Physiological antagonism
Antagonism at receptor level—reversible (competitive), irreversible
Noncompetitive
Chemical antagonism: Two drugs interact chemically to result in inactivation of the effect. For example: Chelating agents
inactivate heavy metals like lead and mercury to form inactive complexes.
Physiological antagonism: Two drugs act at different sites to produce opposing effects, e.g. histamine action on H2 receptors to
produce bronchospasm and hypotension while adrenaline reverses these effects by acting on adrenergic receptors.
Antagonism at receptor level: The antagonists inhibit the binding of the agonist to the receptor. It may be
reversible/competitive antagonism: The agonist and antagonist compete for the same receptor. By increasing the concentration
of the agonist, the antagonism can be overcome. It is thus reversible antagonism. Acetylcholine and atropine compete at
muscarinic receptors.
irreversible antagonism: The antagonist binds so firmly by covalent bonds to the receptor that it dissociates very slowly or not
at all. Thus it blocks the action of the agonists and the blockade cannot be overcome by increasing the dose of the agonist and
hence it is irreversible. For example: Adrenaline and phenoxybenzamine at the a-adrenergic receptors.
SHORT NOTES
 Tachyphylaxis intervals, tolerance develops and is known as tachyphy-
laxis or acute tolerance, e.g. ephedrine, amphetamine, tyramine, and hydroxytryptamine.
1. Tachyphylaxis is the rapid development of tolerance. 2. These drugs act by displacing noradrenaline from the
When the drugs are administered repeatedly at short sympathetic nerve endings.
Noncompetitive inhibition: The antagonists block at the level of receptor–effector linkage.
3. There may be slow dissociation of the drug from the receptor, thereby blocking the receptor. For example:
Epinephrine given repeatedly in bronchial asthma may not give the desired response.
Q. 2. Drug synergism
When the action of one drug is enhanced or facilitated by another drug, the combination is synergistic.
The total effect of the combination is greater than the sum of their independent effects. It is often called potentiation or supra-
additive effect. For example: Acetylcholine
1 physostigmine, levodopa 1 carbidopa
Q. 3. Placebo
Placebo is the Latin word for the term 'I will please'. It is a dummy medicine having no pharmacological effect. Substances
such as starch, lactose are used as placebos.
Uses
They are used for relief of subjective symptoms like anxiety, headache tremors, pain, insomnia.
Used in clinical trials to minimize bias.
Factors affecting placebo effect are as follows:
Patient factor: Patients with neurotic symptoms respond to placebos.
Drug factor: The placebo response can be affected by the presentation or route of administration of the drug. For example:
Colourful tablets such as red, blue, green and injectable preparations give better placebo effect.
Doctor factor: Personality of the doctor, motivation, process of instruction, doctor–patient relationship are important factors
that affect the response to a placebo.
Q. 4. Drug antagonism
One drug inhibiting or opposing the action of another is antagonism.
Based on the mechanisms, antagonism can be of following types:
Chemical antagonism, e.g. chelating agents inactivate heavy metals like lead and mercury to form inactive complexes.
Physiological antagonism, e.g. histamine action on H2 receptors to produce bronchospasm and hypotension while adrenaline
reverses these effects by acting on adrenergic receptors.
Antagonism at receptor level
Reversible (competitive): Acetylcholine and atropine compete at muscarinic receptors.
Irreversible, e.g. adrenaline and phenoxybenzamine at the a-adrenergic receptors
Noncompetitive inhibition: The antagonists block at the level of receptor–effector linkage.
Q. 5. Bioassay
Bioassay is the determination or estimation of the amount of biological activity in a unit quantity of preparation.
Indications of bioassay are as follows:
When the chemical composition is not known but the substance has a specific action, e.g. long-acting thyroid stimulator
(LATS).
When there is no simple chemical means of ensuring a product of constant composition.
When the chemical assay method is too complex or insensitive, e.g. adrenaline and histamine can be bioassayed in microgram
quantities.
When drugs which differ in composition but have same pharmacological action, e.g. digitalis glycosides obtained from various
sources.
When active principle is unknown or cannot be isolated easily, e.g. peptide hormones.
The important methods of bioassay are as follows:
Direct comparison on the same tissues
Direct assay on several animals
Adverse Drug Effects
LONG ESSAYS
Write in detail the drug toxicity in men. Adverse drug reactions
Or,
Indirect assays
Section | IV
ADVERSE DRUG REACTIONS
WHO has defined an adverse drug reaction as any response to a drug that is noxious and unintended and that occurs at doses
used in men for prophylaxis, diagnosis, or therapy. Adverse reactions are classified into two types:
Predictable type-A reaction Unpredictable type-B reactions
Predictable Type-A Reactions
These are based on pharmacological properties of drug. They are more common, dose related and are mostly preventable.
Unpredictable Type-B Reactions
Based on the peculiarities of the patient and not on drug’s known actions. They are less common, nondose related, generally
more serious and drug may need to be withdrawn from the body.
I. Side Effects
These are unwanted but unavoidable effects that occur at therapeutic doses. They are predictable reactions.
A side effect may be based on the following:
Same therapeutic effect of the drug itself. For example: The antisecretory action of atropine used in peptic ulcer causes
dryness of the mouth. Different facet of action
For example:
Promethazine causes sedation, that is unrelated to its antiallergic effect.
Oestrogens cause nausea which is unrelated to their antiovulatory action.
II. Secondary Effects
These are indirect consequences of primary action of drug.
For example:
Corticosteroids cause immunosuppression that may lead to latent TB in patients.
Suppression of bacterial flora by tetracyclines paves the way for superinfections.
III. Toxic Effects
These are a result of excessive pharmacological action due to overdose or prolonged use.
Over dose may be accidental, suicidal or homicidal. CVS, CNS, lungs, kidneys and liver are the most commonly affected
org
 Toxicity may result from overdosage of a therapeutic drug like barbiturates. Poisoning can occur when the dose of the drug
crosses the therapeutic index.
Therapeutic index is the demarcation between therapeu-
tic dose and maximum acceptable dose.
Therapeutic dose = Median lethal dose
Median effective dose
If it is less than or equal to 1 the drug is safe, if it is more
than 1 it causes toxicity.
Treatment of Toxicity
Termination of exposure, exposure of patient to fresh air in case of inhalation poison, induction of emetics, gastric lavage.
Preventing absorption of ingested poison. For example: Acidic drugs are absorbed in acidic medium, by making the medium
basic absorption can be inhibited. Universal antidote is burnt toast, strong tea and milk of magnesia in the ratio 2:1:1.
A suspension of 20–40 g active charcoal in 200 mL water may be used.
Maintaining airway by adequate ventilation or by arti-
ficial respiration
Maintaining BP and heart rate
IV. Intolerance
It is the appearance of characteristic toxic effects of a drug in an individual at therapeutic doses.
It indicates a low threshold of the individual to the action of the drug. For example: Single dose of triflupromazine may
cause muscular dystonias in some individuals especially children.
V. Idiosyncrasy
Idiosyncrasy is a type of intolerance of some patients to specific drugs.
Idiosyncrasy is a genetically determined abnormal reaction to a drug.
For example:
Primaquine and sulphonamides induce haemolysis in patients with G6PD deficiency.
Some patients show excitement with barbiturates.
Chloramphenicol induced agranulocytosis, where no definite genetic background is known, is also included under
idiosyncrasy.
VI. Allergic Reaction
Drugs can induce both types of allergic reaction, i.e. humoral- and cell-mediated immunity.
Humoral-mediated immunity causes immediate allergic reactions, which are as follows:
Type I (anaphylaxis) which occurs due to antigen– antibody reaction when the drug induces IgE antibodies.
Type II (cytolytic reaction): The drug binds to the protein and together they act as antigen and induce the formation of
antibodies.
Type III (arthus reaction): The antigen binds to circulating antibodies and the complexes are deposited on the vessel wall where
it initiates the inflammatory response.
Cell-mediated immunity causes the following reaction:
Type IV (delayed hypersensitivity reaction): It is mediated by T-lymphocytes and macrophages. The antigen reacts with
receptors on T-lymphocytes which produce lymphokines leading to allergic reaction.
VII. Photosensitivity
It is a cutaneous reaction resulting from drug-induced sensitization of skin to UV rays. There are two types of reaction as
follows:
Phototoxic: Drug or its metabolite accumulate in skin absorbs light and undergoes photochemical reactions followed by
photobiological reactions, resulting in local tissue damage, sunburn, blistering hyperpigmentation, e.g. tetracyclines, Tar
products.
Photoallergic: Drug/metabolite-induced cell-mediated immune response on exposure to light of longer wavelength like UV.
Papular/eczematous contact dermatitis is produced, e.g. sulphonamides, sulphonylureas, chloroquine.
VIII. Addictions/Drug Dependence
 Addiction can be described as the dependence of a person to a certain drug to an extent that the behaviour and mood are
influenced. The drugs are misused to obtain a pleasurable effect. Repeated usage of such drugs results in dependence.
Drug dependence/addiction is a state of compulsive use of drugs in spite of the knowledge of the risks associated with its
use.
It could be of two types as follows:
Psychological dependence is a compulsive drug seeking behaviour to obtain its pleasurable effects.
For example: Cigarette smoking
Physical dependence is said to be present when withdrawal of the drug produces adverse symptoms. The body undergoes
physiological changes to adapt itself to the continued presence of a drug in the body. Stopping the drug can result in
withdrawal symptoms. For example: Alcohol, opioids and barbiturates.
IX. Teratogenicity
Teratogenicity is the ability of the drug to cause fetal abnormality when administered to a pregnant lady.
 Depending on the stage of the pregnancy during which the teratogen is administered, it can produce various abnormalities.
Conception to 16 days: Usually resistant to any teratogenic effects. If affected, abortion occurs.
17–55 days (period of organogenesis): Most vulnerable period. Major physical abnormalities occur.
SHORT ESSAYS
56 days onwards (fetal period): Period of growth and development. Hence developmental and functional abnormalities result.
For example: (a) Thalidomide causes phocomelia, (b) sodium valproate causes spina bifida, (c) tetracyclines cause staining of
teeth and (d) smoking causes cleft palate.

Define adverse drug reaction. Describedifferent types of adverse drug reactions.

An adverse drug reaction is any response to a drug that is noxious and unintended and that occurs at doses used in men for
prophylaxis diagnosis or therapy (WHO).
Types of Adverse Drug Reactions
Side effects
Untoward effects
Toxic effects
Allergic and idiosyncratic effects
Side Effects
Side effects are the unrelated pharmacological effects produced with therapeutic dose of a drug.
These side effects which might be troublesome in a particular condition may be useful in other circumstances. For example:
Dryness of mouth produced by atropine may be troublesome in peptic ulcer disorders but is beneficial as preanaesthetic
medication.
Untoward Effects
Untoward effects develop with therapeutic dose of a drug.
 They may be so severe and undesirable that they may necessitate cessation of the treatment. For example:
Section | IV
Resistant staphylococcal diarrhoea following tetracycline therapy or vomiting and diarrhoea due to aspirin therapy
Toxic Effects
These are usually seen when a drug is administered repeatedly or in large doses.
Drug toxicity is usually the primary attribute of a drug and is dose dependent. For example: Respiratory depression due to
morphine or ototoxicity due to aminoglycosides
Allergic and Idiosyncratic Effects
These are the qualitative intolerance due to immune or other than immune mechanisms.
Chloramphenicol causing aplastic anaemia is an exam-
ple of idiosyncratic reaction. For example: Penicillin producing anaphylaxis
Q. 2. Anaphylactic reaction
 Drugs can induce both types of allergic reaction, i.e. humoral- and cell-mediated immunity.
Humoral-mediated immunity causes immediate allergic
reactions, which are as follows: 1. Type I: Anaphylaxis
Type II: Cytolytic reaction
Type III: Arthus reaction
Cell-mediated immunity causes delayed hypersensitivity reaction. In anaphylactic reaction the drug induces synthesis of IgE
antibodies which are fixed to the mast cells.
On subsequent exposure the antigen–antibody complexes cause degranulation of mast cells releasing the mediators of
inflammation like histamine, leukotrienes, prostaglandins and platelet-activating factor.
These mediators of inflammation are responsible for the characteristic signs and symptoms of anaphylaxis, which could be
fatal and are as follows:
Bronchospasm
Laryngeal oedema
SHORT NOTES
Hypotension Allergy develops within minutes and is called immediate hypersensitivity reaction. For example: Penicillin
Skin tests may predict this type of reactions.

Drug resistance
Drug resistance is unresponsiveness of a microorganism to an antimicrobial agent.
Types of drug resistance are as follows:
Natural resistance
Acquired resistance Natural resistance: Some microbes show resistance to certain antimicrobials because they may lack
metabolic process or target site which is affected by the particular drug. For example: Gram-negative bacilli are normally
unaffected by penicillins. Acquired resistance: It is the development of resistance by an organism to an antimicrobial to
which it was susceptible before due to its use over a period of time. For example: Gonococci have shown resistance to
penicillin.
A microorganism becomes resistant to a drug by either
mutation or gene transfer.
Q. 2. Anaphylactic reaction
Anaphylactic reaction is a type I humoral-mediated immunity.
In anaphylactic reaction the drug induces synthesis of IgE antibodies which are fixed to the mast cells.
On subsequent exposure the antigen–antibody complexes cause degranulation of mast cells releasing the mediators of
inflammation like histamine, leukotrienes, prostaglandins and platelet-activating factor.
These mediators of inflammation are responsible for the characteristic signs and symptoms of anaphylaxis, which could be
fatal and are as follows:
Bronchospasm
Laryngeal oedema
Hypotension
Q. 3. Idiosyncrasy
Idiosyncrasy is a type of intolerance of some patients to specific drugs. It is a genetically determined abnormal reaction to a
drug.
For example:
Primaquine and sulphonamides induce haemolysis in patients with G6PD deficiency.
In addition some responses like chloramphenicol induce agranulocytosis, where no definite genetic background is known, are
also included under idiosyncrasy.
Q. 4. Addictions
 Addictions can be described as the dependence of a person to a certain drug to an extent that the behaviour and mood are
influenced. Drug dependence/addiction is a state of compulsive use of drugs in spite of the knowledge of the risks associated
with its use. It is of two types as follows:
Psychological dependence is a compulsive drugseeking behaviour to obtain its pleasurable effects. For example: Cigarette
smoking.
Physical dependence: When withdrawal of the drug produces adverse symptoms it is known as physical dependence. The body
undergoes physiological changes to adapt itself to the continued presence of a drug in the body. Stopping the drug can result in
withdrawal symptoms. For example: Alcohol, opioids and barbiturates.
Q. 5. Teratogenicity
Teratogenicity is the ability of the drug to cause fetal abnormality when administered to a pregnant lady.
Depending on the stage of the pregnancy during which the teratogen is administered, it can produce various abnormalities.
Conception to 16 days: Usually resistant to any teratogenic effects. If affected, abortion occurs.
17–55 days (period of organogenesis): Most vulnerable period. Major physical abnormalities occur.
56 days onwards (fetal period): Period of growth and development. Hence developmental and functional abnormalities result.
For example:
Thalidomide causes phocomelia.
Sodium valproate causes spina bifida.
Tetracyclines causes staining of teeth.
Smoking causes cleft palate.
Q. 6. Adrenaline in anaphylactic shock
Anaphylaxis is a humoral-mediated type I hypersensitivity reaction where degranulation of mast cells releases the mediators
of inflammation like histamines, leukotrienes, prostaglandins and platelet-activating factors which are responsible for the
characteristic signs and symptoms of anaphylaxis like bronchospasm, laryngeal oedema, hypotension, which could be fatal.
 Adrenaline is the drug of choice (0.3–0.5 mL of 1:1000 solution). It promptly reverses all hypotension, laryngeal oedema
and bronchospasm and is life saving in anaphylactic shock. For administration of adrenaline IM route is preferred as
absorption through SC route is not reliable.
Q. 7. Hypersensitive reaction
Drugs can induce both types of allergic reactions, i.e. humoral- and cell-mediated immunity. Humoral-mediated immunity
causes immediate allergic reactions as follows:
Type I (anaphylaxis) which occurs due to antigen– antibody reaction when the drug induces IgE antibodies.
Type II (cytolytic reaction): The drug binds to the protein and together they act as antigen and induce the formation of
antibodies.
Type III (Arthus reaction): The antigen binds to circulating antibodies and the complexes are deposited on the vessel wall
where it initiates the inflammatory response.
The cell-mediated immunity causes the following reaction:
Type IV (delayed hypersensitivity reaction): It is mediated by T-lymphocytes and macrophages. The antigen reacts with
receptors on T-lymphocytes which produce lymphokines leading to allergic reaction.
Q. 8. What is drug cumulation?

Drug cumulation is the build-up of sufficiently high concentration of a drug in the body to produce toxicity on subsequent
administration.
It is usually seen in the drugs which are excreted slowly,
e.g. digitalis, emetine and heavy metals.
Sometime, a cumulative effect is desired, e.g. with phenytoin in the treatment of epilepsy. But most often, however, it is
undesirable.
Substances like lead can remain deposited in bones without producing toxic effects. This is called passive cumulation. It
would produce the toxic manifestations as soon as it is released into the blood.
 To avoid cumulation
stop the drug administration at the appearance of the first warning symptom.
carefully select the form in which the drug is to be administered.
check liver and kidney function before and during drug administration, as even a noncumulative drug would produce
cumulation in the presence of hepatic and renal damage.

Section | IV
Part II
Drugs Acting on Autonomic Nervous System

Cholinergic System and Drugs

LONG ESSAY
 Classify cholinergic drugs with examples. Write Cholinergic drugs are those which produce
actions similar the mechanism of action, uses and adverse effects of to that of
acetylcholine (ACh), either by directly interacting neostigmine. with cholinergic receptors or by increasing availability of
ACh at these sites.
Classification of cholinergic drugs is as follows:

pyridostigmine parathion edrophonium malathion rivastigmine diazinon

donepezil) tabun, sarin, soman)

NEOSTIGMINE
Mechanism of Action
Neostigmine is a synthetic reversible anticholinesterase agent.
Reversible anticholinesterases reversibly inhibit both true and pseudocholinesterases. Thus ACh gets accumulated and
produces cholinergic effects. Hence, anticholinesterases are called indirectly-acting cholinergic drugs. Its actions are
more pronounced on NMJ, GIT and bladder than on CVS or eye. On skeletal muscles, it has both direct and indirect actions.
Indirect actions: By inhibiting cholinesterases, neostigmine increases the ACh concentration at NMJ.
Direct actions: Because of structural similarity with ACh, neostigmine also directly stimulates the NM receptors at NMJ. Thus
it improves muscle power in patients with myasthenia gravis.
Pharmacological Actions
Lipid-insoluble agents like neostigmine and other quaternary ammonium compounds produce more marked effects on skeletal
muscles, stimulate ganglia but muscarinic effects are less prominent and produce no CNS effects.
a. Ganglia
It stimulates ganglia primarily through muscarinic receptors. High doses cause persistent depolarization of the gangli-
onic nicotinic receptors and blockade of transmission.
 Cardiovascular System Bradycardia and hypotension through muscarinic action.
Tachycardia and hypertension through ganglionic
stimulation.
c. Skeletal Muscles (Direct Action)
After treatment with anticholinesterases the acetylcholine released by a single nerve impulse is not immediately destroyed

It rebinds to same receptors and diffuses to act on neigh- bouring receptors and activates prejunctional fibres

Repetitive firing
Twitching and fasciculations
Force of contraction in partially curarized and myasthenic
Force of contraction in partially curarized and myasthenic muscle is increased
Higher doses cause persistent depolarization of endplates resulting in blockade of neuromuscular transmission
Weakness and paralysis
Direct action of neostigmine and its congeners at muscle end plates results in augmentation of these features
Pharmacokinetics
Neostigmine is poorly absorbed orally.
does not penetrate cornea or cross blood-brain barrier.
partially hydrolyzed and partially excreted unchanged
in urine.
Adverse Effects
Muscarinic: Salivation, lacrimation, urination, defaecation, GI distress and emesis (SLUDGE)
Nicotinic: Muscular fasciculation, cramps, weakness, areflexia, muscle paralysis, hypertension, tachycardia, pallor, mydriasis
CNS: Restlessness, emotional lability, headache, tremors, drowsiness, confusion, slurred speech, ataxia, generalized weakness,
coma, convulsions, depression of respiratory and cardiovascular centres.
Contraindications
Sick sinus, AV conduction defects, hypotensive states, peptic ulcer, asthma, COPD and seizure patients.
Therapeutic Uses
As miotic
In glaucoma
To counteract effect of mydriatics after refraction testing
To prevent formation of adhesions between iris and lens or iris and cornea—physostigmine (0.1 %) is used only to supplement
pilocarpine.
Myasthenia gravis: Neostigmine 15 mg orally 6 hourly
Postoperative paralytic ileus or urinary retention: Neostigmine 0.5–1 mg SC
Postoperative decurarization: Neostigmine 0.5–2 mg IV
Cobra bite: Neostigmine along with atropine
Belladona poisoning
Alzheimer’s disease

SHORT ESSAYS

Irreversible anticholinesterases
Irreversible anticholinesterases are powerful inhibitors of ACh enzyme. They bind with the enzyme permanently by covalent
bonds. Their actions are similar to ACh as ACh accumulates in the tissues. They are lipid soluble and are highly absorbable
by all routes including intact skin.
They include the following:
Organophosphates: Dyflos, echothiophate, parathion, malathion
Carbamates: Carbaryl, propoxur (Baygon) Organophosphates are used as agricultural and domestic insecticides.
Organophosphorus poisoning can result as accidental, suicidal or homicidal result.
Symptoms include muscarinic, nicotinic and central effects: vomiting, abdominal cramps, diarrhoea, miosis, sweating,
increased salivary, tracheobronchial and gastric secretions. Hypotension, muscular twitching, weakness, convulsions and coma
may occur. Death occurs due to respiratory paralysis.
Treatment
If poisoning is through skin, remove clothes and wash skin thoroughly. If by oral route, gastric lavage is necessary.
Maintain BP and patent airway.
Atropine is used in the treatment of organophosphorus poisoning and mushroom poisoning.
Atropine is highly effective in counteracting the muscarinic symptoms produced by the organophosphorus compounds. In
high doses it antagonizes the central effects also.
 Pralidoxime and obidoxime are used in the treatment of organophosphorus poisoning. The compounds combine with
cholinesterase organophosphate complex release the binding and set free AChE enzyme. They should be given within a few
hours (, 24 h) after poisoning, preferably immediately because the complex undergoes ageing and then the enzyme cannot be
released.
Q. 2. Neostigmine
Neostigmine is a synthetic reversible anticholinesterase agent.
Reversible anticholinesterases reversibly inhibit both true and pseudocholinesterases. Thus ACh gets accumulated and
produces cholinergic effects. Hence, anticholinesterases are called indirectly-acting cholinergic drugs.
Its actions are more pronounced on NMJ, GIT and bladder than on CVS or eye. On skeletal muscles, it has both direct and
indirect actions.
Indirect actions: By inhibiting cholinesterases, neostigmine increases the ACh concentration at NMJ.
 Direct actions: Because of structural similarity with ACh, neostigmine also directly stimulates the NM receptors at NMJ.
Thus it improves muscle power in patients with myasthenia gravis.
Pharmacokinetics
Neostigmine is poorly absorbed orally. do not penetrate cornea or cross blood-brain barrier.
partially hydrolyzed and partially excreted unchanged
in urine.
Therapeutic Uses
Myasthenia gravis: Neostigmine 15 mg orally 6 hourly Postoperative paralytic ileus or urinary retention: Neostigmine
0.5–1 mg SC
Postoperative decurarization: Neostigmine 0.5–2 mg IV Cobra bite: Neostigmine along with atropine is given.
Q. 3. Compare neostigmine and physostigmine.
Neostigmine and physostigmine are compared based on following parameters:
Comparison Parameters Physostigmine Neostigmine
1. Source Natural alkaloid obtained from Physostigma venenosum Synthetic
2. Chemistry Tertiary amine derivatives Quaternary ammonium compound
3. Oral absorption Good Poor
4. Lipid solubility Soluble Insoluble
5. CNS actions Present Absent
6. Applied to eyePenetrates cornea Poor penetration
7. Direct action on cholinoceptors Absent Present
8. Prominent effect on Autonomic effectors Skeletal muscles
9. Important usesAs miotic in glaucoma and atropine poisoning Postoperative urinary retention and paralytic ileus,
myasthenia gravis and curare poisoning
10. Dose 0.5–1 mg oral/ parenteral, 0.1–1.0% eye drops 0.5–2.5 mg IM/SC,
15–30 mg orally
11. Duration of action Systemic 4–6 h Ocular 6–24 h 3–4 h
Q. 4. Therapeutic uses of atropine
Therapeutic uses of atropine are as follows:
As Antisecretory
Preanaesthetic medication: Prior use of atropine (anticholinergics) is must to check increased salivary and tracheobronchial
secretions when irritant general anaesthetics like ether are used. It also prevents laryngospasm by reducing respiratory
secretions and also prevents vasovagal attack. Peptic ulcer: Atropine reduces gastric secretion in fasting and neurogenic
phase and affords symptomatic relief in peptic ulcer.
Pulmonary embolism: Atropine benefits by reducing reflex secretions. To check excess seating salivation as in
parkinsonism.
As Antispasmodic
 Intestinal and renal colic, abdominal cramps: In absence of mechanical obstruction, atropine offers symptomatic relief but is
less effective in biliary colic.
Nervous and drug-induced diarrhoea, functional diar-
rhoea but not effective in infective diarrhoeas
Spastic constipation, irritable colon Pylorospasm, gastric hypermotility, gastritis, nervous
dyspepsia
Dysmenorrhoea
In Bronchial Asthma, Asthmatic Bronchitis, COPD
Atropine dries up secretions in the respiratory tract lead
to its inspissations and plugging of bronchioles.
As Mydriatics and Cycloplegic
Atropine is very valuable in treatment of iritis, iridocyclitis, choroiditis, keratitis and corneal ulcer.
 It affords rest to intraocular muscles and cuts down their painful spasm. Atropine prevents adhesions between iris and lens
or iris and cornea and may even break them if already formed.
As cardiac vagolytic: Atropine is useful in counteracting bradycardia and partial heart block in patients where increased
vagal tone is responsible as in MI, digitalis toxicity.
Q. 5. Therapeutic uses of reversible anticholinesterases
Reversible Anticholinesterases
Carbamates: Physostigmine, neostigmine, pyridostigmine, edrophonium, rivastigmine, donepezil
Acridine: Tacrine
Therapeutic Uses
As miotic
In glaucoma
To counteract effect of mydriatics after refraction testing
To prevent formation of adhesions between iris and lens or iris and cornea: Physostigmine (0.1%) is used only to supplement
pilocarpine
Myasthenia gravis: Neostigmine 15 mg orally 6 hourly Postoperative paralytic ileus or urinary retention: Neostigmine
0.5–1 mg SC
Postoperative decurarization: Neostigmine 0.5–2 mg IV Cobra bite: Neostigmine along with atropine Belladonna
poisoning: Physostigmine 0.5–2 mg IV Drug overdosages of tricyclic antidepressants, pheno-
thiazines, many antihistamines
Alzheimer’s disease: Rivastigmine
Q. 6. What is the organophosphorus poisoning? Describethe treatment.

Organophosphates are used in agricultural and domestic insecticides. Organophosphorus poisoning can result as accidental,
suicidal or homicidal result.
 Symptoms include muscarinic, nicotinic and central effects: vomiting, abdominal cramps, diarrhoea, miosis, sweating,
increased salivary, tracheobronchial and gastric secretions. Hypotension, muscular twitching, weakness, convulsions and coma
may occur. Death occurs due to respiratory paralysis.
Treatment
If poisoning is through skin, remove clothes and wash skin thoroughly and if by oral route, gastric lavage is necessary.
Maintain BP and patent airway.
Atropine is used in the treatment of organophosphorus poisoning and mushroom poisoning.
Atropine is highly effective in counteracting the muscarinic symptoms produced by the organophosphorus compounds. In
high doses it antagonizes the central effects also.
Pralidoxime and obidoxime are used in the treatment of organophosphorus poisoning. The compounds combine with
cholinesterase organophosphate complex, release the binding and set free AChE enzyme. They should be given within a few
hours (, 24 h) after poisoning, preferably immediately because the complex undergoes ageing and then the enzyme cannot be
released.
SHORT NOTES
Role of atropine in organophosphorus poisoning
Atropine is used in the treatment of organophosphorus poisoning and mushroom poisoning.
Atropine is highly effective in counteracting the muscarinic symptoms produced by the organophosphorus compounds.
In high doses it antagonizes the central effects also. For these reasons atropine is used in organophosphorus poisoning.
Q. 2. Neostigmine
Neostigmine is a synthetic reversible anticholinesterase agent. Its actions are more pronounced on NMJ, GIT and bladder
than on CVS or eye. On skeletal muscles, it has both direct and indirect actions.
Pharmacokinetics
Neostigmine is poorly absorbed orally. does not penetrate cornea or cross blood-brain barrier.
 is partially hydrolyzed and partially excreted unchanged
in urine.
Therapeutic Uses
Myasthenia gravis: Neostigmine 15 mg orally 6 hourly Postoperative paralytic ileus or urinary retention: Neostigmine
0.5–1 mg SC
Postoperative decurarization: Neostigmine 0.5–2 mg SC Cobra bite: Neostigmine along with atropine is given.
Q. 3. Pralidoxime
Or, Oximes in organophosphorus poisoning
Oximes are reactivators of cholinesterase which are used to restore neuromuscular transmission in cases of
organophosphorus poisoning. But its use is secondary to atropine. Pralidoxime and obidoxime are used in the treatment of
organophosphorus poisoning. The compounds combine with cholinesterase organophosphate complex, release the binding and
set free AChE enzyme. They should be given within a few hours (, 24 h) after poisoning, preferably immediately because the
complex undergoes ageing and then the enzyme cannot be released.
Q. 4. Neostigmine in myasthenia gravis
Myasthenia gravis is a chronic autoimmune disease characterized by progressive weakness with rapid and easy fatigability
of skeletal muscles. Antibodies to nicotinic receptors are found, resulting in the number of these receptors at NMJ.
Neostigmine (15mg tab, 6 hourly) or pyridostigmine or a combination of both may be used. They enhance the levels of ACh
at the NMJ by preventing its destruction. Thus they increase the force of contraction and improve muscle power.
Q. 5. Neostigmine—uses and adverse effects
Therapeutic uses and adverse effects of neostigmine are as follows:
As miotic in glaucoma Myasthenia gravis
Postoperative paralytic ileus or urinary retention Postoperative decurarization Cobra bite: Neostigmine along with
atropine
 Belladona poisoning Alzheimer’s disease
Adverse Effects
Muscarinic: Salivation, lacrimation, urination, defection, GI distress and emesis
Nicotinic: Muscular fasciculation, cramps, weakness, areflexia, muscle paralysis, hypertension, tachycardia, pallor and
mydriasis
CNS: Restlessness, emotional lability, headache, tremors, drowsiness, confusion, slurred speech, coma, convulsions,
depression of respiratory and cardiovascular centres
Q. 6. Therapeutic uses of atropine
Therapeutic uses of atropine are as follows:
As antisecretory preanaesthetic medication, peptic ulcer and pulmonary embolism
As antispasmodic Intestinal and renal colic, abdominal cramps Nervous and drug-induced diarrhoea Spastic
constipation, irritable colon
 Pylorospasm, gastric hypermotility, gastritis, nervous
dyspepsia
Dysmenorrhoea
Bronchial asthma, asthmatic bronchitis, COPD: Atropine dries up secretions in the respiratory tract, leading to its inspissations
and plugging of bronchioles.
As mydriatics and cycloplegic: Atropine is very valuable in treatment of iritis, iridocyclitis, choroiditis, keratitis and corneal
ulcer.
Q. 7. Irreversible anticholinesterases
They are powerful inhibitors of ACh enzyme. They bind with the enzyme permanently by covalent bonds.
Their actions are similar to ACh. They are lipid soluble and are highly absorbable by all routes including intact skin. They
include the following:
Organophosphates, e.g. dyflos, echothiophate, parathion, malathion, etc.
Carbamates, e.g. carbaryl, propoxur Organophosphates are used in agricultural and domestic insecticides. Organophosphorus
poisoning can result as accidental, suicidal or homicidal result. Death occurs due to respiratory paralysis.
Treatment
If poisoning is through skin, remove clothes and wash skin thoroughly and if by oral route, gastric lavage is necessary.
Maintain BP and patent airway.
Atropine is used in the treatment of organophosphorus poisoning and mushroom poisoning.
Pralidoxime and obidoxime are used in the treatment of organophosphorus poisoning.
Q. 8. Name few oximes.

Oximes are reactivators of cholinesterase which are used to restore neuromuscular transmission in cases of
organophosphorus poisoning, but its use is secondary to atropine.
Few examples of oximes are as follows:
Pralidoxime (2-PAM)
Obidoxime
Diacetyl monoxime (DAM) Pralidoxime and obidoxime are used in the treatment of organophosphorus poisoning.

Anticholinergic Drugs and Drugs

Acting on Autonomic Ganglia
LONG ESSAY
They should be given within a few hours (, 24 h) after poisoning, preferably immediately.

Classify anticholinergic drugs. Discuss the pharmacology and uses of atropine.Mention

the symptoms of atropine poisoning and line of treatment. Or,
Classify anticholinergic drugs. Discuss the adverse effects and uses of atropine.
Or,
Discuss the pharmacological actions of atropine.Mention some atropine substitutes and their
uses in the therapy.

Anticholinergic drugs are those which block actions of acetylcholine on autonomic effectors and in the CNS exerted through
muscarinic receptors.
Classification
I. Natural alkaloids
Atropine
Hyoscine (scopolamine) II. Semisynthetic derivatives
Homatropine
Atropine methonitrate Hyoscine butyl bromide Ipratropium bromide Tiotropium bromide III. Synthetic
compounds a. Mydriatics
Cyclopentolate Tropicamide
Antisecretory: Antispasmodic
Quaternary compounds: Propantheline, oxyphenonium, clidinium, pipenzolate methyl bromide, isopropamide, glycopyrrolate,
tertiaryamines, dicyclomine, oxybutynin, flavoxate, pirenzepine, telenzepine
Antiparkinsonian: Trihexy phenidyl (benzhexol), procyclidine, biperiden, benztropine, cycrimine, ethopropazine
ATROPINE
Atropine is the prototype drug and the chief alkaloid of belladonna. It is an anticholinergic drug that acts as an antagonist of
muscarinic receptors and is parasympatholytic.
Mechanism of action: Atropine acts by antagonizing the muscarinic receptors. It blocks the action of ACh on autonomic
effectors and in the CNS.
Pharmacological Actions
Pharmacological actions of atropine are as follows:
i. CNS
Atropine has overall CNS stimulant action. In therapeutic doses, atropine has mild CNS-stimulant effect.
It suppresses tremors and rigidity of parkinsonism by blocking the relative cholinergic overactivity in basal ganglia and
extrapyramidal tracts and thus produces antiparkinsonian effect.
It suppresses vestibular disturbances and produces antimotion sickness effect. Large doses can produce excitement,
restlessness, agitation, hallucinations, medullary paralysis, coma and death. ii. CVS
At low doses, atropine causes initial bradycardia due to the blockade of presynaptic muscarinic autoreceptors (M1) on vagal
nerve endings.
In therapeutic doses, tachycardia is seen due to blockade of M2 receptors of the heart and it also improves A–V conduction.
In high doses, flushing of the face and hypotension may
occur due to cutaneous vasodilatation.
iii. Glands
All secretions under cholinergic influence are reduced due to blockade of M3 receptors, i.e. sweat, salivary, nasal, throat,
bronchial, gastric, lacrimal, etc. The milk and bile secretions are not affected. The skin and mucous membranes become dry. iv.
Eye
Topical instillation of atropine causes the following:
Passive mydriasis due to paralysis of constrictor pupillae
(blockade of M3 receptors), lasting 7–10 days
Cycloplegia due to paralysis of ciliary muscle (blockade
M3 receptors) Ciliary muscles recover earlier than sphincter pupillae.
v. Smooth Muscles
Through M3 blockade atropine relaxes all visceral smooth muscles that receive parasympathetic innervation.
GIT: Atropine decreases tone and motility of the gut, but increases the sphincter tone and may cause constipation. It also
relaxes the smooth muscle of the gallbladder.
Urinary bladder: Atropine relaxes the detrusor muscle of the bladder but increases the tone of the trigonal sphincter and may
cause urinary retention, especially in elderly men with enlarged prostate.
Bronchi: Atropine relaxes the bronchial smooth muscle. It also reduces the secretions and mucociliary clearance resulting in
the mucus plug that may block the airway. Atropine causes bronchodilatation and reduces airway resistance especially in
COPD and asthma patients. vi. Body Temperature
At high doses body temperature rises due to inhibition of sweating and stimulation of temperature regulating centres in the
hypothalamus. Children are highly susceptible to atropine fever.
vii. Local Anaesthetics
Atropine has a mild anaesthetic action on the cornea.
THERAPEUTIC USES As Antisecretory
 Preanaesthetic medication
Prior use of atropine (anticholinergics) is must to check increased salivary and tracheobronchial secretions when irritant
general anaesthetics like ether are used. It also prevents laryngospasm by reducing respiratory secretions and also prevents
vasovagal attack. Peptic ulcer: Atropine reduces gastric secretion in fasting and neurogenic phase and affords symptomatic
relief in peptic ulcer. Pulmonary embolism: Atropine benefits by reducing reflex secretions.
In bronchial asthma, asthmatic bronchitis and COPD, atropine dries up secretions in the respiratory tract, leading to its
inspissations and plugging of bronchioles.
To check excess seating salivation as in parkinsonism
As Antispasmodic
Intestinal and renal colic, abdominal cramps: In absence of mechanical obstruction, atropine offers symptomatic relief but less
effective in biliary colic.
It is effective in nervous and drug-induced diarrhoea, func-
tional diarrhoea but not effective in infective diarrhoeas. Spastic constipation, irritable colon Pylorospasm,
gastric hypermotility, gastritis, nervous
dyspepsia
Dysmenorrhoea
As Mydriatics and Cycloplegic
Atropine, homatropine, cyclopentolate or tropicamide are used topically for producing mydriasis and cycloplegia during
refraction testing.
Atropine is very valuable in treatment of iritis, iridocyclitis, choroiditis, keratitis and corneal ulcer.
It affords rest to intraocular muscles and cuts down their painful spasm.
Atropine prevents adhesions between iris and lens or iris and cornea and may even break them if already formed.
In children, atropine is preferred because of its greater
efficacy.
As Cardiac Vagolytic
Atropine is useful in counteracting bradycardia and partial heart block in patients where increased vagal tone is responsible as
in MI, digitalis toxicity. It improves A–V conduction by vagolytic effect.
Poisoning
In organophosphorus poisoning, atropine is the lifesaving drug.
In some types of mushroom poisoning (Inocybe species) atropine is the drug of choice.
Atropine is used in curare poisoning with neostigmine
to counteract the muscarinic effects of neostigmine.
ADVERSE EFFECTS AND
CONTRAINDICATIONS
Adverse effects are due to the extension of pharmacological actions.
GIT: Dryness of mouth and throat, difficulty in swallowing, constipation, etc.
Eye: Photophobia, headache, blurring of vision and in elderly persons with shallow anterior chamber, they may precipitate
acute congestive glaucoma. Hence, anticholinergics are contraindicated in glaucoma. Urinary tract: Difficulty in
micturition and urinary retention especially in elderly men with enlarged prostate CNS: With large doses produce
restlessness, excite-
ment, muttering delirium and hallucinations
SHORT ESSAYS
CVS: Tachycardia, palpitation and hypotension Acute belladonna poisoning: It is more common in children.
Convulsions and coma occur in severe poisoning.

Compare atropine and cocaine.

Comparison between atropine and cocaine is given in Table 6.1.

Q. 2. Atropine
Atropine is an anticholinergic drug that acts as an

TABLE 6.1 Comparison between Atropine and Cocaine

Comparable
Points AtropineCocaine
Acts on Autonomic nervous system Central nervous system
Action Anticholinergic drug Surface anaesthetic
Causes Antispasmodic, mydriatic, cycloplegic, preanaesthetic medication, organophosphorus poisoning, in bronchial asthma
and motion sickness Used earlier for ocular anaesthesia
Adverse effects Blurring of vision, dry mouth and skin dysphagia, fever, constipation, urinary retention Causes constriction
of corneal vessels, clouding and sloughing of cornea
antagonist of muscarinic receptors and is parasympatholytic.
Mechanism of action: Atropine acts by antagonizing the muscarinic receptors. It blocks the action of ACh on autonomic
effectors and in the CNS.
Pharmacological Actions
Central nervous system: Atropine stimulates many medullary centres—vagal, respiratory, vasomotor. It depresses vestibular
excitation and has antimotion sickness property.
Cardiovascular system Heart: Most prominent effect is tachycardia.
Blood pressure: Atropine by itself does not have any consistent or marked effect on blood pressure. However indirectly through
tachycardia and stimulation of vasomotor centre it raises BP.
Eye: Topical instillation of atropine causes mydriasis, abolition of light reflex and cycloplegia lasting 7–10 days. This results in
photophobia and blurring of near vision.
Smooth muscle Tone and amplitude of contractions of stomach and intestine are reduced and it relieves spasms and passage
of chyme is slowed resulting in constipation.
Atropine causes bronchodilatation and reduces airway resistance especially in COPD and asthma patients.
Body temperature: At high doses body temperature rises due to inhibition of sweating and stimulation of temperature
regulating centres in the hypothalamus. Children are highly susceptible to atropine fever.
Local anaesthetics: Atropine has a mild anaesthetic action on the cornea.
Uses
Atropine can be used as antispasmodic, mydriatic, cycloplegic, preanaesthetic medication, organophosphorus
poisoning, in bronchial asthma and motion sickness.
Q. 3. Homatropine
 Belladonna alkaloids lack the selectivity and exert a wide range of effects, thus producing many side effects. To overcome
this, several synthetic and semisynthetic derivatives with selective action were introduced.
Homatropine is an atropine substitute that is used on the eye.
It causes mydriasis and cycloplegia that last for about 6–24 h. They have shorter action than atropine. Homatropine can be
used in case of atropine intolerance.
Q. 4. Atropinepoisoning
Acute belladonna poisoning: It is more common in children.
Cohen described the effects as follows:
Hot as a hare: The body temperature is increased (hyperpyrexia) due to the suppression of sweating (atropine fever). Red
as a beetroot: Hot, red and flushed skin is due to cutaneous vasodilatation (atropine flush).
Dry as a bone: The skin and mucous membranes become dry because of blockade of secretions.
Blind as a bat: Mydriasis and cycloplegia result in photophobia and severe blurring of vision.
 Mad as a hatter: Restlessness, excitement, confusion, disorientation and hallucinations. Severe poisoning: It may cause
respiratory depression, cardiovascular collapse, convulsions, coma and death.
Treatment of belladonna poisoning (atropine poisoning) Mainly symptomatic Hospitalization Gastric lavage in case of
ingested poisoning Tepid sponging to control hyperpyrexia Diazepam to control convulsions The antidote for severe
atropine poisoning is physostigmine. Physostigmine (1–4 mg) is injected slowly intravenously. It is a tertiary amine,
counteracts both peripheral as well as central effects of atropine poisoning. Hence, physostigmine is preferred over
neostigmine.
Q. 5. Uses and adverse effects of atropine
Uses
Atropine can be used as antispasmodic, mydriatic, cycloplegic, preanaesthetic medication, organophosphorus
poisoning, in bronchial asthma and treatment for motion sickness.
Adverse effects of atropine are common but not serious, they are as follows:
 Atropine increases heart rate and in large doses may cause hypotension.
Atropine has an antisecretory effect on all glands and hence secretion is reduced from gastric glands, salivary gland and
sweat glands. It causes dry mouth, dry skin, dysphagia, etc. It reduces GI motility and causes constipation.
Atropine causes mydriasis due to which the iris may block the drainage of aqueous humour leading to raise in intraocular
pressure. It causes blurring of vision and may also cause glaucoma in some patients.
Q. 6. Atropineand scopolamine
Comparison between atropine and scopolamine is given in Table 6.2.
TABLE 6.2 Comparison between Atropine and Scopolamine
Comparable Points AtropineScopolamine (Hyoscine)
1. Chief source Atropa belladonna, Datura stramonium Hyoscyamus niger
2. Alkaloidal ester of Tropic acid with tropine Tropic acid with scopine
3. CNS effect
 Low dose Mild excitation Depression
High dose Strong excitation Excitation
4. Anticholinergic property More potent on heart, bronchial muscle and intestines More potent on eye and
secretory glands
5. Duration of action Longer Shorter
6. Antimotion sickness 11 111
Q. 7. Atropinesubstitutes
Atropine substitutes are semisynthetic derivatives of belladonna alkaloids and synthetic compounds.
They are antagonists of muscarinic receptors and are parasympatholytics. They differ only marginally from the atropine.
Some of them may also possess significant nicotinic
blocking property.
Classification
Quaternary Compounds
Hyoscine butyl bromide Atropine methonitrate Ipratropium bromide Tiotropium bromide
Propantheline Oxyphenonium Clidinium Pipenzolate methyl bromide Isopropamide Glycopyrrolate
Tertiaryamines
Dicyclomine Oxybutynin Flavoxate Pirenzepine Telenzepine
Mydriatics
SHORT NOTES
Homatropine Cyclopentolate Tropicamide

Atropine
Atropine is an anticholinergic drug that acts as an antagonist of muscarinic receptors and is parasympatholytic.
Pharmacological Actions
Central nervous system: Atropine stimulates many medullary centres.
Cardiovascular system: On the heart, most prominent effect is tachycardia.
Eye: Topical instillation of atropine causes mydriasis, abolition of light reflex and cycloplegia.
Smooth muscle: Tone and amplitude of contractions of stomach and intestine are reduced resulting in constipation.
Body temperature: At high doses body temperature rises.
Local anaesthetics: Atropine has a mild anaesthetic action on the cornea.
Uses
Atropine can be used as antispasmodic, mydriatic, cycloplegic, preanaesthetic medication and in treating motion sickness.
Q. 2. Atropinederivatives
Semisynthetic and synthetic antimuscarinic agents or atropine derivatives are as follows:
Atropine derivatives used as mydriatic: Homatropine, cyclopentolate, tropicamide
Atropine derivatives used in chronic obstructive pulmonary disease (COPD) and bronchial asthma: Ipratropium bromide,
tiotropium bromide, oxitropium bromide
Atropine derivatives used in peptic ulcer: Pirenzepine, telenzepine
Atropine derivatives used as antispasmodics: Dicyclomine, flavoxate, oxybutynin, tolterodine

Section | IV
Atropine derivative used as a preanaesthetic agent: Glycopyrrolate
Atropine derivatives used in parkinsonism: Benzhexol (trihexyphenidyl), benztropine, biperidin.
Q. 3. Mention two atropine substitutes.

Belladonna alkaloids lack the selectivity and exert a wide range of effects; thus producing many side effects. To overcome this,
several synthetic and semisynthetic derivatives with selective action were introduced.
Homatropine: Instilled in eye, it produces mydriasis in 45–60 min lasting 1–3 day but accommodation recovers in day or two.
Cyclopentolate: It produces mydriasis and cycloplegia in 30–60 min lasting about a day. It is preferred for cycloplegic
refraction and is also used in iritis and uveitis.
Tropic amide: It acts quickly in 20–40 min and duration of action is short lasting (3–6 h). It is used for refraction testing and as
short-acting mydriatic for fundoscopy.
Q. 4. Therapeutic uses of atropine.

Atropine can be used as antispasmodic, mydriatic, cycloplegic, preanaesthetic medication, organophosphorus

poisoning, in bronchial asthma and treatment for motion sickness.
Q. 5. Atropinepoisoning
Acute belladonna poisoning is more common in children. Cohen described the effects as hot as a hare, red as a beetroot,
dry as a bone, blind as a bat and mad as a hatter.
 Severe poisoning: It may cause respiratory depression, cardiovascular collapse, convulsions, coma and death. Treatment
of belladonna poisoning (atropine poisoning)
Mainly symptomatic
Hospitalization
Gastric lavage in case of ingested poisoning
Tepid sponging to control hyperpyrexia
Diazepam to control convulsions The antidote for severe atropine poisoning is physostigmine. Physostigmine (1–4 mg) is
injected slowly intravenously. It counteracts both peripheral as well as central effects of atropine poisoning. Hence,
physostigmine is preferred over neostigmine.
Q. 6. Scopolamine
 Scopolamine is an anticholinergic drug which is a belladonna alkaloid. It acts by competing with the acetylcholine for
muscarinic receptors and block these receptors. They are muscarinic antagonists. Chief source: It is derived from
Hyoscyamus niger. It forms an alkaloidal ester of tropic acid with scopine.
In low doses it depresses CNS activity and high doses it causes excitation. It has a shorter duration of action compared to
atropine.
It is mainly used for antimotion sickness: Given 30 min before the journey. Transdermal patches of hyoscine are applied
behind the ear for prolonged action.
Q. 7. Uses of hyoscinein motion sickness
Hyoscine or scopolamine acts as antiemetic by blocking the conduction of nerve impulses across a cholinergic link in the
pathway leading from the vestibular apparatus to the vomiting centre. Therefore, scopolamine is used in motion sickness.
 Scopolamine has more prominent actions on eyes and secretory glands. By blocking cholinergic activity, scopolamine
suppresses vestibular disturbances and produces antimotion sickness effect. Scopolamine is the drug of choice for motion
sickness.
It can be administered orally or as a transdermal patch.
It is given minimum 30 min before the journey. Transdermal patches of hyoscine are applied behind the ear for prolonged
action.
Q. 8. Mention four adverse effects of atropine.

Adverse effects of atropine are as follows:

Atropine increases heart rate and in large doses may cause hypotension.
Atropine has an antisecretory effect on all glands and hence it causes dry mouth, dry skin, dysphagia.
It reduces GI motility and causes constipation.
Atropine causes mydriasis.
Q. 9. Rationale of using atropine in preanaesthetic medication
Atropine is used as a preanaesthetic medication.
When administered 30 min before anaesthesia, atropine reduces salivary and respiratory secretions. This prevents the
development of laryngospasm.
It prevents bradycardia during surgery.
It acts as a bronchodilator, reduces risk of asthma related to anaphylactic shock. For example, glycopyrrolate is used mostly as
a preanaesthetic medication.
Q. 10. Rationale of using atropine in organophosphorus poisoning
Atropine is used in the treatment of organophosphorus poisoning and mushroom poisoning.
Atropine is highly effective in counteracting the muscarinic symptoms produced by the organophosphorus compounds. In
high doses it antagonizes the central effects also.
 For these reasons atropine is used in treatment of organophosphorus poisoning.
Q. 11. Explain the rationale of using pralidoxime in organophosphorus poisoning.

Adrenergic System and Drugs

LONG ESSAYS
Pralidoxime and obidoxime are used in the treatment of organophosphorus poisoning. These compounds combine with
cholinesterase organophosphate complex, release the binding and set free AChE enzyme. They should be given within a few
hours (, 24 h) after poisoning, preferably immediately because the complex undergoes ageing and then the enzyme cannot be
released.
 What are sympathomimetics? Classify them. Describepharmacological actions, therapeutic uses
and side effects of adrenaline.
Or,
Discuss the pharmacological actions and some important uses of sympathomimeticdrugs. Or,
Classify sympathomimetics. Write the therapeutic uses and adverse effects of
adrenaline.

Sympathomimetics are also known as adrenergic drugs. These are drugs with action similar to that of adrenaline or sympathetic
stimulation.
CLASSIFICATION OF ADRENERGIC DRUGS (SYMPATHOMIMETICS)
I. On the Basis of Their Mechanism of Action
Direct-acting sympathomimetics: They act directly as agonists on a and/or b adrenoreceptors, e.g. adrenaline, noradrenaline,
isoprenaline, phenylephrine, methoxamine, xylometazoline, salbutamol, etc.
Indirect-acting sympathomimetics: They act on adrenergic neurone to release NA which then acts on the adrenoreceptors, e.g.
tyramine.
Mixed-action sympathomimetics: They act directly as well as indirectly, e.g. ephedrine, amphetamine, mephentermine.
II. On the Basis of Their Chemical Structure
Catecholamines: Sympathomimetics with catechol nucleus are called catecholamines, e.g. adrenaline, noradrenaline, dopamine,
isoprenaline and dobutamine.
Noncatecholamines: Sympathomimetics that lack catechol nucleus are called noncatecholamines, e.g. tyramine, ephedrine,
amphetamine, phenylephrine, salbutamol, etc.
III. On the Basis of Their Therapeutic Use
Drugs that raise blood pressure (pressor agents): Noradrenaline, ephedrine, phenylephrine, methoxamine mephentermine and
dopamine
As cardiac stimulants or inotropic agents: Adrenaline, isoprenaline, dopamine or dobutamine
Drugs used as bronchodilators: Adrenaline, isoprenaline, orciprenaline, salbutamol, terbutaline, salmeterol, formoterol
As CNS stimulants: Ephedrine, amphetamine, dexamphetamine
As anorexiants: Dextroamphetamine, phentermine, fenfluramine
As uterine relaxants and vasodilators: Isoxsuprine, salbutamol, terbutaline and ritodrine
Section | IV
Nasal decongestants: Phenylephrine, xylometazoline, oxymetazoline pseudoephedrine and naphazoline
For allergic reactions (anaphylactic shock): Adrenaline ix. For local vasoconstrictor effect: Adrenaline
PHARMACOLOGICAL ACTIONS OF ADRENALINE
I. Cardiovascular System
i. Heart Adrenaline is a powerful cardiac stimulant. It increases heart rate (positive chronotropic). Increases myocardial
contractility (positive inotropic). Increase in conduction velocity (positive dromotropic) Thus increases cardiac output and
oxygen consumption.
Increase in the excitability and tendency to cause car-
diac arrhythmias.
ii. Blood Vessels and Blood Pressure
Adrenaline constricts blood vessels of skin and mucous membranes which predominantly contain a1 receptors.
It also constricts renal, mesenteric, pulmonary and splanchnic vessels but dilates blood vessels of skeletal muscles and
coronary vessels which contain b2 receptors.
Intravenous administration of adrenaline in moderate doses produces typical biphasic effect. There is an initial rise in blood
pressure due to a1 (blood vessels) and a1 (heart) actions, followed by a fall in BP due to b2-mediated vasodilation in skeletal
muscle.
II. Respiratory System
Adrenaline rapidly relaxes (b2) bronchial smooth muscle. It is a potent bronchodilator but has short duration of action.
It inhibits the release of inflammatory mediators from mast cells (b2).
It reduces secretions and relieves mucosal congestion
by vasoconstrictor effect (a1).
GIT
Adrenergic drugs cause gut relaxation, decrease motility and constrict sphincters.
Bladder
Adrenergic drugs cause detrusor muscle relaxation (b2) and contract the trigone sphincter (a1). As a result it may cause
inhibition or difficulty of micturition.
EYE
Adrenaline has poor penetration through cornea when applied topically into the eye. Hence, it is administered as a prodrug.
CNS
In therapeutic doses, adrenaline does not cross the BBB and hence CNS effects are very minimal.
THERAPEUTIC USES
Therapeutic uses of adrenaline are as follows:
Anaphylactic shock: Adrenaline is a life-saving drug in anaphylactic shock and other type-I hypersensitive reactions. It rapidly
reverses the manifestations of severe allergic reactions. Given as adrenaline 0.3–0.5 mL of 1:1000 solution (1 mg/mL) IM.
Allergic disorders: It rapidly reverses the manifestations of severe allergic reactions.
Along with local anaesthetics it increases duration of action of anaesthesia.
Control epistaxis and other capillary oozing: Adrenaline is used as a local haemostatic to control bleeding following tooth
extraction and during surgical procedures in nose, throat, larynx, etc. because of its vasoconstrictor effect.
Bronchial asthma: Adrenaline is a powerful bronchodilator and has rapid onset but short duration of action. It is useful for
acute attack. Adrenaline 0.3–0.5 mL of 1:1000 solution is given subcutaneously. It can be given by nebulization (as inhalation).
Cardiac resuscitation: In the treatment of cardiac arrest due to drowning or electrocution, adrenaline is injected intravenously in
1:10000 (0.1 mg/mL) concentration along with other supportive measures such as external cardiac massage, as a part of
advanced life support (ALS). vii. Blood pressure: Adrenaline increases systolic blood pressure and decreases
diastolic BP.
viii. Glaucoma: Adrenaline has poor penetration when applied locally into the eye, hence it is administered as a prodrug.
SIDE EFFECTS OF ADRENALINE
The adverse effects are due to the extension of pharmacological actions, they are as follows:
Tachycardia, palpitation, headache, restlessness, tremor and rise in BP
The serious side effects are cerebral haemorrhage and cardiac arrhythmias.
In high concentrations, adrenaline may cause acute pulmonary oedema due to the shift of blood from the systemic to the
pulmonary circulation.
Adrenaline is contraindicated in most of the cardiovascular diseases such as hypertension, angina, cardiac arrhythmias, CCF,
etc. and also in patients on b-blockers, because it may cause hypertensive crisis and cerebral haemorrhage due to unopposed
action on vascular a1 receptors.
On intravenous administration adrenalin rapidly causes sudden rise in BP, ventricular tachycardia, angina, myocardial
infarction and stroke.
Metabolic side effects of adrenaline include hyperglycaemia, hyperlactacidemia and hypokalaemia.
Q. 2. Describethe differences in action of adrenaline, noradrenaline and
isoprenaline. Write their uses indicating the routes of administration.

Sympathomimetics are also known as adrenergic drugs. These are drugs with action similar to that of adrenaline or sympathetic
stimulation.
The differences in pharmacological actions of adrenaline, noradrenaline and isoprenaline are given in Table 7.1.
A. Therapeutic Uses of Adrenaline
Anaphylactic shock Allergic disorders
Used along with local anaesthetics to increase duration of action of anaesthesia.
They control local bleeding from skin, mucous membrane, epistaxis, tooth socket.
Cardiac arrest: IV adrenaline to stimulate heart. Bronchial asthma
Mydriatics: Decreases intraocular tension in glaucoma.
Route of administration of adrenaline: 0.2–0.5 mg can be given SC, IM or 0.5% by aerosol.

TABLE 7.1 Differences in Action of Adrenaline, Noradrenaline and Isoprenaline

Site of Action Adrenaline Noradrenaline Isoprenaline
1. Heart Increases heart rate Does not increase heart rate Powerful cardiac stimulant increases heart rate
2. BP Systolic BP, diastolic BP Both systolic
and diastolic
BP Systolic and diastolic BP
3. Respiration Causes bronchodilation No bronchodilation Causes bronchodilation
4. GIT Causes gut relaxation and decrease in motility and cause constipation
5. Blood sugars

B. Therapeutic Uses of Other Adrenergic Drugs (Noradrenaline and Isoprenaline) Are as Follows:
Anaphylactic shock and allergic disorders Hypotensive state: Vasopressor agent can be used. Neurogenic or cardiogenic
shock: Dopamine or dobutamine is preferred.
Congestive heart failure: Short-term use in decompensated state, i.e. dopamine and dobutamine.
Partial or complete heart block: Ephedrine or isoprenaline can be used as cardiac stimulant.
Control local bleeding from skin and mucous membrane, e.g. epistaxis. NA 8 mg in 100–200 mL saline controls bleeding from
gastric erosions and stress ulcers when put in the stomach through a tube.
Route of administration of noradrenaline or isoprena-
line is as follows:
Noradrenaline 2–4 µg/min IV infusion
Isoprenaline 20 mg sublingual, 1–2 mg IM,
5–10 µg/min IV infusion

SHORT ESSAYS

Adrenaline
Sympathomimetics are also known as adrenergic drugs. These are drugs with action similar to that of adrenaline or sympathetic
stimulation.
PHARMACOLOGICAL ACTIONS
OF ADRENALINE
Cardiovascular System Heart
Adrenaline is a powerful cardiac stimulant.
It increases heart rate (positive chronotropic), myocardial contractility (positive inotropic) and also conduction velocity
(positive dromotropic).
Thus increases cardiac output and oxygen consumption.
Blood Vessels and Blood Pressure
Adrenaline constricts blood vessels of skin and mucous membranes which predominantly contain a 1 receptors but dilates
blood vessels of skeletal muscles and coronary vessels which contain b2 receptors.
 Intravenous administration of adrenaline in moderate doses produces typical biphasic effect. There is an initial rise in blood
pressure due to a1 (blood vessels) and b1 (heart) actions, followed by a fall in BP due to a2-mediated vasodilation in skeletal
muscle.
Respiratory System
Adrenaline rapidly relaxes (b2) bronchial smooth muscle. It is a potent bronchodilator but has short duration of action.
Section | IV
It reduces secretions and relieves mucosal congestion
by vasoconstrictor effect (a1).
GIT
Adrenergic drugs cause gut relaxation, decrease mo-
tility and constrict sphincters.
Bladder
 Adrenergic drugs cause detrusor muscle relaxation (b2) and contract the trigone sphincter (a1), as a result it may cause
inhibition or difficulty of micturition.
EYE
Adrenaline has poor penetration through cornea when applied topically into the eye. Hence, it is administered as a prodrug.
CNS
In therapeutic doses, adrenaline does not cross the BBB
and hence CNS effects are very minimal.
Q. 2. Dopamine
Dopamine (DA) is a catecholamine and the immediate metabolic precursor of NA. It is a directly-acting sympathomimetic
that acts on the receptors of the medulla.
DA, like adrenaline and noradrenaline (NA), is not effective orally. DA is rapidly inactivated by COMT and MAO and is
administered by IV infusion. It is a D1 and D2 as well as adrenergic a and b1 (but not b2) agonist.
 The D1 receptors in renal and mesenteric blood vessels are the most sensitive.
IV infusion of low dose of DA dilates these vessels increasing GFR and Na1 excretion. At doses normally infused IV
doses, it raises cardiac output and systolic BP with little effect on diastolic BP.
Moderately high doses produce a positive inotropic effect on heart. Vasoconstriction (a1 action) occurs only when large
doses are infused. This is useful in cardiogenic and septic shock.
Adverse effects: The adverse effects seen are mainly due to sympathetic stimulation. They are nausea, vomiting, headache,
hypertension, tachycardia, cardiac arrhythmias and anginal pain.
Therapeutic uses
Cardiogenic and septic shock: DA is the drug of choice because it increases BP as well as selectively dilates renal, mesenteric,
coronary blood vessels and improves blood flow to the vital org Hence dopamine is preferred.
Severe heart failure with renal impairment: DA improves both cardiac and renal functions.
Q. 3. Compare adrenaline and ephedrine.
Comparison between adrenaline and ephedrine is given in Table 7.2.
TABLE 7.2 Comparison between Adrenaline and Ephedrine
Comparable
Points Adrenaline Ephedrine
Type Directly-acting sympathomimetics medulla Mixed-acting sympathomimetics medulla
Source Natural Natural: Ephedra vulgaris
Action on receptors Acts on a1, a2, b1, b2 receptors but no D action Mainly acts indirectly but acts on a and b
receptors
Heart rate Increases followed by reflex bradycardia Increases
Cardiac output Increases Increases
Total peripheral resistance Decreases Increases
Mean blood pressure Increases followed by decrease (Dale’s vasomotor phenomenon) Increases
Blood vessels Vasoconstriction Vasoconstriction
Adverse effects Transient restlessness, palpitation, anxiety, tremors. Marked rise in BP leading to cerebral haemorrhage,
ventricular tachycardia, angina, MI Insomnia, tachycardia, palpitation, difficulty in urination and tachyphylaxis on repeated
administration
Route of administration SC, IM Orally
Therapeutic uses Shock, along with local anaesthetics styptics, cardiac arrest, allergic disorders, bronchial asthma Mild
chronic asthma and for hypotension during spinal anaesthesia
Q. 4. Pharmacotherapy of shock
Drugs used in shock are as follows:
Sympathomimetic amines: Noradrenaline, adrenaline, dopamine and dobutamine. These drugs maintain perfusion of vital
organs by increasing myocardial contractility and cardiac output, constricting vessels, venules and dilating arterioles in vital
org
Alpha adrenoceptor blocking agents: Phenoxybenzamine is used in surgical shock after loss of adequate fluid volume by
reducing vasoconstriction by reflex release of noradrenaline.
Oxygen: It is used in patients in cardiogenic shock, reduces cyanosis due to arterial hypoxemia.
Dextran and other plasma expanders: High molecular weight dextran and low molecular weight dextran are used in
hypovolaemic shock. They increase plasma volume temporarily and drawing fluid in vascular space and improve blood flow.
Glucagon: It increases myocardial contractility and improve haemodynamic status.
Corticosteroids: They are used in anaphylactic shock, septic shock and shock due to acute adrenal insufficiency.
Q. 5. Adrenaline and noradrenaline
Comparison between adrenaline and noradrenaline is given in Table 7.3.
TABLE 7.3 Comparison between Adrenaline and
Noradrenaline
Points to be
Compared Adrenaline Noradrenaline
Site of synthesis cells Only in adrenal medulla In adrenergic neurons
Action on a1 1 a 2 1 b1 1 b2 and weak b3 action a 1 1 a 2 1 b1 1 b3 but no b2 action
Pharmacological action on various systems
Cardiovascular system
Heart rate Increased Decreased
Force of contraction Increased Decreased
Excitability of
increased heart muscle Increased No change
Points to be
Compared Adrenaline Noradrenaline
Cardiac output Increased Decreased
Systolic BP Increased Increased
Diastolic BP Decreased Increased
Mean BP Increased Increased
Total peripheral resistance Decreased Increased
Blood vessels Constriction of some but dilatation of blood vessels in muscles, liver and heart Vasoconstrictor
Respiration Stimulated and bronchodilatation Stimulated but no bronchodilation
Uterus (in vivo) Inhibits in late pregnancy and during labour and puerperium Stimulates contractions
Uses For anaphylactic shock As a pressor agent but rarely used nowadays
Q. 6. List at least two drugs from b adrenoceptor stimulants. Describe
pharmacological actions.

b Adrenoceptor Stimulants
b adrenoceptor stimulants are as follows:
Adrenaline
Noradrenaline
Pharmacological Actions Heart
Adrenaline: It increases heart rate, force of contraction, conduction; thus increases the cardiac output.
Noradrenaline: It does not increase the heart rate but
produces bradycardia due to reflex mechanism.
BP
 Adrenaline: It increases systolic BP and decreases diastolic BP.
Noradrenaline: It increases systolic and diastolic BP because b2 action is very weak.
Section | IV
Respiration Bladder
Adrenaline: It is a potent bronchodilator. They cause muscle relaxation, constriction of sphincter Noradrenaline: It does
not cause bronchodilatation. and inhibition of micturition.
GIT Eye
Adrenaline and noradrenaline cause gut relaxation, Contraction of radial muscle of iris causes mydriasis decrease motility
and cause constriction of sphincter.
SHORT NOTE
Ephedrine
Ephedrine is an alkaloid obtained from Ephedra vulgaris.
 Mainly acts indirectly but has some direct action on a and b receptors. Repeated injections produce tachyphylaxis
primarily because the neuronal pool of NA available for displacement is small. It is resistant to MAO therefore effective
orally. It crosses to brain and is a CNS stimulant.
It has vasoconstrictor, cardiac stimulant, nasal decongestant, bronchodilator and mydriatic actions.
Ephedrine is now replaced by more selective drugs and is occasionally used in mild chronic bronchial asthma and for
hypotension during spinal anaesthesia.
Q. 2. Amphetamine
Amphetamine is a synthetic compound having the same pharmacological profile as ephedrine. Orally active with long
duration (4–6 h).
The CNS actions are more prominent, maximal selectivity is exhibited by dextroamphetamine and methamphetamine, which
in the usual doses produce few peripheral effects. The central effects include alertness, increased concentration and attention
span, euphoria, talkativeness and increased work capacity.
Q. 3. Prazocin
Prazocin is first of the highly selective a1 blockers having a1: a2 selectivity ratio 1000:1.
It blocks sympathetically-mediated vasoconstriction and produces fall in BP which is attended by only mild tachycardia.
Prazocin dilates arterioles more than veins.
Prazocin is used as an antihypertensive, in LVF not controlled by diuretics and digitalis, Raynaud’s syndrome and prostatic
hypertrophy.
Q. 4. Write the rationale of combining xylocaine with adrenaline for
local anaesthesia.

Adrenaline combined with xylocaine is used in dental practice for anaesthesia.

Adrenaline causes vasoconstriction and prolongs duration of action of local anaesthetic, reduces blood loss after an
extraction and surgical procedures and also decreases the toxicity.
Q. 5. What is dopamine? Mention one use and route of administration.

Dopamine (DA) is a catecholamine and the immediate metabolic precursor of NA. It is a directly-acting sympathomimetic
that acts on the receptors of the medulla.
DA is not effective orally as it is rapidly inactivated by COMT and MAO and is administered by IV infusion.
It is a D1 and D2 as well as adrenergic a and b1 (but not b2) agonist. The D1 receptors in renal and mesenteric blood
vessels are the most sensitive IV infusion of low dose of DA dilates these vessels increasing GFR and Na1 excretion.
normal dose raises cardiac output and systolic BP with little effect on diastolic BP.
moderately high doses produce a positive inotropic effect on heart.
vasoconstriction (a 1 action) occurs only when large doses are infused. Adverse effects: Nausea, vomiting, headache,
hyperten-
sion, tachycardia, cardiac arrhythmias and anginal pain
 Therapeutic uses
Cardiogenic and septic shock Severe heart failure with renal impairment

Q. 6. Adrenaline in anaphylactic shock

Adrenaline is the drug of choice in anaphylaxis (anaphylactic shock). Adrenaline is the physiological antagonist of
histamine which is an important mediator of anaphylactic shock.
It also raises BP, counteracts accompanying bronchospasm or laryngeal oedema, therefore adrenaline is used in anaphylaxis.
Q. 7. Write basis of use of dopamine in shock.

Dopamine is an adrenergic a and b1 but not b2 agonist.

In IV low dose dopamine dilates the blood vessel and increase GFR and sodium secretion. At normal dose it increases the
cardiac output and systolic blood pressure with little effect on diastolic blood pressure.
 The dopamine increases blood pressure and causes urine outflow, hence it is used in the shock.
Dopamine is the drug of choice in cardiogenic and septic shock because it increases BP as well as selectively dilates renal,
mesenteric, coronary blood vessels and improves blood flow to the vital org

Antiadrenergic Drugs
LONG ESSAY
Dopamine can be used in all types of shocks and in severe CHF. Its normal dose is 0.2–1 mg/min IV.

Enumerate b-blockers. Write their pharmacological actions and adverse effects of

propranolol. Or,
Classify b-blockers. Describethe pharmacological action, therapeutic uses and adverse effects
of propranolol.
b-blockers are drugs that block the actions of catecholamines mediated through the b-receptors.
Classification
Nonselective b-adrenergic blockers
with intrinsic sympathomimetic activity: Propranolol, nadolol, timolol, sotalol
with intrinsic sympathomimetic activity: Partial agonists: Pindolol, oxprenolol
Cardioselective (b 1) adrenergic blockers: Metoprolol, atenolol, acebutolol, esmolol
b-blockers with additional vasodilatory effect: Labetalol, carvedilol, celiprolol
Pharmacological Action A. CVS
b -blockers depress all the cardiac properties.
b -blockers decrease heart rate, force of contraction and cardiac output.
 Blood pressure falls. The effect is more pronounced in presence of increased sympathetic tone than in a normal situation.
AV conduction is delayed.
Myocardial oxygen requirement is reduced due to reduced cardiac work. It also improves exercise tolerance in angina
patients. High dose produces membrane stabilizing activity.
B. Respiratory Tract
Blockade of b2 receptors in the bronchial smooth muscle causes increase in airway resistance. Many precipitate acute attack
in asthmatics.
C. Eye
Many b-blockers reduce intraocular pressure by decreased secretion of aqueous humour.
D. Metabolic
b antagonists and glycogenolysis induced by sympathetic stimulation. Plasma triglycerides may increase and HDL levels
decrease in some patients.
E. CNS
No overt central effects are produced by the propranolol. However, subtle behavioural changes, forgetfulness, increased
dreaming and nightmare have been reported with long-term use of relatively high doses.
F. Local Anaesthetic
Propranolol is as potent a local anaesthetic as lignocaine, but is not used because of its irritant property.
G. Skeletal Muscle
Propranolol inhibits adrenergically provoked tremor. This is a peripheral action exerted directly on muscle fibre through b2
receptors.
Uses
Hypertension: Propranolol is used as a mild antihypertensive. They are the first drugs of choice as patient acceptability is good.
Prophylaxis of angina pectoris: It benefits angina of effort. Taken over a period of time, they decrease frequency of attacks and
increase exercise tolerance. Cardiac arrhythmias: It suppresses extrasystoles and tachycardias, especially those
mediated adrenergically. Myocardial infarction: In cases of MI, propranolol is used for two purposes. Secondary
prophylaxis of MI: Long-term use after recovery from MI has been found to decrease subsequent mortality.
Myocardial salvage during evolution of MI—ad-
ministered IV within 4–6 h of an attack followed by continued oral therapy. It helps to
limit the size of the infarct.
prevent arrhythmias including ventricular fibrillation.
Congestive cardiac failure: Introduced gradually and maintained for long term, it can retard progression of congestive heart
failure and prolong life, e.g. carvedilol, metoprolol and bisoprolol.
Dissecting aortic aneurysm: b -blockers help by reducing cardiac contractile force and aortic pulsation as well as the rate of
development of pressure during systole.
Pheochromocytoma: b-blockers may be added to b-blockers to control cardiac manifestations like tachycardia and arrhythmias.
Thyrotoxicosis: Propranolol rapidly controls symptoms (palpitation, nervousness, tremors, severe myopathy and sweating)
without significantly affecting thyroid status.
Migraine: Propranolol is the most effective drug for chronic migraine.
Anxiety: Propranolol exerts an apparent antianxiety effects especially under conditions which provoke nervousness and panic,
e.g. examination, unaccustomed public appearances, etc.
Essential tremors: Oral propranolol may be used in treatment of essential tremors.
Glaucoma: b-blockers decrease IOP by reducing the production of aqueous humour.
Hypertrophic obstructive cardiomyopathy: The subaortic region is hypertrophic. Propranolol improves cardiac output in these
patients during exercise, by reducing left ventricular outflow.
Adverse Effects
Propranolol can accentuate myocardial insufficiency and worsen CHF.
Bradycardia: Resting HR may be reduced to 60 min or less.
Propranolol worsens chronic obstructive lung disease can precipitate life-threatening bronchial asthma; hence contraindicated
in asthmatics.
Carbohydrate tolerance may be impaired in prediabetics.
Withdrawal of propranolol after chronic use should be gradual, otherwise rebound hypertension, worsening of angina and
sudden death can occur.
Propranolol is contraindicated in partial and complete heart block, arrest may occur.
Cold hands and feet due to blockade of vasodilatory b2 receptors
SHORT ESSAYS
Side effects not overtly due to b blockade are—GIT upset, lack of drive, nightmares, forgetfulness, rarely hallucinations.

Adrenergic a-blockers
These drugs inhibit adrenergic responses mediated through the a-adrenergic receptors, without affecting those mediated
through b-receptors.
Classification
Nonequilibrium type: b-haloalkylamines, phenoxybenzamine
Equilibrium type (competitive)
Nonselective
Ergot alkaloids: Ergotamine, ergotoxine
Hydrogenated ergot alkaloids: Dihydroergotamine
(DHE), dihydroergotoxine
Imidazolines: Tolazoline, phentolamine
Miscellaneous: Chlorpromazine, ketanserin
a1 selective: Prazosin, terazosin, doxazosin, tamsulosin
a2 selective: Yohimbine
Pharmacological Actions
Blockade of vasoconstrictor a1 receptors reduces peripheral resistance, causes pooling of blood in capacitance vessels,
venous return and cardiac output is reduced and there is a fall in BP.
Reflex tachycardia occurs due to fall in mean arterial pressure and increased release of NA due to blockade of presynaptic a
2 receptors.
Nasal stiffness and miosis result from blockade of a receptors in nasal blood vessels and in radial muscles of iris
respectively. Intestinal motility is increased—diarrhoea occurs.
Tone of smooth muscle is reduced in bladder, sphincter
and prostate.
Uses
Pheochromocytoma Hypertension Secondary shock Peripheral vascular diseases Benign hypertrophy of prostate
Q. 2. Classification and pharmacological actions of b-adrenergic blocking drugs.

Classification
Nonselective b-adrenergic blockers
with intrinsic sympathomimetic activity: Propranolol, nadolol, timolol, sotalol
with intrinsic sympathomimetic activity: Partial agonists (indolol, oxprenolol)
Cardioselective b 1-adrenergic blockers: Metoprolol, atenolol, acebutolol, esmolol
b-blockers with additional vasodilatory effect: Labetalol, carvedilol, celiprolol
Pharmacological Actions
CVS: b-blockers depress all the cardiac properties. It improves exercise tolerance in angina patients. High dose produces
membrane stabilizing activity.
 Respiratory tract: Blockade of b2 receptors in the bronchial smooth muscle causes increase in airway resistance. Many
precipitate acute attack in asthmatics.
Eye: Most of the b-blockers reduce intraocular pressure by decreased secretion of aqueous humour.
Metabolic: b-antagonists and glycogenolysis induced by sympathetic stimulation. Plasma triglycerides may increase and
HDL levels decrease in some patients.
CNS: No overt central effects are produced by the propranolol. However, subtle behavioural changes, forgetfulness, increased
dreaming and nightmare have been reported with long-term use of relatively high doses.
Local anaesthetic: Propranolol is as potent a local anaesthetic as lignocaine, but is not used because of its irritant property.
Skeletal muscle: Propranolol inhibits adrenergically provoked tremor. This is a peripheral action exerted directly on muscle
fibre through b2 receptors.
Q. 3. Uses and adverse effects of propranolol
Propranolol is a first generation nonselective b-blocker with intrinsic sympathomimetic activity.
They are the drugs that block the actions of catecholamines mediated through the b receptors.
Uses
Hypertension: Propranolol is used as a mild antihypertensive. b-blockers are the first drugs of choice as patient acceptability
is good. Prophylaxis of angina pectoris: It benefits angina of effort.
Cardiac arrhythmias: It suppresses extrasystoles and tachycardias, especially those mediated adrenergically.
Myocardial infarction: In cases of MI, propranolol is used for two purposes.
Secondary prophylaxis of MI: Long-term use after recovery from MI has been found to decrease subsequent mortality.
Myocardial salvage during evolution of MI: Administered IV within 4–6 h of an attack followed by continued oral therapy.
Congestive cardiac failure: Introduced gradually and maintained for long term, it can retard progression of congestive heart
failure and prolong life, e.g. carvedilol, metoprolol and bisoprolol.
 Pheochromocytoma: b-blockers may be added to b-blockers to control cardiac manifestations like tachycardia and
arrhythmias. Thyrotoxicosis: Propranolol rapidly controls symptoms (palpitation, nervousness, tremors, severe myopathy
and sweating) without significantly affecting thyroid status.
Anxiety: Propranolol exerts an apparent antianxiety effects especially under conditions which provoke nervousness and
panic.
Essential tremors: Oral propranolol may be used in treatment of essential tremors. Glaucoma: b-blockers decrease IOP by
reducing the production of aqueous humour.

Adverse Effects
Propranolol can accentuate myocardial insufficiency and worsen CHF.
Bradycardia
 Propranolol worsens chronic obstructive lung disease can precipitate life-threatening bronchial asthma; hence
contraindicated in asthmatics.
Carbohydrate tolerance may be impaired in prediabetics. Withdrawal of propranolol after chronic use should be
gradual, otherwise rebound hypertension, worsening of angina and sudden death can occur.
Propranolol is contraindicated in partial and complete heart block, arrest may occur.
Cold hands and feet due to blockade of vasodilatory b2 receptors
SHORT NOTES

Classify b-adrenergic receptor blockers. Or, Classification of b-blockers.

b-blockers are drugs that block the actions of catecholamines mediated through the b receptors.
Classification
Nonselective b-adrenergic blockers
with intrinsic sympathomimetic activity: Propranolol, nadolol, timolol, sotalol
with intrinsic sympathomimetic activity: Partial agonists (pindolol, oxprenolol)
Cardioselective b1-adrenergic blockers: Metoprolol, atenolol, acebutolol, esmolol
b-blockers with additional vasodilatory effect: Labetalol, carvedilol, celiprolol
Q. 2. Propranolol
Propranolol is a first generation nonselective b-blocker with intrinsic sympathomimetic activity.
Uses
Hypertension Prophylaxis of angina pectoris Cardiac arrhythmias Myocardial infarction
Congestive cardiac failure Pheochromocytoma Thyrotoxicosis
Essential tremors Glaucoma
Adverse Effects
 Propranolol causes bradycardia and can accentuate myocardial insufficiency and worsen CHF.
Propranolol worsens chronic obstructive lung disease can precipitate life-threatening bronchial asthma; hence
contraindicated in asthmatics. Withdrawal of propranolol after chronic use should be gradual, otherwise rebound
hypertension, worsening of angina and sudden death can occur.
Q. 3. Timolol
Timolol is a nonselective b-blocker with intrinsic sympathomimetic activity. Its ocular hypotensive action is smooth and
well sustained; hence is used as a topical agent in the eye. Used in the treatment of glaucoma. Orally it is a potent b-
blocker and has been used in hypertension, angina and prophylaxis of myocardial infarction.
Q. 4. Name few cardioselective b-blockers.

b-blockers are drugs that block the actions of catecholamines mediated through the b receptors.
Cardioselective b1-adrenergic blockers are as follows:
Metoprolol
Atenolol
Acebutolol
Esmolol
Q. 5. Classify a-adrenergic blocking agents.

These drugs inhibit adrenergic responses mediated through the a-adrenergic receptors, without affecting those mediated
through b receptors.
Classification
Nonequilibrium type: b-haloalkylamines (phenoxybenzamine)
Equilibrium type (competitive)
Nonselective
 Ergot alkaloids: Ergotamine, ergotoxine Hydrogenated ergot alkaloids: Dihydroergota-
mine (DHE), dihydroergotoxine
Imidazolines: Tolazoline, phentolamine Miscellaneous: Chlorpromazine, ketanserin
a1 selective: Prazosin, terazosin, doxazosin, tamsulosin
a2 selective: Yohimbine
Q. 6. Propranolol is contraindicated in bronchial asthma. Why?

Blockade of b2 receptors in the bronchial smooth muscle causes increase in airway resistance. Many precipitate acute attack
in asthmatics.
Propranolol worsens chronic obstructive lung disease, can precipitate life-threatening bronchial asthma; hence is
contraindicated in asthmatics.
Q. 7. Labetalol
 Labetalol is the first adrenergic antagonist of both a and b receptors.
However the potency of blocking b receptor is five times more compared to a receptors.
Pharmacological Action
Causes vasodilatation and fall in both systolic and diastolic BP.
Reduction in both cardiac output and total peripheral
resistance.
Pharmacokinetics
Effective orally but has high first-pass metabolism.
Metabolized by conjugation with glucuronic acid and
excreted in the urine.
Therapeutic Uses
Pheochromocytoma Essential hypertension
Side Effects
Part III
Autocoids and Related Drugs

Histamines and Antihistamines

SHORT ESSAYS
Most important side effect is postural hypotension.

Mention four newer nonsedative antihistamines with four advantages.

Newer nonsedative antihistamines are as follows:
Fexofenadine
Loratadine
Cetirizine
Azelastine
Mizolastine
Terfenadine
Advantages of newer nonsedative antihistaminics are as follows:
They do not impair psychomotor performance.
Produce no subjective effects.
No sleepiness
Do not potentate alcohol or benzodiazepines.
Q. 2. Mention therapeutic uses of H1 blockers.
Therapeutic uses of H1 blockers are as follows: Allergic diseases: H1 antihistamines are used to prevent as well as to treat
the symptoms of allergic reactions, e.g. pruritus, urticaria, dermatitis, rhinitis, conjunctivitis and angioneurotic oedema respond
to these drugs. Type I hypersensitivity to drugs is suppressed. Common cold: They produce symptomatic relief by sedative
and anticholinergic actions.
Preanaesthetic medication: Promethazine is used for its sedative and anticholinergic effects.
Motion sickness: Promethazine, diphenhydramine, dimenhydrinate, etc. are useful especially for prophylaxis of motion
sickness because of their anticholinergic action. They act probably on the vestibular apparatus or cortex. Sedative effect also
contributes to their beneficial effect. These drugs are also useful in morning sickness, drug-induced and postoperative
vomiting. As sedative, hypnotic and anxiolytic Antihistaminics with CNS depressant action are used as sedative and to
induce sleep especially in children, e.g. promethazine and diphenhydramine. Hydroxyzine is used in anxiety associated with
auto-
nomic manifestations.
 Parkinsonism Imbalance between dopamine and acetylcholine in the basal ganglia produces parkinsonism.
Promethazine, diphenhydramine or orphenadrine are used to control tremors, rigidity and sialorrhoea of parkinsonism due to
their anticholinergic and sedative properties.
They are also useful to treat extrapyramidal side effects caused by phenothiazines or metoclopramide.
H1 antihistamines are used to control mild blood transfusion and saline infusion reactions (chills and rigors) and as adjunct
in anaphylaxis. Vertigo: Cinnarizine is widely used in vertigo because of its additional anticholinergic, anti-5-HT sedative
and vasodilator properties.
Dimenhydrinate and meclizine are effective to control vertigo in Meniere’s disease and in other types of vertigo.
Appetite stimulant: Buclizine is used in underweight children because of its appetite stimulating effect.
Cough: Chlorpheniramine, diphenhydramine and promethazine are used in cough due to respiratory allergic states as they
offer symptomatic relief because of their sedative and anticholinergic properties.
 Acute muscle dystonia: Parenteral promethazine or hydroxyzine promptly relieves the acute muscle dystonia caused by
antiemetic or antipsychotic drugs.
Other conditions involving histamine are as follows:
Symptomatic relief is obtained in insect bite and ivy poisoning. Abnormal dermographism is suppressed.
If used in blood or saline infusion-induced rigor, it has prophylactic value.
Q. 3. Autocoids
Autocoids are substances formed in various tissues, have complex physiological and pathological actions and act locally at the
site of synthesis. They have brief action and are destroyed locally. Hence they are called local hormones. But they differ from
true hormones which are produced by specific cells and act at target sites.
Autocoids include the following:
Histamine (H1 and H2)
H1 blockers: Diphenhydramine, chlorphenamine,
cetrizine, loratadine
H2 blockers: Ranitidine, famotidine, roxatidine
5-HT or serotonin
Agonists: Sumatriptan, buspirone, dexfenfluramine
Blockers: Cyproheptadine, ketanserin, ondansetron
Prostaglandins
Analogues: Misoprostol, dinoprostine, carboprost
Synthesis inhibitors: Aspirin, indomethacin,
paracetamol
Kinins: Bradykinin, kallidin
Leukotrienes
Antagonists: Montelukast, zafirlukast
Lipoxygenase inhibitors: Zileuton
Angiotensin
Blockers: Losartan
ACE inhibitors: Captopril, enalapril, ramipril
Q. 4. Antihistamines
H1 receptor antihistaminics are the drugs which competitively antagonize the action of histamine at H1 receptors.
Classification
Highly sedative Diphenhydramine Dimenhydrinate Promethazine Hydroxyzine
Moderately sedative Pheniramine Cyproheptadine Meclizine Buclizine Cinnarizine
Mild sedative Chlorpheniramine Methdilazine Mepyramine Dimethindene Triprolidine
Mebhydroline Cyclizine Clemastine
Nonsedative (second generation) Terfenadine Fexofenadine Astemizole Loratadine Desloratadine Cetirizine
Azelastine Mizolastine
Therapeutic Uses
Allergic diseases: H1 antihistamines are used to prevent as well as to treat the symptoms of allergic reactions, e.g. pruritus,
urticaria, dermatitis, rhinitis, conjunctivitis and angioneurotic oedema respond to these drugs. Type I hypersensitivity to drugs
is suppressed.
Common cold: They produce symptomatic relief by sedative and anticholinergic actions.
Preanaesthetic medication: Promethazine is used for its sedative and anticholinergic effects.
Motion sickness: Promethazine, diphenhydramine, dimenhydrinate, etc. are useful especially for prophylaxis of motion
sickness because of their anticholinergic action. They act probably on the vestibular apparatus or cortex. Sedative effect also
contributes to their beneficial effect. These drugs are also useful in morning sickness, drug-induced and postoperative
vomiting. As sedative, hypnotic and anxiolytic
 Antihistaminics with CNS depressant action are used as sedative and to induce sleep especially in children, e.g.
promethazine and diphenhydramine.
Hydroxyzine is used in anxiety associated with auto-
nomic manifestations.
Parkinsonism Imbalance between dopamine and acetylcholine in the basal ganglia produces parkinsonism.
Promethazine, diphenhydramine or orphenadrine are used to control tremors, rigidity and sialorrhoea of parkinsonism due to
their anticholinergic and sedative properties.
They are also useful to treat extrapyramidal side effects caused by phenothiazines or metoclopramide.
SHORT NOTES
H1 antihistamines are used to control mild blood transfusion and saline infusion reactions (chills and rigors) and as adjunct
in anaphylaxis.
 Autocoids
Autocoids are substances formed in various tissues, have complex physiological and pathological actions and act locally at
the site of synthesis.
They have brief action and are destroyed locally; hence they are called local hormones. But they differ from true hormones
which are produced by specific cells and act at target sites.
Autocoids include the following:
Histamine (H1 and H2) blockers, e.g. diphenhydramine, chlorphenamine, cetirizine, ranitidine, roxatidine, etc.
5-HT or serotonin agonists (dexfenfluramine) and blockers (cyproheptadine)
Prostaglandins: Misoprostol, indomethacin, paracetamol, etc.
Kinins: Bradykinin, kallidin
Leukotrienes: Both antagonists (montelukast, zafirlukast) and lipoxygenase inhibitors (zileuton)
Angiotensin blockers: Losartan and ACE inhibitors
(captopril, enalapril, ramipril)
Q. 2. H1 blockers
H1 receptor antihistaminics are the drugs which competitively antagonize the action of histamine at H1 recep tors.
They are classified as follows:
Highly sedative: Diphenhydramine, promethazine and hydroxyzine
Moderately sedative: Pheniramine, cyproheptadine, cinnarizine
Mild sedative: Chlorpheniramine, mepyramine, cyclizine and clemastine
Nonsedative (second generation): Terfenadine, fexofenadine, astemizole, loratadine, cetirizine
Therapeutic uses of H1 receptor antihistaminics are as follows: 1. Allergic disorders
Other conditions involving histamine
Pruritus
Common cold
Motion sickness
Appetite stimulant
Vertigo
Preanaesthetic medication
Cough
Parkinsonism
Acute muscle dystonia
Q. 3. Cyproheptadine
Cyproheptadine is a serotonin antagonist. It blocks 5-HT2 receptors and cholinergic receptors. It increases appetite and is
used to promote weight gain, especially in children. It is also used in carcinoid tumours.
Q. 4. Nonsedative antihistamines
Newer nonsedative antihistamines are as follows:
Terfenadine
Fexofenadine
Astemizole
Loratadine
Cetirizine
Azelastine
Ebastine
Advantages of newer nonsedative antihistaminics are as follows:
They do not impair psychomotor performance.
Produce no subjective effects.
No sleepiness
Do not potentate alcohol or benzodiazepines.
Q. 5. Cetirizine
Cetirizine is a second generation antihistaminic. It is a metabolite of hydroxyzine with marked affinity for peripheral H1
receptors.
Cetirizine does not have sedative property.
Pharmacological Action
Antagonism of histamine Antiallergic action
Pharmacokinetics
Well absorbed orally, not metabolized Attains high and longer lasting concentration in skin. CNS penetration is poor.
Therapeutic Uses
In a daily dose of 10 mg cetrizine is used in upper respira-
tory allergies, pollinosis, urticaria and atopic dermatitis. Seasonal asthma as adjuvant
Q. 6. Mention therapeutic uses of promethazine.
Promethazine is a highly sedative H1 antagonist and it is used in daily dose of 25–50 mg orally or IM.
Therapeutic Uses
Promethazine is used in cases of allergic disorders,

5-Hydroxytryptamine, Its Antagonists and Drug

Therapy of Migraine, Prostaglandins, Leukotrienes
(Eicosanoids) and Platelet Activating Factor
SHORT ESSAYS
pruritus, common cold, preanaesthetic medication and parkinsonism.

Prostaglandins
Prostaglandins (PGs) are products of long-chain fatty acids. They are widely distributed in the body. The main
PGs in man are PGE2, PGF2a and PGI2.
Arachidonic acid is the precursor for the biosynthesis of all PGs. The enzyme involved in the formation of PGs from
arachidonic acid is cyclooxygenase (COX). Another class of substances obtained from arachidonic acid by the action of
lipoxygenase is leukotrienes.
Pharmacological Actions and Uses
GI tract: PGE2 and PGI2 reduce acid secretion and increase the secretion of mucus in the stomach (cytoprotective

action). Misoprostol (PGE1 analogue) is useful in the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced
ulcers.
CVS and blood vessels
PGE1 (alprostadil) is used to maintain the patency of ductus arteriosus before surgery.
Prostacyclin (PGI2) decreases peripheral, pulmonary and coronary resistance, it is used to treat pulmonary hypertension.
PGI2 inhibits platelet aggregation. Hence, it is used during haemodialysis to prevent platelet aggregation. Eye: PGF2a has
been found to decrease intraocular tension. Its analogue, e.g. latanoprost is used in glaucoma. Uterus
PGF2a and low concentration of PGE2 contract pregnant uterus. PGs are mainly used in mid-term abortion, missed abortion
and in molar pregnancy.
Induction of labour
PGE2 and PGF2a can induce labour at term. But, they are used only when oxytocin is contraindicated-renal failure, toxemia of
pregnancy, etc.
Impotence: PGE1 (alprostadil) is useful in the treatment of erectile dysfunction.
Adverse Effects:
Nausea, vomiting, diarrhoea, fever and backache due to uterine contractions. Injections are painful due to sensitization of
nerve endings.
Q. 2. Ergometrine
Ergometrine or ergonovine is an amine ergot alkaloid. It has a very weak agonistic and no antagonistic action on a-
adrenergic receptors.
It has partial agonistic action on 5-HT receptors in uterus, placental and umbilical blood vessels and in certain brain areas. It is
a moderately potent 5-HT2 antagonist in GI smooth muscles and a weak dopaminergic agonist on the pituitary lactotropes as
well as CTZ. Emetic potential is low. The most prominent action is contraction of myometrium and is used exclusively in
obstetrics.
Ergometrine and methylergometrine are rapidly and nearly completely absorbed from the oral route.
Onset of uterine action is 15 min by oral route, 5 min by IM, almost immediately by IV route.
They are partly metabolized in liver and excreted in urine. Plasma t1/2 is 1–2 h. It is available as 0.25, 0.5 mg tab, 0.5 mg/mL
inj.
Adverse Effects
 They are less toxic and hardly any complications arise when correctly used in obstetrics. Nausea, vomiting and rise
in BP occur occasionally. Ergometrine should be avoided in patients with vascular disease, hypertension, toxaemia. It should
also be avoided in presence of sepsis and as well as liver and kidney diseases.
Uses
To control and prevent postpartum haemorrhage After caesarean section or instrumental delivery to pre-
vent uterine atony To ensure normal involution

SHORT NOTE
Ergot Alkaloid Uses
i. Ergotamine Acute migraine
ii. Ergometrine Postpartum haemorrhage
iii. Dihydroergotoxine Alzheimer's dementia
 iv. Bromocriptine Suppression of lactation and parkinsonism
Q.1. Uses of ergot alkaloids
Ergot alkaloids occur naturally in fungus. Ergot contains many active substances. The most important compounds and their
therapeutic uses are as follows:

Nonsteroidal Anti-inflammatory Drugs and Antipyretic Analgesics

LONG ESSAYS

What are analgesics? Classify analgesics. Describepharmacological action, therapeutic uses

and side effects of acetyl salicylic acid.

Analgesics are drugs that relieve pain without affecting consciousness.

Classification of analgesics is as follows:
Analgesics
↓

Opioids NSAIDs
Natural opium A. Nonselective COX inhibitors
Semisynthetic opiates B. Preferential COX-2 inhibitors C. D iacetylmorphine and phenol C. Selective COX-2
inhibitors codeine
D. Synthetic Opioids D. Analgesic, antipyretic, poor anti-inflammatory
ACETYL SALICYLIC ACID OR ASPIRIN
Acetyl salicylic acid is a derivative of nonselective COX inhibitors.
Pharmacological Actions
Pharmacological actions of acetyl salicylic acid or aspirin are as follows: A. Analgesic action
Anti-inflammatory action
Antipyretic action
Antiplatelet (antithrombotic) effect
Acid-base and electrolyte balance
Action on gastrointestinal tract
Action on respiration
Action on CVS
Action on urate excretion
A. Analgesic Action
Analgesic effect of NSAIDs is mainly used for relieving musculoskeletal pain, dysmenorrhoea and pain associated with
inflammation or tissue damage.
 Mechanisms by which NSAIDs exhibit the analgesic action are as follows:
Inhibition of COX enzyme which is responsible for synthesis of prostaglandins
By sensitizing the free nerve endings to pain stimuli and also increasing pain threshold by acting at subcortical site
By irreversible acetylation of COX enzyme These drugs relieve pain without causing sedation, tolerance or drug
dependence. Acetyl salicylic acid is effective against pain with
inflammation, e.g. dental pain and rheumatic pain.
B. Anti-inflammatory Action
The anti-inflammatory action of NSAIDs is mainly due to inhibition of PG synthesis at the site of injury. They also affect
other mediators of inflammation (bradykinin, histamine, serotonin, etc) and thus inhibit granulocyte adherence to the damaged
vasculature. NSAIDs also cause modulation of T-cell function, stabilization of lysosomal membrane and inhibition of
chemotaxis. Anti-inflammatory effect is seen at high doses (aspirin: 4–6 g/day in divided doses). These drugs produce only
symptomatic relief.
 It suppresses signs and symptoms of inflammation such as pain, tenderness, swelling, vasodilatation and leucocyte
infiltration but does not affect the progression of underlying disease.
C. Antipyretic Action
The antipyretic effect is mainly due to inhibition of PGs in the hypothalamus. Aspirin blocks action of pyrogens due to
which prostaglandin synthesis in hypothalamus is inhibited.
The thermoregulatory centre is situated in the hypothalamus. Fever occurs when there is a disturbance in hypothalamic
thermostat. NSAIDs reset the hypothalamic thermostat and reduce the elevated body temperature during fever. They
promote heat loss by causing cutaneous vasodilatation and sweating.
D. Antiplatelet (Antithrombotic) Effect
A COX enzyme formed irreversibly in platelets. Thus, platelet aggregation is prevented and bleeding time is prolonged.
Aspirin in low doses (50–325 mg) irreversibly inhibits platelet TXA2 synthesis and produces antiplatelet effect. Aspirin in high
doses (2–3 g/day) inhibits both PGI2 and TXA2 synthesis, hence beneficial effect of PGI2 is lost.
E. Acid-base and Electrolyte Balance
In therapeutic doses, salicylates cause respiratory alkalosis, which is compensated by excretion of alkaline urine
(compensated respiratory alkalosis).
In toxic doses, the respiratory centre is depressed and can lead to respiratory acidosis. Later, there is uncompensated
metabolic acidosis.
F. Action on GIT
Aspirin is unionized in GIT at gastric pH and is absorbed in mucosal cell where it gets ionized and cannot diffuse back, this
causes gastric mucosal damage.
Aspirin also inhibits COX-1 which cause decrease in PGE2 and PGI2 synthesis which decreases mucus barrier and causes
gastric mucosal damage.
G. Action on Respiration
At anti-inflammatory doses salicylates increase oxygen consumption by a skeletal muscle, which causes increase in CO2
production and there is hyperventilation due to which CO2 is washed out and hence results in respiratory alkalosis and at
higher doses metabolic acidosis.
H. Action on CVS
Aspirin at large doses increases oxygen demand and increases cardiac output.
I. Action on Urate Excretion
Aspirin at small dose inhibits uric acid secretion by DCT due to which plasma urate level is increased. It also blocks action of
uricosuric drug and hence it is avoided in gout patients.
Therapeutic Uses or Indications of Aspirin or
Acetyl Salicylic Acid
 As analgesics: It is used in headache, toothache, joint pain, dysmenorrhoea and myalgia in dosage 0.3–0.6 g per day. As
antipyretic: It is used in fever of any origin. It is first drug to be used in acute rheumatic fever. It is used in rheumatoid
arthritis and osteoarthritis.
In myocardial infarction and stroke: Aspirin inhibits platelet aggregation by blocking COX enzymes in platelets, thus it
prevents clot formation and lowers the incidence of reinfarction.
In patent ductus arteriosus aspirin can bring about closure and prevent surgery. Aspirin is used in pregnant women to
delay labour. Aspirin is useful in pregnancy-induced hypertension.
Side effects of acetyl salicylic acid or aspirin are as follows:
Aspirin causes nausea, vomiting, hypersensitivity reaction, epigastric distress, gastritis, peptic ulcer, precipitation of asthma.
Anti-inflammatory doses: A syndrome called salicylism is produced.
In salicylism: Dizziness, vertigo, tinnitus, reversible impairment of hearing and of vision, hyperventilation and electrolytic
imbalance
Aspirin use in children with viral infections causes Reye’s syndrome.
Aspirin causes acute salicylate poisoning in adults.
Q. 2. Classify nonsteroidal anti-inflammatory, analgesic agents. Discuss mode of
action, toxicities and contraindications of aspirin.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are classified as follows:

Nonselective COX inhibitors
Salicylate derivatives: Aspirin Propionic acid derivatives: Ibuprofen, ketoprofen, naproxen
Anthranilic acid derivatives: Mephenamic acid Arylacetic acid derivatives: Diclofenac, aceclofenac Oxicam
derivatives: Piroxicam, tenoxicam Pyrrolopyrrole derivatives: Ketorolac vii. Indole derivatives: Indomethacin,
sulindac viii. Pyrazolone derivatives: Phenyl butazone
Preferential COX-2 inhibitors: Nimesulide, meloxicam, nobumetone
Highly selective COX-2 inhibitors: Celecoxib, rofecoxib, valdecoxib, etoricoxib
Analgesic, antipyretic with poor anti-inflammatory action
Para-aminophenol derivatives: Paracetamol (acetaminophen)
Pyrazolone derivatives: Metamizol, propyphenazone
Benzoxazocine derivative: Nefopam
Mode of Action
COX is the enzyme responsible for the biosynthesis of various PGs. The COX-1 and COX-2 are wellrecognized isoforms of
COX enzyme. COX-2 is induced during inflammation by cytokines and endotoxins and is responsible for the production of
prostanoid mediators of inflammation. Aspirin and most of the nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both
COX-1 and COX-2 isoforms, thereby decrease PG and thromboxane synthesis.
Anti-inflammatory effect of NSAIDs is mainly due to inhibition of COX-2. Aspirin causes irreversible inhibition of COX
activity whereas rest of the NSAIDs cause reversible inhibition the enzyme.
Toxicities of Aspirin
Aspirin causes acute salicylate poisoning in adults.
Acute salicylate poisoning is more common in children. Fatal dose in adults is estimated to be 15–30 g, but is considerably
lower in children. Serious toxicity is seen when serum salicylate levels are . 50 mg/dL. Manifestations are vomiting,
dehydration, acid-base and electro-imbalance, hyperpnoea, restlessness, confusion, coma, convulsions, cardiovascular collapse,
pulmonary oedema, hyperpyrexia and death.
Contraindications of Aspirin
The aspirin is contraindicated in hypertensive patients, asthmatic, peptic ulcer patients and patients with bleeding disorders.
Aspirin is contraindicated in children suffering from viral syndrome, i.e. Reye’s syndrome. Aspirin is contraindicated in
hepatic necrosis. It causes premature closure of ductus arteriosus.
SHORT ESSAYS
 During pregnancy it should not be given near or at term because it causes delayed labour and greater postpartum blood loss.
It should be avoided by breastfeeding mothers.

List at least two drugs from NSAIDs. Describepharmacological actions and

therapeutic uses of this class of drugs.

The two drugs from NSAIDs are as follows:

Nonselective COX inhibitor: Salicylates (aspirin)
Selective COX inhibitor: Paracetamol
SALICYLATES (ACETYL SALICYLIC ACID OR ASPIRIN)
Pharmacological Actions
Pharmacological actions of acetyl salicylic acid or aspirin are as follows: 1. Analgesic action
Anti-inflammatory action
Antipyretic action
Antiplatelet (antithrombotic) effect
Acid-base and electrolyte balance
Action on gastrointestinal tract
Action on respiration
Action on CVS
Action on urate excretion
Analgesic Action
Analgesic effect of NSAIDs is mainly used for relieving musculoskeletal pain, dysmenorrhoea and pain associated with
inflammation or tissue damage.
 NSAIDs exhibit the analgesic action mainly by inhibition of COX enzyme which is responsible for synthesis of
prostaglandins. Anti-inflammatory action: The anti-inflammatory action of NSAIDs is mainly due to inhibition of PG
synthesis at the site of injury. They also affect other mediators of inflammation like bradykinin, histamine, serotonin, etc. and
thus inhibit granulocyte adherence to the damaged vasculature.
Antipyretic action: Aspirin blocks action of pyrogens and the antipyretic effect is mainly due to inhibition of PGs in the
hypothalamus. NSAIDs reset the hypothalamic thermostat and reduce the elevated body temperature during fever. They
promote heat loss by causing cutaneous vasodilatation and sweating.
Antiplatelet (Antithrombotic) Effect
A COX enzyme formed irreversibly in platelets. Thus, platelet aggregation is prevented and bleeding time is prolonged.
Aspirin in low doses (50–325 mg) irreversibly inhibits platelet TXA2 synthesis and produces antiplatelet effect.
Aspirin in high doses (2–3 g/day) inhibits both PGI2 and TXA2 synthesis; hence beneficial effect of PGI2 is lost.
Acid- base and Electrolyte Balance
In therapeutic doses, salicylates cause respiratory alkalosis, which is compensated by excretion of alkaline urine (compensated
respiratory alkalosis).
Action on GIT
Aspirin is unionized in GIT at gastric PH and is absorbed in mucosal cell where it gets ionized and cannot diffuse back, this
causes gastric mucosal damage.
Aspirin also inhibits COX-1 which causes decrease in PGE2 and PGI2 synthesis which decreases mucus barrier and causes
gastric mucosal damage.
Action on Respiration
At anti-inflammatory doses salicylates increase oxygen consumption by a skeletal muscle, which causes increase in CO2
production and there is hyperventilation due to which CO2 is washed out and hence results in respiratory alkalosis and at
higher doses metabolic acidosis.
Action on CVS
Aspirin at large doses increases oxygen demand and increases cardiac output.
Action on Urate Excretion
Aspirin at small dose inhibits uric acid secretion by DCT due to which plasma urate level is increased. It also blocks action of
uricosuric drug and hence it is avoided in gout patients.
Therapeutic Uses or Indications of Aspirin or Acetyl Salicylic Acid
As analgesics: It is used in headache, toothache, joint pain, dysmenorrhoea and myalgia in dosage 0.3–0.6 g per day. As
antipyretic: It is used in fever of any origin. It is first drug to be used in acute rheumatic fever. It is used in rheumatoid
arthritis and osteoarthritis.
In myocardial infarction and stroke: Aspirin inhibits platelet aggregation by blocking COX enzymes in platelets, thus it
prevents clot formation and lowers the incidence of reinfarction.
In patent ductus arteriosus aspirin can bring about closure and prevent surgery. Aspirin is used in pregnant women to
delay labour. Aspirin is useful in pregnancy-induced hypertension.
PARACETAMOL
Pharmacological Actions of Paracetamol
Analgesic: Paracetamol inhibits COX in brain and it also raises pain threshold.
Antipyretic: It decreases fever of any origin due to inhibition of COX enzyme. Urate excretion: Paracetamol does not
effect urate
excretion and is given in gout patients.
Therapeutic Uses of NSAIDs
It is one of the best antipyretic drugs.
It is an analgesic for headache, dysmenorrhoeal and musculoskeletal pain.
It has negligible anti-inflammatory action as it poorly
inhibits COX enzyme.
Q. 2. Differences between paracetamol and aspirin
Paracetamol differs from aspirin in the following aspects given in Table 11.1.
TABLE 11.1 Differences between Paracetamol and Aspirin
Paracetamol Aspirin
It does not stimulate respiration It causes hyperventilation
It does not affect acid-base balance It affects acid-base balance
It does not increase cellular metabolism It increases cellular metabolism
It has no effect on CVS It causes increased output in
CVS
It is safer in asthmatics It precipitates asthma in sensitive individuals
Q. 3. Write briefly on selective COX-2 inhibitors.

Highly selective COX-2 inhibitors are as follows: Celecoxib, rofecoxib, valdecoxib, etoricoxib
 COX-2 inhibitors reduce whole body PGI2 production without affecting platelet thromboxane A2 synthesis.
Parecoxib is a prodrug of valdecoxib and is adminis-
tered parenterally. Etoricoxib is given by enteral route.
Celecoxib
It exerts anti-inflammatory, analgesic and antipyretic action with low ulcerogenic potential.
It is approved for use in osteoarthritis and rheumatoid arthritis in a dose of 100–200 mg BD. Platelet aggregation in
response to collagen exposure remains intact in celecoxib recipients and serum TXB2 levels were not reduced.
Rofecoxib
It is the most common COX-2 selective inhibitor.
It is effective in osteoarthritis, rheumatoid arthritis as well as in dysmenorrhoea, dental pain, postoperative and acute
musculoskeletal pain. Used in the dose of 12.5–25 mg OD. Occurrence of peptic ulcer is rare and it has no effect on
TXA2 production by platelets. It should be avoided in presence of severe hepatic or
renal disease.
Valdecoxib
Recently marketed drug with similar efficacy and tolerability as that of rofecoxib.
Used in the dose of 10 mg once daily in osteoarthritis and rheumatoid arthritis.
Q. 4. Write brief account on drugs in dental pain.

NSAIDs are main drugs for management of acute dental pain. The nature of pain, risk factors and individual preference are
to be considered while prescribing an NSAID. For mild to moderate pain with little inflammation: Paracetamol or low dose
ibuprofen is preferred.
Postextraction or acute short-lasting pain: Ketorolac, diclofenac and nimesulide
Gastric intolerance or peptic ulcer patients: Paracetamol or selective COX-2 inhibitor
 During dental analgesia if patient is with history of asthma or anaphylactic reaction to aspirin, then other NSAID
(nimesulide) is given. If dental analgesia is present in paediatric patient paracetamol, ibuprofen or naproxen is given.
If dental analgesia is given during pregnancy, paracetamol is the safest drug to be given. If dental analgesia is in diabetic,
CHF and in epileptics, physician should be consulted before giving the drug during analgesia.
Q. 5. Write briefly on the adverse effects produced by aspirin. How would
you treat a case of salicylate (aspirin) poisoning?

Adverse effects produced by aspirin are as follows:

GIT: Nausea, vomiting, dyspepsia, epigastric pain, acute gastritis, ulcers and GI bleeding. Ulcerogenic effect is the major
drawback of NSAIDs.
Hypersensitivity: It is relatively more common with aspirin. The manifestations are skin rashes, urticaria, rhinitis,
bronchospasm, angioneurotic oedema, rarely anaphylactoid reaction.
Bronchospasm (aspirin-induced asthma) is due to increased production of leukotrienes. Incidence of hypersensitivity is high in
patients with asthma, nasal polyps recurrent rhinitis or urticaria. Therefore, aspirin should be avoided in such patients.
With G6PD deficiency, administration of salicylates may cause haemolytic jaundice. Use of salicylates interferes with action of
vitamin K in the liver and causes decreased synthesis of clotting factors resulting in hypoprothrombinemia.
Reye’s syndrome is a rare form of hepatic encephalopathy. Use of salicylates in children with viral infection like varicella,
influenza, etc. may cause damage to liver with fatty infiltration and encephalopathy. Hence salicylates are contraindicated in
children with viral illness.
Pregnancy: These drugs inhibit PG synthesis, thereby delaying onset of labour and increasing chances of PPH. In the newborn,
inhibition of PG synthesis results in premature closure of the ductus arteriosus.
Analgesic nephropathy: Slowly progressive renal failure occurs on chronic use of high doses of NSAIDs. Renal failure is
usually reversible on stoppage of therapy but rarely NSAIDs may cause irreversible renal damage.
Salicylism
Salicylate intoxication may be mild or severe. The mild form is called salicylism. The effects include headache, tinnitus,
vertigo, confusion, nausea, vomiting, diarrhoea, hyperpnoea, electrolyte imbalance, etc. These symptoms are reversible on
stoppage of therapy.
Salicylate Poisoning
Acute salicylate poisoning is more common in children. Fatal dose in adults is estimated to be 15–30 g, but is considerably
lower in children. Serious toxicity is seen when serum salicylate levels are . 50 mg/dL.
Manifestations are vomiting, dehydration, acid-base and electro-imbalance, hyperpnoea, restlessness, confusion, coma,
convulsions, cardiovascular collapse, pulmonary oedema, hyperpyrexia and death.
Treatment
There is no specific antidote for salicylate poisoning. Treatment is symptomatic and supportive. Normally the treatment
includes the following:
Hospitalization
Gastric lavage to remove unabsorbed drug followed by administration of activated charcoal, the activated charcoal adsorbs the
toxic material-physical antagonism.
Fluid and electrolyte and acid-base balance restoration.
Intravenous sodium bicarbonate to treat metabolic acidosis. It also alkalinizes the urine and enhances renal excretion of
salicylates as the salicylates exist in ionized form in alkaline pH.
Most important is external cooling.
Forced alkaline diuresis or haemodialysis in severe cases to remove absorbed drug.
Vitamin K and blood transfusion is given if bleeding occurs.
Q. 6. Explain why nimesulide is preferred over aspirin as anti-inflammatory
agent.
 Nimesulide is a newer NSAID and is relatively weaker inhibitor of prostaglandin synthesis and exhibits relative COX-2
selectivity.
Nimesulide is completely absorbed orally and is 99% plasma bounded. Its t1/2 is 2–5 h. Inhibition of platelet activated factor
synthesis, so acts as an anti-inflammatory agent. Its anti-inflammatory action is exerted by mainly reducing generation of
superoxide by neutrophils.
Other mechanisms involved in anti-inflammatory action of nimesulide are that it also acts as free radical scavenger and as
well inhibits metalloproteinase activity in cartilage. The anti-inflammatory activity of nimesulide is superior to other NSAIDs.
It is useful for short-lasting painful inflammatory conditions, e.g. dental surgery, ear, nose and throat.
While aspirin as anti-inflammatory produces a syndrome called salicylism. Aspirin therapy in children with rheumatoid
arthritis has been found to raise serum level indicating liver damage. In adult long-term therapy with high dosage can cause
hepatic injury. Aspirin is contraindicated with patients of peptic ulcer, bleeding tendencies and in children suffering from
chickenpox or influenza. It is also contraindicated in chronic liver diseases and is avoided in diabetes and in breastfeeding
mothers.
Q. 7. Compare the action and uses of morphine and aspirin.

Comparison between the action and uses of morphine and aspirin is given Table 11.2.
TABLE 11.2 Comparison between Morphine and Aspirin
Morphine Aspirin
Morphine is an opioid analgesic Aspirin is an NSAID
Morphine has central action and it decreases perception of pain Aspirin has peripheral action and it decreases
sensitization of nerve endings by inhibiting prostaglandin secretion
Morphine can be used in severe pain of any type, i.e. trauma, burn, cancer, pain, etc. Aspirin relieves pain better in
conditions associated with inflammation like dental pain
Morphine is also used in preanaesthetic medication Aspirin is not used in preanaesthetic medication
On GIT morphine causes spasm of sphincters and increases muscle tone On GIT aspirin causes gastric ulcer, bleeding
may occur
Morphine has no antipyretic action Aspirin has antipyretic action, thus reduces body
temperature
Morphine does not show antiplatelet activity Aspirin shows antiplatelet activity. It prevents platelet aggregation by
blocking COX
and preventing formation of thromboxane A2
Morphine induces sedation or euphoria It does not cause euphoria, sedation and sleep
SHORT NOTES
Enumerate the contraindications of aspirin.
Contraindications of aspirin are as follows:
The aspirin is contraindicated in the following:
Hypertensive patients, asthmatic, peptic ulcer patients and patients with hepatic necrosis and bleeding disorders.
Children suffering from viral diseases as they may develop Reye’s syndrome on aspirin usage.
During pregnancy it should not be given near or at term because it may cause delayed labour and greater postpartum blood
loss. It also causes premature closure of ductus arteriosus.
It should be avoided by breastfeeding mothers.
Q. 2. Paracetamol
Paracetamol is a demethylated active metabolite of phenacetin. It is effective by oral and parenteral (IM) routes. It is well
absorbed, distributed all over the body, metabolized in the liver by sulphate and glucuronide conjugation. The metabolites are
excreted in urine.
Uses
As antipyretic, to reduce body temperature during fever
As analgesic, to relieve headache, toothache, myalgia, dysmenorrhoea, etc.
Preferred analgesic and antipyretic in patients with peptic ulcer, haemorrhage, bronchial asthma and children
Adverse Effects
Nausea and rashes occur occasionally.
Leukopenia is rare.
Q. 3. Rationale of using aspirin in postmyocardial infarction
Aspirin in low doses (50–325 mg) irreversibly inhibits platelet TXA2 synthesis and produces antiplatelet effect. Aspirin in
high doses (2–3 g/day) inhibits both PGI2 and TXA2 synthesis; hence beneficial effect of PGI2 is lost.
The antiplatelet effect of low dose aspirin is marked of
in the prophylactic treatment of various thromboembolic disorders like myocardial infarction (MI) to reduce the incidence of
recurrent MI. to decrease mortality in post-MI patients.
Q. 4. Nimesulide
Nimesulide is a newer NSAID and is relatively weaker inhibitor of prostaglandin synthesis and exhibits relative COX-2
selectivity.
Nimesulide is completely absorbed orally and is 99% plasma bounded. Its t1/2 is 2–5 h. Excreted primarily in urine.
The analgesic, antipyretic and anti-inflammatory activity of nimesulide has been rated comparable to other NSAIDs.
It is useful for short-lasting painful inflammatory conditions, e.g. dental surgery, ear, nose and throat.
Considering that it has not been marketed in many countries like the UK, USA, Australia and Canada, the overall safety of
the drug especially in children has been questioned. Most asthmatics and those patients who develop bronchospasm or
intolerance to aspirin and other NSAIDs do not crossreact with nimesulide and it appears to be safer in these patients.
Q. 5. Enumerate and write mode of action of COX-2 inhibitors as
NSAIDs.
The COX-2 inhibitors are as follows: Preferential COX-2 Inhibitors: Nimesulide, meloxicam, nobumetone
Selective COX-2 Inhibitor: Celecoxib, rofecoxib, valde-
coxib
Mode of Action
Preferential COX-2 inhibitor: The COX-2 inhibitors reduce generation of superoxide by neutrophils, inhibition of platelet
activating factor synthesis and tumour necrosis factor a, free radical scavenging, inhibition of metalloproteinase activity in
cartilage. In this way it acts as NSAID.
Selective COX-2 inhibitor: These drugs cause inhibition of COX-2 without affecting the function of COX-1 and hence act as
NSAID.

Additional Drugs for Rheumatoid Arthritis and Drugs for Gout

SHORT NOTES
 Action of probenecid and penicillin in chemotherapy
Or
Rationale of using probenecid with penicillin
Probenecid and penicillin (b-lactum antibiotics) are excreted by active tubular secretion.
When both are administered simultaneously, probenecid competes with penicillin and blocks the tubular secretion of b-
lactum antibiotics and their duration of action increases. Thus treatment becomes more effective.
Q. 2. D-penicillamine
D-penicillamine is a degradation product of penicillin and has cross-reactivity with penicillins. It is effective in treating
copper, mercury, zinc and lead poisoning. It is also useful in treating Wilson’s disease, scleroderma, cystinuria and rheumatoid
arthritis.
D-penicillamine is used in Wilson’s disease as it chelates copper and promotes its excretion. Life-long therapy is required.
Adverse effects: Skin rashes, pruritus, urticaria, pemphi-
goid lesions, pyrexia, etc.
Q. 3. Methotrexate
Methotrexate is the preferred disease modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis.
It is a folate antagonist and has more rapid onset of action than other DMARDs.
The dose of methotrexate used in rheumatoid arthritis is much lower than the dose used in cancer chemotherapy.
Dosage: Orally starting with a dose of 7.5 mg once weekly and increased by 2.5 mg weekly. Maximum weekly dose is 30
mg. It acts probably by inhibiting aminoimidazole carboxamide (AICAR) transformylase and thymidylate enzymes.
It has immunosuppressant and potent antirheumatoid effects.
It can also be used in the treatment of psoriasis, polymyositis, giant cell arteritis, dermatomyositis, etc.
Adverse effects: Nausea, vomiting, mucosal ulcers and dose-dependent hepatotoxicity
It is contraindicated in pregnancy.
Q. 4. Role of glucocorticoids in rheumatic arthritis
 Glucocorticoids (steroids) are used as adjunct to nonsteroidal anti-inflammatory drugs (NSAIDs) and disease modifying
antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis.
Their effects are prompt and they suppress inflammation quickly. They produce an immediate and dramatic symptomatic
relief in rheumatoid arthritis, but do not halt the progression of the disease.
Mechanism of Action
Glucocorticoids induce a protein called lipocortin which inhibits phospholipase A2 and so PGs, leukotrienes and PAF are not
formed.
TNFa is inhibited by glucocorticoids which are necessary for initiating inflammatory process.
Glucocorticoids stabilize the lysosomal membrane and prevent the release of inflammatory mediators.
Intra-articular injection is preferred only if one or two joints are involved.
Part IV
Respiratory System
Drugs for Cough and Bronchial Asthma
SHORT ESSAYS
Salbutamol
Salbutamol is a sympathomimetic, selective b2-adrenergic agonist drug acting as bronchodilator. It is the fastest-acting
bronchodilator, convenient to use and relatively safe. On inhalation salbutamol has rapid onset within 1–5 min and short
duration of action, preferred for acute attack of asthma.
Pharmacology
Pharmacological actions of salbutamol are as follows: Bronchodilatation Relaxation of pregnant uterus Dilatation of
blood vessels supplying the skeletal muscles
Promote hepatic glycogenolysis and uptake of potas-
sium (K1) into the cells
Therapeutic Use
Therapeutic uses of salbutamol are as follows:
In bronchial asthma it is usually administered as aerosol. It produces prompt bronchodilatation with minimum systemic side
effects. Salbutamol is used to delay the premature labour on oral or parenteral administration. It relaxes pregnant uterus by
interacting with b2 receptors.
It is useful in hyperkalaemia as it increases the uptake
of K1 into the cells.
Route and Dose
Inhalation salbutamol 100–200 mcg every 6 h or as and when required through metered dose inhaler
(MDI)
It is available as metered dose inhalers, nebulizers, tablets for oral use.
 Other routes of administration are oral, IM, IV. The proper technique for inhalation is to be taught. Spacers should be used
in children and adults who do not know proper inhalational technique. It is not suitable for round-the-clock prophylaxis.
Side Effects
Cardiac side effects like tachycardia and palpitation are less prominent.
Muscle tremors due to stimulation of b2 receptors of skeletal muscle. Tolerance develops to this effect on continued
administration.
Restlessness, nervousness, throat irritation and ankle oedema can occur.
On parenteral administration hyperglycaemia may occur in diabetics. Hypokalaemia is due to shift of K1 into the cell.
Q. 2. Disodium cromoglycate
Disodium cromoglycate is a mast cell stabilizer belonging to group of antiasthmatic drugs. It is a synthetic chromone
derivative.
Mechanism of Action
 It inhibits the degranulation of mast cells by trigger stimuli and prevents the release of chemical mediators like histamine,
leukotrienes, prostaglandins, plateletactivating factors, interleukins, etc. from mast cells by stabilizing the mast cell membrane.
Pharmacological Actions
Inhibition of chemotaxis of inflammatory cells Cellular inflammatory response is decreased on longterm treatment.
Bronchial hyperreactivity is reduced to variable extent.

Prevents bronchospasm induced by allergens, irritants, cold air and exercise. Antigen–antibody reaction is not interfered
with.
Does not antagonize bronchoconstrictor action of hista-
mine, acetylcholine, leukotrienes, etc.
Pharmacokinetics
Not absorbed orally Administered as an aerosol through metered dose inhaler delivering 1 mg/dose
 Only a small fraction is absorbed systemically. Excreted rapidly unchanged in urine and bile
Adverse Effects
Bronchospasm
Throat irritation and cough Nasal congestion, headache, dizziness
Arthralgia
Rashes Dysuria rarely Therapeutic uses
Allergic asthma As long-term prophylactic agent to prevent bronchospasm induced by allergens and irritants
Frequency and severity of asthma is reduced and lung function is improved.
Benefits extrinsic and exercise-induced asthma especially in younger patients
Used as an alternative to inhaled steroids in mild to
moderate asthma
Allergic rhinitis Regular four times daily prophylactic used as nasal spray produces symptomatic improvement after 4–6
weeks thus reducing need for nasal decongestants. Two squeezes in each nostril of 2% solution four times a day.
SHORT NOTES
Allergic conjunctivitis Regular use may benefit chronic cases. One drop each eye of 2% solution four times a day.

Noscapine
Noscapine is an opium alkaloid, central cough suppressant having potent antitussive effect. It acts by inhibiting cough
centre in the medulla. It is a potent antitussive with minimal CNS effects.
It rarely causes any side effect though nausea may be
seen in a few cases. Dose: 15–30 mg every 6 h Side effects: Nausea and headache
Q. 2. Salbutamol
Salbutamol is a sympathomimetic, selective b2-adrenergic agonist drug acting as bronchodilator.
 Inhaled salbutamol produces rapid onset of bronchodilatation in 1–5 min. Its action lasts for 2–4 h. Short duration of action,
preferred for acute attack of asthma.
It is used to abort or terminate attack of asthma. It is not suitable for round-the-clock prophylaxis.
Side effect: Cardiac side effects are less prominent, muscle tremor, palpitation, restlessness, nervousness, throat irritation
and ankle, oedema can occur.
Q. 3. Aminophylline
Aminophylline is one of the methylxanthines used as bronchodilator.
It is third or fourth line of drugs in the treatment of
asthma due to its narrow margin of safety.
Pharmacological Actions
CNS: It is a CNS stimulant. CVS: It directly stimulates heart.
Smooth muscle: All smooth muscles are relaxed; the prominent effect is exerted on bronchi, especially in asthma.
 Kidney: It is a mild diuretic. Stomach: It enhances secretion of acid and pepsin. Mast cell and inflammatory cell: It
inhibits the release of histamine and other mediators of asthma from mast cells and activated inflammatory cells.
Uses
Bronchial asthma and COPD: Aminophylline benefits by causing bronchodilatation and by reducing release of inflammatory
mediators. Apnoea in premature infants: It reduces the frequency
and duration of episodes of apnoea.
Adverse Effects
They have narrow margin of safety. Tachycardia, palpitation, hypotension and sudden death due to cardiac arrhythmias
Q. 4. Mention two drugs used to suppress dry cough.

Opioids Codeine Pholcodine Ethylmorphine Morphine

Nonopioids Noscapine Dextromethorphan Oxeladin Chlophedianol
Antihistaminics Chlorpheniramine Diphenhydramine Promethazine
Q. 5. Nasal decongestants
Nasal decongestants stimulate the a receptors and cause vasoconstriction in the nasal mucous membrane and thus relieve
nasal congestion. The commonly used a agonists as nasal decongestants are naphazoline, pseudoephedrine, phenylephrine,
imidazoline compounds like xylometazoline and oxymetazoline.
They are used either topically or systemically in allergic rhinitis, common cold, sinusitis etc. They have longer duration of
action than ephedrine.
Atrophic rhinitis, anosmia and local irritation are the other adverse effects seen with topical decongestants. On systemic
absorption these drugs may aggravate hypertension.
Q. 6. Rationale of using salbutamol in bronchial asthma.

Salbutamol is a sympathomimetic bronchodilator. It is highly selective b2 agonist.

 Salbutamol has b2: b1 ratio of about 10. Thus it causes b2-mediated bronchodilatation in bronchial asthma. Inhaled
salbutamol produces bronchodilatation in 5 min. Its action lasts 2–4 h, therefore salbutamol is used primarily in bronchial
asthma.
Q. 7. Beclomethasone
Beclomethasone is a long-acting glucocorticoid.
Beclomethasone is an inhalational steroid that largely minimizes the adverse effects caused by steroids.
It has local action, inhaled steroids suppress bronchial inflammation and hence used in bronchial asthma.
It does not cause bronchodilation but is an antiinflammatory drug, hence suppresses the inflammatory response to antigen–
antibody reaction and thereby reduces mucosal oedema and hyperirritability.
It cannot be used to treat asthma but is used as prophylactic drug to prevent acute attacks of asthma, bronchial
hypersensitivity and effectively controls symptoms.
 It is available as nasal spray for allergic rhinitis and as ointment for skin and mucous membrane lesions. HPA axis
suppression is minimal.
Dose: Beclate inhaler—50, 100, 200 µg, metered dose— 1–2 puffs 3–4 times a day.
Adverse effects: Hoarseness of voice, sore throat, oropharyngeal candidiasis
Q. 8. List three groups of drugs used in bronchial asthma with an
example.

Drugs used in chronic bronchial asthma are as follows:

Bronchodilators
Sympathomimetics: Adrenaline, isoprenaline, salbutamol
Anticholinergic: Atropine, ipratropium bromide
Mast cell stabilizers: Sodium cromoglycate, ketotifen
Glucocorticoids: Beclomethasone, budesonide, hydrocortisone, prednisolone
Q. 9. Describethe mechanism of action of sodium cromoglycate.

It is a synthetic chromone derivative.

Mechanism of action: It inhibits the degranulation of mast cells by trigger stimuli and prevents the release of chemical
mediators like histamine, leukotrienes, prostaglandins, platelet-activating factors, interleukins, etc. from mast cells by
stabilizing the mast cell membrane.
Q. 10. Pharmacotherapy of status asthmaticus
When an attack of asthma is prolonged with severe intractable wheezing it is known as status asthmaticus or acute severe
asthma. It may be triggered by an acute respiratory infection, abrupt withdrawal of steroids, allergens, anaphylaxis,
emotional stress.
Treatment of Status Asthmaticus
 Humidified oxygen inhalation Nebulized b2-adrenergic agonist (salbutamol 5 mg or terbutaline 10 mg) 1 anticholinergic
agent (ipratropium bromide 0.5 mg), intermittent inhalations every 30 min.
Systemic glucocorticoids: Hydrocortisone hemisuccinate 200 mg IV stat followed by 100 mg every 6 hours or prednisolone
30–60 mg/day depending on patient's condition.
Intravenous fluids to correct dehydration Potassium supplements to correct hypokalaemia pro-
duced by repeated doses of salbutamol or terbutaline
Sodium bicarbonate to treat acidosis Antibiotics to treat chest infections Artificial ventilation may be necessary for
extreme cases.
Q. 11. Mention two drugs used in acute bronchial asthma. Write the rationale
of using anyone drug.

Drugs Used in Bronchial Asthma

Bronchodilators
Sympathomimetics: Adrenaline, ephedrine, isoprenaline, salbutamol, terbutaline, salmeterol, formoterol b.
Methylxanthines: Theophylline, aminophylline, etophylline
c. Anticholinergics: Atropine methonitrate, ipratropium bromide, tiotropium bromide
Leukotriene receptor antagonist: Montelukast, zafirlukast
Mast cell stabilizers: Sodium cromoglycate, nedocromil sodium, ketotifen
Glucocorticoids
Systemic: Hydrocortisone, prednisolone
Inhalational: Beclomethasone dipropionate,
budesonide, fluticasone propionate
Rationale of Using Adrenaline in the Treatment of Bronchial Asthma
 Adrenaline acts as a powerful bronchodilator through its action on b2 receptors. This action is more marked when the
bronchi are constricted. Effects of adrenaline in bronchial asthma are depicted
as follows:

Adrenaline

It inhibits the release of inflammatory Causes mediators from mast cells. ↓

(Histamine, bradykinin, Bronchodilatation (β2)
LTs, PAF, PGF 2α) Vasoconstriction ( α1)
↓
Decreases secretions
↓
Relieves mucosal oedema and congestion
It has rapid onset but short duration of action hence useful for acute asthmatic attacks.
Adrenaline given by aerosols additionally decongests bronchial mucosa by its action and also stimulates respiratory centre.
Part V
Hormones and Related Drugs

Anterior Pituitary Hormones, Thyroid

Hormone and Thyroid Inhibitors
LONG ESSAY
Enumerate the antithyroid drugs. Explain the ac-
tion of the thioamides giving the indications, advantages
and adverse effects of each of them. Hyperthyroidism is caused due to excess of circulating thyroid
hormone.
Adrenaline 0.3–0.5 mL of 1:1000 solution is given subcutaneously. It can be given by nebulization.
Drugs used in the treatment of hyperthyroidism are classified as follows:
Thyroid hormone synthesis inhibitors or antithyroid
drugs (thioamides or thiourea derivatives): Propylthiouracil, methimazole, carbimazole
Inhibitors of iodide trapping (inhibitors): Thiocyanates and perchlorates
Hormone release inhibitors: Iodine, iodides of Na1 and
K1 and organic iodide Thyroid tissue destroying agent: Radioactive iodine
(131I, 125I, 123I)
Others: Propranolol, atenolol, diltiazem, dexamethasone
The mechanism of action of thioamides (thiourea derivatives), e.g. propylthiouracil, methimazole, carbimazole are as follows:
Thioamides act by reducing hormone synthesis.
They inhibit thyroid peroxidase enzyme, which converts iodide to iodine.
They inhibit iodination of tyrosine residues in thyroglobulin.
They inhibit coupling of iodotyrosine residues (MIT
and DIT).
Propylthiouracil
Propylthiouracil is less potent and most rapidly absorbed. It has short half-life and needs to be given every 6–8 h.
It also inhibits the peripheral deiodination of T4 to T3. Other thioamides inhibit this process to a much lesser extent.
Dose: 50–150 mg TDS followed by 25–50 mg BD or
TDS for maintenance Available as PTU 50 mg
Carbimazole
 Carbimazole is a commonly used drug as it is more potent and long acting. Carbimazole acts largely by getting converted to
methimazole in the body.
Dose: 5–15 mg TDS initially, maintenance dose is 2.5–10 mg daily in 1–2 divided doses.
Available as Neomercazole, Thyrozol and Antithyrox 5 mg tab.
Adverse Effects
Allergic reactions or skin rashes are most common.
Hypothyroidism due to overtreatment is common but reversible on stopping the drug.
Important side effects are GI intolerance, joint pain, hepatitis, nephritis, etc.
Rare complications include loss or greying of hair, loss of taste, fever and liver damage.
A less common but most dangerous adverse effect is
agranulocytosis. It is mostly reversible.
Uses
They are used in the long-term treatment of thyrotoxicosis where surgery is contraindicated or not feasible and radioactive
iodine is contraindicated.
Graves’ disease is diffuse toxic goitre and needs treatment for long term (1–5 years).
Toxic nodular goitre as an alternative when surgery is not indicated as in elderly patients.
Preoperatively, hyperthyroid patients are made euthyroid with antithyroid drugs and then operated.
They are used along with radioactive iodine to hasten recovery in thyrotoxicosis.
They are used for treatment of thyrotoxic crisis along with iodide and propranolol.
Thyroid storm or thyrotoxic crisis is sudden, severe exacerbation of thyrotoxicosis and can be life threatening. Propylthiouracil,
oral or rectal potassium iodide, IV hydrocortisone and supportive therapy are needed immediately.
Advantages
Advantages of antithyroid drugs over surgery or 131I are as follows:
 No surgical risks and no chances of injury to parathyroids or recurrent laryngeal nerve. Hypothyroidism, if induced, is
reversible. Can be used in children and young adults also.
Disadvantages
Disadvantages of antithyroid drugs are as follows:
SHORT ESSAY
Radioactive iodine Radioiodine 131I is used therapeutically while sodium iodide 123I is
used for diagnostic scan.
131I given is rapidly absorbed and is concentrated
Radioactive iodine (131I, 125I, 123I) is a thyroid tissue by the thyroid in the follicles. It emits g rays and destroying
agent. b particles.
Prolonged treatment is needed as relapse rate is high. Not useful in uncooperative or unintelligent patients.
Drug toxicity
The b particles which penetrate up to 0.5–2 mm of the tissue, destroys only the thyroid tissues and does not damage the
surrounding structures.
They cause destruction of the follicular cells leading to fibrosis and correction of hyperthyroid state.
The indications or uses of radioactive iodine are as follows: They are most commonly used as sodium salts and taken orally
as solution or capsules in hyperthyroidism.
It emits b particles which destroy thyroid cells, so they are used in carcinoma of thyroid. It is used for diagnostic purposes.
Advantages
Treatment is simple and convenient. Cost effective No risk of surgery Hyperthyroidism is permanently cured.
Disadvantages
Slow acting, long-time treatment necessary for maximum response (3 months)
High incidence of hypothyroidism
SHORT NOTES
 Not suitable for pregnant women, children and young patients

Lugol’s iodine
Lugol’s iodine is a solution containing 5% iodine and 10% potassium iodide solution. A daily dose of 5–15 drops can be
used.
It can be used as an expectorant.
as prophylaxis in endemic goitre. as an antiseptic. for preoperative preparation for thyroidectomy. in patients with
thyroid storm.
Q. 2. Iodine
Iodine is used in the treatment of hyperthyroidism. It includes usage of iodides and radioactive iodine.
Iodides inhibit the release of thyroid hormone and in thyrotoxic patients; symptoms subside in 1–2 days. The gland becomes
firm and shrinks in size over a period of 10–14 days. Effects are transient and decrease after
15 days Adverse effects: Allergic reactions like skin rashes, conjunctivitis, swelling of the lips and salivary glands, fever and
lymphadenopathy.
Uses
Preoperative preparation for thyroidectomy In thyroid storm iodine is used to reduce release of
thyroid hormone. Prophylaxis to prevent endemic goitre As an antiseptic and expectorant
Q. 3. Carbimazole
Carbimazole is a thioamide, acting as thyroid hormone synthesis inhibitor. It is a commonly used drug as it is more potent
and long acting. Carbimazole acts largely by getting converted to methimazole which is active in the body.
Less protein bound and is 10 times more potent than propylthiouracil.
Crosses placental barrier and causes fetal hypothy-
roidism.
Adverse Effects
 Allergic reactions Hypothyroidism GI intolerance, joint pain, hepatitis, nephritis, etc.
A less common but most dangerous adverse effect is
agranulocytosis.
Uses
They are used in the long-term treatment of thyrotoxicosis where surgery is contraindicated or not feasible and radioactive
iodine is contraindicated.
They are used along with radioactive iodine to hasten recovery in thyrotoxicosis.
They are used for treatment of thyrotoxic crisis along with iodide and propranolol.

Insulin, Oral Hypoglycaemics and Glucagon

LONG ESSAYS
Classify antidiabetic drugs and write about the oral antidiabetic drugs.
 Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and altered metabolism of carbohydrates.
It is of two types as follows:
Type I insulin-dependent diabetes mellitus (IDDM)
Type II noninsulin-dependent diabetes mellitus
(NIDDM)
Usually type I IDDM is treated with insulin supplements while type II NIDDM is treated with oral hypoglycaemic agents.
ANTIDIABETIC DRUGS
They are classified as follows:
Insulin
Ultra short-acting (rapid acting)
Insulin lispro (lysine 1 proline) Insulin aspart
Short-acting (rapid acting)
Regular crystalline insulin (rapid action) Insulin zinc suspension (semilente amorphous)
Intermediate-acting
Isophane insulin suspension (NPH) Insulin zinc suspension (lente) Biphasic insulin (ready-made PPN)
Glargine (clear, no buffer, no protein)
Long-acting
Glargine Extended insulin zinc suspension (ultralente) Protamine zinc suspension (PZT)
Oral hypoglycaemics
Sulphonylureas
First generation: Tolbutamide, chlorpropamide Second generation: Glibenclamide (glyburide),
glipizide, gliclazide, glimepiride
Biguanides: Phenformin, metformin III. Meglitinide analogues: Repaglinide, Nateglinide
Thiazolidinediones: Rosiglitazone, Pioglitazone
a -Glucosidase inhibitors: Acarbose, Miglitol
ORAL HYPOGLYCAEMIC DRUGS
These drugs are used in cases of early and mild noninsulindependent diabetes mellitus as they lower blood glucose levels. They
are noninvasive drugs as the necessity of injections is avoided here.
CLASSIFICATION
I. Sulphonylureas
Sulphonylureas were the first oral hypoglycaemic drugs to be introduced. They are divided into two generations. All these
drugs have same mechanism of action, but differ in potency and duration of action. The second generation drugs are about 100
times more potent than first generation drugs.
Mechanism of action
Sulphonylureas
 Bind to specific receptors on β cells of islets of pancreas

Block the ATP-sensitive potassium channels

Depolarization and influx of Ca2+ ions into β cells

Degranulation and increased release of stored insulin from β cells

They are metabolized in the liver and mainly excreted in urine.
Use
Sulphonylureas are useful in patients with type II diabetes mellitus.
Various drugs included in sulphonylureas are as follows:
A. First generation Tolbutamide
Weaker, short acting, safer in patients prone to hypoglycaemia
Daily dose: 0.5–3 g; half-life: 6–8 h; duration of
action: 6–8h
Chlorpropamide
Longest acting, can cause prolonged hypoglycaemia, potentiates ADH action, more cholestatic jaundice, alcohol flush.

Daily dose: 0.1–0.5 g; half-life: 30–36 h; duration

of action: 36–48 h B. Second generation Glibenclamide (glyburide)
Potent but slow acting, marked initial insulinaemic action in urine as well as bile, single dose is sufficient despite short half-
life.
 Daily dose: 5–15 mg; half-life: 4–6 h; duration of action: 18–24 h Glipizide
Fast acting, insulinaemic action persists even after prolonged use, can be given once daily despite short half-life.
Daily dose: 5–20 mg; half-life: 3–5 h; duration of action: 12–18 h Gliclazide
Has antiplatelet action, reduces free radicals, delays diabetic retinopathy, less weight gain.
Daily dose: 40–240 mg; half-life: 8–20 h; duration of action: 12–24 h
Stronger extrapancreatic action, less hyperinsulinaemia Daily dose: 1–6 mg; half-life: 5–7 h; duration of action: 24 h
II. Biguanides
Metformin is the only biguanide used clinically.
Mechanism of Action
They inhibit hepatic gluconeogenesis and enhance insulinmediated glucose disposal from muscles and fat. They promote
peripheral glucose utilization by enhancing anaerobic glycolysis and inhibit alimentary absorption of glucose.
Metformin is taken orally, well absorbed through GIT and is excreted mostly unchanged in urine.
Use
Metformin is useful in obese patients with type II DM either alone or in combination withsulphonylureas.
Phenformin
Lactic acidosis is more common. Drug usage is withdrawn in many countries.
Metformin
It is not metabolized in the body at all. Lactic acidosis is less common. Very high doses can cause hypoglycaemia or vitamin
B12 deficiency. Daily dose: 0.5–2 g; half-life: 1.5–3 h; duration of action: 6–8 h
III. Meglitinide Analogues
Recently developed quick and short-acting insulin releases.
Repaglinide
 Acts similar to sulphonylureas, by binding to their receptors and other distinct receptors, causing closure of ATP dependent
K1 channels. This causes depolarization and there is insulin release. It is indicated only in type II diabetes as an alternate to
sulphonylureas or to supplement metformin. It is given half an hour before a meal to control postprandial hyperglycaemia.
Nateglinide
It has more rapid onset and shorter duration of hypoglycaemic action than repaglinide. There is little effect on fasting blood
glucose level. Episodes of hypoglycaemia are less frequent.
Daily dose: 180–480 mg; half-life: 1.5 h; duration of
action: 2–3 h
IV. Thiazolidinediones
They are selective agonists for the nuclear peroxisome proliferator-activated receptor g which enhances the transcription of
several insulin responsive genes. Hepatic gluconeogenesis is also suppressed. They are well tolerated. Weight gain, headache,
myalgia and mild anaemia are common.
They are used to supplement sulphonylureas or metformin.
Rosiglitazone
Reverses insulin resistance. No hypoglycaemia occurs.
Daily dose: 4–8 mg; half-life: 4 h; duration of action: 12–24 h
Pioglitazone
Reverses insulin resistance. No hypoglycaemic action occurs. It may cause failure of oral contraceptives. Daily dose:
15–45 mg; half-life: 3–5 h; duration of action: 24 h
Glucosidase Inhibitors
Acarbose is a complex oligosaccharide which irreversibly inhibits a-glucosidases, the final enzymes for the metabolism of
carbohydrates in the small intestines. It slows down digestion and absorption of polysaccharides and sucrose. It is a mild
antihyperglycaemic and not a hypoglycaemic. It is used as an adjuvant to diet in obese diabetics.
Q. 2. Describethe different preparations of insulin. Add a note on their
merits and demerits. Or,
Mention the various insulin preparations with their advantages and disadvantages.
Or,
Mention insulin preparations and discuss their pharmacological actions and adverse effects.

Insulin is a hormone synthesized in the beta cells of pancreatic islets from a single chain polypeptide precursor called
preproinsulin. It maintains blood glucose levels by oxidizing it.
Various preparations of insulin are as follows (Table 15.1):
The conventional commercial preparations of insulin are derived from beef and pork pancreas. It has been modified by adding
zinc with or without protamine.
TABLE 15.1 Insulin Preparations Based on Onset and
Duration of Action
Class Type of Insulin Onset Duration of Action (h)
1. Ultra short- acting (rapid acting) Insulin lispro (lysine 1 praline) 2–6
Insulin aspart 0.25 3–6
2. Short-acting
(rapid acting) Regular crystalline insulin (rapid action) 0.5–1 6–8
Insulin zinc suspension (semilente amorphous) 1 12–16
3. Intermediate- acting Isophane insulin suspension (NPH1) 1–2 18–24
Insulin zinc suspension (lente) 1–2 18–24
4. Long-acting Protamine zinc insulin (PZI) 4–6 24–36
Extended insulin zinc suspension (ultralente) 4–6 24–36
Glargine2–5 20–24
INSULIN PREPARATIONS BASED ON SOURCE AS BOVINE, PORCINE AND
HUMAN INSULINS
i. Bovine (Beef) Insulin
It differs from human insulin by three amino acid residues and is more antigenic to man. ii. Porcine (Pig) Insulin
It differs from human insulin by only one amino acid residue and is less immunogenic.
iii. Human Insulin
It is prepared either by enzymatic modification of porcine insulin (semisynthetic human insulin) or by DNA recombinant
technology. Human insulin is least immunogenic.
Mechanism of Action

(Insulin binds with specific receptorsinsulin receptors) on cell membrane

 Activates the tyrosine protein kinase enzyme

The tyrosine gets autophosphorylated to each insulin receptor substrate proteins (IRS-1, IRS-2, etc)

The cascade of phosphorylation and dephosphorylation reactions results in

Activation or inhibition of enzymes involved in rapid metabolic actions of insulin.
Actions of Insulin
Carbohydrate metabolism: Insulin decreases blood glucose level by inhibiting hepatic glycogenolysis, gluconeogenesis and
lipolysis in adipose tissue. It promotes glycogenesis in muscle and liver and increases rate of utilization of glucose.
Protein metabolism: It promotes protein synthesis and inhibits protein breakdown.
Fat metabolism: Insulin promotes synthesis of free fatty acids and triglyceride and inhibits lipolysis.
It increases potassium entry into the cells and decreases
urea output from liver.
Uses or Indications for Insulin
In juvenile diabetes, it is essential.
In noninsulin-dependent diabetes mellitus, it is required
when diabetes is not controlled by diet or exercise. When oral hypoglycaemics fail Stress of surgery, infections,
trauma, pregnancy and labour Gangrene of extremities Diabetic ketoacidosis (diabetic coma)
Adverse Effects of Insulin
Hypoglycaemia
It is the most common and dangerous complication. Prolonged hypoglycaemia may cause permanent brain damage.
Hypoglycaemia can occur in any diabetic and may be due to delay in taking food, too much of physical activity or excess dose
of insulin.
 Treatment: All these manifestations are relieved by administration of glucose. If patient is conscious, oral glucose or if
hypoglycaemia is severe (unconscious patient) 50 mL of 50% glucose is injected IV.
Glucagon 1 mg IV or adrenaline 0.2 mg SC may be
given for severe hypoglycaemia.
Hypersensitivity Allergic reactions are rare; they may cause local skin reactions at the site of injection.
Rashes, photosensitivity, purpura, transient leukope-
nia, rarely agranulocytosis.
Local reactions
Swelling, erythema, and stinging can occur some-
time, especially in the beginning. Lipodystrophy at the site of injection after long use
Lipodystrophy may be avoided by using purified insulin preparations and changing injection site by rotation.
Nonspecific side effects
 Nausea, vomiting, flatulence, diarrhoea, or constipa-
tion, headache, paraesthesia and weight gain
Oedema due to salt and water retention
Insulin resistance
It may be acute or chronic. Acute insulin resistance develops rapidly and is due to stressful conditions like trauma, infection,
surgery, psychological stress, etc.
Chronic insulin resistance is common in patients on prolonged conventional beef or pork insulins. Such patients should be
treated with highly purified newer insulins.
Q. 3. Mention the hormones secreted by pancreas. What is diabetic coma?
What are the principles of treatment?
The pancreas has small cells on it called the islets of Langerhans that secrete two hormones which are insulin and
glucagon.
i. Insulin
Insulin is a hormone which maintains normal levels of blood glucose. It is synthesized in the beta cells of pancreatic islets.
It facilitates glucose transport across cell membrane and alters the activity of enzymes involved in metabolism of
carbohydrates, fats and proteins in liver, muscle and adipose tissue to lower blood glucose levels.
It prevents rise in free fatty acid level, ketone body pro-
duction and protein breakdown of diabetic state.
ii. Glucagon
The alpha cells secrete glucagon which is a hyperglycaemic hormone. It increases the force and rate of contraction.
It activates adenyl cyclase and increases cAMP in liver, fat cells, heart and other tissues. It is used to counteract the actions
of insulin hypoglycaemia and occasionally to stimulate the heart in cardiogenic shock.
Diabetic Coma
Diabetic coma is seen in insulin-dependent diabetes mellitus and less in noninsulin diabetes mellitus.
 The symptoms of diabetic coma are hyperglycaemia, acidosis, hyperventilation, dehydration, hypotension, shock and
impaired consciousness.
Management of Diabetic Coma
Regular insulin is given 0.1–0.2/kg IV followed by 0.14 kg/h infusion till 4–6 h. Rate of infusion is decreased in blood
glucose level. IV fluids are given as normal saline IV L/h.
IV KCl infusion is given to correct the hypokalaemia. Sodium bicarbonate is given to correct acidosis.
SHORT ESSAYS
Antibiotics and other symptomatic and supportive treatment are given.

Mention different insulin preparations.

The various preparations of insulin are as follows:

Conventional Insulin Preparations
Conventional commercial preparations of insulin are derived from beef and pork pancreas. Zinc and protamine are added for
slow absorption and longer duration of action. Insulin is degraded in GIT and hence not given orally. Commonly used
preparations are as follows: 1. Regular insulin: SC, IV, IM
Lente insulin: SC
Isophane insulin: SC
Highly Purified Insulin Preparation
They are nonantigenic and are indicated in insulin resistance, allergy to conventional preparations, diabetics undergoing
surgery, trauma and infection. According to purification method used preparations are of two types, i.e.
Single peak insulin: It is purified by gel filtration and repeated crystallization. They contain 50–200 ppm proinsulin.
Monocomponent insulin: After gel filtration it is further purified by ion exchange chromatography.
Human Insulin
They were produced by recombinant DNA technology in Escherichia coli.
Insulin preparations based on onset and duration of action are as follows:
Ultra short-acting (rapid acting)
Insulin lispro (lysine 1 proline)
Insulin aspart
Short-acting (rapid acting)
Regular crystalline insulin (rapid action)
Insulin zinc suspension (semilente amorphous)
Intermediate-acting
Isophane insulin suspension (NPH1)
Insulin zinc suspension (lente)
Long-acting
Protamine zinc insulin (PZI)
Extended insulin zinc suspension (ultralente)
Glargine
Q. 2. Antidiabetic action of sulphonylureas
Sulphonylureas were the first oral hypoglycaemic drugs to be introduced. They are divided into two generations. All these
drugs have same mechanism of action, but differ in potency and duration of action. The second generation drugs are about 100
times more potent than first generation drugs.
Mechanism of Action
Various drugs included in sulphonylureas are as follows:
First generation: Tolbutamide and chlorpropamide
Second generation: Glibenclamide, glipizide, gliclazide and glimepiride
Pharmacological Actions
 These drugs lower blood sugar level on oral and parenteral administration.
They lower blood sugar level in some of the diabetics and all nondiabetic patients. They are effective only in presence of
functional pancreas. They produce increase in body weight.
Q. 3. Oral antidiabetic drugs
Oral antidiabetic drugs or hypoglycaemic drugs are the drugs used in cases of early and mild noninsulin-dependent diabetes
mellitus as they lower blood glucose levels. They are noninvasive drugs as the necessity of injections is avoided here.
Classification of oral antidiabetic drugs is as follows:
Sulphonylureas
First generation: Tolbutamide and chlorpropamide
Second generation: Glibenclamide, glipizide, glicla-
zide and glimepiride
Biguanides: Phenformin, metformin
Meglitinides: Repaglinide, nateglinide
Thiazolidinediones: Rosiglitazone, pioglitazone
a-glucosidase inhibitors: Acarbose, miglitol

Sulphonylureas

Bind to specific receptors on β cells of islets of pancreas

Block the ATP-sensitive potassium channels

Depolarization and influx of Ca2+ ions into β cells

Degranulation and increased release of stored insulin from β cells
Absorption, Fate and Excretion
Sulphonylureas are rapidly absorbed from gastrointestinal tract. They are partly bound to plasma proteins. They are
metabolized in liver and are excreted in urine.
Therapeutic Uses
Sulphonylureas are used in treatment of maturity onset diabetes, insulin-resistant diabetes and diabetes insipidus.
Mechanism of Action
Sulphonylureas: They act by blocking ATP sensitive potassium channels on the pancreatic b cell membrane. This increases
calcium influx and increases insulin release. Biguanides: They suppress gluconeogenesis in liver and promote peripheral
utilization of glucose. They also inhibit intestinal absorption of glucose, amino acid and vitamin B12.
Uses of Oral Antidiabetic Drugs
Sulphonylureas are used in treatment of maturity onset diabetes, insulin-resistant diabetes and diabetes insipidus.
 Biguanides are used in obese mild diabetics, nondiabetic obese patients and in patients allergic to sulphonylureas.
Q. 4. Insulin and sulphonylureas
Comparison between insulin and sulphonylureas is given in Table 15.2.
TABLE 15.2 Comparison between Insulin and Sulphonylureas
Insulin Sulphonylureas
The insulin is used in insulindependent diabetes mellitus and noninsulin-dependent diabetes mellitus Sulphonylurea is
used in nondependent-diabetes mellitus
The insulin should be given parenterally, i.e. SC/IM It is given either parenterally or orally
For functioning of insulin b cells are not required For functioning of sulphonylurea b cells are required
It is used in therapy of diabetic coma It is not used in therapy of diabetic coma
Insulin can be given to nursing mothers Sulphonylurea is not given to nursing mothers because it is secreted in milk
Q. 5. Mention four adverse effects of insulins.
 Insulin is a hormone which helps in maintenance of normal blood glucose levels by oxidizing it. It is synthesized in the beta
cells of pancreatic islets. It facilitates glucose transport across cell membrane and alters the activity of enzymes involved in
metabolism of carbohydrates, fat and protein in liver, muscle and adipose tissue to lower blood glucose levels.
Adverse effects of insulin are as follows:
Hypoglycaemia It is the most common and dangerous complication. Prolonged hypoglycaemia may cause permanent brain
damage. Hypoglycaemia can occur in any diabetic and may be due to delay in taking food, too much of physical activity or
excess dose of insulin.
Treatment: All these manifestations are relieved by administration of glucose. If patient is conscious, oral glucose or if
hypoglycaemia is severe (unconscious patient) 50 mL of 50% glucose is injected IV. Glucagon 1 mg IV or adrenaline 0.2 mg
SC may be given for severe hypoglycaemia.
Hypersensitivity Allergic reactions are rare, they may cause local skin reactions at the site of injection.
Rashes, photosensitivity, purpura, transient leukope-
nia, rarely agranulocytosis.
Local reactions Swelling, erythema and stinging can occur sometime, especially in the beginning. Lipodystrophy at the site
of injection after long use.
Lipodystrophy may be avoided by using purified insulin preparations and changing injection site by rotation.
Nonspecific side effects Nausea, vomiting, flatulence, diarrhoea, or constipation, headache, paraesthesia and weight gain.
Oedema due to salt and water retention.
Insulin resistance It may be acute or chronic. Acute insulin resistance develops rapidly and is due to stressful conditions like
trauma, infection, surgery, psychological stress, etc.
Chronic insulin resistance is common in patients on prolonged conventional beef or pork insulins. Such patients should be
treated with highly purified newer insulins.
Q. 6. Mention four advantages of newer insulins.
 Insulin is a hormone which helps to maintain normal blood glucose levels by oxidizing it. It is synthesized in the beta cells
of pancreatic islets. It facilitates glucose transport across cell membrane and alters the activity of enzymes involved in
metabolism of carbohydrates, fats and proteins in liver, muscle and adipose tissue to lower blood glucose levels and prevent
rise in free fatty acid level, ketone body production and protein breakdown of diabetic state. Conventional insulins are
obtained from pork and beef pancreas. It has to be injected 2–3 times a day. Newer insulins are derived from human
pancreas.
Advantages of newer insulin over conventional preparations are as follows:
The risk of antigen–antibody reactions are avoided since it is derived from human pancreas. Thus allergies caused by
conventional preparations can be overcome.
They are highly purified preparations. They can be used in cases of insulin resistance.
They can be used during pregnancy without fear of affecting the mother or the fetus.
 They can be used in case of injection site lipodystrophy caused by conventional preparations.
Q. 7. Give reason—glibenclamide is not useful in treating childhood diabetes
mellitus.

Glibenclamide is a second generation sulphonylurea.

Sulphonylureas provoke a brisk release of insulin from pancreas. They act on the so-called sulphonylurea receptors on the
pancreatic beta cell membrane—cause depolarization by reducing conductance of ATP sensitive K1 channels. This enhances
Ca21 influx degeneration and insulin release.
Sulphonylureas cannot cause hypoglycaemia in pancreatectomized animals or in type I diabetes mellitus.
Since type I diabetes mellitus occurs in children (at an early age) glibenclamide cannot be used to treat it.
Q. 8. Compare and contrast conventional insulin with newer insulin.
 Comparison between conventional insulin and newer TABLE 15.4 Comparison between Sulphonylurea insulin is
listed in Table 15.3. or Tolbutamide and Biguanides or Metformin
Sulphonylurea or Tolbutamide Biguanides or Metformin
They lower blood sugar levels in some of diabetic and all noninsulin-dependent diabetic individuals Biguanides lower
blood sugar levels only in diabetic individual but not in normal individuals
For action of sulphonylureas the release of insulin is from b cells of Langerhans For action of biguanide the insulin is not
released from b cells of Langerhans
They are rapidly absorbed from gastrointestinal tract They are well absorbed from gastrointestinal tract
They are metabolized in liver and excreted in urine They are eliminated through urine in 24 h
They cause increase in body weight They cause decrease in body weight
They are used in treatment of maturity onset diabetes, insulin-resistant diabetes and diabetes insipidus They are used in
obese mild diabetics and nondiabetic obese patients
Conventional Insulin Newer Insulin
They are derived from beef and pork pancreas They are produced by recombinant DNA technology
They are less water soluble They are more water soluble
It has slow SC absorption It has more rapid SC absorption
It has more duration of action It has less duration of action
It produces local reactions Local reactions are not present
TABLE 15.3 Comparison between Conventional Insulin and Newer Insulin
Q. 9. Compare and contrast sulphonylureas and biguanides.
Or,
Compare and contrast tolbutamide and metformin.
Comparison between sulphonylurea or tolbutamide and biguanides or metformin is listed in Table 15.4.
SHORT NOTES
 Mention four advantages of newer insulins. Or,
Newer insulins are preferred to conventional insulins.
Why?

Advantages of newer insulin over conventional preparations are as follows: Conventional insulin preparations are derived
from beef and pork pancreas; hence the risk of antigen–antibody reaction is very high whereas newer insulins are derived from
human pancreas, the risks of antigen–antibody reactions are avoided. Thus allergies caused by conventional preparations can
be overcome. Newer insulins are highly purified preparations. Newer insulins can be used in cases of insulin resistance.
They can be used during pregnancy without fear of affecting the mother or the fetus. Newer insulins can be used in case of
injection site lipo-
dystrophy caused by conventional preparations.
Q. 2. Sulphonylurea
 Sulphonylureas were the first oral hypoglycaemic drugs to be introduced. They are divided into two generations. All these
drugs have same mechanism of action, but differ in potency and duration of action.
Types of sulphonylureas
First generation: Tolbutamide and chlorpropamide
Second generation: Glibenclamide, glipizide, gliclazide and glimepiride
Mechanism of action: Sulphonylureas act by blocking ATP-sensitive potassium channels on the pancreatic b cell membrane.
This increases calcium influx and increases insulin release.
Uses: Sulphonylureas are used in treatment of maturity onset diabetes, insulin-resistant diabetes and diabetes insipidus.
Q. 3. Give reason—glibenclamide is not useful in treating childhood diabetes
mellitus.

Glibenclamide is a second generation sulphonylurea; they provoke a brisk release of insulin from pancreas.
They act on the so-called sulphonylurea receptors on the pancreatic beta cell membrane and cause depolarization by reducing
conductance of ATP-sensitive K1 channels. This enhances Ca21 influx, degeneration and insulin release.
Sulphonylureas cannot cause hypoglycaemia in pancreatectomized animals or in type I diabetes mellitus. Since type-I diabetes
mellitus occurs in children (at an early age) glibenclamide cannot be used to treat it.
Q. 4. Tolbutamide

Tolbutamide is an oral hypoglycaemic drug that is categorized under first generation sulphonylureas.
It is weaker, short acting, safer in patients prone to hypoglycaemia. Daily dose: 0.5–3 g; half-life: 6–8 h; duration of
action:
6–8 h They provoke a brisk release of insulin from pancreas and act on the so-called sulphonylurea receptors on the
pancreatic beta cell membrane.
 They cause depolarization by reducing conductance of ATP sensitive K1 channels. This enhances Ca21 influx,
degranulation and insulin release. They are used only in type II diabetes mellitus.
Q. 5. Glibenclamide
Glibenclamide (glyburide) is an oral hypoglycaemic drug that is categorized under second generation sulphonylureas.
Potent but slow acting, marked initial insulinaemic action in urine as well as bile
Single dose is sufficient despite short half-life. Daily dose: 5–15 mg; half-life: 4–6 h; duration of action:
18–24 h They provoke a brisk release of insulin from pancreas. They act on the so-called sulphonylurea receptors on the
pancreatic beta cell membrane and cause depolarization by reducing conductance of ATP-sensitive K1 channels. This enhances
Ca21 influx degranulation and insulin release. They are used only in type II diabetes mellitus.
Q. 6. Newer insulins
Newer insulins are derived from human pancreas.
 Since they are derived from human pancreas, the risk of antigen–antibody reactions are avoided. Thus allergies caused by
conventional preparations can be overcome.
They are highly purified preparations. They can be used in cases of insulin resistance.
They can be used during pregnancy without fear of affecting the mother or the fetus.
Q. 7. Mention preparations of insulin based on duration of action.

Insulin preparations based on onset and duration of action are as follows:

Ultra short-acting (rapid acting)
Insulin lispro (lysine 1 proline)
Insulin aspart
Short-acting (rapid acting)
Regular crystalline insulin (rapid action)
Insulin zinc suspension (semilente amorphous)
Intermediate-acting
Isophane insulin suspension (NPH1)
Insulin zinc suspension (lente)
Long-acting
Protamine zinc insulin (PZI)
Extended insulin zinc suspension (ultra lente)
Glargine
Q. 8. Compare insulin and sulphonylurea.

Insulin Sulphonylureas
Administered by parenteral route Oral hypoglycaemic drugs
Used in type I diabetes mellitus Affective only in type II diabetes
They act on insulin receptors They act on sulphonylurea receptors
They act by reducing blood glucose level They provoke brisk release of insulin from pancreas
Q. 9. Write basic use of insulin in type I diabetes.

Insulin is needed in type I diabetic cases in the following conditions:

When diabetes is not controlled by diet or exercise Primary or secondary failure of oral hypoglycaemics or
when these drugs are not tolerated
In underweight patients Temporarily to tide over infections, trauma, surgery, etc.
Q. 10. Write the drug treatment of juvenile diabetes.
 Juvenile diabetes is an insulin-dependent diabetes mellitus. It is immune-mediated and there is destruction of b cells due to
which deficiency of insulin occurs.
Treatment of juvenile diabetes consists of insulin therapy along with diet. Insulin therapy is generally started with regular
insulin administered parenterally before each major meal. The requirement is assessed by testing urine or blood glucose level.

Corticosteroids
LONG ESSAY

Classify glucocorticoids. Describethe mechanism of action, adverse effects and

therapeutic uses. Or,
Enumerate glucocorticoids. Describetherapeutic uses and adverse effects of any one
of them. Or,
Describethe therapeutic uses and adverse effects of glucocorticoids.

Corticosteroids are the hormones produced by the cortex of the adrenal gland. They are
glucocorticoids—cortisol, mineralocorticoids—aldosterone and a small amount of androgens.
The secretion of adrenal cortex is under the control of ACTH secreted by the anterior pituitary which in turn is regulated by
corticotropin releasing factor (CRF). This is termed as hypothalamic pituitary-adrenal axis.
CLASSIFICATION OF CORTICOSTEROIDS
Short-acting (8–12 h)
Hydrocortisone Cortisone
Intermediate-acting (18–36 h)
Prednisolone Methylprednisolone Triamcinolone C. Long-acting (36–54 h)
Paramethasone Dexamethasone Betamethasone
MECHANISM OF ACTION
Corticosteroids bind to specific receptors in the cytoplasm, the drug-receptor complex is transported into the nucleus where it
binds to specific sites on DNA and regulates the synthesis of new proteins that bring about the hormone effects.

Steroid hormone enters the cells of target organ

In the cytoplasm it binds to specific receptors

 Steroid receptor complex becomes activated

Enters the nucleus

Binds to specific site on the DNA

Protein synthesis regulation

Shows response
THERAPEUTIC USES OF GLUCOCORTICOIDS
Endocrinal Uses A. Replacement Therapy
Acute adrenal insufficiency: This is an emergency condition that could be precipitated by an infection or sudden withdrawal of
steroids. Hydrocortisone hemisuccinate 100 mg bolus followed by infusion is given immediately.
Chronic adrenal insufficiency (Addison’s disease): Oral hydrocortisone 20–40 mg dialysis the most commonly used drug along
with adequate salt and water allowance. Some patients may need additional fludrocortisones or DOCA are added.
Nonendocrinal Uses
B. Pharmacotherapy
Arthritides
Rheumatoid arthritis: In progressive disease steroids are given as one of the last resort drugs in conjunction with nonsteroidal
anti-inflammatory drugs (NSAIDs). If one or two joints are involved, intra-articular injections are preferred.
Osteoarthritis: Intra-articular injections are given to patients with osteoarthritis.
Rheumatic fever: Only in severely ill patients with fever, carditis and congestive heart failure (CHF) and not responding to
NSAIDs require glucocorticoids.
Acute gout: When treatment with NSAIDs has not
been successful, prednisolone is used as an adjuvant. Severe allergic reactions
Corticosteroids may be used for short periods in angioneurotic oedema, hay fever, serum sickness, contact dermatitis and
anaphylaxis.
They are slow acting and in less severe cases, antihis-
tamines should be preferred.
Bronchial asthma
Glucocorticoids may be used either for
status asthmaticus—intravenous hydrocortisone hemisuccinate or
severe chronic asthma—steroids are used as supplement to bronchodilators.
Inhalational steroids are used and in more severe cases low dose oral prednisolone is indicated.
Collagen diseases
Most cases of polyarthritis nodosa, lupus erythematosus, polymyositis, Wegener’s granulomatosis, and other rheumatoid
disorders respond to glucocorticoids.
They may be life saving. Therapy is generally started with high doses which are tapered to maintenance dose when
remission occurs.
Eye diseases Corticosteroids are used in a large number of inflammatory ocular diseases and may prevent the blindness.
Allergic conjunctivitis, uveitis, optic neuritis, and other inflammatory conditions are treated with steroids. Renal diseases:
Glucocorticoids are the first line of
drugs in nephrotic syndrome.
Skin diseases
Atopic dermatitis, seborrhoeic dermatitis, inflammatory dermatoses and other local conditions are treated with topical
steroids.
 Systemic therapy is needed and may be life saving in pemphigus vulgaris, exfoliative dermatitis, Stevens- Johnson syndrome
and other severe afflictions.
Gastrointestinal diseases: Mild inflammatory bowel diseases are treated with steroids and in severe cases oral prednisolone
may be used. ix. Liver diseases: Steroids are used in chronic active and alcoholic hepatitis.
Haematologic disorders Autoimmune haemolytic anaemias usually respond to glucocorticoids. Because of their
lympholytic action, glucocorticoids are used usually in combination with antineoplastic drugs to treat certain malignancies,
leukaemia, lymphomas, Hodgkin’s disease, multiple myeloma, etc.
Cerebral oedema: A steroid without salt and water retaining activity, e.g. large dose of dexamethasone is preferred. xii.
Lung diseases: Glucocorticoids are used in the treatment of aspiration pneumonia and prevention of infant respiratory
distress syndrome. xiii. Organ transplantation: For prevention and treatment of graft rejection, high doses of
prednisolone are given at the time of surgery with immunosuppressive agents. xiv. Other uses include Bell’s palsy, acute
polyneuritis and myotonia.
ADVERSE EFFECTS OF GLUCOCORTICOIDS
Most of the adverse effects of glucocorticoids are extension of pharmacological actions and are dependent on dose, duration of
therapy and the relative potency of additional mineralocorticoid effects.
Cushing’s syndrome: Abnormal fat distribution causes moon face, buffalo hump, truncal obesity, muscle wasting, thinning of
limbs and skin, easy bruising, purple striae and acne. Hyperglycaemia: Precipitation of diabetes mellitus or aggravation of
pre-existing diabetes. Susceptibility of infection: Long-term therapy with steroids leads to immunosuppression, which
makes the patient more vulnerable to various opportunistic infections like fungal, viral and bacterial, etc.
Osteoporosis: Especially of the vertebrae is more common in the elderly.
Avascular necrosis: Avascular necrosis of the bone due to restriction of blood flow through bone capillaries may cause pain
and restriction of movement.
Growth in children may be suppressed.
Peptic ulceration: This may sometimes occur on prolonged therapy especially when other ulcerogenic drugs are (e.g. NSAIDs)
used concurrently.
Mental disturbance: Euphoria, psychosis, depression viii. Eye: Cataract and glaucoma may occur on prolonged therapy.
Delayed wound healing
Other effects: Raised intracranial pressure, convulsions, hypercoagulability of the blood and menstrual disorders
Mineralocorticoid effects: This includes salt and water retention, oedema, hypokalaemia and hypertension are rare with
selective glucocorticoids. xii. Thinning of muscles: Steroid treatment can cause hypokalaemia leading to muscle
weakness and fatigability.
Long-term steroid therapy leads to steroid myopathy.
xiii. HPA axis suppression: The most undesirable and dangerous outcome of long-term steroid therapy leads HPA axis
suppression.
SHORT ESSAYS
 Synthetic corticosteroids
Synthetic corticosteroids are more selective corticosteroids. They do not have mineralocorticoid action.
They are more potent than the natural corticoids. They generally have intermediate to long duration of action.
Synthetic glucocorticoids include the following:
Prednisolone: It is more selective glucocorticoid and is four times more potent than hydrocortisone. Used for allergic,
inflammatory, autoimmune diseases and in malignancies.
For example: Available as Deltacortril, HostacortinH, 5, 10 mg tab., 20 mg/mL for IM, intra-articular injection, Wysolone,
Nucort, 5, 10, 20 mg tab.
Methylprednisolone: Slightly more potent and more selective than prednisolone; 4–32 mg/day oral. For example: Available as
Solu-Medrol methylprednisolone (as sodium succinate) 0.5 g (8 mL) and 1.0 g (16 mL) inj. for IM, slow IV inj.
Triamcinolone: Slightly more potent but highly selective glucocorticoid than prednisolone. 4–32 mg/day oral, 5–40 mg IM,
intra-articular injection. Also used topically.
For example: Available as Kenacort, Tricort 1, 4, 8 mg tab, 10 mg/mL, 40 mg/mL (as acetonide) for IM, intra-articular
injection Ledercort 4 mg tab.
Dexamethasone: Very potent and highly selective glucocorticoid than prednisolone. It is used for inflammatory and allergic
conditions in a dose of 0.5–5 mg/day oral.
In shock, cerebral oedema, etc 4–20 mg/day IV, IM, injection. Also used topically.
For example: Available as Decadron, Dexona 0.5 mg tab, 4 mg/mL (as sodium phosphate) for IV, IM inj., 0.5 mL oral drops,
etc.
Betamethasone: Same as that of dexamethasone. 0.5–5 mg/day oral, 4–20 mg/day IV, IM, injection or infusion, also topical.
For example: Available as Betnesol, Betacortril, Celestone 0.5 mg, 1 mg tab, 4 mg/mL (as sodium phosphate) for IV, IM inj.,
0.5 mL oral drops, etc.
Q. 2. Adverse effects of corticosteroids Or,
Side effects of glucocorticoids
 Most of the adverse effects of glucocorticoids are extension pharmacological actions and are dependent on dose,
duration of therapy and the relative potency of additional mineralocorticoid effects.
Cushing’s syndrome: Abnormal fat distribution causes moon face, buffalo hump, truncal obesity, muscle wasting, thinning of
limbs and skin, easy bruising, purple striae and acne.
Hyperglycaemia: Precipitation of diabetes mellitus or aggravation of pre-existing diabetes.
Susceptibility of infection: Long-term therapy with steroids leads to immunosuppression, which makes the patient more
vulnerable to various opportunistic infections like fungal, viral and bacterial, etc.
Osteoporosis: Especially of the vertebrae is more common in the elderly.
Avascular necrosis: Avascular necrosis of the bone due to restriction of blood flow through bone capillaries may cause pain
and restriction of movement. Growth in children may be suppressed.
Peptic ulceration: This may sometimes occur on prolonged therapy especially when other ulcerogenic drugs (e.g. NSAIDs) are
used concurrently.
Mental disturbance include euphoria, psychosis, depression.
Eye: Cataract and glaucoma may occur on prolonged therapy.
Delayed wound healing
Other effects: Raised intracranial pressure, convulsions, hypercoagulability of the blood and menstrual disorders
Mineralocorticoid effects: This includes salt and water retention, oedema, hypokalaemia and hypertension are rare with
selective glucocorticoids.
Thinning of muscles: Steroid treatment can cause hypokalaemia leading to muscle weakness and fatigability. Long-term steroid
therapy leads to steroid myopathy.
HPA axis suppression: The most undesirable and dangerous outcome of long-term steroid therapy leads HPA axis suppression.
Q. 3. Therapeutic uses of glucocorticoids
Therapeutic uses of glucocorticoids are as follows:
Endocrinal Uses
Replacement Therapy
Acute adrenal insufficiency: This is an emergency condition that could be precipitated by an infection or sudden withdrawal of
steroids. Hydrocortisone hemisuccinate 100 mg bolus followed by infusion is given immediately.
Chronic adrenal insufficiency (Addison’s disease): Oral hydrocortisone 20–40 mg during dialysis is the most commonly used
drug along with adequate salt and water allowance. Some patients may need additional fludrocortisones or DOCA are added.
Nonendocrinal Uses
Pharmacotherapy
Arthritides
Rheumatoid arthritis: In progressive disease steroids are given as one of the last resort drugs in conjunction with NSAIDs. If
one or two joints are involved, intra-articular injections are preferred.
Osteoarthritis: Intra-articular injections are given to patients with osteoarthritis.
Rheumatic fever: Only in severely ill patients with fever, carditis and CHF and not responding to NSAIDs require
glucocorticoids.
Acute gout: When treatment with NSAIDs has not
been successful, prednisolone is used as an adjuvant.
Severe allergic reactions Corticosteroids may be used for short periods in angioneurotic oedema, hay fever, serum sickness,
contact dermatitis and anaphylaxis.
They are slow acting and in less severe cases, antihistamines should be preferred.
Bronchial asthma: Glucocorticoids may be used either for
status asthmaticus: intravenous hydrocortisone hemisuccinate or
Severe chronic asthma: steroids are used as supplement to bronchodilators.
Inhalational steroids are used and in more severe cases low dose oral prednisolone is indicated.
Collagen diseases: Most cases of polyarthritis nodosa, lupus erythematosus, polymyositis, Wegener’s granulomatosis and other
rheumatoid disorders respond to glucocorticoids. They may be life saving. Therapy is generally started with high doses which
are tapered to maintenance dose when remission occurs.
Eye diseases and renal diseases: Glucocorticoids are the first line of drugs in nephrotic syndrome.
Skin diseases: May be used either topically as in atopic dermatitis, seborrhoeic dermatitis and other local conditions or
systemically may be as life-saving drugs in pemphigus vulgaris, Stevens-Johnson syndrome and other severe afflictions.
Gastrointestinal diseases: Mild inflammatory bowel diseases treated with steroids and in severe cases oral prednisolone may be
used.
Liver diseases: Steroids are used in chronic active and alcoholic hepatitis.
Haematologic disorders: Autoimmune haemolytic anaemiae usually respond to glucocorticoids.
Cerebral oedema: A steroid without salt and water retaining activity, e.g. large dose of dexamethasone is preferred.
Organ transplantation: For prevention and treatment of graft rejection, high doses of prednisolone are given at time of surgery
with immunosuppressive agents.
Other uses include Bell’s palsy, acute polyneuritis and myotonia.
Q. 4. Mention the actions and adverse effects of dexamethasone.

Dexamethasone is a synthetic corticosteroid. It is a potent and highly selective glucocorticoid.

It is used in cases of inflammatory and allergic conditions, shock and cerebral oedema.
Actions of dexamethasone are as follows:
Anti-inflammatory action: It suppresses the inflammatory response, mainly by suppressing the recruitment of inflammatory
cells at cellular level. Production of prostaglandins (PGs) and other inflammatory regulators like lymphotoxins (LTs), platelet-
activating factor (PAF), tumour necrosis factor a (TNF a) and cytokines are interfered. It reduces increased capillary
permeability, local exudation, cellular infiltration, phagocytic activity and late response like capillary proliferation, collagen
deposition, fibroblastic activity and finally scar formation. It also produces anti-inflammatory protein lipocortin.
Antiallergic action: It impairs immunological competence and suppresses all types of hypersensitization and allergic
phenomena. It suppresses the recruitment of leucocytes at the site of contact with antigen and of inflammatory response to
immunological injury.
Adverse effects include the following:
Cushing’s syndrome: Moon face, buffalo hump, truncal obesity, muscle wasting, thinning of limbs and skin, easy bruising,
purple striae and acne.
Hyperglycaemia: Diabetes mellitus
Susceptibility to infection: It is increased and sensitivity of any injection is more due to immunosuppression.
Osteoporosis: Especially more common in the elderly.
Avascular necrosis: Avascular necrosis of the bone due to restricted blood flow through bone capillaries.
Peptic ulceration: This may sometimes occur on prolonged therapy especially when other ulcerogenic drugs (e.g. NSAIDs) are
used concurrently.
Mental disturbance: Euphoria, psychosis, depression
Cataract and glaucoma
Delayed wound healing
HPA axis suppression
Q. 5. Explain why glucocorticoid therapy should not be stopped abruptly.
Or,
Abrupt cessation of prolonged administration of glucocorticoids is hazardous.
Explain.

Glucocorticoid therapy should be gradually decreased before stopping it completely.

Sudden cessation of the drug may cause suppression of hypothalamic pituitary adrenal axis which leads to the following:

Precipitation or flaring up of the underlying disease being treated and can cause reactivation of the disease.
Withdrawal symptoms like fever, myalgia, arthralgia, malaise, etc.
Subjected to stress, these patients can go to acute adrenal insufficiency manifesting as anorexia, nausea, vomiting, abdominal
pain, hypotension, dehydration, hyponatraemia, hyperkalaemia, etc.
Any patient who has received more than 20–25mg/day of hydrocortisone should be put on the scheme of gradual withdrawal.
Such patients may need protection with steroids if a stressful situation develops up to 1 year after withdrawal.
SHORT NOTES
Side effects of glucocorticoids Or,
Adverse effects of glucocorticoids
Or,
Adverse effects of adrenocorticosteroids
Adverse effects of glucocorticoids include the following:
Cushing’s syndrome: Moon face, buffalo hump, truncal obesity, muscle wasting, thinning of limbs and skin, easy bruising,
purple striae and acne
Hyperglycaemia: Diabetes mellitus
Susceptibility to infection
Osteoporosis
Avascular necrosis of the bone due to restricted blood flow through bone capillaries
Peptic ulceration: This may sometimes occur on prolonged therapy especially when other ulcerogenic drugs (e.g. NSAIDs) are
used concurrently.
Mental disturbance: Euphoria, psychosis, depression
Cataract and glaucoma
Delayed wound healing
HPA axis suppression
Q. 2. Prednisolone
Prednisolone is synthetic glucocorticoid, more selective and is four times more potent than hydrocortisone.
Has intermediate duration of action. Fluid retention occurs with high doses. Causes less pituitary-adrenal suppression
when a single morning dose or alternate day treatment is given.
Used for allergic, inflammatory, autoimmune diseases and in malignancies. For example: Available as Deltacortril,
Hostacortin-H, 5, 10 mg tab, 20 mg/mL for IM, intraarticular injection, Wysolone, Nucort, 5, 10, 20 mg tab
Q. 3. Betamethasone
Betamethasone is a long-acting, potent and highly selective glucocorticoid. It causes marked pituitary-adrenal suppression.
Does not cause water retention and hence can be used in cerebral oedema, can also be used in inflammatory and allergic
conditions, shock, etc.
 It is same as that of dexamethasone—0.5–5 mg/day oral, 4–20 mg/day IV, IM, injection or infusion, also topical.
For example: Available as Betnesol, Betacortril, Celestone 0.5 mg, 1 mg tab, 4 mg/mL (as sodium phosphate) for IV, IM
inj., 0.5 mL oral drops, etc.
Q. 4. Hydrocortisone
Hydrocortisone is a short-acting corticosteroid.
May be natural or synthetic. It has mineralocorticoid action.
Normal rate of secretion in man is 10 mg/day of which more than half is secreted during morning hours.
It has anti-inflammatory, antiallergic action. Delays
wound healing.
Q. 5. Uses of glucocorticoids
Therapeutic uses of glucocorticoids are as follows:
Endocrinal Uses
As a replacement therapy in acute adrenal insufficiency and chronic adrenal insufficiency (Addison’s disease).
Nonendocrinal Uses
In various arthritides like rheumatoid arthritis, osteoarthritis, rheumatic fever and acute gout.
In severe allergic reactions like angioneurotic oedema, hay fever, serum sickness, contact dermatitis and anaphylaxis,
corticosteroids may be used for short periods.
Bronchial asthma: Glucocorticoids may be used either for status asthmaticus or severe chronic asthma.
Collagen diseases, e.g. polyarteritis nodosa, lupus erythematosus, etc.
Eye diseases, renal diseases and gastrointestinal diseases
Haematologic disorders, e.g. autoimmune haemolytic anaemiae
Cerebral oedema
Organ transplantation for prevention and treatment of graft rejection
Other uses include Bell’s palsy, acute polyneuritis, myotonia, etc.
Q. 6. ACTH
Adrenocorticotropic hormone (ACTH) is secreted in the anterior pituitary gland. It regulates the release of corticosteroid
from the adrenal gland. Adrenal steroidogenesis takes place under the influence of ACTH which makes more cholesterol
available for conversion to pregnenolone and induces steroidogenic enzymes.
Therapeutic Uses
It mainly serves as a diagnostic tool for differentiating between primary and secondary adrenal insufficiency.
ACTH is used in the treatment of infantile spasm (West syndrome).
Q. 7. Mention four nonhormonal uses of glucocorticoids.
Nonendocrinal uses or nonhormonal uses of glucocorticoids are as follows:
Arthritides
Rheumatoid arthritis: In progressive disease steroids are given as one of the last resort drugs in conjunction with NSAIDs. If
one or two joints are involved, intra-articular injections are preferred.
Osteoarthritis: Intra-articular injections are given to patients with osteoarthritis.
Rheumatic fever: Only in severely ill patients with fever, carditis and CHF and not responding to NSAIDs require
glucocorticoids.
Acute gout: When treatment with NSAIDs has not been successful, prednisolone is used as an adjuvant.
Severe allergic reactions: Corticosteroids may be used for short periods in angioneurotic oedema, hay fever, serum sickness,
contact dermatitis and anaphylaxis.
Bronchial asthma: Glucocorticoids may be used either for status asthmaticus or severe chronic asthma. Steroids are used as
supplement to bronchodilators.
Collagen diseases: Most cases of polyarteritis nodosa, lupus erythematosus, polymyositis, Wegener’s granulomatosis and other
rheumatoid disorders respond to glucocorticoids. They may be life saving.
Q. 8. Two differences between hydrocortisone and dexamethasone
Differences between hydrocortisone and dexamethasone are given in Table 16.1.
TABLE 16.1 Differences between Hydrocortisone and
Dexamethasone
Hydrocortisone Dexamethasone
Short-acting corticosteroid Long-acting corticosteroid
Has mineralocorticoid activity It is highly selective glucocorticoid
Natural and synthetic Synthetic
Used mostly in replacement therapy Used more as anti-inflammatory,
antiallergic, in shock and cerebral oedema
Q. 9. Name four glucocorticoids.

Glucocorticoids are secreted in the adrenal cortex.

 Two glucocorticoids secreted naturally are: hydrocortisone and aldosterone. Synthetic glucocorticoids include
prednisolone, methylprednisolone, triamcinolone, dexamethasone and betamethasone.
Q. 10. Synthetic corticosteroids
Synthetic corticosteroids are more selective corticosteroids. They are more potent than the natural corticoids.
They do not have mineralocorticoid action. They generally have intermediate to long duration of action.
Examples of synthetic glucocorticoids include prednisolone, methylprednisolone, triamcinolone, dexamethasone and
betamethasone.

Gonadal Hormones (Sex Hormones) and Their Antagonists

SHORT ESSAYS
Anabolic steroids
Anabolic asteroids are synthetic androgens with higher anabolic and low androgenic activity. They are believed to enhance
protein synthesis and increase muscle mass. But with higher doses, the relative anabolic activity is lost.
Uses
In catabolic states: It corrects negative nitrogen balance and gives a state of well-being. Anabolic steroids may benefit patients
following surgery, trauma, prolonged illness and debilitating conditions.
Senile osteoporosis: Older males respond by formation of new bone tissue.
Growth stimulation in children: Anabolic steroids promote vertical growth in prepubertal boys.
Anabolic steroids are used for benefit in refractory anaemiae.
Abuse in athletes: Anabolic steroids are abused in athletes to achieve an improvement in athletic performance. 1.

2.
3.
4.
An

Contraindications
Pregnancy
Carcinoma of prostate or breast in males
Infants and children
Renal/cardiac/liver disease
Q. 2. Combination of oestrogen and progesterone in oral contraceptives
s.
Combined pill contains low doses of an oestrogen and a progestin.
They are highly efficacious (success rate: 98%). Ethinyl estradiol or mestranol (in the dose of 30–50 mg) are the oestrogens
used.
Newer progestins like desogestrel and norgestimate cause least effects.
The pill is started on fifth day of the menstrual cycle, taken daily for 21 days followed by a gap of 7 days during which
bleeding occurs. This is monophasic regimen. They are also available as biphasic or triphasic preparations.
This reduces the amount of hormones needed and more closely mimics menstrual cycles.
SHORT NOTES

Oral contraceptives
Various types of oral contraceptives are as follows:
Combined pill: They contain low doses of an oestrogen and a progestin. They are highly efficacious (success rate: 98%).
Ethinyl estradiol or mestranol (in the dose of 30–50 mg) are the oestrogens used. Newer progestins like desogestrel and
norgestimate causes least effects. The pill is started on fifth day of the menstrual cycle, taken daily for 21 days followed by a
gap of 7 days during which bleeding occurs. This is monophasic regimen. They are also available as biphasic or triphasic
preparations.
Mini pill: A low dose progestin is taken daily without gap. Oestrogen and its accompanied long-term adverse effects are also
eliminated. But efficacy is lower, menstrual cycles may be irregular and is therefore not popular.
Postcoital contraceptives: High dose of an oestrogen was used earlier. The combination is now preferred due
to lower doses needed and lesser side effects reported. The pill should be started within 72 h of coitus and has an efficacy of
90–98%. It is advocated as an emergency method in situations following rape or failure of regular contraceptive methods.
Q. 2. Anabolic steroids
Anabolic steroids are synthetic androgens with higher anabolic and low androgenic activity. They are believed to enhance
protein synthesis and increase muscle mass. But with higher doses, the relative anabolic activity is lost.
Uses
1. Used in catabolic states to correct negative nitrogen balance and give a state of wellbeing.
Senile osteoporosis: Older males respond by formation 4. Anabolic steroids are used for benefit in refractory of
new bone tissue. anaemias.
Growth stimulation in children: Anabolic steroids pro- 5. Abuse in athletes: Anabolic steroids are abused in
athmote vertical growth in prepubertal boys. letes to achieve an improvement in athletic performance.

Oxytocin and Drugs Acting on Uterus

Oxytocin

Oxytocin is an octapeptide secreted by the posterior pituitary gland.

Actions
It increases the force and the frequency of uterine contractions. With low doses full relaxation occurs between contractions.
 It contracts myoepithelium of mammary glands and helps in milk ejection.
Uses
It is used before delivery to induce labour in case of postmaturity or to augment it in case of uterine inertia.
It is also used to control postpartum haemorrhage as an alternative to ergometrine.
Adverse Effects

Drugs Affecting Calcium Balance

LONG ESSAYS
Improper administration or overdosage causes too strong contractions forcing the presenting part through incompletely dilated
birth canal, causing maternal and fetal soft tissue injury, rupture of uterus, fetus asphyxia and death.
 Write drugs acting on calcium metabolism. Describethe pharmacological actions of
parathyroid hormone.

Calcium is essential for tissue excitability, muscular excitation-contraction coupling, secretion from glands, myocardial
contractility and formation of bone and teeth. It also maintains the integrity of mucous membranes and cell membrane.
Calcium is essential for normal blood coagulation.
Calcium is absorbed from the small intestines by a carriermediated active transport. Normal plasma calcium level is 9–11
mg/dL. It is excreted in faeces, urine and sweat.
Drugs acting on calcium metabolism are as follows: Phosphate Parathyroid hormone
Vitamin D Calcitonin
Bisphosphonates: Etidronate, pamidronate, alendronate
PARATHYROID HORMONE
 Parathyroid hormone (PTH) is a polypeptide hormone secreted by the parathyroid gland. It is also known as parathormone.
Secretion of PTH is regulated by concentration of free plasma Ca21 concentration. A low plasma Ca21 stimulates PTH
release, while high levels inhibit secretion.
Parathormone maintains plasma concentration levels by mobilizing calcium from the bones, promoting reabsorption of Ca21
levels from the kidneys and by stimulating the synthesis of calcitriol which in turn enhances calcium absorption from the
intestines.
PTH activates the adenylyl cyclase enzyme present in the cell membrane, via G-protein coupled receptors, which in turn
increases the intracellular cAMP concentration and the intracellular Ca1, leading to various effects. PTH also promotes
phosphate excretion.
Actions of PTH can be summarized as follows:
Hypoparathyroidism
Hypoparathyroidism is characterized by low plasma calcium levels with its associated manifestations.
Aetiology
Following thyroidectomy Idiopathic Genetic
Autoimmune
Clinical features of acute hypoparathyroidism are as follows:
Hypocalcaemia Tetany Carpopedal spasm Laryngospasm
Tingling of lips, hands, muscles Convulsions
Clinical features of chronic hypoparathyroidism are as follows:
Loss of hair Brittle finger nails Caries of the teeth Cataract
Anxiety and depression
Hyperparathyroidism
Hyperparathyroidism which is most commonly due to parathyroid tumour produces hypercalcaemia and deformities of the
bone.
PTH is not therapeutically used. It is used for the diagnosis of pseudohypoparathyroidism.
Q. 2. What is normal plasma calcium level in the body? Describethe role
of different hormones and vitamins influencing body calcium levels.

Calcium is essential for tissue excitability, muscular excitation-contraction coupling, secretion from glands, myocardial
contractility and formation of bone and teeth. It also maintains the integrity of mucous membranes and cell membrane.
Calcium is essential for normal blood coagulation. Calcium is absorbed from the small intestines by a carrier-mediated
active transport. Normally about 30% of the dietary calcium is absorbed. Normal plasma calcium level is 9–11 mg/dL. It is
excreted in faeces, urine and sweat.
Drugs acting on calcium metabolism are as follows: Parathyroid hormone Vitamin D Calcitonin
Bisphosphonates: Etidronate, pamidronate, alendronate
The role of different hormones and vitamins influencing body calcium levels are as follows:
Parathyroid Hormone
Parathyroid hormone (PTH) is a polypeptide hormone secreted by the parathyroid gland. It is also known as parathormone.
Secretion of PTH is regulated by concentration of free plasma Ca21 concentration. A low plasma Ca21 stimulates PTH
release, while high levels inhibit secretion.
Parathormone maintains plasma concentration levels by mobilizing calcium from the bones, promoting reabsorption of Ca21
levels from the kidneys and by stimulating the synthesis of calcitriol which in turn enhances calcium absorption from the
intestines. PTH activates the adenylyl cyclase enzyme present in the cell membrane, via G-protein coupled receptors, which
in turn increases the intracellular cAMP concentration and the intracellular Ca1, leading to various effects. PTH also
promotes phosphate excretion. Role of PTH in influencing body calcium levels can be summarized as follows:
Actions
It enhances calcium and phosphate absorption from the intestine.
Calcitriol enhances mobilization of calcium from bone by promoting osteoclastic activity.
Increases tubular reabsorption of Ca21 and phosphate in the kidney tubules, but the action is less marked than that of PTH.
Calcitriol is essential for normal bone mineralization
and for skeletal muscles, cellular growth and differen tiation.

Calcitonin
The role of calcitonin influencing body calcium levels is as follows:
1. Calcitonin is a peptide hormone secreted by the parafol licular C cells of the thyroid gland. Secretion is regu
lated by plasma concentrations—high plasma levels of Ca21 levels stimulating calcitonin release.
↓ Plasma phosphate Actions
Vitamin D
The role of vitamin D in influencing body calcium levels is as follows:
It is a fat-soluble vitamin, prehormone produced in the skin from 7-dehydrocholesterol under the influence of UV rays and gets
converted to active metabolites in the body which regulates plasma calcium level and various functions of the cells. The chief
effects of calcitonin are to lower serum calcium level and phosphate by its action on the bones and kidney.
It inhibits osteoclastic bone resorption and in the kidney, reduces both calcium and phosphate reabsorption.
In general the effects are opposite to parathormone. Calcitonin is used to control hypercalcaemia, Paget’s disease, metastatic
bone cancer and osteoporosis and to increase bone mineral density.
↑ Plasma calcium
SHORT ESSAY
Agonists influencing calcium metabolism
The agonists influencing calcium metabolism are as follows:
Parathyroid Hormone
Parathyroid hormone (PTH) is a polypeptide hormone secreted by the parathyroid gland. It is also known as parathormone.
Secretion of PTH is regulated by concentration of free plasma Ca21 concentration. A low plasma Ca21 stimulates PTH
release, while high levels inhibit secretion.
Parathormone maintains plasma concentration levels by mobilizing calcium from the bones, promoting reabsorption of Ca21
levels from the kidneys and by stimulating the synthesis of calcitriol which in turn enhances calcium absorption from the
intestines.
PTH activates the adenylyl cyclase enzyme present in the cell membrane via G-protein coupled receptors, which in turn
increases the intracellular cAMP concentration and the intracellular Ca1, leading to various effects. PTH also promotes
phosphate excretion. Hypoparathyroidism is characterized by low plasma calcium levels with its associated manifestations.
Hyperparathyroidism which is most commonly due to parathyroid tumour produces hypercalcaemia and deformities of the
bone. PTH is not therapeutically used. It is used for the diagnosis of pseudohypoparathyroidism.
Vitamin D
Vitamin D is a fat-soluble vitamin and is a prehormone produced in the skin from 7-dehydrocholesterol under the influence of
UV rays and gets converted to active metabolites in the body which regulates plasma calcium level and various functions of the
cells.
Actions
It enhances calcium and phosphate absorption from the intestine.
Calcitriol enhances mobilization of calcium from bone by promoting osteoclastic activity.
Increases tubular reabsorption of Ca21 and phosphate in the kidney tubules, but the action is less marked than that of PTH.
5. Dose required: 400 IU (10 mg)
SHORT NOTES
Calcitriol is essential for normal bone mineralization and for skeletal muscles, cellular growth and differentiation.

Calcium carbonate
Calcium carbonate (40% Ca) is insoluble, tasteless and nonirritating.
It has been used as an antacid, reacts with HCl to form chloride which may be absorbed from intestine.
Side Effects
Only GI side effects like constipation, bloating and excess gas have been reported.
Some combined formulations are as follows:
Calcinol-RB: It contains calcium carbonate 0.375 g, calcium phosphate 75 mg, vitamin D 250 IU tab.
Shelcal: It contains calcium carbonate 625 mg, vitamin D3 125 IU tab.
Q. 2. Vitamin D
Vitamin D is a fat-soluble vitamin.
Prehormone, produced in the skin from 7-dehydrocholesterol under the influence of UV rays is converted to active metabolites
in the body which regulates plasma Ca level and various functions of the cells.
Source
1. Diet as ergocalciferol (vitamin D2) from plants 2. Cholecalciferol (vitamin D3) is synthesized in skin
from 7-dihydrocholesterol.
Dose Required
400 IU (10 mg)
Actions
Stimulates calcium and phosphate absorption in the intestine.
Mobilizes calcium from bone by promoting osteoclastic activity.
Increases reabsorption of Ca21 from kidney tubules.
Calcitriol is essential for normal bone, mineralization and for skeletal muscles, cellular growth and differentiation.
Deficiency
Results in low plasma calcium and phosphate levels with abnormal mineralization of the bone, causes rickets in children and
osteomalacia in adults.
Q. 3. Parathyroid hormone
Parathyroid hormone (PTH) is a polypeptide hormone secreted by the parathyroid gland. It is also known as parathormone.
Secretion of PTH is regulated by concentration of free plasma Ca21 concentration. A low plasma Ca21 stimulates PTH
release, while high levels inhibit secretion. Parathormone maintains plasma concentration levels by mobilizing calcium from
the bones, promoting reabsorption of Ca21 levels from the kidneys and by stimulating the synthesis of calcitriol which in turn
enhances calcium absorption from the intestines. PTH also promotes phosphate excretion.
Hypoparathyroidism is characterized by low plasma calcium levels with its associated manifestations.
Hyperparathyroidism which is most commonly due to parathyroid tumour produces hypercalcaemia and deformities of the
bone.
PTH is not therapeutically used. It is used for the diagnosis of pseudohypoparathyroidism.
Q. 4. Vitamin D deficiency
Vitamin D is a fat-soluble vitamin. Prehormone, produced in the skin from 7-dehydrocholesterol under the influence of
UV rays is converted to active metabolites in the body which regulates plasma calcium level and various functions of the cells.
Deficiency of vitamin D results in low plasma calcium and phosphate levels with abnormal mineralization of the bone
causes rickets in children and osteomalacia in adults.
Part VI
Drugs Acting on Peripheral Nervous System

Skeletal Muscle Relaxants

LONG ESSAYS
 Classify skeletal muscle relaxants. Describethe pharmacological actions, therapeutic uses
and adverse effects of d-tubocurarine.

Skeletal muscle relaxants are drugs that act peripherally at the neuromuscular junction or muscle fibre itself or centrally in
cerebrospinal axis to reduce muscle tone and/or cause paralysis.
The neuromuscular blocking agents are used in conjunction with the general anaesthetics to provide muscle relaxation for
surgery and centrally acting agents are used primarily for painful muscle spasm and spastic neurological diseases.
CLASSIFICATION
A. Peripherally Acting Skeletal Muscle Relaxants
I. Neuromuscular blocking agents
Nondepolarizing (competitive) blockers: Agent which block acetylcholine at muscle end plate
Long-acting: D-tubocurarine, pancuronium, doxacurium, pipecuronium
Intermediate-acting: Atracurium, vecuronium, cisa-
tracurium, rocuronium, rapacuronium
Short-acting: Mivacurium
Depolarizing blockers: Agents which persistently depo-
larize motor end plate Succinylcholine (SCh) or suxamethonium Decamethonium II. Directly Acting Agents
Dantrolene sodium
Quinine
B. Centrally Acting Skeletal Muscle Relaxants
These drugs reduce skeletal muscle tone by acting on selective areas of CNS without loss of consciousness.
Mephenesin group: Mephenesin, carisoprodol, chlor-
zoxazone, chlormezanone and methocarbamol
Benzodiazepines: Diazepam and others GABA derivatives: Baclofen Central a2 agonist: Tizanidine
D-tubocurarine
D-tubocurarine is a peripherally acting skeletal muscle relaxant. It is a long-acting, nondepolarizing, competitive
neuromuscular blocking agent.
It acts at the neuromuscular junction preventing the combination of acetylcholine released from the motor nerve endings
with its receptors to generate the end plate potential.
Therapeutic Uses
Once d-tubocurarine was used
as adjuvant to general anaesthetics.
to promote skeletal muscle relaxation during abdominal surgery and in dentistry for setting of mandibular fractures. in severe
cases of tetanus and status epilepticus.
Adverse Effects
Now d-tubocurarine (d-TC) is no longer used because of its prominent histamine releasing, ganglion blocking and
cardiovascular actions as well as long duration and need for pharmacological reversal.
Q. 2. List two classes of skeletal muscle relaxants acting at neuromuscular
junction.Mention two therapeutic uses of peripherally acting muscle relaxants.

Section | IV

Skeletal muscle relaxants are drugs that act peripherally at the neuromuscular junction or muscle fibre itself or centrally in
cerebrospinal axis to reduce muscle tone and/or cause paralysis.
The neuromuscular blocking agents are used in conjunction with the general anaesthetics to provide muscle relaxation for
surgery and centrally acting agents are used primarily for painful muscle spasm and spastic neurological disease. Skeletal
muscle relaxants acting at neuromuscular junction are called neuromuscular blocking agents.
The two classes of neuromuscular blocking agents are as follows:
Nondepolarizing (competitive) blockers: Agents which block acetylcholine at muscle end plate
Long-acting: D-tubocurarine, pancuronium, doxacurium, pipecuronium
Intermediate-acting: Atracurium, vecuronium, cisa-
tracurium, rocuronium, rapacuronium
Short-acting: Mivacurium
Depolarizing blockers: Agents which persistently depolarize motor end plate Succinylcholine (SCh) or suxamethonium
Decamethonium
Therapeutic uses of peripherally acting skeletal muscle relaxants are as follows:
As adjuvant to general anaesthetics They are used to promote skeletal muscle relaxation during abdominal surgery
and in dentistry for treating of mandibular fractures.
SHORT ESSAYS
 Compare d-tubocurarine and succinylcholine. TABLE 20.2 Comparison between Succinylcholine and
Pancuronium
Parameters to
Be Compared Succinylcholine Pancuronium
Type Depolarizing blocker Nondepolarizing blocker
Onset of action 1–1.5 min 4–6 min
Duration of action Short, 3–6 min Long, 60–120 min
Histamine release Present May or may not be present
Action on vagus Fasciculations— flaccid Spastic contractions
Order of paralysis Neck, limbs or face, jaw, eyes, pharynx, trunk and respiratory function Fingers, eyes, limbs, neck,
face, trunk and respiratory function
Therapeutic uses Manipulative procedures of short duration like endotracheal intubation Prolonged operations like
neurosurgery
The comparison between d-tubocurarine and succinylcholine is listed in Table 20.1.
TABLE 20.1 Comparison between d-tubocurarine and
Succinylcholine
They are used in severe cases of tetanus and status epilepticus.

Parameters
Compared D-tubocurarine Succinylcholine
Type of muscle relaxant Nondepolarizing blocker Depolarizing blocker
Onset of action 4–6 min 1–1.5 min
Duration of action Long, 30–60 min Short, 3–6 min
Histamine releasePresent Present
Action on ganglion Blockade Stimulation
Action on vagus Blockade Stimulation
Order of paralysis Fingers, eyes, limbs, neck, face, trunk Neck, limbs, face, jaw, eyes, pharynx , trunk,
respiratory
Neostigmine Antagonizes block No effect
Ether anaesthesia Synergistic No effect
Q. 2. Compare succinylcholine and pancuronium.

The comparison between succinylcholine and pancuronium is listed in Table 20.2.

Q. 3. Describethe uses of centrally and peripherally acting skeletal muscle relaxants.
Therapeutic uses of centrally acting skeletal muscle relaxants are as follows:
During acute muscle spasm diazepam or other muscle relaxants are combined with analgesic.
They are used to cure torticollis, backache and neuralgia.
These are used in spastic neurological disorders like hemiplegia and paraplegia.
During tetanus IV diazepam is given.
During electroconvulsive therapy diazepam may be void to suppress convulsions.
Orthopaedic manipulations may be performed under diazepam influence.
Therapeutic uses of peripherally acting skeletal muscle relaxants are as follows: 1. As adjuvant to general anaesthetics
They are used to promote skeletal muscle relaxation during abdominal surgery and in dentistry for treating of mandibular
fractures.
They are used in severe cases of tetanus and status epilepticus.
Q. 4. Classify skeletal muscle relaxants.
Skeletal muscle relaxants are drugs that act peripherally at the neuromuscular junction or muscle fibre itself or centrally in
cerebrospinal axis to reduce muscle tone and/or cause paralysis. They are classified as follows:
PERIPHERALLY ACTING SKELETAL MUSCLE RELAXANTS
Neuromuscular Blocking Agents
Nondepolarizing (competitive) blockers: Agent which block acetylcholine at muscle end plate
Long-acting: D-tubocurarine, pancuronium, doxacurium, pipecuronium
Intermediate-acting: Atracurium, vecuronium, cisatracurium, rocuronium, rapacuronium
Short-acting: Mivacurium
Depolarizing blockers: Agents which persistently depolarizes motor end plate
Succinylcholine (SCh) or suxamethonium
Decamethonium
Directly acting agents
Dantrolene sodium
Quinine
Centrally Acting Skeletal Muscle Relaxants
These drugs reduce skeletal muscle tone by acting on selective areas of CNS without loss of consciousness.
Mephenesin group: Mephenesin, carisoprodol, chlorzoxazone, chlormezanone and methocarbamol
Benzodiazepines: Diazepam and others
GABA derivatives: Baclofen
Central a 2 agonist: Tizanidine
Q. 5. Succinylcholine
Succinylcholine is peripherally acting skeletal muscle relaxant. It is a depolarizing neuromuscular blocking agent.
Mechanism of Action
 Succinylcholine has affinity for nicotinic cholinoceptors. It depolarizes muscle end plates by opening Na1 channels and
initially produces twitching and fasciculations. These drugs do not dissociate rapidly from the receptors n Induce prolonged
partial depolarization of the region around muscle end plate n Inactivation of Na1 channels nACh released from motor nerve
ending is unable to generate propagated MAP n Flaccid paralysis n In other words a zone of inexcitability is created round the
end plate preventing activation of muscle fibres.
Uses
It is used as adjuvant in general anaesthesia.
It is the commonly used skeletal muscle relaxant for passing endotracheal tube.
It is employed for brief procedures like laryngoscopy, bronchoscopy, oesophagoscopy, reduction of fracture and dislocation,
etc.
It can be used to avoid convulsions and trauma from electroconvulsive therapy without decreasing therapeutic benefit.
Adverse Effects
It causes increase in intraocular pressure.
It causes increase in postoperative muscle pain.
It may cause apnoea in patient with atypical plasma cholinesterase by prolonged neuromuscular block by succinylcholine.
Q. 6. Uses of diazepam
Diazepam is a benzodiazepine used for the following purposes:
As hypnotics—used to shorten sleep latency, reduce nocturnal awakening or to provide anxiolytic effect the day after
As anxiolytic and for daytime sedation
As anticonvulsants—benzodiazepines increase seizure threshold and can be used as an anticonvulsant.
Section | IV
As centrally acting muscle relaxant
As IV anaesthetic used for inducing, maintaining and supplementing anaesthesia
As preanaesthetic medication
Before electroconvulsive therapy, electrical cardioversion of arrhythmias, cardiac catheterization, endoscopies in obstetrics and
many minor procedures
Alcohol withdrawal
Q. 7. Rationale of using neostigmine in myasthenia gravis
Myasthenia gravis is a chronic autoimmune disease characterized by progressive weakness with rapid and easy fatigability
of skeletal muscles.
Antibodies to nicotinic receptors are found, resulting in the number of these receptors at NMJ.
Neostigmine (15 mg tab, 6 hourly) or pyridostigmine or a combination of both may be used.
They enhance the levels of acetylcholine (ACh) at the NMJ by preventing its destruction. Thus they increase the force of
contraction and improve muscle power.
Q. 8. Write rationale of using neostigmine in d-tubocurarine poisoning.
 D-tubocurarine acts at the neuromuscular junction preventing the combination of acetylcholine released from the motor
nerve endings with its receptors to generate the end plate potential.
SHORT NOTES
This antagonism can be overcome only by increasing the concentration of the acetylcholine at the neuromuscular junction by
anticholinesterase. Neostigmine (anticholinesterase) is lipid soluble and produces more marked effect on the skeletal
muscles, i.e. they have direct action on the muscle end plate cholinoceptors. Therefore neostigmine is used in treatment of
diaphragmatic paralysis caused by d-tubocurarine.

Skeletal muscle relaxants

Skeletal muscle relaxants are drugs that act peripherally at the neuromuscular junction or muscle fibre itself or centrally in
cerebrospinal axis to reduce muscle tone and/or cause paralysis. The peripherally acting agents (neuromuscular blocking
agents) are used in conjunction with the general anaesthetics to provide muscle relaxation for surgery, e.g. d-tubocurarine,
pancuronium, doxacurium, etc.
The centrally acting agents are used primarily for painful muscle spasm and spastic neurological diseases, e.g. diazepam,
mephenesin, baclofen, carisoprodol and chlorzoxazone.
Q. 2. Pancuronium
Pancuronium is a peripherally acting skeletal muscle relaxant. It is a long-acting, nondepolarizing, competitive neuro-
muscular blocking agent.
Uses
As adjuvant to general anaesthetics
They are used to promote skeletal muscle relaxation during abdominal surgery and treatment of mandibular fractures.
They are used in severe cases of tetanus and status epilepticus.
Q. 3. D-tubocurarine
 D-tubocurarine is a peripherally acting skeletal muscle relaxant. It is a long-acting, nondepolarizing, competitive
neuromuscular blocking agent.
It acts at the neuromuscular junction preventing the combination of acetylcholine released from the motor nerve endings
with its receptors to generate the end plate potential.
Used as an adjuvant to general anaesthetics, to promote skeletal muscle relaxation during abdominal surgery and in
treatment of mandibular fractures. They are also used in severe cases of tetanus and status epilepticus.
Q. 4. Lioresal
Lioresal is the trade name of baclofen, which is an analogue of inhibitory transmitter GABA. The primary site of action is
considered to be in spinal cord where it depresses both polysynaptic and monosynaptic reflexes, as such it produces muscle
weakness.
It reduces spasticity in many neurological disorders like multiple sclerosis, amyotrophic lateral sclerosis, spinal injuries and
flexor spasms. It has also been tried in trigeminal neuralgia and tardive dyskinesia. Intrathecal injection of baclofen is used
in severe spasticity of spinal cord origin. It is well-absorbed orally and excreted primarily through urine. Usual
recommended dosage is 10 mg BD to 25 mg TDS.
Side effects are drowsiness, mental confusion, weakness and ataxia. Sudden withdrawal after chronic use may cause
hallucinations, tachycardia and seizures.

Local Anaesthetics
LONG ESSAY
Classify local anaesthetics and write in detail about xylocaine.
Or,
Classify local anaesthetics. Describetheir mechanism of action. Mention the types of
local anaesthetics.
 Local anaesthetics are the agents which cause reversible loss of sensation caused by either depression in excitation of
conducting nerve or suppression of excitation of peripheral nerves.
CLASSIFICATION OF LOCAL ANAESTHETICS
I. Based on Chemical Structure
Amides: Lignocaine, mepivacaine, bupivacaine and
ropivacaine
Esters
Esters of benzoic acid: Butacaine, cocaine, tetracaine
Esters of para-aminobenzoic acid: Chloroprocaine,
procaine, propoxycaine
Quinolones: Centbucridine
II. Based on Duration of Action
A. Injectable anaesthetics
Low potency and short duration: Procaine, chloroprocaine
Intermediate potency and duration: Lignocaine and prilocaine
High potency and long duration: Tetracaine, bupiva-
caine, ropivacaine and dibucaine
B. Surface anaesthetic
Soluble: Cocaine, lignocaine, tetracaine, benoxinate
Insoluble: Benzocaine and butyl aminobenzoate, oxethazaine
III. Based on Biological Site and Mode of
Action
Class A Agents acting at receptor site on external surface of nerve membrane Biotoxins, e.g. tetrodotoxins, and saxitoxins
Class B Agents acting at receptor sites on internal surface of nerve membrane Quaternary ammonium analogues of
lidocaine, scorpion venom
Class C Agents acting by a receptor-independent
physical-chemical mechanism Benzocaine
Class D Agents acting by combination of receptor and
receptor-independent mechanisms Most clinically useful local anaesthetic agents, e.g. articaine, lidocaine, mepivacaine,
prilocaine
MECHANISM OF ACTION
The main site of action of local anaesthetics (LA) is the cell membrane. The LA in unionized form easily penetrates the nerve
sheath and axon membrane within the axoplasm. The molecules become ionized and block the voltage-gated Na1 channels as
shown in the flowchart below (Fig. 21.1):
Local anaesthetics
↓
Block the voltage-gated Na+ channels
↓
No entry of Na+ ions into the cell
↓
No depolarization
↓
No generation of action potential
↓
No generation and conduction of impulse to CNS
↓
Local anaesthesia
FIGURE 21.1 Mechanism of action of local anaesthetics.
The local anaesthetics block nerve conduction by decreasing the entry of Na1 ions during upstroke of action potential.
Conduction is slowed as the concentration of local anaesthetic rises and as the rate of rise of action potential and maximum
depolarization decreases. Finally local depolarization fails to reach the threshold potential and conduction block ensures. The
local anaesthetics interact with the local anaesthetic receptor located within the channel in its intracellular half of the voltage
sensitive Na1 channel.
Section | IV
The cationic form of local anaesthetic can approach the receptor only when the channel is open at the inner face and it binds
more avidly to the inactive state of the channel. On binding to the receptors, they raise the threshold of channel opening and
thus Na1 permeability fails to increase in response to an impulse or stimulus.
A resting nerve is rather resistant to blockade and blockade develops rapidly then the nerve is stimulated repeatedly.
Degree of blockade is frequency dependent, i.e. greater blockade at higher frequency of stimulation.
 Exposure to higher concentration of Ca21 reduces inactivation of Na1 channels and lessens the degree of block.
Local anaesthetics with lower pKa (76–78) are fast acting, e.g. lignocaine and those with higher pKa (81–89) are slow
acting. The time of onset of blockade varies with the pKa of the local anaesthetic.
Pharmacological Actions
A. Local Actions
It blocks the sensory nerve endings, nerve trunks, neuromuscular junction, ganglionic synapses and receptors. Reduces
release of acetylcholine from motor nerve endings and it can cause anaesthesia of skin and paralysis of voluntary muscles
supplied by mixed nerve if injected around it. The order of nerve fibres affected is autonomic fibres— pain-touch–
temperature deep pressure and motor fibres.
B. Systemic Actions
i. Nervous System (CNS)
 All local anaesthetics initially cause stimulation followed by depression. Most of the local anaesthetics cross the blood-
brain barrier (BBB) and they initially cause CNS stimulation and then depression in higher doses.
Sequence of events are euphorianexcitement—mental confusion—restlessness—tremors and twitching of muscles—
convulsions—unconsciousness—respiratory depression—coma and death.
ii. Cardiovascular System (CVS)
A. Heart
Local anaesthetics by blocking Na1 channels, decrease abnormal pacemaker activity, contractility, conductivity, excitability,
heart rate, cardiac output and increase effective refractory period.
At higher concentrations, the intravenous administration of LA may precipitate cardiac arrhythmias.
Bupivacaine is more cardiotoxic when compared to other local anaesthetics and may precipitate cardiovascular collapse and
death.
All local anaesthetics are cardiac depressants but not at conventional doses. Higher dose or on inadvertent IV injection
decreases automaticity and excitability, hence lignocaine is useful in ventricular arrhythmias.
B. Blood vessels Local anaesthetics produce hypotension due to vasodilatation and myocardial depression. The fall
in BP is due to sympathetic blockade or direct relaxation of arteriolar smooth muscles at higher doses.
Pharmacokinetics
Most of the ester-linked local anaesthetics are hydrolyzed by plasma cholinesterase and amide-linked local anaesthetics are
metabolized mainly in liver by microsomes. Soluble surface anaesthetics are rapidly absorbed from mucosa and abraded areas
but absorption is poor from intact skin.
Local anaesthetics like procaine, lignocaine, etc. are not effective orally because of high first-pass effect.
In liver diseases, the metabolism of lignocaine may be
impaired hence dose must be reduced accordingly.
Adverse Effects
CNS effects: Local anaesthetics initially stimulation followed by depression. The stimulatory symptoms are drowsiness, mental
clouding, altered taste and tinnitus. Overdoses produce muscle twitching, convulsions, cardiac arrhythmias, fall in BP, coma
and respiratory arrest.
CVS effects are bradycardia, hypotension, cardiac arrhythmias and vascular collapse. Bupivacaine is more cardiotoxic.
Injections are painful and may delay the wound healing.
Therapeutic Uses Anaesthesia
Local anaesthetics are used for surface application, infiltration, nerve blocks, epidural, spinal and intravenous regional block
anaesthesia.
Antiarrhythmic
Lignocaine is also a popular antiarrhythmic. It is a first choice drug for acute therapy for ventricular extrasystoles,
ventricular tachycardia.
It is an alternative for acute therapy for ventricular fibrillation.
 50–100 mg bolus IV followed by 20–40 mg every
10–20 min or 1–3 mg/min infusion
SHORT ESSAYS
Lignocaine
Lignocaine is most commonly used anaesthetic that can be used as an infiltration, surface anaesthetic, nerve block, spinal
anaesthetic and epidural anaesthetic.
Mechanism of Action
Advantages
Addition of vasoconstrictor or adrenaline to local anaesthetic, i.e. lignocaine has following advantages:
It prolongs duration of action of local anaesthetics by decreasing their rate of absorption from the site into systemic circulation.
It increases the intensity of nerve block.
Adrenaline provides bloodless field for surgery.
It reduces systemic toxicity of local anaesthetic by reducing rate of absorption of local anaesthetics.
Disadvantages
Disadvantages and contraindications of addition of vasoconstrictor or adrenaline to local anaesthetic, i.e. lignocaine

The main site of action of local anaesthetics is the cell membrane. It acts by blocking sodium channels due to which
there is no entry of sodium and generation of action potential.
This action affects process of depolarization, leading to failure of propagation of impulse without affective resting potential
also known as membrane stabilizing effect. Brief description of mechanism of action of local anaesthetics is shown in the
flowchart (Fig. 21.2):
Local anaesthetics
↓
Block the voltage-gated Na+ channels
↓
No entry of Na+ ions into the cell
↓
No depolarization
↓
No generation of action potential
↓
No generation and conduction of impulse to CNS
↓
Local anaesthesia are as follows:
Intense vasospasm and ischaemia in the tissues with end arteries may cause gangrene of the part either of fingers, toes, penis,
tip of the nose, etc.
Absorption of adrenaline may cause systemic toxicity. Hence combined preparation of LA with adrenaline is contraindicated in
patients with cardiovascular disorders like hypertension, congestive cardiac failure (CCF), arrhythmias and ischaemic heart
disease.
It may delay wound healing by reducing the blood flow to the affected area.
Q. 3. Compare lidocaine and mepivacaine.
Comparison between lidocaine and mepivacaine is listed in Table 21.1.
FIGURE 21.2 Mechanism of action of local anaesthetics.

Uses of Lignocaine
 It is used in nerve block, e.g. tooth extraction by giving a nerve block. It is given subcutaneously in field block and mainly
used in dental procedures.
It is used in surface anaesthesia, epidural anaesthesia and in spinal anaesthesia. It is used as antiarrhythmic agent.
Q. 2. Advantages and disadvantages of addition of adrenaline to local
anaesthesia Or,
Write the rationale of combining xylocaine with adrenaline for local
anaesthesia.
TABLE 21.1 Comparison between Lidocaine and Mepivacaine
Points to Compare Lidocaine Mepivacaine
Duration of action Intermediate-acting Long-acting
Onset of action Fast Faster than lignocaine
Uses Infiltration, surface anaesthetic, spinal and epidural anaesthetic Injectable anaesthetic
Q. 4. Differentiate general anaesthetics and local anaesthetics.
The differences between general anaesthetics and local anaesthetics are listed in Table 21.2.
Section | IV
TABLE 21.2 Differences between General Anaesthetics Q. 5. Compare ester and amide local
anaesthetics. and Local Anaesthetics
Parameters to Be
Compared General Anaesthetic Local Anaesthetic
Site of action CNS Peripheral nerves
Area of body involved Whole body Site of administration
Consciousness Lost Unaltered
Care of vital functions Essential Not needed usually
Physiological trespass High Low
In medically compromised and patient with poor health Risky to use Safe to use
Use in noncooperative patient Possible Not possible
Uses Major surgical procedures Minor surgical procedures
Ester Local Anaesthetics Amide Local Anaesthetics
They include cocaine, procaine, chloroprocaine, benzocaine and tetracaine They include lignocaine, mepivacaine,
bupivacaine and ropivacaine
Short acting and low potency Intermediate acting and potency
Slow onset of action Rapid onset of action
Metabolized by plasma cholinesterase Metabolized by liver microsomal enzymes
No surface anaesthetic effect due to poor tissue penetrability Has surface anaesthetic effect due to good tissue penetrability
Comparison between ester and amide local anaesthetics is listed in Table 21.3.
TABLE 21.3 Comparison between Ester and Amide Local Anaesthetics
SHORT NOTES
Mention some uses of lignocaine or xylocaine.
Lignocaine is most commonly used anaesthetic.
Uses of lignocaine are as follows:
It is used in nerve block, e.g. tooth extraction by giving a nerve block.
It is given subcutaneously in field block and mainly used in dental procedures.
It is used in surface anaesthesia, epidural anaesthesia and in spinal anaesthesia.
It is used as antiarrhythmic agent.
Q. 2. Toxicity of lignocaine
Toxic effects of lignocaine are manifested as follows:
CNS effects are drowsiness, mental clouding, altered taste and tinnitus.
CVS effects are bradycardia, hypotension, cardiac arrhythmias and vascular collapse.
Injections are painful and may delay the wound healing.
Overdoses produce muscle twitching, convulsions, cardiac arrhythmias, fall in BP, coma and respiratory arrest.
Q. 3. Procaine hydrochloride
It is a synthetic injectable ester type of local anaesthetic. It has low potency and short duration of action. It forms poorly
soluble salts with benzyl penicillin. It is rapidly absorbed following parenteral administration. It is ineffective when
applied topically thus not used as
surface anaesthetic.
Q. 4. Topical local anaesthetics
Topical anaesthetics are also known as surface anaesthetics and are available as solutions, ointment, gel, cream, spray
lozenges, etc. Commonly used drugs for topical application are: lignocaine 2–10%, tetracaine 2%, benzocaine 1–2%,
cocaine 1–4%, etc.
Therapeutic Uses
Topical anaesthetics are applied on the mucous membrane of the nose, mouth, eyes, throat, upper respiratory tract, oesophagus
and urethra.
It is also used in many diagnostic procedures like tonometry in eye and during endoscopes.
Q. 5. Adrenaline in local anaesthetics
Addition of vasoconstrictor or adrenaline to local anaesthetic, i.e. lignocaine has following advantages:
It prolongs duration of action of local anaesthetics.
It increases the intensity of nerve block.
Adrenaline provides bloodless field for surgery.
It reduces systemic toxicity of local anaesthetic by reducing rate of absorption of local anaesthetics.
Q. 6. Cocaine
It is a natural alkaloid derived from leaves of erythroxylon coca. It is a surface anaesthetic that is rapidly absorbed. It is
used in ocular anaesthesia. It is never injected as it is a protoplasmic poison and
causes tissue necrosis.
Adverse Effects
It stimulates
vagal centre—causes bradycardia.
vasomotor centre—causes rise in BP.
vomiting centre—causes nausea and vomiting.
temperature regulating centre—causes pyrexia.
Q. 7. Mention different types of techniques of local anaesthesia.

Various techniques of local anaesthetics (LA) are as follows:

Surface anaesthesia (topical anaesthesia): Here the LA is applied on mucous membranes, e.g. lignocaine 2–10%, cocaine 1–
4%.
Infiltration anaesthesia: LA is injected directly into tissues to be operated; it blocks sensory nerve endings, e.g. lignocaine 0.5–
1%.
Nerve block anaesthesia: LA is injected very close to or around the peripheral nerve or nerve plexuses. It produces larger areas
of anaesthesia, e.g. lignocaine 2%.
Spinal anaesthesia: Here the LA is injected into subarachnoid space to anaesthetize spinal roots usually at level of L2–3 or L3–
4 below the lower end of spinal cord.
5 Epidural anaesthesia: LA is injected into epidural space where it acts on spinal nerve roots. Commonly used drugs are
lignocaine and bupivacaine. It is mainly useful in obstetric analgesia.
6. Intravenous regional anaesthesia (Bier’s block): Here the LA is injected into the vein of upper limb whose blood flow is
occluded by tourniquet. Lignocaine and prilocaine are commonly used. It is mainly used in anaesthetizing the upper limb.
Q. 8. Intravenous anaesthetics
Intravenous regional anaesthesia is also known as Bier’s block.
 Here the local anaesthesia (LA) is injected into the vein of upper limb whose blood flow is occluded by tourniquet.
Lignocaine 0.5% and prilocaine 0.5% are commonly used drugs. It is mainly used in anaesthetizing the upper limb.
Q. 9. Lidocaine and mepivacaine
Comparison between lidocaine and mepivacaine is listed in Table 21.4.
TABLE 21.4 Comparison between Lidocaine and Mepivacaine
Parameters Lidocaine Mepivacaine
Duration of action Intermediate acting Long acting
Onset Fast Faster than lignocaine
Uses Infiltration, surface anaesthetic, spinal and epidural anaesthetic Injectable anaesthetic
Q. 10. Classification of local anaesthetic agents
Local anaesthetics are the agents which cause reversible loss of sensation caused by either depression in excitation of
conducting nerve or suppression of excitation of peripheral nerves.
Classification of Local Anaesthetics
Based on Chemical Structures
Amides, e.g. lidocaine
Esters
Esters of benzoic acid, e.g. butacaine, cocaine, tetracaine
Esters of para-aminobenzoic acid, e.g. chloropro-
caine, procaine, propoxycaine 3. Quinolones: Centbucridine
Based on Duration of Action
1. Injectable anaesthetics Low potency and duration: Procaine Intermediate potency and duration: Lignocaine and
prilocaine
High potency and long duration: Tetracaine, bupiva-
caine, ropivacaine and dibucaine 2. Surface anaesthetics
 Soluble: Cocaine, lignocaine, tetracaine, benoxinate Insoluble: Benzocaine and butyl aminobenzoate
Section | IV
Part VII
Drugs Acting on Central Nervous System

General Anaesthetics
LONG ESSAYS
Enumerate stages of general anaesthesia. Describethe pharmacological actions, merits and
demerits of nitrous oxide as a sole general anaesthetic agent. Or,
Classify general anaesthetics. Write pharmacology of nitrous oxide.
General anaesthetics are agents that bring about reversible loss of sensation and consciousness. There are different stages of
general anaesthesia.
STAGES OF GENERAL ANAESTHESIA
i. Stage of analgesia: This stage is the beginning of inhalation to loss of consciousness. Stage of delirium: This stage is
from loss of consciousness to beginning of surgical anaesthesia. It may be with excitement, shouting, crying and violent
behaviour.
Stage of surgical anaesthesia
Passes to deeper planes
Respiratory depression
Gradual loss of reflexes
Relaxation of skeletal muscles
Stage of medullary paralysis: This is due to the overdose. It is the stage of medullary depression, followed by cessation of
breathing, circulatory failure and death.
IDEAL ANAESTHESIA
It should be pleasant and nonirritating.
It should provide adequate analgesia, immobility and muscle relaxation. It should be noninflammable.
Administration should be easy, controllable and wide margin of safety.
Induction and recovery should be smooth.
It should not affect cardiovascular function and should be inexpensive.
CLASSIFICATION
Inhalational
Gases: Nitrous oxide, cyclopropane
Liquids: Ether, halothane, enflurane, isoflurane,
methoxyflurane
Intravenous
Inducing agents: Thiopentone sodium, methohexi-
tone, propofol, etomidate
Dissociative anaesthesia: Ketamine
Neuroleptanalgesia: Fentanyl-droperidol
Benzodiazepines: Diazepam, lorazepam, midazolam
General anaesthetics are also classified as follows:

General anaesthetics
i. Ether i. Nitrous oxide Inducing drugs Slow-acting drugs
Halothane

Enflurane

Isoflurane i. Thiopentone ii. Propofol iii. Etomidate i. Benzodiazepines,

e.g. diazepam ii. Ketamine, e.g. dissociative anaesthesia iii. Opioids, e.g.
fentanyl
v. Desflurane vi. Sevoflurane
Nitrous Oxide
It is a slightly sweetish odour gas and produces light anaesthesia without significant depression of respiration or vasomotor
centre.
Actions
 Moderate increase in pain threshold Slight amnesia effect Euphoria is frequent. Decreased sense of smell
Improved hearing Slight myocardial depression Minimal effect on respiration Reduces MAC of other gaseous agents by
50%
Metabolism
Exhaled primarily unchanged via lungs.
Small amounts are excreted through skin, sweat glands, urine, etc.
Side Effects of N2O
Postoperative nausea and vomiting Chronic use causes bone marrow depression, vitamin B12 and folate metabolic
disturbances. Teratogenic effects in the first trimester of pregnancy It augments the respiratory depressant effect of
thiopen-
tone and opiates.
Four Zones of N2O Anaesthesia
Moderate analgesia (6–25%): 25% N2O is more potent than 10 mg morphine.
Dissociative analgesia (26–45%): Psychological symptoms and lack of ability to concentrate.
Analgesic anaesthesia (46–65%): Near complete analgesia. Patient may respond to commands.
Light anaesthesia (66–80%): Complete analgesia and amnesia.
Advantages of N2O
Strong analgesic Induction is rapid and smooth. It is nonirritating and noninflammable. Recovery is rapid.
No postoperative nausea.
It has little effect on respiration and cardiovascular function.
It is nontoxic to liver, kidney, brain and quickly
removed from lungs.
Disadvantages
It is less potent and should be used with other agents. Poor muscle relaxant
Q. 2. Preanaesthetic medication

Preanaesthetic medication is used before administration

of an anaesthetic agent.
It helps to
reduce anxiety and fear.
reduce secretions.
enhance the hypnotic effect of GA agents.
reduce postoperative nausea and vomiting.
produce amnesia.
reduce the volume and pH of gastric contents.
attenuate vagal reflexes.
attenuate sympathoadrenal responses.
Drugs used for premedication are as follows:
Benzodiazepines: Diazepam, midazolam, oxazepam, lorazepam
Opioid analgesics: Morphine, fentanyl, pethidine, pentazocine
Anticholinergic agents: Atropine, glycopyrrolate, sco-
polamine
Benzodiazepines
They produce anxiolysis, sedation and amnesia. Reversal agent is flumazenil.
Opioid Analgesics
They produce sedation and analgesia.
Anticholinergic Agents
Vagolytic effect: It increases the heart rate by blocking the action of acetylcholine on muscarinic receptors in SA node.
Atropine is very useful in preventing intraoperative bradycardia resulting from stimulation of carotid sinus or vagal
stimulation.
Antisialagogue action: It includes drying of secretions of salivary, gastric, tracheobronchial and sweat glands.
Glycopyrrolate is more potent and long-acting drying agent and is likely to increase the heart rate.
Scopolamine is more effective antisialagogue than atropine.
Sedation and amnesia: Glycopyrrolate does not cross blood-brain barrier and hence does not cause sedation or amnesia.
Scopolamine has good sedative and amnesic effect. Atropine causes delirium in elderly individuals, so glycopyrrolate is better
than atropine for elderly individuals.
Side Effects
Papillary dilatation Tachycardia
Section | IV
 Delirium, confusion and restlessness Increase in body temperature
Dosage
Atropine: 0.12 mg/kg Glycopyrrolate: 0.44 mg/kg
Aspiration Prophylaxis
Several pharmaceutical agents have been used to alter gastric pH and fluid volume. It includes the following:
Histamine receptor (H2 receptor) blocking agents
Gastrokinetic drugs
Antacids
Anticholinergic agents
A. Histamine Receptor (H2 Receptor)
Blocking Agents (Cimetidine, Ranitidine and
Famotidine)
 The drugs raise the gastric pH by blocking histaminemediated secretions of gastric hydrogen ion.
They reduce the acidity, but have no effect on volume of
gastric secretions or stomach emptying time.
Dosage
Cimetidine: 150–300 mg orally or parenteral, 60–90 min prior to surgery and should be repeated 8 hourly.
Ranitidine: 50–100 mg orally or parenterally. It can be given 1 night before surgery and 1 hour prior to surgery. Duration of
action: 9–10 h. Ranitidine will prolong the sedative effect of midazolam.
Famotidine: 40 mg one night before surgery and 40 mg on the morning of surgery, orally. Onset of action: 1 h and duration of
action: 10–12 h.
B. Gastrokinetic Drugs (Metoclopramide)
It is a dopamine antagonist that stimulates the upper GI motility, increases gastroesophageal sphincter tone and relaxes
pylorus and duodenum. It reduces the volume of gastric fluids and thus reduces the risk of aspiration. Its rapid injection
can cause abdominal cramping. Dosage: 10 mg orally, 30–60 min prior to surgery or 5–20 mg parenterally, 15–30 min prior to
surgery.
C. Antacid
It is used to neutralize the pH of gastric fluid.
A single dose of clear antacid given 15–30 min prior to anaesthesia is effective in raising gastric pH above 2.5, e.g. 30 mL of
0.3 mg sodium citrate solution can be used. Aspiration prophylaxis is indicated in
obesity, pregnancy, diabetic patients, alcoholics, patients on long-term steroid therapy, ascites, hiatus hernia
and patients with gastroesophageal reflex.
D. Antiemetics
Example: Droperidol, metoclopramide, phenothiazines
(like ondansetron, prochlorperazine) It can be given as a premedication or just prior to the emergence from GA or during
recovery period.
SHORT ESSAYS
Some amount of blood enters the stomach during surgery and can cause irritation to the stomach mucosa to induce vomiting
postoperatively. To prevent this antiemetic can be used.

Ether Or,
Mention advantages and disadvantages of ether as general anaesthetic.

Ether is a highly volatile and colourless liquid. As it is inflammable in air and explosive with oxygen, it should not be used
when cautery is being used for surgery. About 85–90% of the drug will get excreted through the lungs.
It stimulates the sympathetic system yielding to increase in heart rate and to depress the vagus nerve. BP falls in the deeper
planes of anaesthesia. The respiratory movement’s first increase due to stimulation of respiratory centre and later on they
decrease as the anaesthesia deepens.
 It stimulates salivation, so atropine premedication is advised. It is irritating to the respiratory tract and produces cough and
laryngeal spasm.
On induction it induces analgesia followed by excitement and then anaesthesia.
It increases CSF pressure and blood glucose levels. It produces postoperative nausea and vomiting in 50% of patients.
Advantages of Ether
Potent and reliable good anaesthetic. Effect on cardiovascular, respiratory functions are not significant. Reflexes are well
maintained.
It is a bronchodilator. Provides full muscle relaxation.
Does not sensitize the heart to adrenaline. Easy to administer and inexpensive.
Disadvantages of Ether
It is inflammable. Highly soluble in body. Induction is slow and unpleasant.
 It is irritating, so enhances respiratory secretions. Premedication with atropine is essential. Laryngeal spasm may occur
during induction. Postoperative nausea and vomiting are frequent. Recovery is slow.
Status in Anaesthesia
Ether is not preferred because of flammability and irritant property. But is used in developing countries like India because it is
cheap, easy to administer and relatively safe.
Q. 2. Compare nitrous oxide and diethyl ether.
Comparison between nitrous oxide and diethyl ether is given in Table 22.1.
Q. 3. Compare nitrous oxide and halothane.
Comparison between nitrous oxide and halothane is given in Table 22.2.
TABLE 22.2 Comparison between Nitrous Oxide and
Halothane
Nitrous oxide Halothane
It is an inhalational gas It is an inhalational liquid
It is colourless, odourless, noninflammable It is volatile, noninflammable, with sweet odours
It produces good analgesia but poor muscle relaxation It is neither a good analgesic nor a muscle relaxant, but it
potentiates competitive neuromuscular blocking
Onset is rapid, it is short acting, and recovery is fast and smooth Induction is intermediate and pleasant, recovery is
smooth
No marked postanaesthetic nausea Postanaesthetic effects include shivering, malignant hyperthermia, but nausea and
vomiting rarely occur
Used in obstetrics, dental practice, to produce conscious sedation, and along with another general anaesthetic in major surgeries
Mostly used anaesthetic in dental and surgical procedures
Economical Expensive
TABLE 22.1 Comparison between Nitrous Oxide and Diethyl Ether
Nitrous oxide Diethyl ether
It is an inhalational gas It is an inhalational liquid
It is colourless, odourless, noninflammable It is highly volatile, inflammable and produces irritating vapours
It produces good analgesia but poor muscle relaxation It is a good analgesic and a muscle relaxant
Onset is rapid, it is short acting and recovery is fast Highly soluble in blood hence induction is prolonged, recovery is slow
Recovery is smooth. No marked postanaesthetic nausea Postanaesthetic nausea,
vomiting and retching are
marked
Used in obstetrics, dental practice, to produce conscious sedation and along with another general anaesthetic in major surgeries
Rarely used in developed countries. It is used in developing countries because it is cheap. Used to produce general
anaesthesia for dental and surgical procedures
Q. 4. Benzodiazepine
Benzodiazepines are one of the drugs used for premedication, e.g. diazepam, midazolam, oxazepam, lorazepam. They
produce anxiolysis, sedation and amnesia.
Site of action: Thalamus, hypothalamus, gamma-ami-
nobutyric acid (GABA) receptors
Action
Mild decrease in BP by decreasing anxiety and causing muscle relaxation
Minimal changes in respiration when given slowly in small doses
Antiemetic property is present.
It produces amnesia which increases as the dose increases.
It produces emotional responses in adolescent females.
Metabolizes in the liver as desmethyldiazepam.

Section | IV
Uses
Benzodiazepines are used as slow-acting general anaesthetics.
They are used to induce conscious sedation in small repeated doses or by slow infusion. This state lasts for about 1 h and
psychomotor impairment persists for 6–24 h.
They are used as sedative hypnotics, antianxiety drugs.
They are used as centrally acting skeletal muscle relaxants.
Combined with analgesics they can be used for the treatment of rheumatic disorders associated with muscle spasms.
They are used as antiepileptic drugs.
Q. 5. Two advantages and two disadvantages of halothane
Halothane is a colourless, volatile liquid with sweet odour, which is nonirritating and noninflammable.
Advantages
It is potent, noninflammable.
Induction is smooth and rapid.
Nonirritant
Recovery is rapid and postoperative nausea and vomiting is low.
Disadvantages
It is neither a good analgesic nor muscle relaxant.
It is a direct myocardial depressant. As cardiac output and BP start falling, heart rate may decrease. It sensitizes the heart to the
arrhythmogenic action of adrenaline.
It causes some respiratory depression.
Malignant hyperthermia: Intracellular release of calcium from the sarcoplasmic reticulum causes muscle contraction and
increased heat production. It is treated with dantrolene.
It is expensive.
Status of Anaesthesia
Halothane is most popular anaesthetics. Analgesics and muscle relaxants are used as adjuvants.
Q. 6. Diazepam and its uses
Diazepam belongs to the benzodiazepine group.
Dosage
0.2–0.5 mg/kg
Site of Action
Thalamus, hypothalamus, gamma-aminobutyric acid (GABA) receptors
Actions
Mild decrease in BP by decreasing anxiety and causing muscle relaxation
Minimal changes in respiration when given slowly in small doses
Antiemetic property is present.
It produces amnesia which increases as the dose increases.
It produces emotional responses in adolescent females.
Metabolizes in the liver as desmethyldiazepam.
Uses
Diazepam is used as a slow-acting general anaesthetic.
It is used to induce conscious sedation in small repeated doses or by slow infusion. This state lasts for about 1 h and
psychomotor impairment persists for 6–24 h.
It is used as a sedative hypnotic, antianxiety drug.
It is used as a centrally acting skeletal muscle relaxant.
Combined with analgesics it can be used for the treatment of rheumatic disorders associated with muscle spasms.
It is used as an antiepileptic drug.
Q. 7. Compare ether and halothane.
Comparison between ether and halothane is given in Table 22.3.
TABLE 22.3 Comparison between Ether and Halothane
Diethyl ether Halothane
It is an inhalational liquid It is an inhalational liquid
It is highly volatile, inflammable and produces irritating vapours It is volatile, noninflammable with sweet odours
It is a good analgesic and a muscle relaxant It is neither a good analgesic nor a muscle relaxant, but it potentiates competitive
neuromuscular blocking
Highly soluble in blood, hence induction is prolonged, recovery is slow Induction is intermediate and pleasant, recovery is
smooth
Postanaesthetic nausea,
vomiting and retching are
marked Postanaesthetic effects include shivering, malignant hyperthermia, but nausea and vomiting rarely occur
Economical Expensive
SHORT NOTES
Classify general anaesthetics.

General anaesthetics are agents that bring about reversible loss of sensation and consciousness. They are classified as follows:
Inhalational
Gases: Nitrous oxide, cyclopropane
Liquids: Ether, halothane, enflurane, isoflurane,
methoxyflurane
Intravenous
Inducing agents: Thiopentone sodium, methohexi-
tone, propofol, etomidate
Dissociative anaesthesia: Ketamine
Neuroleptanalgesia: Fentanyl 1 droperidol
Benzodiazepines: Diazepam, lorazepam, midazolam
Q. 2. Ether Or,
Diethyl ether
This is a highly volatile and colourless liquid. About 85–90% of the drug will get excreted through the lungs.
Advantages
Potent and reliable anaesthetic
Effect on cardiovascular, respiratory functions are not significant.
Provides full muscle relaxation.
Does not sensitize the heart to adrenaline.
Easy to administer and economical.
Disadvantages
As it is inflammable in air and explosive with oxygen, it should not be used when cautery is being used for surgery.
Highly soluble in body. Induction is slow and unpleasant and recovery is also slow.
Postoperative nausea and vomiting are frequent.
Q. 3. Actions of nitrous oxide
Nitrous oxide is a slightly sweetish odour gas and produces light anaesthesia without significant depression of respiration or
vasomotor centre.
Actions
Actions of nitrous oxide are as follows: Moderate increase in pain threshold Slight amnesia effect Euphoria is frequent.
Decreased sense of smell Improved hearing Slight myocardial depression and minimal effect on
respiration
Metabolism
Exhaled primarily unchanged via lungs. Small amounts are excreted through skin, sweat glands, urine, etc.
Q. 4. Uses of diazepam
Diazepam belongs to the benzodiazepine group.
Uses of diazepam are as follows:
It is used to induce conscious sedation in small repeated doses or by slow infusion.
It is used as a sedative hypnotic, antianxiety drug.
It is used as a centrally acting skeletal muscle relaxant.
Combined with analgesics it can be used for the treatment of rheumatic disorders associated with muscle spasms.
It is used as an antiepileptic drug.
Q. 5. Ketamine
It produces dissociative anaesthesia characterized by profound analgesia, immobility, amnesia with light sleep and feeling
dissociation from one’s own body and surroundings.
Primary site of action: Cortex and subcortical area Respiration is not depressed, reflexes are not abolished and muscle tone
increases.
Heart rate, cardiac output and BP are elevated due to sympathetic stimulation.
Ketamine is available as 100 mg and 500 mg/10 mL injection and is used in dosage of 1–4 mg/kg IV or 6.5–15 mg/kg IM.
Children tolerate the drug well. Onset of action: Within 1–3 min and recovery starts after 10–15 min
It is indicated in surgeries on the head and neck.
It is contraindicated in hypertensive and ischaemic heart disease patients.
Q. 6. Halothane
It is colourless, volatile liquid with sweet odour which is nonirritating and noninflammable.
Advantages
Induction is smooth and rapid.
Recovery is rapid.
Postoperative nausea and vomiting is low.
Disadvantages
It is neither a good analgesic nor a muscle relaxant. It is a direct myocardiac depressant.
It causes some respiratory depressions, severe hepatitis and malignant hyperthermia. It is expensive.
Q. 7. Methohexitone
Methohexitone is three times more potent than thiopentone. Quicker and brief actions. Unconsciousness is usually induced
in 15–30 s. Consciousness will regain within 2–3 min.
Actions
1. Less hypotensive compared to thiopentone 2. Slight increase in heart rate and moderate hypoventilation
Short period of apnoea may be seen after IV injection.
This drug is contraindicated in epileptic patients.
Q. 8. Thiopentone sodium
Thiopentone sodium is an ultra short-acting thiobarbiturate.
If given intravenously it produces unconsciousness in 15–20 s and consciousness will be regained in 10–20 min.
It produces CNS depression which persists for more than 12 h.
This is a poor analgesic and weak muscle relaxant. Respiratory depression with inducing doses of thiopentone is generally
transient, but with large dose it will be severe.
Adverse Effects
Laryngospasm occurs generally when respiratory secretions or other irritants are present, or when intubation is attempted while
anaesthesia is light.
Shivering and delirium during recovery
Pain in the postoperative period
Q. 9. Preanaesthetic medication
Preanaesthetic medication is used before administration
of an anaesthetic agent.
It helps to 1. reduce anxiety and fear.
reduce secretions.
enhance the hypnotic effect of GA agents.
reduce postoperative nausea and vomiting.
produce amnesia.
reduce the volume and pH of gastric contents.
attenuate vagal reflexes.
attenuate sympathoadrenal responses.
Drugs used for premedication are
Benzodiazepines: Diazepam, midazolam, oxazepam, lorazepam
Opioid analgesics: Morphine, fentanyl, pethidine, pentazocine
Anticholinergic agents: Atropine, glycopyrrolate, scopolamine
Q. 10. Benzodiazepine
Benzodiazepines are now frequently used for inducing, maintaining and supplementing anaesthesia, e.g. diazepam, lorazepam,
midazolam.
Actions
Mild decrease in BP by decreasing anxiety and causing muscle relaxation
 Antiemetic property is present.
It produces amnesia which increases as the dose increases. It produces emotional responses in adolescent fe-
males.
Uses
Benzodiazepines are used as slow-acting general anaesthetics.
They are also used to induce conscious sedation and also as sedative hypnotics, antianxiety drugs.
They are used as centrally acting skeletal muscle relaxants. They are used as antiepileptic drugs.

Ethyl and Methyl Alcohols

SHORT ESSAY
Ethyl alcohol is used in methyl alcohol poisoning. Write the rationale.
 Methanol is a mild CNS depressant. It is metabolized to formaldehyde and formic acid which in turn causes metabolic
acidosis, retinal damage and blindness.
The signs and symptoms of methanol poisoning are nausea, vomiting, abdominal pain, headache, vertigo, confusion,
hypotension, convulsions and coma.
Since ethyl alcohol is an antidote for methyl alcohol which counteracts the effect of methanol poisoning it is used in
treating methyl alcohol poisoning.
Ethanol 10% is given intravenously. It competes with methanol for metabolic enzymes and saturates them, thus preventing the
formation of toxic metabolites like formaldehyde and formic acid. Methanol gets excreted unchanged in urine and breath.
SHORT NOTES
Clinical uses of ethyl alcohol Methanol is a CNS depressant, but it is less
potent than ethanol.
The steps in treating methyl alcohol poisoning are as follows:
Patient should be kept in dark room to protect the eyes from light.
Maintain air way, breathing and circulation.
Gastric lavage is done after endotracheal intubation.
Sodium bicarbonate is given intravenously to correct acidosis.
Ethanol 10% is given intravenously.
Haemodialysis is done to promote excretion of methanol and its toxic metabolites.
Fomepizole is a specific inhibitor of alcohol dehydrogenase and retards methanol metabolism.
Folate therapy: Calcium leucovorin injected repeatedly to reduce blood formate levels by enhancing its metabolism. This is a
promising adjuvant approach.
Ethyl alcohol is a hydroxy derivative of aliphatic hydrocarbons.
Medicinal uses of ethanol are as follows:
As antiseptic
Rubefacient and counterirritant for sprains, joint pains, etc.
Alcoholic sponges may be used to reduce body temperature during fever.
As appetite stimulant and carminative
In treating intractable neuralgias like trigeminal neuralgia and also in severe cancer pain, etc.
In treating methanol poisoning
Q. 2. Treatment of methyl alcohol poisoning

Sedatives/Hypnotics
LONG ESSAYS
 Classify hypnotics. Mention the pharmacological Classify hypnotics. Describethe uses,
adverse effects actions, management of poisoning of barbiturates. and treatment
of barbiturate poisoning.
Or,

Sedative is a drug that produces a calming effect and reduces excitability. It may induce drowsiness.
Hypnotic is a drug that induces sleep resembling natural sleep.
Classification of hypnotics is as follows:
Benzodiazepines
Hypnotic Antianxiety Anticonvulsant
Diazepam Diazepam Diazepam
Flurazepam Chlordiazepoxide Clonazepam
Nitrazepam Oxazepam Clobazam
Triazolam Alprazolam
Midazolam Lorazepam
Temazepam
Barbiturates
Long-acting Short-acting Ultra short-acting
Phenobarbitone Pentobarbitone Thiopentone
Mephobarbitone Secobarbitone Methohexitone
Newer nonbenzodiazepine drugs
Zopiclone
Zolpidem
Zaleplon
BARBITURATES
All barbiturates are the drugs derived from barbituric acid. They are nonselective CNS depressants.
They were the longest group of drugs in use till newer drugs like benzodiazepines were discovered in about 1960.
Classification
Long-acting: Phenobarbitone, mephobarbitone Short-acting: Pentobarbitone, secobarbitone, butobarbitone Ultra short-
acting: Thiopentone sodium, methohexitone
Mechanism of Action
Barbiturates bind to specific site on the GABA receptor Cl2 channel complex. They facilitate inhibitory neurotransmission
by opening chloride ion channels and hyperpolarize the neural membrane.
Mechanism of action of barbiturates can be summa-
rized as follows:
Barbiturates
Bind to GABAA receptor Cl− channel complex
Potentiate GABAergic inhibition
The duration of Cl− channel kept open is increased

Increased chloride conductance

Membrane hyperpolarization
CNS depression
Pharmacological Actions
Barbiturates depress all excitable tissues. The CNS is most sensitive and effect is dose dependent; with increase in dose there is
sedation n sleep n anaesthesia n coma.
Barbiturates have an anticonvulsant action in a subhypnotic dose and are used in the treatment of status epilepticus and
generalized tonic-clonic seizures.
Respiration: Increase in dose causes depression of respiratory centre.
CVS: At hypnotic doses there is slight fall in BP and decrease in heart rate.
Kidney: Barbiturate anaesthesia results in decrease in urinary output.
Barbiturates induce microsomal enzyme and increase the
rate of their own metabolism as well as for other drugs.
Uses
Phenobarbitone is used in epilepsy.
As preanaesthetic and anaesthetic medication Now they are seldom used as sedatives and hypnotics. They are
used in treating congenital nonhaemolytic jaundice due to enzyme-inducing property of phenobarbitone, which is utilized to
hasten clearance of congenital nonhaemolytic jaundice and kernicterus.
They are occasionally employed as adjuvants in psy-
chosomatic disorders.
Adverse Effects
The common side effects are drowsiness, hangover,
mental confusion, impaired performance and judgement.
Nausea, vomiting, diarrhoea Idiosyncrasy—excitement Hypersensitivity reactions like skin rashes, itching
and swelling of face, especially eyelids may occur.
Tolerance and dependence develop due to their sedative and hypnotic actions on repeated use.
Physical and psychological dependence develop on repeated use. vii. Prolonged use of phenobarbitone may cause
megaloblastic anaemia by interfering with absorption of folic acid from gut.
Barbiturate Poisoning
Dosage of barbiturates above 6–10 g causes acute barbiturate poisoning.
Manifestations
Respiratory depression with slow shallow breathing
Hypotension Skin eruptions Swelling of eyelids Cardiovascular collapse Renal failure
Management of Acute Barbiturate Poisoning
Maintain airway, breathing and circulation Gastric lavage using activated charcoal to prevent further absorption of the drugs
Vasopressors, i.e. noradrenaline, dopamine, ephedrine. Haemodialysis should be done especially in severe cases of
renal failure and is highly effective in removing long-acting barbiturates.
 Forced alkaline diuresis with mannitol, frusimide or sodium bicarbonate and administration of IV fluids will help in faster
excretion of the drug, since they are acidic drugs.
Q. 2. Classify hypnosedatives. Discuss the pharmacological actions, uses and adverse effects
of benzodiazepines. What are the advantages of benzodiazepines over
barbiturates as sedative hypnotics?
Or,
Classify benzodiazepines. Explain their mechanism of action and therapeutic uses. Mention
their advantages over barbiturates as sedative hypnotics.

Sedative is a drug that produces a calming effect and reduces excitability. It may induce drowsiness.
Hypnotic is a drug that induces sleep resembling natural sleep.
Classification of hypnotics is as follows:
Benzodiazepines
Hypnotic Antianxiety Anticonvulsant
Diazepam Diazepam Diazepam
Flurazepam Chlordiazepoxide Clonazepam
Nitrazepam Oxazepam Clobazam
Triazolam Alprazolam
Midazolam Lorazepam
Temazepam
Barbiturates
Long-acting Short-acting Ultra short-acting
Phenobarbitone Pentobarbitone Thiopentone
Mephobarbitone Secobarbitone Methohexitone
Newer nonbenzodiazepine drugs
Zopiclone
Zolpidem
Zaleplon
BENZODIAZEPINES
All benzodiazepines have a benzene ring fused to a seven-membered diazepine ring.
Their sites of action are midbrain, limbic system, ascend-
ing reticular activating system (ARAS).
Mechanism of Action
The benzodiazepines have no GABA-mimetic action.
Mechanism of action of benzodiazepines can be summa-
rized as follows:
Benzodiazepines

Bind to specific site on GABA A–BZD receptor

Cl− channel complex

Potentiate the inhibitory effect of GABA

Increase in frequency of opening Cl − channels

Increased chloride conductance

Membrane hyperpolarization
t

CNS depression
Pharmacological Actions and Therapeutic Uses
The most important actions of benzodiazepines are on CNS and include the following:
Sedation and hypnotic action: At larger doses diazepam produces sleep, decreases awakening during sleep, increases total sleep
time, shorter REM (rapid eye movement) sleep.
Benzodiazepines are one of the most prescribed drugs.
a. As hypnotics At present benzodiazepines are the hypnotics of choice. They are used to shorten sleep latency,
reduce nocturnal awakening or to provide anxiolytic effect the day after.
The benzodiazepines are chosen depending on their
onset and duration of action.
Chronic insomnia (. 3 weeks) Intermittent use of hypnotics is tried like once every 3 days. A slowly eliminated drug is
preferable because rebound insomnia and withdrawal symptoms are least marked.
There is increased risk of tolerance and abuse. Short-term insomnia (3–21 days) Generally a benzodiazepine free of
residual effects is selected.
When anxiety is the dominant feature, benzodiazepines with longer duration of action are better. In elderly, short-acting
benzodiazepines are preferred.
The use of benzodiazepines should be limited to 2–3 weeks.
Transient insomnia (1–3 days)
 Rapidly eliminating or widely distributing benzodiazepines are preferred to avoid residual effect next morning.
As anxiolytic and for daytime sedation Benzodiazepines reduce anxiety and aggression and
thus produce a calming effect.
As anticonvulsants Benzodiazepines increase seizure threshold and can be used as anticonvulsants. Diazepam is used in
situations like status epilepticus, febrile convulsions.
Clonazepam is used in absence seizures and myo-
clonic seizures in children.
As centrally acting muscle relaxants
Benzodiazepines reduce muscle tone by central action.
Increased muscle tone and aches associated with anxiety can be reduced using benzodiazepines.
As IV anaesthetic: Benzodiazepines can be used for inducing, maintaining and supplementing anaesthesia, e.g. diazepam,
lorazepam, midazolam.
As preanaesthetic medication: These drugs are used as preanaesthetic medication because of their sedative-amnesic and
anxiolytic effects, e.g. diazepam, lorazepam.
Diagnostic (endoscopies) and minor operative procedures: Benzodiazepines are used before electroconvulsive therapy,
electrical cardioversion of arrhythmias, cardiac catheterization, endoscopies in obstetrics and many minor surgical procedures.
To treat alcohol withdrawal symptoms in dependent
subjects to reduce intensity of withdrawal symptoms.
Adverse Effects
Benzodiazepines (BDZ) have a wide margin of safety. They are generally well tolerated.
The common side effects are as follows:
Drowsiness, dizziness, vertigo, ataxia, amnesia and
prolongation of reaction time
 Blurring of vision Dry mouth and sweating Tolerance, cross-tolerance and drug dependence Drug abuse:
Flunitrazepam Newborn infants show withdrawal if mother used BDZs during pregnancy.
vii. BDZs during labour can have effects on newborn like
depressed respiration and feeding and
floppy baby syndrome.
Benzodiazepines are preferred to barbiturates as hypnosedatives because of following reasons:
Benzodiazepines have high therapeutic index.
Even at the hypnotic doses, there is no loss of consciousness and respiration is not depressed. Hypnotic doses do not affect
respiration or cardiovascular functions. They have practically no action on other body systems.
They cause less distortion of sleep architecture.
They do not alter disposition of other drugs by microsomal enzyme induction. They have lower abuse liability.
vii. They have a specific antagonist (flumazenil) which can be used in case of poisoning whereas in phenobarbitone
poisoning there is no specific antagonist. viii. Rebound phenomenon on discontinuation of drug is less marked.
ix. Tolerance is mild and psychological and physical dependence and withdrawal syndrome is less marked.
SHORT ESSAYS
Classify barbiturates and write their uses.

Barbiturates
Barbiturates are drugs derived from barbituric acid.
They were the longest group of drugs in use till newer
drugs like benzodiazepines were discovered in about 1960.
Classification
Long-acting: Phenobarbitone, mephobarbitone
Short-acting: Butobarbitone, secobarbitone, pentobarbitone
Ultra short-acting: Thiopentone, methohexitone, hexobarbitone
Uses
Phenobarbitone is used in epilepsy.
As preanaesthetic anaesthetic medication
Now they are seldom used as sedatives and hypnotics.
They are used in treating congenital nonhaemolytic jaundice due to enzyme-inducing property of phenobarbitone, which is
utilized to hasten clearance of congenital nonhaemolytic jaundice and kernicterus.
They are occasionally employed as adjuvants in psychosomatic disorders.
Q. 2. Mention few advantages of diazepam over phenobarbitones as hypnotic.

Diazepam is preferred to phenobarbiturate as hypnotic due to following advantages:

 Diazepam has a higher therapeutic index compared to phenobarbitone.
Even at hypnotic doses, there is no loss of consciousness and respiration is not depressed. It causes less distortion of sleep
architecture. Hypnotic doses do not affect respiration or cardiovascular functions. Diazepam practically has no action on
other body systems.
It does not alter disposition of other drugs by microsomal enzyme induction. Diazepam has lower abuse liability. It has
a specific antagonist (flumazenil) which can be used in case of poisoning whereas in phenobarbitone poisoning there is no
specific antagonist. Activated charcoal is used to stop absorption and forced alkaline diuresis is used to facilitate excretion of
phenobarbitone.
Rebound phenomenon on discontinuation of drug is less marked with diazepam. Tolerance of diazepam is mild.
Psychological and physical dependence and withdrawal
syndrome is less marked compared to phenobarbitone.
Q. 3. Therapeutic uses of benzodiazepine
The therapeutic uses of benzodiazepines are as follows:
As hypnotics At present benzodiazepines are the hypnotics of choice. They are used to shorten sleep latency, reduce
nocturnal awakening or to provide anxiolytic effect the day after.
The benzodiazepines are chosen depending on their onset and duration of action.
As anxiolytic and for daytime sedation: Benzodiazepines reduce anxiety and aggression and thus produce a calming effect.
As anticonvulsants Benzodiazepines increase seizure threshold and can be used as an anticonvulsant. Diazepam is used in
situations like status epilepticus, febrile convulsions.
Clonazepam is used in absence seizures and myo-
clonic seizures in children.
As centrally acting muscle relaxants Benzodiazepines reduce muscle tone by central action.
Increased muscle tone and aches associated with anxiety can be reduced using benzodiazepines.
As IV anaesthetic: Benzodiazepines can be used for inducing, maintaining and supplementing anaesthesia, e.g. diazepam,
lorazepam, midazolam.
As preanaesthetic medication: These drugs are used as preanaesthetic medication because of their sedative-amnesic and
anxiolytic effects, e.g. diazepam, lorazepam.
Diagnostic (endoscopies) and minor operative procedures: Benzodiazepines are used before electroconvulsive therapy,
electrical cardioversion of arrhythmias, cardiac catheterization, endoscopies in obstetrics and many minor surgical procedures.
To treat alcohol withdrawal symptoms in dependent subjects to reduce intensity of withdrawal symptoms.
Q. 4. Benzodiazepines as preanaesthetic medication
Antianxiety agents like benzodiazepines are used extensively as preanaesthetic medication.
Diazepam 5–10 mg is given orally. 4. to make anaesthesia safer.
It is given in order to 5. to reduce side effects of anaesthetics like gastric acidity.
1. decrease anxiety.
Barbiturates are not preferred as preanaesthetic medication 2. provide amnesia for preoperative period. as they
produce respiratory depression.
3. to relieve preoperative pain.
SHORT NOTES
Adverse effects of barbiturates
Adverse effects of barbiturates are as follows:
The common side effects are drowsiness, hangover, mental confusion, impaired performance and judgement.
Nausea, vomiting, diarrhoea
Idiosyncrasy—excitement
Hypersensitivity reactions like skin rashes and swelling in eyelids
Tolerance and dependence
Physical and psychological dependence
Prolonged use of phenobarbitone may cause megaloblastic anaemia.
Q. 2. Uses of benzodiazepine
Benzodiazepines can be used as
hypnotics—used to shorten sleep latency, reduce nocturnal awakening.
anxiolytic and for daytime sedation.
anticonvulsants.
centrally acting muscle relaxant.
IV anaesthetic used for inducing, maintaining and supplementing anaesthesia.
preanaesthetic medication.
before electroconvulsive therapy, cardiac catheterization, endoscopies in obstetrics and many minor procedures.
alcohol withdrawal therapy.
Q. 3. Flumazenil
 Flumazenil is a benzodiazepine antagonist.
It acts by competing with benzodiazepines for the receptor and reverses the depressant or stimulant actions.
It abolishes the hypogenic, psychomotor, cognitive and EEG effects of benzodiazepines. The action starts seconds after IV
administration and
lasts for 1–2 h. Mainly used to
reverse the action of benzodiazepine sedation or anaesthesia and
in benzodiazepine overdose or poisoning.
Q. 4. Classify barbiturates. Discuss thiopentone sodium.

All barbiturates are the drugs derived from barbituric acid. They are nonselective CNS depressants.
Classification
Long-acting: Phenobarbitone, mephobarbitone
Short-acting: Pentobarbitone, secobarbitone, butobarbitone
Ultra short-acting: Thiopentone sodium, methohexitone
Thiopentone Sodium
It is an ultra short-acting barbiturate.
Highly soluble in water, produces unconsciousness in 15–20 s. Injected IV dosage: 3–5 mg/kg, as 2.5% solution.
Produces CNS depression which persists for more
than 12 h. Poor analgesic and weak muscle relaxant Respiratory depression with inducing doses of thiopentone is
generally transient, but with large dose it will be severe.
Thiopentone is the commonest inducing agent used. It can be used as the sole anaesthetic for short nonpainful operations.
It may be occasionally used to control convulsions.
Q. 5. Define sedatives, hypnotics and tranquilizers.
 Sedative is a drug that reduces excitability and calms the patient without inducing sleep though it may induce drowsiness.
Sedation refers to decreased responsiveness to any level of stimulation.
Hypnotic is a drug that induces or maintains sleep resembling natural arousable sleep. A hypnotic at lower dose acts as a
sedative.
Tranquilizer is an old term meaning a drug which reduces mental tension and produces calmness without inducing sleep or
depressing mental faculties. It was mainly used to describe the effects of reserpine.
Q. 6. Indications of diazepam
Diazepam may be indicated
as hypnotic—used to shorten sleep latency, reduce nocturnal awakening.
as anxiolytic and for daytime sedation.
as anticonvulsant.
as centrally acting muscle relaxant.
as IV anaesthetic used for inducing, maintaining and supplementing anaesthesia.
as preanaesthetic medication.
before electroconvulsive therapy, cardiac catheterization, endoscopies in obstetrics and many minor procedures.
in treatment of alcohol withdrawal.
Q. 7. Write the uses and doses of barbiturates.

Barbiturates are drugs derived from barbituric acid. They were the longest group of drugs in use till newer drugs like
benzodiazepines were discovered in about 1960.
Uses
Epilepsy
Preanaesthetic and anaesthetic medication
Seldom as sedatives and hypnotics
Congenital nonhaemolytic jaundice
Dose
Dose depends on lipid solubility. Higher lipid solubility indicates for lower dose. Highly lipid-soluble agents like shortacting
barbiturates have a dose as low as 1–2 g. Phenobarbitone is less lipid soluble and has a dose threshold up to 5 g.
Q. 8. Urine should be alkalized in acute barbiturate poisoning. Why?

Antiepileptic Drugs
LONG ESSAY
Classify the drugs used in epilepsy.Write the mechanism of action and
adverse effects of diphenyl hydantoin sodium.
Or,
Enumerate the antiepileptic drugs belonging to different groups. Explain the actions
of phenytoin. How will you manage a case of convulsion
precipitated during tooth extraction?
Antiepileptic drugs are the drugs used during epilepsy.
Classification of antiepileptic drugs is as follows: Barbiturate: Phenobarbitone, mephobarbitone
Deoxybarbiturate: Primidone
Hydantoin: Phenytoin, mephenytoin
Iminostilbene: Carbamazepine
Succinimide: Ethosuximide
Aliphatic carboxylic acid: Valproic acid (sodium valproate), Divalproex
Benzodiazepines: Diazepam, clonazepam, clobazam, lorazepam
Cyclic GABA analogue: Gabapentin
Newer drugs: Vigabatrin, topiramate, tiagabine, levetiracetam

Dosage of barbiturates above 6–10 g causes acute barbiturate poisoning. Forced alkaline diuresis is done in acute
barbiturate poisoning with mannitol, sodium bicarbonate and frusemide because it helps in the rapid elimination of long-acting
barbiturates like phenobarbitone, which are eliminated primarily by renal excretion. Alkaline diuresis is the main treatment
for acute barbiturate poisoning as there is no specific antidote for barbiturate poisoning. Intravenous NaHCO3 alkalinizes
urine. Barbiturates are weakly acidic drugs. In alkaline urine, barbiturates exist in ionized form, so they are not reabsorbed
while passing through renal tubules and are rapidly excreted in urine.
PHENYTOIN SODIUM
Phenytoin sodium or diphenylhydantoin sodium is a barbiturate analogue and is a major antiepileptic drug.
Pharmacological Action (Mechanism of Action)
 Phenytoin prolongs the inactivated state of voltage sensitive neuronal Na1 channel and governs the refractory period of the
neurons. As a result, high frequency discharges are inhibited with little effect on normal low frequency discharges.
It has a stabilizing influence on the neuronal membrane and thus prevents the spread of seizure discharges.
This stabilizing influence consists of a synchronous and unusually large depolarization over which action potentials are
superimposed.
At higher concentrations, phenytoin inhibits Ca21 influx into the neuron, reduces glutamate levels and causes facilitation of
GABA responses.
Therapeutic Uses
Phenytoin is used for the treatment of the following:
Generalized tonic-clonic seizures (grand mal epilepsy) Simple and complex partial seizures: First choice drug—100
mg BD, maximum of 400 mg/day (children:
5–8 mg/kg/day) Status epilepticus: 25 mg/min slow IV, as alternate to diazepam
Trigeminal neuralgia and other neuralgia: Second choice to carbamazepine
Cardiac arrhythmias: Alternative in acute therapy of digitalis-induced ventricular extrasystole—100 mg IV every 10 min (max
600 mg) or 100–200 mg orally
2–6 hourly followed by 400 mg/day for maintenance
MANAGEMENT OF CONVULSION
PRECIPITATED DURING TOOTH EXTRACTION
Diazepam 10 mg IV bolus injection followed by fractional doses every 10 min or slow infusion titrated to control the fits or
phenobarbitone 100–200 mg IM/IV or phenytoin 25 mg/min IV may be used alternatively.
SHORT ESSAYS
Maintenance of airway, oxygenation, fluid and electrolyte balance, BP, normal cardiac rhythm, euglycaemia and care of
unconsciousness.
 Diphenylhydantoin sodium
Phenytoin sodium or diphenylhydantoin sodium is a barbiturate analogue and is a major antiepileptic drug.
Pharmacological Action (Mechanism of Action)
Phenytoin acts by stabilizing the neuronal membrane and thus prevents the spread of seizure discharges.
Prolongs the inactivated state of voltage sensitive neuronal Na1 channel and governs the refractory period of the neurons. As
a result, high frequency discharges are inhibited with little effect on normal low frequency discharges. At higher
concentrations, phenytoin inhibits Ca21 influx into the neuron, reduces glutamate levels and causes facilitation of GABA
responses
Therapeutic Uses
First choice drug in generalized tonic-clonic seizures, simple and complex partial seizures
In status epilepticus 25 mg/min slow IV, used as alternative to diazepam
It is second choice to carbamazepine in trigeminal neuralgia and other neuralgias.
As an antiarrhythmic in cardiac arrhythmias
Adverse Reactions
Phenytoin has dose-dependent toxicity. The adverse effects are as follows:
Hypertrophy and hyperplasia of gums
It produces hypersensitivity reactions like urticaria, skin rashes, neutropenia and rarely hepatic necrosis.
It causes hirsutism, acne and coarsening of facial features.
Phenytoin is a potent microsomal inducer and increases its own metabolism and also of other drugs.
It causes osteomalacia due to increased metabolism of vitamin D.
Phenytoin decreases folate absorption and increases its excretion causing megaloblastic anaemia.
If it is used during pregnancy it causes fetal hydantoin syndrome: cleft lip, cleft palate, digital hypoplasia, etc.
During higher doses zero order kinetics is ensued, slight increase in dose causes marked toxicity.
Q. 2. Sodium valproate
 Sodium valproate or valproic acid is a broad-spectrum anticonvulsant. It is a branched chain aliphatic carboxylic acid and
is more potent in blocking PTZ seizures than in modifying maximal electroshock.
Mechanism of Action
Valproate delays the recovery of Na1 channels from inactivation like phenytoin and carbamazepine.
Attenuation of Ca21-mediated T current in thalamic neurons like ethosuximide. Augmentation of release of inhibitory
transmitter GABA
by inhibiting its degradation and increasing its synthesis.
Adverse Effects
Common side effects related to GIT tract are anorexia,
vomiting, drowsiness, ataxia and tremor—dose related
CNS side effects include sedation, ataxia and tremor The other adverse effects include skin rashes, alopecia and curling of
hair. A symptomatic rise in serum transaminase is common.
 Fulminate hepatitis: Rare but serious and occurs in children below 3 years.
Teratogenicity: Neural tube defects in the offspring if
used during pregnancy
Therapeutic Uses
It is highly effective and first drug of choice in absence seizures. It is also effective against myoclonic and atonic seizures.
Second choice drug in
generalized tonic-clonic seizures and
simple partial seizures with or without generalization.
Alternative or add on drugs: In mania and bipolar illness it is used as alternative to lithium.
Q. 3. Phenytoin sodium in grand mal epilepsy
Phenytoin prolongs the inactivated state of voltage sensitive neuronal Na1 channel and it also governs the refractory period
of the neurons.
 As a result high frequency discharges are inhibited with little effect on normal low frequency discharges.
It has a stabilizing influence on the neuronal membrane and thus prevents repetitive detonation of normal brain cells during
depolarization shift. This stabilizing influence consists of a synchronous and unusually large depolarization over which
action potentials are superimposed.
At high doses it reduces Ca21 influx during depolarization. inhibits glutamate. facilitates GABA responses.
prevents intracellular accumulation of Na1 occurring during repetitive firing.
SHORT NOTES
Therefore phenytoin sodium is used in grand mal epilepsy.

Phenytoin is contraindicated during pregnancy.

Phenytoin is a teratogenic drug. When taken during

pregnancy, phenytoin induces fetal hydantoin syndrome.
This syndrome is characterized by
1. cleft lip and cleft palate, 2. hypoplastic phalanges and 3. microcephaly.
Q. 2. Phenobarbitone
Phenobarbitone is an important drug of choice in the treatment of epilepsy. Phenobarbitone inhibits the neurotransmitory
action by enhancing the GABA receptors thus facilitating them to open the chloride ion channels.
Phenobarbitone raises the seizure threshold and thus prevents epileptic attacks. It is used in generalized tonic-clonic
seizures and partial seizures. It is preferred due to its efficacy and low cost.
Q. 3. Carbamazepine
Carbamazepine is an antiepileptic drug chemically related to imipramine.
Mechanism of Action
Carbamazepine modifies maximal electroshock seizures as well as raises threshold to PTZ and electroshock convulsions. It
prolongs inactivated state of Na1 channel.
Adverse Effects
Dose-related neurotoxicity—sedation, dizziness, vertigo, diplopia and ataxia
Higher doses cause vomiting, diarrhoea, worsening of seizures. Hypersensitivity—rashes, photosensitivity, hepatitis,
lupus-
like syndrome, leukopenia and rarely agranulocytosis and aplastic anaemia
Minor fetal malformations
Therapeutic Uses
Epilepsy—generalized tonic-clonic and simple partial
seizures
Trigeminal and related neuralgias Manic depressive illness and acute mania
Q. 4. Sodium valproate
Sodium valproate or valproic acid is a broad-spectrum anticonvulsant.
Mechanism of Action
Valproate delays the recovery of Na1 channels from inactivation and causes attenuation of Ca21-mediated T current in
thalamic neurons. Augmentation of release of inhibitory transmitter GABA.
Adverse Effects
Common side effects are anorexia, vomiting, drowsiness, ataxia and tremor—dose-related. CNS side effects include
sedation, ataxia and tremor.
The other adverse effects include skin rashes, alopecia and curling of hair and teratogenicity.
Therapeutic Uses
It is highly effective and first drug of choice in absence seizures. Second choice drug in generalized tonic-clonic seizures
and simple partial seizures. Alternative or add-on drugs in mania and bipolar illness.
Q.5. Phenytoin sodium
Or, Diphenylhydantoin sodium
Phenytoin sodium or diphenylhydantoin sodium is a barbiturate analogue and is a major antiepileptic drug.
Pharmacological Action (Mechanism of Action)
Phenytoin acts by stabilizing the neuronal membrane and thus prevents the spread of seizure discharges.
Therapeutic Uses
First choice drug in generalized tonic-clonic seizures, simple and complex partial seizures. It is second choice to
carbamazepine in trigeminal neu-
ralgia and other neuralgias. As an antiarrhythmic in cardiac arrhythmias
Adverse Reactions
The adverse effects include hypertrophy and hyperplasia of gums, hypersensitivity reactions, osteomalacia.
Antiparkinsonian Drugs
LONG ESSAY
Classify the drugs used in parkinsonism and dis- Antiparkinsonian drugs are drugs that
help to reduce the cuss pharmacology and adverse effects of L-DOPA. symptoms of parkinsonism in two
ways, either by enhanc-
ing the dopamine activity or by depressing cholinergic
overactivity.
If it is used during pregnancy it causes fetal hydantoin syndrome.
Classification
Drugs that increase dopamine levels
Dopamine precursor: Levodopa Drugs that release dopamine agonists: Amantadine Dopamine agonists: Bromocriptine,
pergolide, pramipexole, ropinirole
 Inhibit dopamine metabolism: MAO inhibitors,
deprenyl (selegiline)
Drugs influencing cholinergic receptors
Centrally acting anticholinergics: Benztropine, benzhexol, biperidine, trihexyphenidyl
Antihistamines (H1 blockers) with anticholinergic ac-
tivity: Diphenhydramine, orphenadrine, promethazine
LEVODOPA
Levodopa is a dopamine precursor that is converted to dopamine with the help of decarboxylase.
Mechanism of Action
Levodopa crosses blood-brain barrier and is taken up by presynaptic terminals of dopaminergic neurons and is
dehydroxylated to dopamine. Levodopa is converted to dopamine in peripheral tissue and dopamine thus formed acts on
heart, blood vessels and peripheral org
Pharmacological Actions
i CNS: Hypokinesia, rigidity, tremors improve first, later other symptoms like gait, speech, sialorrhoea, mood is
normalized. ii CVS: It causes tachycardia. CTZ: It causes nausea and vomiting. Endocrine: It
inhibits prolactin release.
Adverse Reactions
GIT: Gastrointestinal side effects like nausea, vomiting and anorexia are common early in the treatment with -DOPA.
Tolerance to emetic effect develops slowly. Antiemitics such as domperidone is preferred to control -DOPA induced
vomiting.
CVS: Postural hypotension is the commonest side effect, which is usually asymptomatic. It can also cause tachycardia,
palpitation, cardiac arrhythmia and angina.
Abnormal movements: Dyskinesias, tics, tremors and
choreoathetoid movements may occur. Alteration in smell and taste sensation
SHORT ESSAYS
Behavioural effects like insomnia, agitation, anxiety, nightmares, depression, confusion and mania may be seen.

What is dopamine? Mention one use and route of administration.

Dopamine is an enzyme whose deficiency results from degeneration of nigrostriatal neurons in the basal ganglia.
This deficiency results in parkinsonism, which is characterized by rigidity, tremors, bradykinesia, seborrhoea and mood
changes. Though dopamine helps to reduce the symptoms of parkinsonism, it is not administered directly as it is of no
therapeutical use since it does not cross the bloodbrain barrier (BBB). It is administered as levodopa which crosses the BBB
and then gets converted to dopamine with the help of decarboxylase.
Uses: Dopamine in the form of levodopa is an effective drug of choice in the treatment of idiopathic parkinsonism.
Q. 2. Levodopa is used in parkinsonism.
Levodopa is a dopamine precursor that is converted to dopamine with the help of decarboxylase.
Mechanism of Action
Levodopa crosses blood-brain barrier and is taken up by presynaptic terminals of dopaminergic neurons and is
dehydroxylated to dopamine. Levodopa is converted to dopamine in peripheral tissue and dopamine thus formed acts on
heart, blood vessels and peripheral org
Pharmacological Actions
CNS: Hypokinesia, rigidity, tremors improve first, later other symptoms like gait, speech, sialorrhoea, mood is normalized.
CVS: It causes tachycardia. CTZ: It causes nausea and vomiting. Endocrine: It inhibits prolactin release.
Q. 3. Explain why levodopa is given along with carbidopa.
Decarboxylase inhibitor, i.e. carbidopa prevents conversion of levodopa to dopamine outside brain by inhibiting DOPA
decarboxylase enzyme peripherally. Thus, greater concentration of levodopa can cross blood-brain barrier and reach its site of
action in brain.
Benefits obtained on combining levodopa with carbidopa are as follows:
Doses of levodopa can be reduced up to three-fourth its original dose.
Systemic concentration of dopamine is decreased due to which nausea, vomiting and cardiac effects are prevented.
SHORT NOTES
Pyridoxine cannot increase decarboxylase activity in presence of carbidopa. On–off effect is decreased.

Is pyridoxine given with levodopa?

Pyridoxine enhances decarboxylation of levodopa and reduces the amount of drug available to convert to dopamine to act on
CNS. This may result in the need for greater doses of levodopa for the same desired result. Hence pyridoxine is not given with
levodopa.
Q. 2. Levodopa
Levodopa is a dopamine precursor that is converted to dopamine with the help of decarboxylase.
Levodopa crosses blood-brain barrier and there it is converted to dopamine which helps to treat parkinsonism.
Uses: Dopamine in the form of levodopa is an effective drug of choice in the treatment of idiopathic parkinsonism.
Adverse Reactions
GIT: It causes nausea, vomiting and anorexia.
CVS: It causes postural hypotension, palpitation, cardiac arrhythmia and angina.
Abnormal movements
Drugs Used in Mental Illness: Antipsychotic and Antianxiety Drugs
SHORT ESSAYS
Behavioural effects: Agitation, anxiety, nightmares, depression, confusion and mania

Chlorpromazine
Chlorpromazine is a phenothiazine with aliphatic side chain and is the prototype drug.
Mechanism of Action
Chlorpromazine has potent dopamine D2 receptor blocking action. Antipsychotic action of chlorpromazine is contributed
to the blockade of dopaminergic receptors in the mesolimbic system.
Pharmacological Actions of Chlorpromazine
Central Nervous System
In normal individuals: Chlorpromazine produces neuroleptic syndrome characterized by indifference to surroundings, paucity
of through psychomotor slowing, emotional quietening, reduction in initiative, tendency to go off to easily arousable sleep and
minimized spontaneous movements.
In a psychotic patient Irrational behaviour, agitation and aggressiveness is reduced. Psychotic symptomatology is
controlled.
Disturbed through and behaviour are gradually normalized and anxiety is relieved. Hyperactivity, hallucinations and
delusions are suppressed. The sedative effect is produced immediately while antipsychotic effect takes weeks to develop as
chlorpromazine has low potency. Vigilance is impaired while intelligence is not affected.
It lowers seizure threshold and can precipitate fits in untreated epileptics. At higher doses, temperature control is knocked off
thus body temperature can fall if surroundings are cold.
Chlorpromazine has potent antiemetic action medi-
ated through CTZ.
Autonomic Nervous System
Chlorpromazine has potent adrenergic blocking activity and weak anticholinergic property.
Local Anaesthetic
Chlorpromazine is a potent local anaesthetic.
Cardiovascular System
Chlorpromazine by its central and peripheral action on sympathetic tone produces postural hypotension accompanied by
reflex tachycardia especially after parenteral administration. In high doses it directly depresses the heart and shows ECG
changes in form of QT prolongation and suppression of T-wave.
Due to its membrane stabilizing action, it also produces
antiarrhythmic action.
Skeletal muscle
Chlorpromazine through its action on basal ganglia or medulla oblongata reduces certain types of spasticity though they do not
have any direct effect on skeletal muscles or neuromuscular transmission.
Endocrine
Chlorpromazine increases the prolactin release by blocking the inhibitory action of dopamine on pituitary lactotropes
resulting in galactorrhoea and gynaecomastia. Gonadotropin secretion is reduced but amenorrhoea and infertility occur only
occasionally.
ACTH release in response to stress is diminished; thus corticosteroid level fails to increase in stress.
Urinary volume may be increased due to decreased ADH release and direct action on kidney tubules.
Therapeutic Uses
Psychoses
Schizophrenia
 Chlorpromazine has definite therapeutic effect in all forms of functional psychoses and used primarily in them.
Chlorpromazine is preferred in agitated, combative and violent patients.
Produces wide range of symptomatic relief of positive symptoms, like hallucinations, delusions, restlessness, insomnia,
anxiety, fighting, aggression than negative symptoms.
Restores cognitive, affective and motor disturbances.
Mania: Given IM for 1–3 weeks for rapid control simultaneously with antimania drugs.
Organic brain syndromes: Used on short-term basis to avoid mental confusion, hypotension and precipitation of seizures.
Anxiety: Used only in cases with psychotic basis or those not responding to antianxiety drugs.
Antiemetic: Useful in drug and disease-induced vomiting at dose lower than antipsychotic dose
Other uses To potentiate hypnotics, analgesics and anaesthetics in anaesthetic practice
Used parenterally in intractable hiccups.
 In tetanus as secondary drug to achieve muscle relaxation Alcoholic hallucinations, Huntington’s disease and Gilles de la
Tourette’s syndrome are rare indications.
Q. 2. Neuroleptanalgesia
Neuroleptanalgesia is a state of analgesia characterized by quiescence, psychic indifference and intense analgesia without
loss of consciousness. It is obtained when 0.05 mg fentanyl and 4–6 mL droperidol (2.5 mg/mL) are combined infused over
10 minutes.
Advantages: Patient cooperative though he or she is drowsy. Disadvantages: Respiratory depression, fall in BP
and heart rate are seen.
Indications
Endoscopies
Burn dressings
Angiographies
Minor surgeries
Q. 3. Classification of antipsychotic drugs
Antipsychotic drugs are the drugs having a salutary therapeutic effect in psychoses.
Classification
Phenothiazines
Aliphatic side chain: Chlorpromazine, triflupromazine
Piperidine side chain: Thioridazine
Piperazine side chain: Trifluoperazine, fluphenazine
Butyrophenones: Haloperidol, trifluperidol, droperidol, penfluridol
Thioxanthenes: Thiothixene, flupenthixol
Other heterocyclics: Pimozide, loxapine, reserpine
Atypical neuroleptics: Clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone
SHORT NOTES
Chlorpromazine
Chlorpromazine is a phenothiazine with aliphatic side chain.
Mechanism of Action
Antipsychotic action of chlorpromazine is contributed to potent dopamine D2 receptor blocking action in the limbic system and
in mesocortical area.
Therapeutic Uses
Psychoses
Schizophrenia: Chlorpromazine has definite therapeutic effect in all forms of functional psychoses and used primarily in them.
Restores cognitive affective and motor disturbances.
Mania: Given IM for 1–3 weeks for rapid control simultaneously with antimania drugs.
Organic brain syndromes: Used on short-term basis
to avoid mental confusion, hypotension and precipitation of seizures
Anxiety: Used only in cases with psychotic basis or those not responding to antianxiety drugs
Antiemetic: Useful in drug and disease induced vomiting at dose lower than antipsychotic dose
Other uses To potentiate hypnotics, analgesics and anaesthetics Intractable hiccups In tetanus as secondary drug to
achieve muscle
relaxation
Alcoholic hallucinations, Huntington’s disease and Gilles de la Tourette’s syndrome are rare indications.
Q. 2. Mention two uses and two adverse effects of chlorpromazine.

Chlorpromazine is a phenothiazine with aliphatic side chain.

Therapeutic Uses
Used in treating psychoses like schizophrenia, mania and various organic brain syndromes. Chlorpromazine has definite
therapeutic effect in all forms of functional psychoses.
Restores cognitive affective and motor disturbances.
Used in anxiety cases with psychotic basis or those not responding to antianxiety drugs.
As an antiemetic in drug and disease-induced vomiting at dose lower than antipsychotic dose.
Adverse Effects
Central nervous system
Drowsiness, lethargy, mental confusion
Increased appetite and weight gain
Aggravation of epilepsy
Development of tolerance Adrenergic blockade: Produces postural hypotension, palpitation and inhibition of ejaculation
Opioid Analgesics and Antagonists
LONG ESSAY
Classify narcotic analgesic group of drugs and Classify narcotic analgesics. Describe
the actions, therawrite about morphine. peutic uses and toxic effects of morphine.
Or, Or,
Classify narcotic analgesics. Discuss the uses and dan- What are narcotic analgesics?
Describethe pharmacogers of morphine. Name morphine antagonists available.
logical actions, uses and toxicity of opium alkaloids.
Or,
Anticholinergic action results in dry mouth, blurring of vision constipation, urinary hesitancy.
Opioid analgesics are the analgesics which are either derived from the opium or resemble opium in action.
CLASSIFICATION
Natural opium alkaloids: Morphine, codeine, thebaine, papaverine and noscapine
Semisynthetic opioids: Diacetylmorphine (heroin), pholcodine, hydromorphone and oxymorphone
Synthetic opioids: Pethidine (meperidine), fentanyl,
methadone, dextropropoxyphene, tramadol, ethoheptazine, alfentanil, sufentanil and remifentanil
MORPHINE
Morphine is a natural opioid and the principal alkaloid in opium.
Pharmacology Actions
a. Central Nervous System
Morphine has site specific depressant and stimulant actions.
I. Depressant Actions
Analgesia: Morphine is a strong analgesic. Dull, poorly localized visceral pain is relieved better than sharply defined
somatic pain. Degree of analgesia increases with increasing dose.
 Nociceptive pain arising from stimulation of peripheral pain receptors is relieved better than neurotic pain due to
inflammation or damage of neural structures.
Intrathecal injection of morphine causes segmental analgesia without affecting other modalities.
Release of substance P from primary pain afferents in the spinal cord and its postsynaptic action on dorsal horn neurons is
inhibited by morphine.
Sedation: Drowsiness and indifference to surroundings as well as to own body occurs without motor incoordination, ataxia or
apparent excitement. Higher doses progressively cause sleep and coma. Mood and subjective effects (euphoria)
The mood and subjective effects are prominent and are called euphoria. Morphine has a calming effect.
There is loss of apprehension, feeling of detachment, lack of initiative; limbs feel heavy and body warm, mental clouding
and inability to concentrate.
However patients in pain or anxiety and addicts spe-
cially perceive it as pleasure.
Respiratory depression Morphine depresses respiratory centre in a dosedependent manner.
Rate and tidal volume are both decreased and in poisoning death occurs by respiratory failure. There is indifference to
breathing. Cough suppression by direct action on cough centre in the medulla.
Temperature regulating centre: It is depressed. Hypothermia occurs in cold surroundings.
Vasomotor centre: It is depressed at higher doses and
contributes to the fall in BP.
II. Stimulant Effects
Nausea and vomiting Morphine appears to sensitize the CTZ to vestibular and other impulses. Nausea and vomiting occur
as side effects specially if stomach is full and the patient stands or moves about.
However larger doses depress vomiting centre directly.
Miosis: By central stimulating action on Edinger-Westphal nucleus of third nerve, morphine causes constriction of pupils
(miosis) and also decreases intraocular tension. Vagal centre: It is stimulated and can cause bradycardia. Certain
cortical areas and hippocampal cells: Muscular rigidity and immobility is consistently manifested at high doses. Excitation is
seen in occasional individuals.
b. Neuroendocrine
Influence of hypothalamus on pituitary is reduced. As a result FSH, LH, ACTH levels are reduced while prolactine and GH
levels are increased. Sex hormone and corticosteroid levels are lowered in the short term but tolerance develops in the long
term.
Few chronic abusers suffer from infertility.
Morphine can release ADH and reduce urine volume.
Cardiovascular System Morphine causes vasodilatation due to the following:
Direct action on decreasing tone of blood vessels Histamine release Depression of vasomotor centre (VMC)
Postural hypertension and fainting occurs due to impairment of vascular reflexes but therapeutic doses causes little change in
BP.
 Intracranial tension tends to rise as a consequence of CO2 retention leading to cerebral vasodilatation.
d. Gastrointestinal Tract
Morphine causes constipation by acting directly on intestines and the CNS action increases tone and segmentation but
decreases propulsive movements.
decrease in all gastrointestinal secretions, reduction in
transfer of water and electrolytes from mucosa to lumen.
e. Other Smooth Muscles
Biliary tract: Morphine causes spasm of sphincter. Intrabiliary pressure is increased.
Urinary bladder: Morphine increases tone of both detrusor and sphincter. Contractions of ureter are also increased.
Uterus: It may prolong labour but it is clinically insignificant.
Bronchi: Morphine releases histamine which causes
bronchoconstriction.
f. Autonomic Nervous System
Morphine causes mild hyperglycaemia due to central sympathetic stimulation.
Therapeutic Uses
As analgesic: Morphine is indicated in severe pain of any type. It is specially indicated in traumatic, visceral, ischaemic,
postoperative, burn, cancer pain and like.
It should be promptly given in myocardial infarction to allay apprehension and reflex sympathetic stimulation.
It may prevent neurogenic shock and other autonomic effects of excruciating pain.
10–50 mg orally, 10–15 mg IM or SC or 2–6 mg IV,
2–3 mg as epidural or intrathecal injection
Preanaesthetic medication: l0 mg of morphine IM to allay anxiety and apprehension of the operation, produce pre- and
postoperative analgesia, smoothen induction, reduce the dose of anaesthetic required and supplement poor analgesics or weak
anaesthetics
In acute left ventricular failure (cardiac asthma) morphine affords dramatic relief by the following:
Reducing preload on heart due to vasodilatation and peripheral pooling of blood
Tending to shift blood from pulmonary to systemic circuit, relieves pulmonary congestion and oedema. Allays air hunger
by depressing respiratory centre.
Cuts down sympathetic stimulation by calming the patient, reduces cardiac work.
To relieve pulmonary oedema due to infarction of lung and other causes
In balanced anaesthesia and surgical analgesia
For relief of anxiety, apprehension in MI and in-
ternal bleeding
Contraindications
Infants and the elderly are more susceptible to the respiratory depression by morphine.
 In patients with respiratory insufficiency like emphysema, pulmonary fibrosis, cor pulmonale and bronchial asthma, it can
precipitate an attack by its histamine releasing action. Head injury: By retaining CO2 it increases intracranial tension, which
will add to that, caused by head injury itself.
Even therapeutic doses can cause marked respiratory depression in these patients.
Vomiting, miosis and altered mentation produced by morphine interfere with assessment of progress in head injury cases.
Hypotensive states and hypovolaemia exaggerate fall in BP due to morphine. In undiagnosed acute abdominal pain
morphine can aggravate diverticulitis, biliary colic, pancreatitis, etc. Elderly male: Chances of urinary retention are high.
Hypothyroidism, liver and kidney diseases are more likely to develop.
SHORT ESSAYS
Unstable personalities are more liable to continue its use and become addicted.

Morphine is contraindicated in head injury. Explain.

 Morphine is contraindicated in head injury because of the following:
By retaining CO2 it increases intracranial tension, which will add to that tension caused by head injury itself.
Even therapeutic doses can cause marked respiratory depression in these patients.
Vomiting, miosis and altered mentation produced by morphine interferes with assessment of progress in head injury cases.
Q. 2. Pentazocine
Pentazocine is a kappa receptor agonist which has lesser addiction liability compared to morphine.
Onset of action Low Rapid
Duration of action Longer (4–6 h) Shorter (3–4 h)
Suppression of cough Effective Not effective
Spasmodic action on smooth muscle Marked miosis, constipation and urinary retention Less marked miosis,
constipation and urinary retention
Local anaesthetic action Absent Present
Heart rate Bradycardia Tachycardia
Status in asthmatics Contraindicated Safer
Oral absorption Unreliable Well absorbed
Metabolism In liver by glucuronide conjugation In liver by hydrolysis and demethylation
Tolerance and physical dependence High and develops rapidly Low and develops slowly
Withdrawal symptoms Develop slowly Develop rapidly and the autonomic disturbances are less marked
Route of administration IV, IM, SC Oral, IV
Therapeutic uses 1. Analgesic in traumatic, visceral, ischaemic
pain, postopera-
tive,
burn and cancer pain 1. Postoperative or chronic pain, labour pain
2. Preanaesthetic medication 2. Preanaesthetic medication
3. Balanced anaesthesia and surgical analgesia 3. Balanced anaesthesia and surgical analgesia
4. Antianxiety and antiapprehension
5. Acute left ventricular failure
6. Cough and diarrhoea
Compared to morphine, the sedation, and respiratory depression are less marked while BP and heart rate are increased.
Pentazocine can be given orally (50–100 mg) or intra-
muscularly (30–60 mg).
Uses
Pentazocine is the preferred analgesic for postoperative and chronic pain.
Adverse Effects
Dizziness, sedation, nausea, sweating and hallucinations
Sterile abscess at the site of the injection
Q. 3. Dextropropoxyphene
Dextropropoxyphene is a congener of methadone and is structurally similar to it.
It binds to the opioid receptor and produces pharmacological effects similar to morphine, though it has less constipating
effect. Actions and side effects are similar to codeine, but less potent than codeine when given orally. The side effects are
nausea, constipation, sedation, abdominal pain, etc. It is irritating when injected parenterally and has equal abuse potential as
morphine. It is used orally in mild to moderate dose usually in combination with aspirin as they have synergistic action:
Dextropropoxyphene 32 mg 1 aspirin 600 mg
Q. 4. Morphine is used in acute left ventricular failure.
Morphine is used in acute left ventricular failure (cardiac asthma) as it affords dramatic relief by the following:
Reducing preload on heart due to vasodilatation and peripheral pooling of blood
Tending to shift blood from pulmonary to systemic circuit, relieves pulmonary congestion and oedema. Allays air hunger
by depressing respiratory centre.
 Cuts down sympathetic stimulation by calming the patient, reduces cardiac work.
Q. 5. Compare morphine and pethidine.
Both morphine and pethidine are opioid analgesics.
Parameters to
Be Compared Morphine Pethidine
Source Natural opium alkaloid Synthetic

Q. 6. Rationale of using imipramine in mental depression

Imipramine is a tricyclic antidepressant used for the treatment of mental depression.
The patient responds to the treatment 2–3 weeks after 3. They cause an elevation in the mood of the patient and
the initiation of dosage. It blocks the reuptake of nor- normalize the sleep patterns. The patient shows more adrenaline or 5-
hydroxytryptamine and prolongs their interest in the surroundings. action on the CNS.
SHORT NOTES

Pentazocine
Pentazocine is an opioid agonist-antagonist.
Pentazocine can be given orally in dose of 50–100 mg or intramuscularly in dose of 30–60 mg. Uses: Pentazocine is
preferred analgesic for postopera-
tive and chronic pain. Adverse effects
Dizziness, sedation, nausea, sweating, hallucinations
Sterile abscess at the site of the injection
Q. 2. Codeine
Codeine is a natural opium alkaloid that is less potent compared to morphine as an analgesic. It produces lesser respiratory
depression and constipating effect compared to morphine. It is also has lesser tendency for addiction liability.
 Codeine is used as antitussive and is usually combined with paracetamol for analgesic effect. It is well absorbed orally and
has a duration of action of 4–6 h.
Q. 3. Therapeutic uses of morphine
As analgesic: Morphine is indicated in severe pain of any type. It is specially indicated in traumatic, visceral, ischaemic,
postoperative, burn, cancer pain, in myocardial infarction.
Preanaesthetic medication—10 mg IM to allay anxiety and apprehension of the operation, produce pre- and postoperative
analgesia, smoothen induction, reduce the dose of anaesthetic required and supplement poor analgesics or weak anaesthetics.
Acute left ventricular failure (cardiac asthma)— morphine affords dramatic relief. To relieve pulmonary oedema due to
infarction of lung
and other causes In balanced anaesthesia and surgical analgesia For relief of anxiety, apprehension in MI and internal
bleeding
Q. 4. Mention two contraindications of morphine.
Morphine is contraindicated in the following:
Infants and the elderly: As they are more susceptible to the respiratory depression by morphine.
Patients with respiratory insufficiency like emphysema, pulmonary fibrosis, cor pulmonale
In bronchial asthma: It can precipitate an attack by its histamine releasing action.
Q. 5. Write the depressant CNS pharmacological actions of morphine.
Morphine has site specific depressant and stimulant actions. The CNS depressant actions of morphine are as follows:
Analgesia: Morphine is a strong analgesic.
Sedation: Drowsiness and indifference to surroundings, higher doses progressively cause sleep and coma.
Mood and subjective effects (euphoria): Morphine has a calming effect.
Respiratory depression: Depression of temperature regulating centre and vasomotor centre which contributes to the fall in BP.
Q. 6. Four drugs used in mental depression
Drugs used for the treatment of mental depression are called antidepressants.
Various drugs used as antidepressants are classified as follows:
Tricyclic antidepressants (TCAs): Imipramine, desipramine, amitriptyline, doxepin
Selective serotonin (5-HT) reuptake inhibitors (SSRIs): Fluoxetine, fluvoxamine, paroxetine
Monoamine oxidase inhibitors (MAO) inhibitors: Phenelzine, tranylcypromine
Atypical antidepressants: Trazodone, bupropion, mianserin

CNS Stimulants and Cognition Enhancers

SHORT ESSAYS
Classify neuroleptic drugs.
Neuroleptics are also known as antipsychotics or ataractics or major tranquilizers. These drugs have salutary
therapeutic effect in psychosis.
They are classified as follows:
Phenothiazines
Aliphatic side chain: Chlorpromazine, triflupromazine
Piperidine side chain: Thioridazine
Piperazine side chain: Trifluoperazine, fluphenazine, thioproperazine
Butyrophenones: Haloperidol, trifluperidol, droperidol
Thioxanthenes: Chlorprothixene, thiothixene, flupenthixol
Others: Pimozide, molindone, sulpiride, loxapine, reserpine
Atypical neuroleptics: Clozapine, risperidone
Q. 2. Neuroleptics
 Neuroleptics are antipsychotics or major tranquilizers used to treat patients of psychosis or schizophrenia. The
pharmacological actions of these neuroleptics are due to their ability to block dopamine receptors in specific areas of brain.
Chlorpromazine is the first effective phenothiazine neuroleptic.
They have very high therapeutic index.
Actions
Causes emotional quietening and psychomotor slowing in psychotics.
They have antiemetic effect, anticholinergic effect and weak antihistaminic and antiserotonin action.
They cause hypothermia, hypotension and failure of ejaculation.
Therapeutic Uses
Schizophrenia and allied psychiatric disturbances As a preanaesthetic medication Neuroleptanalgesia
To control a wide range of drug and disease-induced vomiting
To treat intractable hiccoughs
Side Effects
Parkinson-like syndrome Tardive dyskinesia
Anticholinergic and adrenergic blocking effect
SHORT NOTES

Analeptic drugs
Analeptics are the drugs which stimulate respiration and have resuscitative in fainting or coma.
Toxic Effects
The patients may get convulsions still in coma if he is on analeptic therapy.
Postictal depression adds to existing depression which
may worsen the condition.
Therapeutic Uses
The role of analeptics in therapeutics is very limited. They are used in hypnotic drug poisoning, suffocation on drowning,
respiratory failure due to removal of hypoxic drive and apnoea in premature infants.
Part VIII
Cardiovascular Drugs

Drugs Affecting Renin-Angiotensin System and Plasmakinins

SHORT NOTES
Enalapril
Enalapril is an angiotensin converting enzyme inhibitor. It is a prodrug and is long-acting (24 h).
It prevents the formation of angiotensin II and raises bradykinin levels which contributes to the fall in BP.
It maintains adequate blood flow to the vital organs like kidney, brain and heart.
It is well absorbed in the body.
Uses
Hypertension
Congestive cardiac failure Myocardial infarction
Adverse Effects
Hyperkalaemia
Alteration in the taste
Skin rashes, headache, nausea, abdominal pain Hypotension
Q. 2. Angiotensin antagonists
Angiotensin antagonists are drugs that inhibit the action of angiotensin receptors like AT1 and AT2. For example: Losartan
is the most widely used angiotensin inhibitor.
They relax smooth muscles, promotes salt and water excretion and reduces plasma volume.
 Compared to ACE inhibitors, angiotensin antagonists show no increase in bradykinin levels and so the adverse effects are
lesser. They include hypotension and hyperkalaemia.
Persistent dry cough

Cardiac Glycosides and Drugs for CHF

SHORT ESSAYS
Therapeutic uses and adverse effects of digoxin. It is the most widely used cardiac glycoside.
Mechanism of action: It acts by inhibiting the Na1/K1
ATPase present on the cardiac myocytes. This causes an
Digoxin is a cardiac glycoside obtained from the seeds increase in the intracellular sodium and calcium. The extra of
Strophanthus gratus (digitalis or foxglove plant). calcium causes contraction with greater force and velocity.
Uses: They are used in the treatment of hypertension.
Uses
Cardiac arrhythmias: Atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia.
Digoxin therapy is indicated in patients with severe left ventricular systolic dysfunction after initiation of ACE inhibitor and
diuretic therapy.
Digoxin major indication is congestive cardiac failure with atrial fibrillation.
Adverse Effects
Digitalis toxicity is one of the most commonly encountered adverse drug reactions. Types of adverse effects include the
following:
Cardiac effects: Arrhythmias like extrasystoles, bradycardia, pulse bigeminy, AV block
GIT effects: Anorexia, nausea and vomiting are commonly encountered adverse effects.
CNS effects: These include headache, fatigue, confusion, hallucinations, blurred vision and gynaecomastia.
Q. 2. Digoxin is used in congestive cardiac failure.
 Congestive cardiac failure is a condition where the heart is not able to provide enough blood supply to meet the demand of
the body. Digoxin is used in the treatment of congestive cardiac failure that cannot be controlled with diuretics or
vasodilators.
Digoxin improves cardiac performance: Administration of digoxin shifts the ventricular function curve towards normal.
Increased contractility leads to increased cardiac output and decreased sympathetic reflexes and vascular tone cause a decrease
in the ventricular end diastolic pressure.
SHORT NOTES
It restores the cardiac output and relieves congestion and thereby reduces morbidity and mortality.

Digitoxin
Digitoxin is a cardiac glycoside obtained from the seeds of Strophanthus gratus and is the most widely used cardiac glycoside.
Pharmacokinetics
It has a plasma half-life of 5–7 days.
Its onset of action is in about 30–120 min.
Uses
Cardiac arrhythmias: Atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia
Congestive cardiac failure
Adverse Effects
Cardiac effects: Arrhythmias like extrasystoles, bradycardia, pulse bigeminy, AV block
Extracardiac effects: Anorexia, nausea, vomiting, diarrhoea, weakness, confusion, hallucinations, blurred vision and
gynaecomastia
Q. 2. Rationale of using digoxin in atrial fibrillation
 Digoxin reduces ventricular rate in atrial fibrillation by decreasing the number of impulses that are able to pass down the AV
node and bundle of hiss. It increases effective refractory period of AV node by direct vagomimetic and antiadrenergic action.
Therefore, digoxin is the drug of choice for controlling ventricular rate in atrial fibrillations.
Q. 3. Therapeutic uses of digoxin
Digoxin is the most widely used cardiac glycoside because it has favourable pharmacokinetic properties.
Therapeutic Uses
Cardiac arrhythmias: Atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia
Congestive cardiac failure: Digoxin is used in the treatment of congestive cardiac failure that cannot be controlled with
diuretics or vasodilators. Digoxin improves cardiac performance in the dilated failing patient. It restores the cardiac output and
relieves congestion.
Q. 4. Write the cardiac toxicity of digoxin.
 Digoxin has a low safety threshold and has high incidence of adverse effects.
Digoxin produces cardiac toxicity characterized by arrhythmias like extrasystoles, bradycardia, pulse bigeminy, AV block—
ventricular tachycardia and fibrillation. Cardiac toxicity is enhanced by hypokalaemia.
Treatment 3. Arrhythmias are treated with IV phenytoin.
4. Bradycardia is treated with atropine and supraventricu-
Stop administration of digoxin. lar arrhythmias with propranolol.
Oral or parenteral potassium supplements are administered.

Antiarrhythmic Drugs
SHORT NOTES
Why procainamide is preferred to procaine?
 Procainamide is a derivative of procaine.
It is preferred to procaine as it has a weak anticholinergic action. It has antiarrhythmic action while procaine has only local
anaesthetic effect. It is better tolerated compared to procaine.
Q. 2. Verapamil
Verapamil is a phenylalkylamine that acts as a calcium channel blocker.
Mechanism of Action
It blocks all type of calcium channels and decreases availability of calcium ions; thus causing relaxation of smooth muscle
cell or cardiac cell. Effect is more on arterioles and less on veins. Negative, chronotropic, ionotropic and dromotropic action.
Calcium channel blockers inhibit calcium movement inside cell in depolarization phase, thus inhibiting contraction of
cardiac muscle. Cardiac work and oxygen consumption is decreased. Calcium channel blockers inhibit refractory period of
AV node, decrease SA nodal discharge, suppress ectopic foci, produce antiarrhythmic action.
Q. 3. Uses of calcium channel blockers
Various uses of calcium channel blockers are as follows:
Angina pectoris: It is useful in both types of angina, i.e. classical and variant angina.
Hypertension: They are first line drugs in hypertension. Calcium channel blockers decrease total peripheral resistance and
hence decreases BP.
Arrhythmias: Calcium channel blockers are preferred in supraventricular tachycardia.
Calcium channel blockers are also used in hypertensive emergencies.
Q. 4. Classification of antiarrhythmic drugs
Antiarrhythmic drugs were classified by Vaughan Williams based on the cardiac cycle as follows:
Class I: Sodium channel blockers
Prolong repolarization: Quinidine, procainamide, disopyramide
Shorten repolarization: Lignocaine, mexiletine, phenytoin
Little or no effect on repolarization: Encainide,
flecainide
Class II: b-adrenergic blockers
Reduce sympathetic tone: Propranolol, acebutolol,
esmolol
Class III: K1 channel blockers
Prolong repolarization: Amiodarone, sotalol
Class IV: Ca21 channel blockers
Prolong conduction and refractoriness (especially in
SA and AV nodes): Verapamil, diltiazem

Antianginal and Other Anti-ischaemic Drugs

LONG ESSAY
Classify antianginal drugs. Describethe pharmacological actions of nitrates, their clinical
uses and side effects.

The antianginal drugs are classified as follows: a. Organic nitrates Short-acting: Glycerol trinitrate
(nitroglycerin) There is reduced availability of active phosphorylated
MLCK.
Hence myosin is not activated and it fails to interact with actin, as a result contraction does not occur.
The mechanism of action of nitrates can be summarized as follows:
Nitrates
Long-acting: Isosorbide dinitrate, isosorbide mononi- Denitrated in the smooth muscle trate, erythrityl tetranitrate,
pentaerythritol tetranitratecell and release
b-blockers: Propranolol, metoprolol, atenolol, acebutolol Nitric oxide
Calcium channel blockers: Amlodipine, verapamil, dil-
tiazem, nifedipine, felodipine, nitrendipine, nicardipine, stimulates

lacidipine
Potassium channel openers: Nicorandil
Others: Dipyridamole, trimetazidine, oxyfedrine
ORGANIC NITRATES
Organic nitrates are prodrugs and they include shortacting drugs like glycerol trinitrate and long-acting drugs like isosorbide
dinitrate, isosorbide mononitrate, erythri- Guanylyl cyclase
↓
Increased cGMP
↓
Dephosphorylation of myosin light chain
(Reduced Ca+ concentration in the cytosol)
↓
Relaxation of vascular smooth muscle fibres

tyl tetranitrate and pentaerythritol tetranitrate. Mainly venodilation Arterial dilation Dilatation of coronary
vessels
tors, but also cause arteriolar dilatation and as a result reduce both preload and after load.
Since nitroglycerin tablet disintegrates in liver its bioavailability is decreased but when it is kept under tongue it is well
absorbed from buccal mucosa. So, when nitroglycerin tablet is given sublingually it is more effective.
Mechanism of Action
 Nitrates decrease coronary vasoconstriction or spasm and increase perfusion of myocardium by relaxing coronary arteries.
Organic nitrates are rapidly denitrated enzymatically in the smooth muscle cell. This causes relaxation of the muscle and
there is release of reactive-free radical nitric oxide (NO) that activates cytosolic guanylyl cyclase.
There is increased intracellular cGMP and Ca21 entry is reduced.
This causes dephosphorylation of myosin light chain kinase (MLCK) through a cGMP-dependent protein kinase. Adverse
Effects
Adverse affects are mostly due to vasodilatation and are as follows:
Fullness in head, throbbing headache, some degree of tolerance on continued use
Flushing, weakness, sweating, palpitation, dizziness and fainting. These are mitigated by lying down and accentuated by
erect posture and alcohol.
Methemoglobinemia and reduced O2 carrying capacity of blood in severe anaemia
Rashes are rare though relatively more common with pentaerythritol tetranitrate.
Therapeutic Uses
Angina Pectoris
Nitrates are effective in exertional and Prinzmetal’s angina, i.e. classical as well as variant angina.
For aborting or terminating an anginal attack, sublingual nitroglycerin tablet (0.5 mg) or spray (0.4–0.8 mg) or isosorbide
dinitrate (5–10 mg) is taken on as and when required basis.
The only major action of nitrates is direct nonspecific smooth muscle relaxation. They are mainly venodila-

Glycerol trinitrate (nitroglycerin) produces relief within 3 min in 75% of patients. The rest may require another dose or take
longer time.
They increase exercise tolerance and postpone ECG changes of ischaemia. Longer acting formulations of glycerol
trinitrate or other nitrates are used orally on regular schedule for chronic prophylaxis. Even transdermal patches of glycerol
trinitrate containing 5–10 mg of the drug are available. One patch is applied for 14–16 h per day.
 The dosage of various drugs for chronic prophylaxis:
Glycerol trinitrate: 5–10 mg
Isosorbide dinitrate: 20–40 mg
Isosorbide 5 mononitrate: 20–40 mg
Erythrityl tetranitrate: 15–60 mg
Pentaerythritol tetranitrate: 80 mg Six to eight drug-free hours are advised to prevent development of tolerance and
dependence.
b. Congestive Cardiac Failure and Acute Left Ventricular Failure
Nitrates afford relief by causing venous pooling of blood that reduces venous return (preload). This in turn decreases end
diastolic volume. This causes an improvement in left ventricular function by Laplace’s law and regression of pulmonary
congestion.
Preparation of choice is 5–10 mg/min IV infusion of
glycerol trinitrate for emergency use.
c. Myocardial Infarction
IV infusion of glycerol trinitrate started soon after the atrial occlusion, prevents tachycardia and reduces the area
of necrosis by favourably altering balance in the marginal partially ischaemic zone by reducing cardiac work.
They do not alter the mortality but are used for relief of
angina.
d. Interventional Cardiac Procedures
Glycerol trinitrate is used as adjuvant therapy to dilate coronaries in percutaneous coronary angioplasty, thrombolytic therapy
of acute MI, etc.
e. Biliary Colic
Sublingual glycerol trinitrate or isosorbide dinitrate relieves the biliary colic produced due to disease states or morphine.
f. Oesophageal Spasm Sublingual glycerol trinitrate promptly relieves pain.
 Nitrates taken before a meal facilitate feeding in
oesophageal achalasia by reducing oesophageal tone.
g. Cyanide Poisoning
Nitrates generate methaemoglobin, which has high affinity for cyanide radical and forms cyanomethaemoglobin.
SHORT NOTES
Then sodium thiosulphate is given to prevent dissociation and release of cyanide by forming sodium thiocyanate which is
poorly dissociable and is excreted in urine. The antidote should be repeated as required. Thus cytochrome and other
oxidative enzymes are protected from cyanide.

Classify drugs used in treatment of angina pectoris. Or,

List three groups of drugs used in angina pectoris with one example for each
group.
Drugs used in the treatment of angina pectoris are classified as follows:
Nitrates
Short-acting: Glycerol trinitrate (GTN) or nitroglycerine
Long-acting: Isosorbide dinitrate (short-acting by sublingual route), isosorbide mononitrate, erythrityl tetranitrate,
pentaerythritol tetranitrate
b-blockers: Propranolol, metoprolol, atenolol
Calcium channel blockers
Phenylalkylamine: Verapamil
Benzothiazepine: Diltiazem
Dihydropyridines: Nifedipine, felodipine, amlodipine, nitrendipine, nimodipine, lacidipine
Potassium channel openers: Nicorandil
Others: Dipyridamole, trimetazidine, oxyfedrine
Q. 2. Nifedipine
Nifedipine is dihydropyridine, a class of calcium channel blockers (CCBs) which blocks voltage sensitive calcium channels.
Mechanism of Action
CCBs cause relaxation of smooth muscle by decreasing intracellular availability of Ca21.
Nifedipine releases NO from the vascular endothelium and inhibit cAMP-phosphodiesterase resulting in raised smooth muscle
cAMP.
Action on Heart
In the working atrial and ventricular fibres Ca21 moves in during plateau phase of action potential and it releases more Ca21
from sarcoplasmic retinaculum and causes contraction through binding to troponin and allowing interaction of myosin with
actin. Thus, nifedipine has negative inotropic action. The overriding action of nifedipine is arteriolar. The total peripheral
resistance decreases and BP falls. Reflex sympathetic stimulation of heart predominates and causes tachycardia, increased
cardiac contractility and cardiac output. As a net result coronary flow is increased.
It also has mild natriuretic action but does not produce
significant diuresis.
Pharmacokinetics
The bioavailability is 30–60%. All are highly plasma protein bound. All are . 90% metabolized in liver and excreted in
urine.
Adverse Effects
Palpitations, flushing, ankle oedema, hypotension, headache, drowsiness and nausea are frequent. These are related to peaks
of drug level in blood and can be minimized by low starting dose, fractionation of dose or use of retard formulations.
Paradoxically increases the frequency of angina in some patients. Increases the urine voiding difficulty in elderly males by
its relaxant action on the bladder.
Therapeutic Uses Angina Pectoris
Nifedipine is effective in reducing frequency and severity of classical as well as variant angina.
Benefit is primarily due to reduction in cardiac work as a result of reduced afterload in classical angina. They can increase
coronary flow in normal individuals. Exercise tolerance is increased. Capacity to prevent arterial spasm is beneficial in
variant angina. Nifedipine is used as add-on therapy in patients unresponsive to nitrates and b-blockers.
Hypertension: Nifedipine lowers BP by decreasing peripheral resistance without compromising cardiac output and
vasodilatation.
Other uses: Nifedipine is an alternative drug for premature labour.
Contraindications
Myocardial inadequacy CCF Conduction defects, sick sinus IHD, post-MI cases Left ventricular hypertrophy
Males with prostate enlargement Gastroesophageal reflux
Q. 3. Calcium channel blockers in cardiovascular disorders
Calcium channel blocking agents are the drugs which block voltage sensitive calcium channels.
They have wide application in the diseases of cardiovascular system. They are used as antiarrhythmic agents, antianginal drugs
and antihypertensives.
Classification of Calcium Channel Blockers (CCBs)
Phenylalkylamine: Verapamil
Benzothiazepine: Diltiazem
Dihydropyridines: Nifedipine, felodipine, amlodipine, nitrendipine, nimodipine, lacidipine
Pharmacological Actions
The common property of all three subclasses of CCBs is to inhibit Ca21-mediated slow channel component of action potential
in smooth and cardiac muscle cells.
The two most important actions of CCBs are as follows:
Smooth muscle relaxation
Negative chronotropic, inotropic and dromotropic action on heart
Mechanism of Action
Voltage sensitive Ca21 channels are of five subtypes. They are L, N, T, P and R subtypes. L type is predominantly present in
cardiac and smooth muscle cells.
Smooth Muscle
They markedly relax the arterioles but have mild effect on veins. Extravascular smooth muscles like bronchial, biliary,
intestinal, vesical, uterine are also relaxed. CCBs cause relaxation of smooth muscle by decreasing intracellular availability
of Ca21.
Nitrendipine and some other dihydropyridines (DHPs) release NO from the vascular endothelium and inhibit cAMP-
phosphodiesterase resulting in raised smooth muscle cAMP.
Heart
 In the working atrial and ventricular fibres Ca21 moves in during plateau phase of action potential. It releases more Ca21
from sarcoplasmic retinaculum and causes contraction through binding to troponin and allowing interaction of myosin with
actin. Thus CCBs have negative inotropic action.
CCBs have negative chronotropic and dromotropic action except DHPs.
Mechanism of action can be summarized as follows:

CCBs block voltage-sensitive L-type Ca+ channels by bind ing to specific site on the α1 subunit.

Prevent entry of Ca2+ into the cell.

No excitation–contraction coupling in the heart and vascular smooth muscles.

Therapeutic Uses
Angina Pectoris
Calcium channel blockers are effective in reducing frequency and severity of classical as well as variant angina.
Hypertension
Calcium channel blockers lower BP by decreasing peripheral resistance without compromising cardiac output and
vasodilatation.
Other Uses
They are alternative drugs for premature labour.
Q. 4. List one cardioselective and one nonselective b receptor antagonist.
Mention two therapeutic uses of them.

Cardioselective b-blockers
 Cardioselective b-blockers selectively block b 1 receptors and weakly b 2 receptors, e.g. atenolol, metoprolol and esmolol.
They are safe to use in diabetics as their inhibition of glycogenolysis is low and incidence of bronchospasm is less or
negligible. There is reduced chances of peripheral vascular diseases. The exercise performance impaired to a lesser
degree.
They are used in the treatment of cardiac arrhythmias,
angina pectoris and hypertension.
Nonselective Beta Receptor Antagonists
SHORT NOTES
They include drugs like timolol, nadolol, sotalol, propranolol. They are used in the treatment of glaucoma, anxiety,
pheochromocytoma, thyrotoxicosis and prophylaxis of migraine.

Nifedipine
 Nifedipine is dihydropyridine, a class of calcium channel blocker which blocks voltage sensitive calcium channels.
It acts by causing relaxation of smooth muscle by de-
creasing intracellular availability of Ca21.
Adverse Effects
Palpitations, flushing, ankle oedema, hypotension, headache, drowsiness and nausea are frequent.
Paradoxically increases the frequency of angina in some patients.
Increases the urine voiding difficulty in elderly males by its relaxant action on the bladder.
Therapeutic Uses
Angina pectoris
Hypertension
As an alternative drug for premature labour
Q. 2. Name of drugs causing gingival hyperplasia.
 Noninflammatory type of gingivitis or drug induced gingival hyperplasia is caused by three groups of drugs: anticonvulsants,
antihypertensives and immunosuppressants.
Anticonvulsants: Phenytoin sodium, phenobarbitone, carbamazepine, sodium valproate, primidone
Antihypertensives: Nifedipine, amlodipine, nimodip-
ine, nicardipine, diltiazem
Immunosuppressants: Cyclosporine
Q. 3. Nitroglycerine
Nitroglycerine or glycerol trinitrate is a short-acting antianginal drug that is converted to nitric oxide to cause relaxation of
vascular smooth muscles which leads to vasodilation, mainly that of veins.
This venodilation reduces venous return and reduces the preload on the heart. When nitroglycerine tablet is given
sublingually it is more effective as it is well absorbed from buccal mucosa.
 Uses: Nitroglycerine is used in the treatment of angina, cardiac failure, myocardial infarction and cyanide poisoning.
Q. 4. Name organic nitrates used in the treatment of angina pectoris.

The organic nitrates used in the treatment of angina pectoris are as follows:
Short-acting: Glycerol trinitrate (nitroglycerine)
Long-acting: Isosorbide dinitrate, isosorbide mononitrate, erythrityl tetranitrate, pentaerythritol tetranitrate
Q. 5. Cardioselective b-blockers
Cardioselective b–blockers selectively block b 1 receptors and weakly b 2 receptors, e.g. atenolol, metoprolol and esmolol.
They are safe to use in diabetics as their inhibition of glycogenolysis is low and incidence of bronchospasm is less or
negligible.

Antihypertensive Drugs
LONG ESSAY
They are used in the treatment of cardiac arrhythmias, angina pectoris and hypertension.

Classify antihypertensive drugs. Describethe pharmacological actions of any two commonly

used drugs.
Or,
Classify the drugs used on the treatment of hypertension. State the
mechanism of action, indications and adverse effects of any three of
them. Or,
Classify the drugs used in hypertension. Write the pharmacological actions and adverse
effects of angiotensin converting enzyme (ACE) inhibitors.
 Hypertension is a very common disorder, particularly past middle age. Hypertension is not a disease in itself but is an
important risk factor for cardiovascular morbidity and mortality.
Hypertension risk appears to increase progressively with BP values over 120/80 mm Hg.
Hypertension has been defined by WHO-ISH guidelines to be values above 140/90 mm Hg.
ANTIHYPERTENSIVE DRUGS
These are the drugs used to lower BP in hypertension.
Classification of antihypertensive drugs is as follows:
ACE inhibitors: Captopril, enalapril, lisinopril, perindo-
pril, ramipril
Angiotensin (AT1) antagonists: Losartan, candesartan, irbesartan, valsartan
Calcium channel blockers: Verapamil, diltiazem, nifedipine SR, felodipine, amlodipine, nitrendipine, lacidipine
Diuretics
Thiazides: Hydrochlorothiazide, chlorthalidone, indapamide
High ceiling (loop) diuretics: Frusemide, bumetanide, torsemide
Potassium sparing diuretics: Amiloride, triamterene, spironolactone
b adrenergic blockers: Propranolol, metoprolol, atenolol b 1 a adrenergic blockers: Labetalol, carvedilol
a adrenergic blockers: Prazosin, terazosin, doxazosin, phentolamine, phenoxybenzamine
Central sympatholytics: Clonidine, methyldopa ix. Vasodilators:
Arteriolar: Hydralazine, minoxidil, diazoxide
Arteriolar 1 venous: Sodium nitroprusside
Detail description of few antihypertensive drugs is as follows:
A. DIURETICS
Diuretics act as antihypertensives as follows:
Thiazide Diuretics
 Thiazides are the first-line antihypertensives. They are used in uncomplicated mild to moderate hypertension and have a
long duration of action.

Mechanism of Action
Diuretics enhance the excretion of sodium and water resulting in
gPlasma volume n g Cardiac output n g BP or
gBody sodium n Relaxation of vascular smooth muscles (due to Na1 depletion) gPVR n BP.
Adverse Effects
Hypokalaemia, hyperglycaemia, hyperuricaemia, hyperlipidaemia, impotence and decreased libido
Loop Diuretics
These have shorter duration of action. Therefore, they are not used in hypertension except in the presence of renal or cardiac
failure.
B. SYMPATHOLYTIC DRUGS
i. Drugs Acting Centrally
Clonidine Clonidine, an imidazoline derivative, is a selective a2 agonist. It is centrally-acting antihypertensive drug.
Major haemodynamic effects result from stimulation of a 2 receptors in the CNS. They decrease central sympathetic
outflow, block the release of noradrenaline from the nerve terminals leading to a fall in BP and bradycardia.
a -methyldopa: It is a prodrug and is an analogue of dopa. It is metabolized in the body to a -methyl norepinephrine which is an
a 2 agonist and acts like clonidine.
Ganglion Blockers
Trimethaphan: These drugs block both sympathetic and parasympathetic ganglia resulting in decreased sympathetic tone and a
fall in BP. It has rapid and short duration of action (15 min).
Adrenergic Neuron Blockers
Guanethidine: This depletes the stores of noradrenaline in the adrenergic neurons and also blocks its release. Because of the
adverse effects like postural hypertension diarrhoea and sexual dysfunction, it is not used.
Reserpine: This is an alkaloid obtained from Rauvolfia serpentina (sarpagandha) that grows in India. In the neurons it binds to
the vesicles that store monoamines like noradrenaline, dopamine and 5-HT and destroys these vesicles. It thus depletes the
stores of these monoamines.
iv. Adrenergic Receptor Blockers
b-blockers: These are mild antihypertensives. They reduce the BP due to a fall in the cardiac output. They also lower plasma
renin activity and have an additional central antihypertensive action.
a -blockers: Prazosin is a selective a 1 blocker. It dilates both arterioles and venules. Peripherally vascular resistance is
decreased leading to a fall in BP with only mild tachycardia.
a - and b -blockers: Labetalol blocks both a 1 and b receptors. It is used in treatment of hypertension in pheochromocytoma and
in hypertensive emergencies.
v. Vasodilators
They reflex the vascular smooth muscles thus reducing BP due to decreased peripheral resistance.
Hydralazine is a directly acting arteriolar dilator. The fall in BP is associated with tachycardia, renin release and fluid retention.
Minoxidil is a directly acting arteriolar dilator used in severe hypertension not responding to other drugs. It acts by opening the
K1 channels.
Diazoxide is a relative thiazide diuretic and is potent arteriolar dilator. It is used in hypertensive emergencies.
Sodium nitroprusside is a rapidly acting vasodilator. It dilates both arterioles and venules. Both peripheral resistance and
cardiac output are reduced resulting in lower myocardial oxygen consumption.
Calcium Channel Blockers
These are important antihypertensive drugs that dilate the arterioles resulting in reduced peripheral vascular resistance.
Nifedipine produces reflex tachycardia.
Angiotensin Converting Enzyme
(ACE) Inhibitors
Angiotensin II is powerful vasoconstrictor. Aldosterone also rises the BP by increasing plasma volume.
ACE inhibitors prevent the formation of angiotensin II and aldosterone. ACE inhibitors also raise bradykinin levels all of
which contribute to the fall in BP.
It maintains adequate blood flow to the vital organs like kidney, brain and heart.
ACE inhibitors are well absorbed in the body. Except captopril and lisinopril all the other ACE inhibitors are prodrugs.
The duration of action varies for each drug, captopril acts for about 6–12 h, lisinopril with a duration more than 24 h, enalapril
acts for 24 h and ramipril for about 8–48 h.
Uses
Hypertension
Congestive cardiac failure
Myocardial infarction
Adverse Effects
Persistent dry cough
Hyperkalaemia Alteration in the taste
Skin rashes, headache, nausea, abdominal pain
Hypotension
Blood disorders
viii. Angiotensin II Receptor Antagonists
Losartan is an angiotensin II antagonist. It relaxes smooth muscles, promotes salt and water excretion and reduces plasma
volume. Thus there is a fall in BP.
SHORT ESSAYS
Captopril
Captopril is an angiotensin converting enzyme (ACE) inhibitor.
 Captopril prevents the generation of angiotensin II which is a powerful vasoconstrictor. There is vasodilation and decrease in
PVR resulting in decrease in BP.
It also inhibits the degradation of bradykinin, which is a potent vasodilator and stimulates the synthesis of vasodilating PGs
through bradykinin.
It reduces sympathetic nervous system activity, all of which contribute to the fall in BP. Captopril is not a prodrug. Its
daily dose in hypertension is about 12.5–50 mg BD and duration of action lasts from about 6 to 12 h.
Mechanism of Action
ACE inhibitors also reduce aldosterone production, hence sodium and water retention. Captopril-induced hypotension is a
result of decrease in total peripheral resistance.
The arterioles dilate and compliance of larger arteries is increased. Both systolic and diastolic BP fall. It has no effect on
cardiac output. Cardiovascular reflexes are not interfered with and there is little dilatation of capacitance vessels. As such,
postural hypotension is not a problem. The renal blood flow is not compromised even when BP falls substantially. Cerebral and
coronary blood flow also not compromised.
Adverse Effects
Persistent brassy dry cough Hypotension
Hyperkalaemia
Alteration of taste sensation, urticaria, skin rashes and angioedema
Headache, dizziness, nausea, abdominal pain and bowel upset Blood disorders like granulocytopenia and proteinurea
Q. 2. Calcium channel blocking drugs in treatment of hypertension
Calcium channel blockers are important antihypertensive drugs that dilate the arterioles resulting in reduced peripheral
vascular resistance, e.g. verapamil, diltiazem and dihydropyridines. Dihydropyridines like nifedipine, amlodipine,
felodipine, nicardipine, etc. are preferred among calcium channel blockers because of their more selective action on blood
vessels. The long-acting DHPs are often used as first-line antihypertensive drugs.
 The antihypertensive effect of DHPs is mainly due to the reduction of total peripheral resistance.
Nifedipine produces some reflex tachycardia, though it is not seen with verapamil or diltiazem as they are cardiac
depressants. Fluid retention is negligible compared to other arteriolar dilators. They are well tolerated, safe and effective.
They have special value in people who also have angina.
Calcium channel blockers are used in treatment of short periods to control hypertension.
Nifedipine is administered sublingually and is used in patients for hypertensive emergencies. It effectively lowers BP in 10
min.
Q. 3. List two centrally acting antihypertensive drugs. Mention the adverse effects of
anyone of them.

Drugs acting centrally to reduce BP are clonidine and a-methyl dopa.

Clonidine
Clonidine, an imidazoline derivative, is a selective a 2 agonist. Stimulation of a 2 receptors in the CNS (in the vasomotor centre
and hypothalamus), decreases central sympathetic outflow, blocks the release of noradrenaline from the nerve terminals
leading to a fall in BP and bradycardia.
Adverse Effects
Drowsiness
Dryness of eyes (xerophthalmia), mouth, nose Parotid gland swelling and pain Fluid retention Constipation
Impotence
a -Methyl Dopa
This is an analogue of dopa prodrug. It is metabolized in the body to a -methyl norepinephrine which is an a 2 agonist and acts
like clonidine.
Adverse Effects
Sedation
 Dryness of eyes (xerophthalmia), mouth, nose Postural hypotension Impotence
Fluid retention Headache
Q. 4. Rationale of using clonidine in hypertension
Clonidine, an imidazoline derivative, is a selective a 2 agonist. Stimulation of a 2 receptors in the CNS (in the vasomotor
centre and hypothalamus); decreases central sympathetic outflow; blocks the release of noradrenaline from the nerve terminals
leading to a fall in BP and bradycardia.
Adverse effects are lesser compared to other antihypertensives and include drowsiness, dryness of eyes (xerophthalmia),
mouth, nose, parotid gland swelling and pain, fluid retention, constipation and impotence.
In addition it has other benefits like it reduces withdrawal symptoms of opioid analgesics, may be used in diabetic
neuropathy, it stimulates the a 2 receptors in the intestine to improve NaCl and water absorption thus controlling diarrhoea.
Q. 5. Rationale of using b-blockers in hypertension
b-blockers are the first- line of drugs used to treat patients with mild hypertension, e.g. propranolol, atenolol, metoprolol.
 They reduce the cardiac output and lower the plasma rennin activity. These two actions help in reducing the BP.
They can also be used in patients with angina and cardiac arrhythmias.
They can be used in combination with other antihypertensive drugs.
They are well tolerated and do not have many adverse effects.
Due to these reasons b-blockers like propranolol and
atenolol are used in treatment of hypertension.
Q. 6. Prazosin
Or,
What is prazosin? Mention one therapeutic use of it.

Prazosin is a selective a1 adrenergic blocker used in the treatment of mild to moderate hypertension.
 It is a vasodilator as it dilates both arterioles and venules thus decreasing the peripheral resistance that helps in reducing the
BP.
Prazosin dosage is started with an initial dose of 0.5 mg given at bed time. The dosage is gradually increased. Prazosin
can be used in combination with diuretics and b-blockers. It is usually combined with b-blockers in cases of emergency and in
pheochromocytoma.
Q. 7. Propranolol
Propranolol is a b-blocker and is the first-line of drug used to treat patients with mild hypertension.
It reduces the BP by decreasing the cardiac output and lowering the plasma rennin activity.
It can also be used in patients with angina and cardiac arrhythmias.
SHORT NOTES
Clonidine Stimulation of a2 receptors in the CNS and decreases central sympathetic outflow; blocks the release of nor
adrenaline from the nerve terminals leading to a fall in
 Clonidine, an imidazoline derivative, is a selective a2 BP and bradycardia.
agonist. Adverse effects are lesser compared to other antihy-
pertensives and include drowsiness, dryness of eyes
It is usually used in combination with other antihypertensive drugs. It is well tolerated and does not have many adverse
effects. Its dosage is usually tapered while withdrawing. (xerophthalmia), mouth, nose, parotid gland swelling and pain, fluid
retention, constipation and impotence.
In addition it has other benefits like it reduces withdrawal symptoms of opioid analgesics, may be used in diabetic
neuropathy.
Q. 2. Reserpine
Reserpine is an alkaloid obtained from an Indian plant called Rauvolfia serpentina.
The monoamine stores which store noradrenaline, dopamine and 5-hydroxytryptamine are depleted by the destruction of the
vesicles by reserpine.
 It is not usually preferred due to high incidence of adverse effects like drowsiness, depression, oedema, parkinsonism,
postural hypotension and impotence.
Q. 3. Mention two uses and two adverse effects of thiazide.
Chlorothiazide, hydrochlorothiazide and chlorthalidone are the thiazides used in the treatment of hypertension.
Uses
Thiazide diuretics are used in the treatment of mild hypertension. It takes about 2–4 weeks for the blood pressure to
decrease by about 15–20 mm of Hg. They decrease the plasma volume that decreases the cardiac output and decrease the
body sodium that reduces the PVR, both processes causing excretion of sodium and water from the body leading to fall in BP.
Adverse Effects
Hypokalaemia, hyperglycaemia, hyperuricaemia, hyperlipidaemia, impotence and decreased libido.
Q. 4. Name four drugs used in hypertension.
Drugs used in hypertension are as follows:
ACE inhibitors: Enalapril, lisinopril, perindopril, ramipril
Calcium channel blockers: Verapamil, diltiazem, nifedipine, felodipine, amlodipine, nitrendipine, lacidipine
Diuretics
Thiazides: Hydrochlorothiazide, chlorthalidone, in-
dapamide
High ceiling: Frusemide
b adrenergic blockers: Propranolol, metoprolol, atenolol
Q. 5. Enalapril
Enalapril is an angiotensin converting enzyme (ACE) inhibitor which prevents the formation of angiotensin II and raises
bradykinin levels which contributes to the fall in BP.
It maintains adequate blood flow to the vital organs like kidney, brain and heart. It is well absorbed in the body.
Uses
Hypertension Congestive cardiac failure Myocardial infarction
Adverse Effects
Persistent dry cough
Hyperkalaemia
Alteration in the taste
Q. 6. Captopril
Captopril is an angiotensin converting enzyme (ACE) inhibitor which prevents the formation of angiotensin II and raises
bradykinin levels which contributes to the fall in BP.
It maintains adequate blood flow to the vital organs like kidney, brain and heart.
It is well absorbed in the body. Unlike all the ACE
inhibitors it is not a prodrug and acts for 6–12 h.
Uses
Hypertension Congestive cardiac failure Myocardial infarction
Adverse Effects
Persistent dry cough
Hyperkalaemia
Alteration in the taste
Q. 7. Chlorothiazide diuretics in hypertension Or, Mention thiazidesas an antihypertensive
drug.

Chlorothiazide, hydrochlorothiazide and chlorthalidone are the thiazides used in the treatment of hypertension.

Section | IV
 Chlorothiazide is a thiazide diuretic that is used in the PVR, both processes causing excretion of sodium and treatment of
mild hypertension. water from the body leading to fall in BP.
It decreases the plasma volume that decreases the cardiac They may cause hypokalaemia and hence they are to be
output and it decreases the body sodium that reduces the used in combination with potassium sparing diuretics like
spironolactone, amiloride and triamterene.
Part IX
Diuretics and Antidiuretics

Diuretics and Antidiuretics

SHORT ESSAYS

Classify diuretics and write mechanism of action of thiazides.

The drugs that increase urine and solute excretion causing loss of sodium and water from the body are called diuretics.
CLASSIFICATION OF DIURETICS
Based on the efficacy of action diuretics are classified as follows:
High efficacy (loop) diuretics
Sulphamoyl derivatives: Frusemide, bumetanide
Phenoxyacetic acid derivatives: Ethacrynic acid
Organomercurials: Mersalyl
Medium efficacy diuretics
Benzothiadiazines (thiazides): Chlorothiazide, hydrochlorothiazide, polythiazide, benzthiazide, hydroflumethiazide, clopamide
Thiazide-like drugs (related heterocyclics): Chlortha-
lidone, indapamide, metolazone, xipamide
Low efficacy or weak or adjunctive diuretics
Potassium sparing diuretics: Triamterene, amiloride,
spironolactone
Carbonic anhydrase inhibitors: Acetazolamide
Osmotic diuretics: Mannitol, urea, isosorbide, glycerol
Xanthines: Theophylline
MECHANISM OF ACTION OF THIAZIDES
Thiazides are medium efficacy diuretics that act in the early parts of distal convoluted tubule and inhibit the Na1Cl2 symport
and increase sodium and chloride excretion. They act in two ways to prevent uptake and induce excretion of sodium and
chloride ions as follows:
By the organic acid secretory pathway: They are initially secreted in the proximal convoluted tubule, from there they are
transported to the distal convoluted tubule via tubular fluid where they bind to the sodium and chloride symporter situated on
the membrane. This inhibits the uptake of sodium and chloride ions by the cells and promotes their excretion.
They have weak carbonic anhydrase inhibitory action in the proximal convoluted tubule. This causes increased amounts of
sodium that is presented to the distal convoluted tubule. Here again the sodium chloride symporter is inhibited and they are
excreted in the urine.
The sodium presented to the distal convoluted tubule may also be exchanged for potassium ions which may be excreted in the
urine. This may lead to hypokalaemia. There is a net loss of Na1, K1Cl2, HCO32 in the urine. This is the reason for which
thiazides are usually combined with potassium sparing diuretics.
Q. 2. Compare frusemide and spironolactone.
Frusemide and spironolactone are compared based on parameters which are given in Table 35.1.
TABLE 35.1 Comparison between Frusemide and
Spironolactone
Parameters Frusemide Spironolactone
Type High ceiling (loop) diuretic Weak or adjuvant potassium sparing diuretic
Mechanism of action Inhibits Na1–K1–2Cl cotransport Antagonizes the action of aldosterone
Site of action Thick ascending limb of Henle’s loop Late section of distal convoluted tubule and collecting duct
cells
Free water clearance Blockade of positive and negative free water clearance No effect on free water clearance
Excretion of electrolytes Excretes sodium, potassium and chloride ions Excretes sodium and chloride ions but retains
potassium ions
Glomerular filtration rate Unchanged Decreases
Enterohepatic circulation Absent Present
Adverse effects Acute salt depletion— hypokalaemia, hypocalcaemia, hepatic coma in cirrhotics, photosensitivity, headache,
giddiness, nausea, vomiting,
paraesthesia, impotence Hyperkalaemia, acidosis, peptic ulcer, stomach upset, drowsiness, confusion, hirsutism,
gynaecomastia, impotence, menstrual
irregularities
Uses Oedema—acute pulmonary and cerebral oedema, hypertension, forced diuresis, hypercalcaemia and renal stones
along with blood transfusion to prevent vascular overload More useful in
oedema—
cirrhotic and nephrotic oedema, hypertension, to counteract potassium loss due to thiazide and loop diuretics, congestive
cardiac failure
Q. 3. Compare chlorothiazide and spironolactone.
Chlorothiazide and spironolactone are compared based on parameters which are given in Table 35.2.
TABLE 35.2 Comparison between Chlorothiazide and
Spironolactone
Parameters to Be
Compared Spironolactone Chlorothiazide
Type and efficacy Weak or adjuvant— potassium sparing diuretic Medium efficacy— thiazide diuretic
Parameters to Be
Compared Spironolactone Chlorothiazide
Mechanism of action Antagonizes the action of aldosterone Inhibits Na1Cl2 symport
Site of action Late section of distal convoluted tubule and collecting duct Early section of distal convoluted tubule
Free water clearance No effect on free water clearance No effect on negative free water clearance but decreases
positive free water clearance
Excretion of electrolytes Excretes sodium and chloride but retains potassium ions Excretes sodium, potassium and
chloride ions
Carbonic anhydrase inhibitory action Present Absent
Adverse effects Acute salt depletion— hypokalaemia, hypocalcaemia hepatic coma in cirrhotics, photosensitivity, headache,
giddiness, nausea, vomiting, paraesthesia, impotence Acute salt depletion— hypokalaemia, hypocalcaemia, hepatic coma in
cirrhotics, photosensitivity, headache, giddiness, nausea, vomiting,
paraesthesia, impotence
Uses More useful in
oedema—
cirrhotic and nephrotic oedema, hypertension, to counteract potassium loss due to thiazide and loop diuretics, congestive
cardiac failure Oedema, hyperten-
sion, diabetes insipidus, hypercalcaemia and renal stones
Q. 4. Chlorothiazide
Chlorothiazide is a drug of thiazide group of medium efficacy diuretics. The primary site of action of these diuretics is
cortical diluting segment or the early DT. They inhibit the Na1Cl2 symport at the luminal membrane.
 It acts in two ways to increase sodium and chloride excretion from the body as follows:
It is secreted initially in the proximal convoluted tubule by the organic acid secretory pathway. From here it is transported to
the distal convoluted tubule where it binds to the sodium and chloride symporter situated on
Section | IV
the membrane. This inhibits the uptake of sodium and chloride ions by the cells and promotes its excretion.
It has weak carbonic anhydrase inhibitory action in the proximal convoluted tubule. This causes increased amounts sodium that
is presented to the distal convoluted tubule. Here again the sodium chloride symporter is inhibited and they are excreted in the
urine. The sodium presented to the distal convoluted tubule may also be exchanged for potassium ions which may be excreted
in the urine. This may lead to hypokalaemia. For this reason chlorothiazide is usually combined with potassium sparing
diuretics like spironolactone, amiloride and triamterene.
Uses of Chlorothiazide
Oedema: Thiazides are the preferred drugs for treating mild to moderate cases of oedema. They are used to reduce oedema
caused by congestive cardiac failure (CCF).
Hypertension: It is one of the first-line drugs used in the treatment of mild hypertension. It takes about 2–4 weeks for the blood
pressure to decrease by about 15–20 mm of Hg. It decreases the plasma volume that decreases the cardiac output and it
decreases the body sodium that reduces the peripheral vascular resistance (PVR), both processes causing excretion of sodium
and water from the body leading to fall in BP.
Hypercalciuria: It is used in treating hypercalciuria with recurrent calcium stones in the kidney as it acts by reducing calcium
excretion.
Diabetes insipidus: It is used in treatment of diabetes insipidus as it reduces plasma volume and glomerular filtration rate
(GFR).
Adverse Effects
Thiazides cause electrolytic disturbances which include hypokalaemia, hyponatraemia, i.e. acute salt depletion, metabolic
alkalosis, hypomagnesaemia and hypercalcaemia.
Hypokalaemia is more common with thiazides because of its long duration of action.
Hypercalcaemia is due to decreased urinary excretion of Ca21.
The metabolic disturbances are also same as that of loop diuretics—hyperglycaemia, hyperlipidaemia and
hyperuricaemia.
They may cause photosensitivity, headache, giddiness, nausea, vomiting, paraesthesia and impotence.
Q. 5. Compare hydrochlorothiazide and frusemide.
Comparison between and hydrochlorothiazide and frusemide is listed in Table 35.3.
TABLE 35.3 Comparison between Hydrochlorothiazide and Frusemide
Parameter to Be Compared Frusemide Hydrochlorothiazide
Type High ceiling (loop) diuretic Medium efficacy thiazide diuretic
Mechanism of action Inhibits Na1–K1– 2Cl cotransport Inhibits Na1Cl2 symport
Site of action Thick ascending limb of Henle’s loop Early section of distal convoluted tubule
Free water clearance Blockade of positive and negative free water clearance No effect on negative free water
clearance but decreases positive free water clearance
Excretion of electrolytes Excretes sodium, potassium and chloride ions Excretes sodium, potassium and chloride
ions
Glomerular filtration rate Unaltered Decreases
Glucose levels Increases and causes hyperglycaemia No effect on glucose levels
Adverse effects Acute salt depletion— hypokalaemia, hypocalcaemia hepatic coma in cirrhotics, photosensitivity, headache,
giddiness, nausea, vomiting,
paraesthesia, impotence Acute salt depletion— hypokalaemia, hypocalcaemia hepatic coma in cirrhotics, photosensitivity,
headache, giddiness, nausea, vomiting,
paraesthesia, impotence
Uses Oedema—acute pulmonary and cerebral oedema, hypertension, forced diuresis, hypercalcaemia and renal stones,
during blood transfusion Oedema, hyperten-
sion, diabetes insipidus, hypercalcaemia and renal stones
Q. 6. Compare frusemide and triamterene.
Comparison between frusemide and triamterene is listed in Table 35.4.
TABLE 35.4 Comparison between Frusemide and
Triamterene
Parameters to Be
Compared Frusemide Triamterene
Type High ceiling (loop) diuretic Low ceiling potassium sparing diuretic
Mechanism of action Inhibits Na1–K1– 2Cl cotransport Inhibits sodium channels on the renal epithelium
Parameters to Be
Compared Frusemide Triamterene Parameters to Be
Compared Frusemide Triamterene
Site of action Thick ascending limb of Henle’s loop Early section of distal convoluting tubule Adverse
effects Acute salt depletion— hypokalaemia, hypocalcaemia, hepatic coma in cirrhotics, photosensitivity, headache,
giddiness, nausea, vomiting, paraesthesia, impotence Muscle cramps, increased blood urea levels, photosensitivity,
hyperkalaemia, impaired glucose tolerance
Free water clearance Blockade of positive and negative free water clearance No effect on positive or negative
free water clearance
Excretion of electrolytes Excretes sodium, potassium and chloride ions Excretes sodium and chloride ions, but does
not allow potassium secretion
 Uses Oedema—acute pulmonary and cerebral oedema, hypertension, forced diuresis,
hypercalcaemia and renal stones, during blood transfusion It is used in the treatment of hypertension along with other
diuretics to reduce potassium loss, in renal oedema and cirrhosis
Glomerular filtration rate Unaltered Decreases
Glucose levels Increases and causes hyperglycaemia No effect on glucose levels

SHORT NOTES
Mention two therapeutic uses and two adverse effects of frusemide.

Frusemide is a high efficacy loop diuretic that acts in the Henle’s loop to inhibit the sodium-potassium-chloride ion
cotransport.
Therapeutic Uses
Oedema: During the initial stages of renal, hepatic and cardiac oedema loop diuretics are preferred.
May be used in cerebral oedema.
Hypertension: Frusemide is used in the presence of renal failure, congestive cardiac failure (CCF) or hypertensive emergency.
Forced diuresis
Hypercalcaemia and renal stones
Adverse Effects
Electrolyte disturbances like acute salt depletion, hypokalaemia, hyponatraemia and hypocalcaemia
Metabolic disturbances like hyperglycaemia, hyperuricaemia and hyperlipidaemia
Ototoxicity and hypersensitivity
Headache, giddiness, nausea, vomiting, paraesthesia and impotence
Q. 2. Chlorothiazide
 Chlorothiazide is a drug of thiazide group of medium efficacy diuretics. The primary site of action of these diuretics is
cortical diluting segment or the early DT.
They inhibit the Na1Cl2 symport at the luminal mem-
brane.
Uses
Oedema: Thiazides are the preferred drugs for treating mild to moderate cases of oedema. They are used to reduce oedema
caused by congestive cardiac failure (CCF).
Hypertension: It is one of the first-line drugs used in the treatment of mild hypertension.
Hypercalciuria: It is used in treating hypercalciuria with recurrent calcium stones in the kidney as it acts by reducing calcium
excretion.
Diabetes insipidus: It is used in treatment of diabetes insipidus as it reduces plasma volume and glomerular filtration rate
(GFR).
Adverse Effects
Thiazides cause electrolytic disturbances which include hypokalaemia, hyponatraemia, metabolic alkalosis, hypomagnesaemia
and hypercalcaemia.
Hypokalaemia is more common with thiazides because of its long duration of action.
Hypercalcaemia is due to decreased urinary excretion of Ca21.
Section | IV
The metabolic disturbances are also same as that of loop diuretics—hyperglycaemia, hyperlipidaemia and hyperuricaemia.
It may cause impotence, hence is not preferred antihypertensive in young males.
Q. 3. Potassium sparing diuretics
Potassium sparing diuretics do not cause excretion of potassium from the body and hence are named so. They include
spironolactone, triamterene and amiloride.
 Aldosterone facilitates reabsorption of sodium and secretion of potassium. Spironolactone acts by inhibiting the action of
aldosterone.
Triamterene and amiloride act directly by enhancing sodium excretion and reduce the loss potassium.
Uses: They are mostly used along with thiazides and loop diuretics to prevent potassium loss, oedema, hypertension and
aldosteronism.
Q. 4. Spironolactone
Spironolactone is an aldosterone antagonist which competes with aldosterone by binding to the receptors in the distal
convoluting tubule and collecting duct.
It inhibits the action of aldosterone and hence stops the reabsorption of sodium and potassium secretion.
It is a low efficacy diuretic. It is generally used along with other diuretics to reduce the loss of potassium caused by them.
Uses
It can be used in treatment of hypercalcaemia and renal stones.
It can be used along with other diuretics in the treatment of hypertension, to reduce hypokalaemia.
It is used in the treatment of aldosteronism.
Adverse Effects
Drowsiness, hyperkalaemia in patients with renal insufficiency, gynaecomastia, skin rashes
Q. 5. Osmotic diuretics
Osmotic diuretics help to retain water in the proximal convoluted tubule and the descending limb of the Henle’s loop by
osmosis. This causes water diuresis and loss of sodium. They include inert drugs like mannitol, urea and glycerol.
They are ineffective when administered orally as they cannot be absorbed and hence are given IV.
Uses
They are used to maintain urine volume and prevent oliguria during haemolysis and shock.
They are used in the reduction of intracranial and intraocular pressure.
Adverse Effects
Dehydration, ECF volume expansion, headache and hyperallergic reactions.
Q. 6. Mannitol
Mannitol helps to retain water in the proximal convoluted tubule and the descending limb of the Henle’s loop by osmosis.
This causes water diuresis and loss of sodium.
They are ineffective when administered orally as they
cannot be absorbed and hence are given IV.
Uses
They are used to maintain urine volume and prevent oliguria during haemolysis and shock.
They are used in the reduction of intracranial and intraocular pressure.
Adverse Effects
Dehydration, ECF volume expansion, headache and hyperallergic reactions
Q. 7. Loop diuretics. Name two loop diuretics. Mention two uses of
them.

Loop diuretics are high efficacy diuretics that act by inhibiting sodium chloride reabsorption in the ascending limb of
Henle’s loop and stop the sodium potassium chloride ion cotransport.
They include frusemide, bumetanide, piretanide, ethacrynic acid and mersalyl.
They block positive and negative free water clearance and promote excretion of sodium potassium and chloride ions. In
addition they cause loss of water and salts like calcium and magnesium. Given IV they are rapid acting taking about 2–5 min
to act, while when given orally they are slow acting as it takes long time to be absorbed and to reach the site of action it takes
about 3–6 h.
Uses
They are used in the treatment of cardiac, cerebral, hepatic and renal oedema. It reduces pulmonary oedema by vasodilator and
diuretic effect.
It is used in the treatment of hypertension along with potassium sparing diuretics.
It is used in cases of hypercalcaemia, renal stones and hyperkalaemia.
They are used in cases of poisoning with barbiturates to induce forced diuresis.
Q. 8. Name four diuretics. Enlist three diuretic drugs and one different use
for each.

Diuretics are drugs that increase urine and solute excretion causing loss of sodium and water from the body.
Classification
Diuretics are classified based on the efficacy of action as follows:
High efficacy (loop) diuretics: Frusemide, bumetanide, piretanide, ethacrynic acid, mersalyl
Use: They are used in treatment of pulmonary, cardiac, renal and hepatic oedema, in poisoning with barbiturates to enhance
forced diuresis, in treatment of hypertension.
Moderate efficacy diuretics
Thiazides: Benzothiadiazines like chlorothiazide,
hydrochlorothiazide, polythiazide, bendroflumethiazide
Thiazide-related drugs: Chlorthalidone, clopamide, indapamide, metolazone, xipamide Use: Used in the treatment of mild
hypertension, oedema due to congestive cardiac failure, renal stones due to hypercalciuria, diabetes insipidus.
Low efficacy diuretics
Potassium sparing diuretics: Triamterene, amiloride, spironolactone
Use: They are used along with other diuretics in hypertension to reduce loss of potassium and in treatment of aldosteronism.
Carbonic anhydrase inhibitors: Acetazolamide Use: They are used to inhibit formation of aqueous humour and cerebrospinal
fluid (CSF) and reduce intraocular pressure and intracranial pressure respectively.
Osmotic diuretics: Mannitol, urea, glycerol Use: They are used in the treatment of cranial and intraocular pressure.
Methylxanthines: Theophylline
Q. 9. Rationale of combining thiazideswith spironolactone Or, Spironolactone with
frusemide
Thiazides and frusemide cause excess excretion of potassium from the body. The sodium presented to the distal convoluted
tubule may also be exchanged for potassium ions which may be excreted in the urine. This may lead to hypokalaemia.
Spironolactone reduces potassium loss by inhibiting the action of aldosterone that is responsible for potassium secretion.
Part X
Drugs Affecting Blood and Blood Formation

Haematinics and Erythropoietin

LONG ESSAY
 Explain the mechanism of iron absorption and Iron is essential component of
haemoglobin, myoglostorage in the body. Add a note on different iron prepa-
bin and a number of enzymes necessary for oxygen rations. transfer.
Total amount of iron in the body is 2.5–5 g, two-thirds of which is present in haemoglobin.
Iron, vitamin B12 and folic acid are essential for normal Each molecule of haemoglobin has four iron-containing
erythropoiesis. residues.
This is why thiazides are usually combined with potassium sparing diuretics like spironolactone, amiloride and triamterene.
Section | IV
DIETERY SOURCES OF IRON
Liver, egg yolk, meat, fish, chicken, spinach, dry fruits, wheat and apple
PHARMACOKINETICS
Absorption and Storage (Fig 36.1)
 Only 10% of iron is absorbed as haeme or as inorganic iron. Dietary iron exists in the ferric form, which is reduced to
ferrous iron with the help of HCl in the stomach.
Absorption of most of the iron takes place in the duodenum and upper jejunum.
Iron absorption is regulated by a protein apoferritin in the intestinal mucosal cells. Ferrous iron is oxidized in the mucosal
cells to ferric iron and it combines with apoferritin to form ferritin. Iron will be in the mucosal cells for a long time and is
very slowly released in to plasma. The released iron in the plasma is oxidized again to ferric iron which gets incorporated into
transferring, a transport protein.
This transferrin is taken up by various tissues like reticulocytes in the bone marrow for haemoglobin synthesis,
reticuloendothelial cells in liver, spleen, etc. and stored. Small amount of iron is excreted from the body mainly by shedding
of GI mucosal cells, desquamated skin, very little in the bile, sweat and least in urine.
Factors that Influence Iron Absorption
Increase absorption: Ascorbic acid, amino acids, meat, gastric acidity
 Decrease absorption: Presence of food in the stomach, antacids, phosphates, phytates, tetracyclines
Transportation and distribution: Iron is transported with the help of glycoprotein called transferrin.
Stored as ferritin and haemosiderin in liver, spleen and
bone marrow
Excretion: 0.5–1 mg of iron is excreted daily
PREPARATION OF IRON
Iron is generally given orally or parenterally.

Dietary iron (mostly Fe3+)

Bone marrow, liver, spleen (stored)

FIGURE 36.1 Schematic representation of absorption and storage of iron.
1. Oral Iron
a. Preparations
Ferrous sulphate contains 20% hydrated salt and 32% dried salt or elemental iron—200 mg tab. It is the oldest and cheapest
iron preparation.
Ferrous fumarate contains 33% elemental iron— 200 mg tab.
Ferrous gluconate contains 12% elemental iron in a 300 mg tab. It causes less gastric irritation.
Ferrous succinate: 100 mg
Iron calcium complex: 5% iron Ferrous salts are better absorbed than ferric salts. Last three preparations are better
tolerated.
b. Indications
Iron deficiency anaemia, prophylactic treatment. For 3–6 months to replenish iron stores. Dose: Ferrous sulphate 3–4
tablets daily
 Adverse Effects
Epigastric pain Nausea, vomiting, gastritis Metallic taste
Constipation (due to astringent effect) or diarrhoea Liquid preparations stain the teeth
2. Parenteral Iron
Intramuscular injection is given deep IM in the gluteal region using ‘Z’ technique to avoid skin staining. Intravenous iron
is given slowly 5–10 min or as infusion.
a. Indications
1. Parenteral iron is indicated when
oral iron is not tolerated, failure of absorption, noncompliance and deficiency with bleeding.
b. Preparations
Iron dextran (Imferon) has 50 mg (2 mL ampoule) can be given IM/IV.
Iron–sorbitol–citric acid complex (Jectofer)—50 mg/mL given IM but never IV.
The total dose of parenteral iron is calculated using the formula:
Iron requirement (mg) 5 4.4 3 body weight (kg) 3 Hb
deficit (g/dL)
Adverse Effects
Local: Pain at the site of injection
Systemic: Fever, headache, joint pain, palpitation, difficulty in breathing, lymph node enlargement and rarely anaphylaxis
Acute iron poisoning Intake of 10 tablets or more can be lethal. Results in vomiting, abdominal pain, haematemesis,
bloody diarrhoea, shock, drowsiness, cyanosis, acidosis, dehydration, cardiovascular collapse and coma. Death may occur in
6–12 h.
TREATMENT
SHORT ESSAYS
Gastric lavage with sodium bicarbonate Desferrioxamine is injected IV/IM. Correction of acidosis and shock
 Parental iron preparations
Parenteral iron preparations are as follows:
Iron dextran (Imferon) has 50 mg (2 mL ampoule) can be given IM/IV. It is most commonly used parenteral iron preparation.
Iron–sorbitol–citric acid complex (Jectofer): 50 mg/mL. It is given IM but never IV.
Sodium ferric gluconate: Recently approved preparation for IV use has much low risk of anaphylactic reaction than iron
dextran.
The total dose of parenteral iron is calculated using the formula:
Iron requirement (mg) 5 4.4 3 body weight (kg) 3 Hb deficit (g/dL)
Intramuscular injection is given deep IM in the gluteal region using ‘Z’ technique to avoid skin staining.
Intravenous iron is given slowly 5–10 min or as infusion.
Indications
Parenteral iron is indicated when
oral iron is not tolerated,
failure of absorption,
noncompliance and
deficiency with bleeding.
Adverse Effects
Local: Pain at the site of injection
Systemic: Fever, headache, joint pain, palpitation, difficulty in breathing, lymph node enlargement and rarely anaphylaxis
Q. 2. Cyanocobalamin
Cyanocobalamin and hydroxocobalamin are complex cobalt containing compounds present in diet and referred to as vitamin
B12.
Synthesized by microorganisms
Sources: Liver, fish, egg yolk, meat, cheese, pulses
Physiological Functions
Acts as coenzyme for several vital metabolic reactions.
Essential for DNA synthesis
Causes of Vitamin B12 Deficiency
Addisonian pernicious anaemia due to deficiency of intrinsic factor, due to destruction of parietal cells, resulting in failure of
B12 absorption.
Other causes are gastrectomy, chronic gastritis, malabsorption and fish tape worm infestation (consumes

vitamin B12), nutritional deficiency and increased demand during pregnancy and lactation.
Manifestations of Deficiency
Megaloblastic anaemia
Glossitis
Neurological symptoms
Preparations, Dose and Administration
Cyanocobalamin: Redisol, Macrabin 35 µg/5 mL liq.; 100, 500, 1000 µg inj. daily
Hydroxocobalamin: Redisol-H, Macrabin-H 500, 1000 µg inj. daily
Methylcobalamin: Biocobal, Diacobal 0.5 mg tab
Q. 3. Oral preparations of iron
Iron is generally given orally or parenterally.
Oral Iron Preparations
Ferrous sulphate contains 20% hydrated salt and 32% dried salt or elemental iron—200 mg tab. It is the oldest and cheapest
iron preparation.
Ferrous fumarate contains 33% elemental iron— 200 mg tab.
Ferrous gluconate contains 12% elemental iron—
300 mg tab. It cause less gastric irritation.
Ferrous succinate—100 mg
Iron calcium complex—5% iron
Ferrous salts are better absorbed than ferric salts.
Last three preparations are better tolerated.
Indications of Oral Iron
Iron deficiency anaemia, prophylactic treatment. For 3–6 months to replenish iron stores.
Dose: Ferrous sulphate 3–4 tablets daily
Adverse Effects of Oral Iron
Epigastric pain
Nausea, vomiting, gastritis
Metallic taste
Constipation (due to astringent effect) or diarrhoea
Liquid preparations stain the teeth.
Acute Iron Poisoning
Intake of 10 tablets or more can be lethal.
Results in vomiting, abdominal pain, haematemesis, bloody diarrhoea, shock, drowsiness, cyanosis, acidosis, dehydration,
cardiovascular collapse and coma.
Death may occur in 6–12 h.
Treatment
Gastric lavage with sodium bicarbonate
Desferrioxamine is injected IV/IM
Correction of acidosis and shock
Q. 4. Iron–sorbitol–citric acid
Iron–sorbitol–citric acid complex (Jectofer) is a type of parenteral iron preparation.
Citric acid improves iron absorption.
It is low molecular weight compound, used only intramuscularly. Absorbed directly into circulation and about 30% is excreted
in urine.
It is indicated when
oral iron is not tolerated,
failure of absorption,
noncompliance and
deficiency with bleeding.
Iron–sorbitol–citric acid complex: 50 mg iron/mL; Jectofer 1.5 mL ampoule
Intramuscular injection is given deep IM in the gluteal region using ‘Z’ technique to avoid skin staining.
Intravenous iron is given slowly 5–10 min or as infusion.
Adverse Effects
Local: Pain at the site of injection.
Systemic: Fever, headache, joint pain, palpitation, difficulty in breathing, lymph node enlargement and rarely anaphylaxis
Q. 5. Acute iron poisoning and role of desferrioxamine in iron poisoning
ACUTE IRON POISONING
Occurs on intake of 10 tablets or more can be lethal.
Results in vomiting, abdominal pain, haematemesis, bloody diarrhoea, shock, drowsiness, cyanosis, acidosis, dehydration,
cardiovascular collapse and coma.
Death may occur in 6–12 h.
Treatment
1. Gastric lavage with sodium bicarbonate 2. Desferrioxamine is injected IV/IM.
3. Correction of acidosis and shock
Role of Desferrioxamine
The role of desferrioxamine is as follows:
Desferrioxamine is isolated from Streptomyces pilosus.
It chelates iron and has a high affinity for iron, forms stable complex and removes loosely bound iron as well
as that from haemosiderin and ferritin but not from haemoglobin and cytochromes. One gram desferrioxamine is capable of
chelating 85 mg of elemental iron.
The straight chain desferrioxamine molecule winds round ferric iron and forms a stable nontoxic compound which is excreted
in urine.
Uses
Acute iron poisoning
SHORT NOTES
Chronic iron poisoning—as in thalassaemia patients who receive repeated blood transfusions.

Aetiology and drugs for anaemia

ANAEMIA
Aetiology
It occurs when the balance between production and destruction of RBC is disturbed by the following:
Blood loss
Impaired red cell formation due to deficiency of essential factors like iron, vitamin B12, folic acid
Bone marrow depression and increased destruction of RBC
Treatment
Haematinics are drugs used for the formation of blood and treatment of anaemia.
Different drugs used for the treatment of anaemia are as follows:
Iron
Oral ferrous gluconate, ferrous sulphate, ferrous fumarate, colloidal ferric hydroxide
Parenteral iron dextran, iron–sorbitol–citric acid
complex
Vitamin B12
Folic acid
Q. 2. Ferrous sulphate
Ferrous sulphate is a type of oral iron preparation.
Dose: Ferrous sulphate 3–4 tablets daily, 200 mg tab.
Indications
Iron deficiency anaemia, prophylactic treatment. For
3–6 months to replenish iron stores
Ferrous salts are better absorbed than ferric salts.
Adverse Effects of Oral Iron
Epigastric pain
Nausea, vomiting, gastritis
Metallic taste
Constipation (due to astringent effect) or diarrhoea
Liquid preparations stain the teeth.
Q. 3. Folic acid
Folic acid is pteroylglutamic acid from spinach and named as folic acid (from leaf).
Dietary source: Green vegetables, liver, yeast, egg, milk and some fruits
Absorption: It takes place in the duodenum and is transported by active and passive transport.
Widely distributed in the body and is stored in the liver.
Functions
Folic acid is converted to dihydrofolic acid and then to tetrahydrofolic acid which serves as a coenzyme for many vital (one-
carbon transfer) reactions necessary for DNA synthesis.
Deficiency
Foliate deficiency may be due to dietary foliate deficiency.
Malabsorption and other diseases of the small intestine or drug-induced phenytoin phenobarbitone, oral contraceptives,
methotrexate, increased requirements like growing, pregnancy, etc. can cause folic acid deficiency.
Manifestations include megaloblastic anaemia, glossitis, diarrhoea and weakness.
Dosage: Folic acid 2–5 mg/day orally
Uses
In folic acid deficiency due to malabsorption syndromes, folic acid is given IM.
Prophylactically in pregnancy, lactation, infancy require 500 µg daily orally.
Q. 4. Indications for parenteral use of iron
Iron is generally given parenterally as follows:
Intramuscular injection deep IM in the gluteal region using ‘Z’ technique to avoid skin staining.
Intravenous iron is given slowly 5–10 min or as infusion.
Indications
Parenteral iron is indicated when
oral iron is not tolerated,
failure of absorption,
noncompliance and
deficiency with bleeding.
Q. 5. Mention two oral and parenteral preparations.
Oral Iron Preparations
Ferrous sulphate contains 20% hydrated salt and 32% dried salt or elemental iron—200 mg tab. It is the oldest and cheapest
iron preparation.
Ferrous fumarate contains 33% elemental iron— 200 mg tab.
Ferrous gluconate contains 12% elemental iron—300 mg tab. It causes less gastric irritation.
Ferrous salts are better absorbed than ferric salts.
Parenteral Iron Preparations
Iron dextran (Imferon) has 50 mg (2 mL ampoule) can be given IM/IV.
Iron–sorbitol–citric acid complex (Jectofer)—50 mg/mL given IM but never IV.
Q. 6. Vitamin C is given with iron in the treatment of anaemia
of scurvy.
Vitamin C and citric acid improve the absorption of iron in the intestines.

Drugs Affecting Coagulation, Bleeding and Thrombosis

LONG ESSAYS
Thrombin Fibrinogen
Fibrin glue Antihaemophilic factor
Gelatin Adrenochrome
Calcium alginate Adrenochrome monosemicarbazone
Oxidized cellulose Ethamsylate
Russell’s viper venom Desmopressin
Enumerate the agents used to control bleeding. Discuss the actions and uses
of systemic coagulants.
 The agents that help in controlling bleeding and are used in preventing or treating haemorrhagic conditions are known as
coagulants. The coagulants are classified as follows:
Local Agents (Styptics) Systemic Agents
Astringents Fresh whole blood
Adrenalin Vitamin K
Pharmacological actions and uses of various coagulants are as follows:
Ascorbic acid enhances iron absorption and is frequently combined with ferrous salts as it maintains them in reduced state.
Anaemia of scurvy is corrected by ascorbic acid, but no adjuvant value in other anaemias. Hence vitamin C is used in the
treatment of anaemia of scurvy.
SYSTEMIC AGENTS A. Whole Blood or Plasma
Fresh blood or plasma provides all the factors needed for coagulation.
 It is the best treatment for deficiency of any clotting factor. It acts immediately.
Uses: Emergency conditions to stop blood flow to prevent
excess loss of blood.
B. Vitamin K
It is available as follows:
K1 (from plants): Phytonadione (phylloquinone) K2 (produced by bacteria): Menaquinones K3 (synthetic)
Fat-soluble: Menadione, acetomenaphthone
Water-soluble: Menadione sodium bisulphate, menadione sodium diphosphate
It is a dietary supplement required for the synthesis of the clotting factors.
Actions
Vitamin K acts as a cofactor at a late stage in the liver for the synthesis of coagulation proteins: Prothrombin, factors VII, IX,
and X. Vitamin K is also required for the carboxylation of glutamic acid residues of osteocalcin, which is important for bone
development. It participates in coagulation cascade. Fat-soluble forms of vitamin K are absorbed from intestine via lymph
and require bile for absorption, while water-soluble forms are directly absorbed into the portal blood.
Uses
Vitamin K is used in the prophylaxis and treatment of bleeding due to deficiency of clotting factors.
All newborns are recommended 1 mg IM of vitamin K soon after birth as they have low levels of prothrombin and other
clotting factors.
To reverse the overdose of oral anticoagulants Water-soluble derivatives like menadione are used in G-6-PD deficient
patients.
C. Fibrinogen (Human)
It is obtained from human plasma.
Fibrinogen initiates formation of fibrin clot and helps in coagulation.
Uses: Used in patients with haemophilia, antihaemophilic globulin deficiency and acute afibrinogenic states.
D. Antihaemophilic Factor
It is short-acting agent and is concentrated in human antihaemophilic globulin (AHG) prepared from pooled human plasma.
It contains coagulation factor VIII with von Willebrand’s factor.
Uses: Used in patients with haemophilia, antihaemo-
philic globulin deficiency.
E. Ethamsylate
It is a haemostatic, available for oral, IM and IV administration.
It reduces capillary bleeding when platelets are adequate, exerts antihyaluronidase action improves capillary wall stability.
It inhibits PGI2 production and corrects abnormal platelet function.
Uses: In prevention and treatment of capillary bleeding in menorrhagia, after abortion, epistaxis, melena, haematuria and
after tooth extraction.
F. Desmopressin
It is synthetic analogue of vasopressin. It is used to control mild to moderate bleeding in haemophilia A and von Willebrand’s
disease. It is administered intravenously slowly.
Q. 2. Classify anticoagulants. Discuss the mechanism of action, uses and adverse
effects of the coumarin derivatives.

Anticoagulants are drugs used to reduce the coagulability of blood. They may be classified according to their use as follows:
Used in vivo
Parenteral anticoagulants
Heparin Low molecular weight heparins (LMWHs):
Enoxaparin, dalteparin, tinzaparin and ardeparin Heparinoids: Heparan sulphate, lepirudin and danaparoid
Oral anticoagulants
Coumarin derivatives: Bishydroxycoumarin, warfarin sodium, acenocoumarol, ethylbiscoumacetate
Indanedione derivative: Phenindione
Used in vitro
Heparin
Calcium complexing agents
Sodium citrate (used in blood banks to store the blood)
Sodium oxalate Sodium edetate
Coumarin Derivatives
Coumarin derivatives like bishydroxycoumarin, warfarin sodium, acenocoumarol, ethylbiscoumacetate act as anticoagulants
only in vivo and not in vitro.
This is because they act indirectly by interfering with the synthesis of vitamin K-dependent clotting factors (II, VII, IX and
X) in the liver.
 They behave as competitive antagonists of vitamin K and reduce the plasma levels of functional clotting factors in a dose
dependent manner. They interfere with the regeneration of active hydroquinone form of vitamin K which carries out the final
step of gamma carboxylating glutamate residues of prothrombin and factors VII, IX and X.
Uses
Deep vein thrombosis and pulmonary embolism
Myocardial infarction Unstable angina Rheumatic heart disease, atrial fibrillation
Vascular surgery, prosthetic heart valves, retinal vessel
thrombosis, extracorporeal circulation, haemodialysis
Adverse Effects
Bleeding: Bleeding is most important and common side effect of warfarin. It can occur anywhere like skin, GIT, urinary tract,
cerebral, hepatic, uterine, etc.
Teratogenic effect: Warfarin is contraindicated during pregnancy as it may cause CNS abnormalities, fetal haemorrhage,
abortion or intrauterine death.
Skin necrosis: It is a rare complication that occurs within the first week of therapy. Skin lesions are commonly seen on breast,
buttocks, abdomen and thighs.
Other rare side effects: They include diarrhoea, alopecia, urticaria, abdominal cramps and anorexia.
Commonly seen adverse effects associated with individual drugs are as follows:
Bishydroxycoumarin: Frequent GIT disturbances
Warfarin sodium: Alopecia, dermatitis, diarrhoea
Acenocoumarol: Oral ulceration, GIT disturbances,
dermatitis, urticaria, alopecia
Ethylbiscoumacetate: Alopecia, bad taste
Q. 3. Enumerate styptics. Describethe role of vitamin K when bleeding is
due to oral anticoagulation therapy.

Styptics are local haemostatic substances used to stop bleeding from a local approachable site. They are particularly
effective on oozing surfaces like tooth sockets.
They are to be applied topically and are not to be injected.
Commonly used styptics or local haemostatic agents are
as follows:
Thrombin Fibrin Gelatin foam
Russell’s viper snake venom Adrenaline Astringents
Thrombin
 It is a freeze-dried powder obtained from bovine plasma and applied topically as a dry powder or freshly prepared solution
on bleeding surfaces.
Used in haemophilia, neurosurgery, skin grafting. It can cause hypersensitivity reactions.
Fibrin
It is prepared from the human plasma and used topically as sheets or foam for covering or packing the bleeding surfaces and
left in the site as it is absorbed.
Gelatin Foam
It is a protein and is used as a haemostatic in surgical procedures. Spongy gelatin that is moistened with saline or thrombin
solution and used for packing wounds. It also gets absorbed in 1–2 months.
Russell’s viper snake venom It contains proteolytic enzymes. It acts as thromboplastin when applied locally and is used to
stop external bleeding in haemophilics.
Vasoconstrictors
 One percent adrenaline soaked in sterile cotton gauze may stop epistaxis or some other similar bleeding.
Two percent adrenaline is used in local anaesthetics to
control bleeding during tooth extraction.
e. Astringents
They precipitate proteins locally in the bleeding site and control capillary oozing, e.g. 20% tannic acid mixed in glycerine is
used for bleeding gums, bleeding piles.
Role of Vitamin K
Role of vitamin K in bleeding due to oral anticoagulation therapy is as follows: Oral anticoagulants act by interfering with
the synthesis of vitamin K-dependent clotting factors in the liver.
They behave as competitive antagonist of vitamin K and reduce the plasma levels of functional clotting factors in a dose-
dependent manner. It interferes with regeneration of the active hydroquinone form of vitamin K which carries out the final
step of g-carboxylating residues of prothrombin and factors VII, IX and X. This carboxylation is essential for the ability of
the clotting factors to bind Ca21 and to get bound phospholipid surface necessary for the coagulation sequence to proceed.
Vitamin K acts as an antidote for warfarin.
Administration of vitamin K by competitive antagonism with oral anticoagulants reduces the anticoagulant action and brings
about carboxylation of glumate residues of prothrombin and factor VII, IX and X necessary for coagulation sequence to
proceed.
Hence vitamin K is used for bleeding due to oral anticoagulant therapy.
Q. 4. Describehow heparin and dicumarol act as anticoagulants. Indicate their
route of administration, duration of action and name their antagonists.
Heparin
Heparin is named so because of its high concentration in the liver. It is a fast-acting anticoagulant used in vitro and vivo. It
is a mucopolysaccharide, found in the mast cells of liver, lung and intestinal mucosa. It is the strongest organic acid in the
body.
 Heparin acts as an anticoagulant, clears lipaemia and also has antiplatelet activity.
Mechanism of action: Heparin acts by activating plasma antithrombin III which binds to and inactivates clotting factors Xa
and thrombin-mediated conversion of fibrinogen to fibrin.
Heparin–antithrombin complex binds to the clotting factors of intrinsic as well as extrinsic pathways. Thus heparin
inactivates the clotting factors halting the progression of coagulation pathway and increases the clotting time.
Uses
Prophylaxis of deep vein thrombosis in high risk pa-
tients undergoing surgery
Treatment of established deep vein thrombosis Unstable angina
To maintain patency of the canula and shunts in dialysis
patients and in extracorporeal circulation
Adverse Effects
 Bleeding due to overdose Thrombocytopenia Osteoporosis and alopecia
Heparin Antagonist
Protamine sulphate is a highly basic, low molecular weight protein obtained from the sperm of fish. It neutralizes heparin
weight. One milligram is required for every 100 U of heparin. It is used when heparin action needs to be terminated rapidly as
in after cardiac or vascular surgery and for heparin-induced bleeding.
Warfarin Sodium
Warfarin sodium is an oral anticoagulant derived from coumarin.
They are used in vivo and not vitro. This is because they act indirectly by interfering with the synthesis of vitamin K-
dependent clotting factors in the liver.
Mechanism of action: They behave as competitive antagonists of vitamin K and reduce the plasma levels of functional
clotting factors in a dose-dependent manner.
 They interfere with the regeneration of active hydroquinone form of vitamin K which carries out the final step of gamma
carboxylating glutamate residues of prothrombin and factors VII, IX, X.
Uses
Deep vein thrombosis and pulmonary embolism
Myocardial infarction Unstable angina Rheumatic heart disease, atrial fibrillation
Vascular surgery, prosthetic heart valves, retinal vessel
thrombosis, extracorporeal circulation, haemodialysis
Adverse Effects
i. Bishydroxycoumarin: Frequent GIT disturbances Warfarin sodium: Alopecia, dermatitis, diarrhoea Acenocoumarol:
Oral ulceration, GIT disturbances,
dermatitis, urticaria, alopecia
Ethyl biscoumacetate: Alopecia, bad taste
Role of vitamin K in bleeding due to oral anticoagulation therapy as follows: Oral anticoagulants act by interfering with the
synthesis of vitamin K-dependent clotting factors in the liver.
They behave as competitive antagonist of vitamin K and reduce the plasma levels of functional clotting factors in a dose-
dependent manner.
Vitamin K acts as an antidote for warfarin.
Administration of vitamin K by competitive antagonism with oral anticoagulants, reduces the anticoagulant action and
brings about carboxylation of glumate residues of prothrombin and factor VII, IX and X necessary for coagulation sequence to
proceed. Hence vitamin K is used for bleeding due to oral anticoagulant therapy.
Q. 5. Classify anticoagulants and explain in detail about pharmacological action,
pharmacodynamics, therapeutic uses and toxicity of heparin.

Anticoagulants are drugs used to reduce the coagulability of blood. They may be classified according to their use as follows:
Used in vivo
Parenteral anticoagulant—heparin, low molecular
weight heparin
Oral anticoagulants
Coumarin derivatives—bishydroxycoumarin, warfarin sodium, acenocoumarol, ethylbiscoumacetate
Indanedione derivative—phenindione
Used in vitro
Heparin
Calcium complexing agent
Sodium citrate Sodium oxalate Sodium edentate
Heparin
Heparin is a fast-acting anticoagulant used in vitro and vivo.
 It is a mucopolysaccharide, found in the mast cells of liver, lung and intestinal mucosa. It is the strongest acid in the body.
Heparin acts as an anticoagulant, clears lipaemia and also has antiplatelet activity.
Mechanism of action: Heparin acts by activating plasma antithrombin III which binds to and inactivates clotting factors Xa
and thrombin-mediated conversion of fibrinogen to fibrin.
Heparin–antithrombin complex binds to the clotting factors of intrinsic as well as extrinsic pathways. Thus heparin
inactivates the clotting factors halting the progression of coagulation pathway and increases the clotting time.
Uses
Prophylaxis of deep vein thrombosis in high risk pa-
tients undergoing surgery
Treatment of established deep vein thrombosis Unstable angina
To maintain patency of the canula and shunts in dialysis
patients and in extracorporeal circulation
Adverse Effects
Bleeding due to overdose Thrombocytopenia Osteoporosis and alopecia
Heparin Antagonist
SHORT ESSAYS
Styptics 5. Adrenaline
6. Astringents
Styptics are local haemostatic substances used to stop Thrombin bleeding from a local approachable site.
They are particularly effective on oozing surfaces like It is obtained from bovine plasma and applied as a dry tooth
sockets. powder or freshly prepared solution on bleeding surface. They are to be applied topically and are not to be injected.
Used in haemophilia, neurosurgery, skin grafting.
Commonly used styptics or local haemostatic agents are
as follows: Fibrin
Thrombin
Fibrin It is prepared from the human plasma and used as sheets or
Gelatin foam foam for covering or packing the bleeding surface and left 4. Russell’s viper snake venom in the
site as it is absorbed.
Protamine sulphate is a highly basic, low molecular weight protein obtained from the sperm of fish. It neutralizes heparin
weight. One milligram is required for every 100 U of heparin. It is used when heparin action needs to be terminated rapidly as
in after cardiac or vascular surgery and for heparin-induced bleeding.
Gelatin Foam
It is spongy gelatin and used for packing wounds. It also gets absorbed in 1–2 months.
Russell’s Viper Snake Venom
It acts as thromboplastin when applied locally and is
used to stop external bleeding in haemophilics.
Vasoconstrictors
One percent adrenaline soaked in sterile cotton gauze
may stop epistaxis or some other similar bleeding.
Astringents
One percent tannic acid mixed in glycerine is used for bleeding gums, bleeding piles.
Q. 2. Anticoagulants
Anticoagulants are drugs used to reduce the coagulability of blood. They may be classified according to their use as follows:
Used in vivo
Parenteral anticoagulant—heparin, low molecular
weight heparin
Oral anticoagulants
Coumarin derivatives—bishydroxycoumarin, warfarin sodium, acenocoumarol
Indanedione derivative—phenindione
Used in vitro
Heparin
Calcium complexing agent
Sodium citrate Sodium oxalate Sodium edentate
Uses of anticoagulants
Deep vein thrombosis and pulmonary embolism
Myocardial infarction
Unstable angina
Rheumatic heart disease, atrial fibrillation
Vascular surgery, prosthetic heart valves, retinal vessel thrombosis, extracorporeal circulation, haemodialysis
Q. 3. Compare heparin and oral anticoagulants Or,
Compare heparin and dicumarol
Comparison between heparin and dicumarol is listed in Table 37.1.
TABLE 37.1 Comparison between Heparin and Dicumarol
Parameters to Be
Compared Heparin Warfarin (Oral Anticoagulant)
Chemistry Mucopolysaccharide Coumarin derivative
Source Beef lung, pig intestine Synthetic
Route of administration Parenteral (IV infusion or IV intermittent injection) Oral
Onset of action Immediate Delayed (3–4 days)
Duration of action 4–6 h 3–6 h
Activity In vivo and vitro In vivo only
Mechanism Blocks action of factor X and thrombin Inhibits synthesis of clotting factors
Antagonist Prothrombin sulphate Vitamin K
Variability in response Little Marked
Drug interaction Few and insignificant Many and significant
Use To initiate anticoagulant therapy For maintenance
Q. 4. Name two oral anticoagulants. Mention one drug treating toxicity of oral
anticoagulants. Or, Dicumarol poisoning
Oral anticoagulants are drugs given orally used to reduce the coagulability of blood. They may be classified as follows:
1. Coumarin derivatives—bishydroxycoumarin, warfarin sodium, acenocoumarol, ethylbiscoumacetate 2.
Indanedione derivative—phenindione
Role of vitamin K in bleeding due to oral anticoagulation therapy: Oral anticoagulants act by interfering with the synthesis of
vitamin K-dependent clotting factors in the liver.
 They behave as competitive antagonist of vitamin K and reduce the plasma levels of functional clotting factors in a dose-
dependent manner.
It interferes with regeneration of the active hydroquinone form of vitamin K. Vitamin K acts as an antidote for warfarin.
Administration of vitamin K by competitive antagonism with oral anticoagulants, reduces the anticoagulant action and
brings about carboxylation of glumate residues of prothrombin and factor VII, IX and X necessary for coagulation sequence to
proceed. Hence vitamin K is used for bleeding due to oral anticoagulant therapy.
Q. 5. Adverse effects of cyanocobalamin or vitamin B12
Vitamin B12 also known as cyanacobalamin, antipernicious vitamin or extrinsic factor of Castle, is a watersoluble vitamin,
synthesized by microorganisms. Sources: Liver, fish, egg yolk, meat, cheese, pulses Physiological functions: Acts as
coenzyme for several
vital metabolic reactions, essential for DNA synthesis.
Daily requirement
 Adults: 1–3 µg Pregnancy and lactation: 3–4 µg
Causes of deficiency: Addisonian anaemia due to deficiency of intrinsic factor or due to destruction of parietal cells resulting
in failure of B12 absorption.
Other causes: Gastrectomy, chronic gastritis, malab-
sorption and fish tape worm infestation (consumes vitamin B12)
Uses
Treatment of vitamin B12 deficiency
Cyanocobalamin: 100 mL inj. daily
Hydroxocobalamin: 100–500, 1000 mg daily.
Multivitamins for oral use
B12 deficiency: Prophylaxis 3–10 mg daily
Treatment of megaloblastic anaemia
B12 neuropathies, psychiatric disorders, cutaneous sarcoid and as general tonic to allay fatigue and improve growth
Adverse Effects
Anaphyloid reaction on IV injection due to sulphite contained in the formulation.
Q. 6. Explain the mechanism of action of streptokinase and mention one
use of it.

It is a fibrinolytic obtained from b haemolytic streptococci group C. It is inactive till it combines with circulating
plasminogen to form an activator complex, which then causes limited proteolysis of other plasminogen molecules to plasmin.
If antistreptococcal antibodies are present in the body, they inactivate a considerable amount of initial dose.
Mechanism of Action
Streptokinase combines with plasminogen to form plasmin, which helps in the conversion of insoluble fibrin to soluble fibrin
fragments.
Streptokinase 1 PlasminogennPlasmin g
Insoluble fibrinnSoluble fibrin fragments
Pharmacological Actions
Venous thrombi are lysed more easily than arterial thrombi. Recent thrombi respond better. Effect on thrombi more
than 3 days old is less.
Disadvantages
It is antigenic and can cause hypersensitivity reactions and anaphylaxis. Can be neutralized by antibodies. Fever,
hypotension and arrhythmias can occur.
Uses
Myocardial infarction: 7.5 lakh IU infused over 1 h
DVT and pulmonary embolism: 2.5 lakh IU loading dose over ½–1 h followed by 1 lakh IU/h for 24 h
Advantage
SHORT NOTES
1. Cheap to use among all fibrinolytics

Vitamin K deficiency
Vitamin K acts as a cofactor in the synthesis of coagulation proteins—prothrombin, factors VII, IX and X in the liver.
Deficiency of vitamin K occurs due to liver diseases, obstructive jaundice, malabsorption and long-term antimicrobial
therapy which alters intestinal flora.
Deficiency causes bleeding tendencies which manifests itself first as haematuria and then in the GIT, nose and under skin
such as ecchymoses.
Q. 2. Styptics
Styptics are local haemostatic substances used to stop bleeding from a local approachable site.
 They are particularly effective on oozing surfaces like tooth sockets. They are to be applied topically and are not to be
injected.
Commonly used styptics are as follows:
Thrombin
Fibrin
Gelatin foam
Russell’s viper snake venom
Vasoconstrictors
Astringents
Q. 3. Streptokinase
It is a fibrinolytic obtained from b haemolytic streptococci of group C. It is inactive till it combines with circulating
plasminogen to form an activator complex, which then causes limited proteolysis of other plasminogen molecules to plasmin.
Mechanism of Action
Streptokinase combines with plasminogen to form plasmin, which helps in the conversion of insoluble fibrin to soluble fibrin
fragments.
Disadvantages
It is antigenic and can cause hypersensitivity reactions and anaphylaxis. Can be neutralized by antibodies. Fever,
hypotension and arrhythmias can occur.
Uses
Myocardial infarction DVT and pulmonary embolism
Q. 4. Heparin
Heparin is named so because of its high concentration in the liver.
It is found in the mast cells of liver, lung and intestinal mucosa. Heparin acts as an anticoagulant and is used in vitro and
vivo.
Uses
Treatment of established deep vein thrombosis
Unstable angina
To maintain patency of the cannula and shunts in dialysis patients and in extracorporeal circulation
Adverse Effects
Bleeding due to overdose, thrombocytopenia, osteoporosis and alopecia
Q. 5. Vitamin K
Vitamin K is a fat-soluble dietary principle required for the synthesis of clotting factors. Vitamin K acts as a cofactor in
the synthesis of coagulation
proteins—prothrombin, factors VII, IX and X in the liver.
Uses
In vitamin K deficiency
Newborn babies lack intestinal flora and have low levels of prothrombin and other clotting factors. Routine administration of
vitamin K—1 mg IM prevents haemorrhagic diesease of the newborn. Deficiency of vitamin K occurs due to liver diseases,
obstructive jaundice, malabsorption, and long-term antimicrobial therapy which alters intestinal flora.
Q. 6. Fibrinolytic agents
Fibrinolytics or thrombolytics are drugs that lyse the clot or thrombus by activating the natural fibrinolytic system. The
fibrinolytic agents are streptokinase, urokinase and alteplase. Mechanism of action: Fibrinolytics combine with circulating
plasminogen to form plasmin, which helps in the conversion of insoluble fibrin to soluble fibrin fragments.
Uses
Acute myocardial infarction
Deep vein thrombosis, pulmonary emboli Adverse effects: Bleeding, hypotension, fever. Anaphylactic reactions are common
with streptokinase.
 They are contraindicated in recent surgeries, injury, gastrointestinal bleeding, stroke, severe hypertension and bleeding
disorders.
Q. 7. Haemostasis
Haemostasis is the process of stopping bleeding postsurgically or from a site of injury.
Haemostasis may be achieved by applying pressure at the bleeding site or by suturing it. Uncontrolled bleeding may be
stopped using styptics. Styptics are local haemostatic substances, which are applied topically, used to stop bleeding from a
local approachable site. Commonly used styptics are thrombin, fibrin, gelatin foam, etc.
Q. 8. Warfarin sodium
Warfarin sodium is an oral anticoagulant derived from coumarin.
They are used in vivo and not vitro. This is because they act indirectly by interfering with the synthesis of vitamin K-
dependent clotting factors in the liver.
 They behave as competitive antagonists of vitamin K and reduce the plasma levels of functional clotting factors in a dose-
dependent manner.
Used in
Deep vein thrombosis and pulmonary embolism, myocardial infarction
Unstable angina, vascular surgery, prosthetic heart valves, retinal vessel thrombosis, extracorporeal circulation, haemodialysis,
etc.
Q. 9. Oral anticoagulants
Oral anticoagulants are drugs given orally used to reduce the coagulability of blood.
They may be classified as follows:
Coumarin derivatives—bishydroxycoumarin, warfarin sodium, acenocoumarol, ethylbiscoumacetate
Indanedione derivative—phenindione They are used in vivo and not vitro. This is because they act indirectly by interfering
with the synthesis of vitamin K-dependent clotting factors in the liver.
 They behave as competitive antagonists of vitamin K and reduce the plasma levels of functional clotting factors in a dose-
dependent manner.
Q. 10. Mechanism of action of heparin

Heparin acts by activating plasma antithrombin III which binds to and inactivates clotting factors Xa and thrombin-mediated
conversion of fibrinogen to fibrin.
Heparin–antithrombin complex binds to the clotting factors of intrinsic as well as extrinsic pathways.
Thus heparin inactivates the clotting factors halting the progression of coagulation pathway and increasing the clotting time.
Q. 11. Drugs used in pernicious anaemia
Deficiency of vitamin B12 occurs due to absence of intrinsic factor and manifests itself as pernicious anaemia in which there
is autoimmune gastric mucosal damage or chronic gastritis, gastric carcinoma. It can be treated with vitamin B12
supplements along with 1–5 mg of folic acid and an iron preparation. The folic acid and iron preparations are added because
reconstitution of brisk haemopoiesis may unmask deficiency of these factors.
Q. 12. Classification of anticoagulants
Anticoagulants are drugs used to reduce the coagulability of blood.
They may be classified according to their use as follows:
Used in vivo
Parenteral anticoagulant: Heparin, low molecular
weight heparin
Oral anticoagulants
Coumarin derivatives: Bishydroxycoumarin, warfarin sodium, acenocoumarol, ethylbiscoumacetate
Indanedione derivative: Phenindione
Used in vitro
Heparin
Calcium complexing agents: Sodium citrate, sodium

Hypolipoproteinaemic Drugs and Plasma Expanders

SHORT ESSAYS
What is plasma expander? Give two examples and when infused intravenously they
retain fluid in the vascular briefly describe them. compartment. For example: Human albumin, dextran, de-
The plasma expanders are high molecular weight graded gelatinpolymer (polygeline), hydroxyethyl starch substances which
exert colloidal osmotic pressure and (HES, hetastarch), polyvinyl pyrrolidone (PVP).
oxalate and sodium edentate
Human Albumin
 Available as Albudac, Albupan 50, 100 mL inj, Albumed 5%, 20% infusion (100 mL). It is obtained from pooled human
plasma; 100 mL of 20% human albumin solution is osmotically equivalent to 400 mL of fresh frozen plasma or 800 mL of
whole blood.
Advantages
It can be used irrespective of patient's blood group.
It does not interfere with coagulation.
As the preparation is heat treated it is free from risk of transmitting serum hepatitis.
No risk of sensitization on repeated infusions
Disadvantages
Occasionally febrile reaction occurs to human albumin.
It is expensive.
Dextran
 Most commonly used plasma expander. Available in two forms Dextran 70 and Dextran 40.
It is a polysaccharide obtained from sugar beat.
Dextran 70 is most commonly used preparation. It expands plasma volume for nearly 24 h. It is slowly excreted by
glomerular filtration and as well oxidized in the body over a period of weeks.
Dextran 40 acts more rapidly than Dextran 70 and it reduces blood viscosity and prevents RBC sludging. Advantage of
dextran: Dextran can be stored for 10 years and is economical.
Q. 2. Classify the hypolipidemic drugs.

Hypolipidemic drugs are classified as follows:

HMG–CoA reductase inhibitors (statins): Lovastatin, simvastatin, atorvastatin
Bile acid sequestrants (resins): Cholestyramine, colestipol
Active lipoprotein lipase (fibric acid derivatives): Clofibrate, gemfibrozil, fenofibrate
Inhibit triglyceride synthesis and lipolysis: Nicotinic acid
SHORT NOTES
Others include: Ezetimibe, gugulipid

Plasma expanders
The plasma expanders are high molecular weight substances which exert colloidal osmotic pressure and when infused
intravenously they retain fluid in the vascular compartment, e.g. human albumin, dextran, hydroxyethyl starch (HES,
hetastarch), etc.
They are primarily used as substitutes for plasma in conditions like burns, severe trauma, etc.
Contraindications to plasma expanders are severe anaemia, cardiac failure, pulmonary oedema renal insufficiency.
Q. 2. Atorvastatin
 It is the latest statin and is more potent and has highest LDL-CH lowering efficacy and also has additional antioxidant
property. Available as Aztor, Atorva, Atorlip 10, 20 mg tablets.
Should be given in the doses of 10–40 mg/day with maximum limit of 80 mg.
Uses: It is the first choice of drug in primary hyperlipidemias and secondary hypercholesterolemia.
Adverse effects: Headache, nausea, sleep disturbances, muscle tenderness, etc.
Part XI
Gastrointestinal Drugs

Drugs for Peptic Ulcer

SHORT ESSAYS
 What is antacid? Describethe properties and mechanism of action. Classify them
with suitable examples. Mention the merits and demerits of NaHCO3 as
an antacid.

Antacids are basic substances, which chemically react with gastric acid to form salts and water and increase the pH of the
gastric contents above 4, thereby reducing gastric acidity immediately. Antacids do not decrease acid production and hence
the potency of an antacid is generally expressed in terms of its acid neutralizing capacity (ANC).
Mechanism of Action
Antacids do not reduce the acid production but raise the antral pH, which causes reflex gastrin release. This causes more
secretion of gastric acid. Then acid rebound occurs and the gastric motility is increased causing rapid gastric emptying.
Mechanism of action of antacids is depicted as follows:
Administration of antacid

Increase in antral pH above 4

Reflux gastrin release

Increased gastric acid production

Increased gastric motility

 Rapid gastric emptying
Gastric acidity reduced
Most of the antacids have either magnesium hydroxide or aluminium hydroxide or calcium carbonate alone or in
combination with their main components. They are effective in relieving pain of peptic ulcer.
Antacids are potent drugs in gastroesophageal reflux
disease.
Classification
The antacids are classified into following two types:
Systemic antacids, e.g. sodium bicarbonate and sodium citrate
Nonsystemic antacids, e.g. magnesium hydroxide, aluminium hydroxide gel, calcium carbonate
Systemic Antacids
They are water soluble. They act instantaneously but duration of action is short.
 They are potent neutralizers as they may rise the pH up
to above 7.
Nonsystemic Antacids
They are insoluble and poorly absorbed basic compounds and react in stomach to form corresponding chloride salt. When
this reaches the intestine, the chloride salt reacts with bicarbonate, so HCO3 is not available for absorption hence there is no
systemic alkalosis.
Sodium Bicarbonate NAHCO3
It is water soluble, acts instantaneously. It is very effective and rapidly neutralizes gastric acid, but the duration of action is
short.
The demerits of NaHCO3 are as follows: It is absorbed systemically, large doses will induce metabolic alkalosis.
 It produces carbon dioxide in the stomach which may cause distension, discomfort, belching and risk of ulcer formation.
Increased sodium retention causes oedema and congestive heart failure (CHF). It should be avoided in the patients with
hypertension and congestive cardiac failure as it causes sodium retention. It produces rebound acidity.
Uses
Sodium bicarbonate is used to alkalinize the urine and to treat acidosis.
Combination of antacids produces various benefits which are as follows:
A combination of two or more antacids is frequently used, e.g. acidin, digene, gelusil and mucaine.
Aluminium hydroxide gel and magnesium trisilicate are combined and used as antacids to maximize the wanted effects and
minimize the adverse effects.
Magnesium containing antacids can cause diarrhoea while aluminium and calcium containing antacids cause constipation.
Magnesium trisilicate is a fast-acting drug and hastens gastric emptying, while aluminium hydroxide is slow acting and delays
gastric emptying. Combining the drugs prolong the action of the drug to a required level and makes it intermediate acting.
Combining the drugs neutralizes the laxating effect of magnesium trisilicate and constipating effect of aluminium hydroxide.
Q. 2. Classify drugs used in treatment of peptic ulcer.

The gastric mucosa is protected due to its ability to secrete mucous, bicarbonate and prostaglandins.
Classification of drugs used in the treatment of peptic ulcer is as follows:
Drugs that inhibit gastric acid secretion
Proton pump inhibitors: Omeprazole, lansoprazole, pantoprazole, rabeprazole
H2 receptor antagonists: Cimetidine, ranitidine, famotidine, nizatidine and roxatidine
Antimuscarinic agents (anticholinergic agents):
Pirenzepine, telenzepine
Prostaglandin analogues: Misoprostol, enprostil
Drugs that neutralize gastric acid secretion (antacids)
Systemic antacids: Sodium bicarbonate, sodium citrate
Nonsystemic antacids: Aluminium hydroxide, mag-
nesium hydroxide, magnesium trisilicate, calcium carbonate
Ulcer protectives: Sucralfate, colloidal bismuth sub-
citrate (CBS)
Ulcer healing drugs: Carbenoxolone sodium
Anti-H. pylori drugs: Amoxicillin, clarithromycin,
metronidazole, tinidazole and tetracycline
Q. 3. Antihistaminic drugs in peptic ulcer Or, H2 blockers
The antihistamines used in the treatment of peptic ulcer are H2 receptor antagonists or H2 blockers.
 They include cimetidine, ranitidine, famotidine, loxatidine and roxatidine. They competitively block the effects of
histamine and inhibit its action on H2 receptors on parietal cells and this in turn inhibits gastric acid secretion.
They suppress the secretion of acid in all the phases (basal, cephalic and gastric). They mainly suppress nocturnal gastric
acid secretion. They also reduce acid secretion stimulated by acetylcholine (ACh), food, gastrin, etc. They heal about 90% of
the ulcerations in one dose. These help in effectively promoting healing of peptic ulcer and preventing its recurrence.
They play important role in Zollinger-Ellison syndrome and in gastroesophageal reflex.
They are highly selective and have no effect on H1
mediated responses.
Q. 4. Cimetidine
Cimetidine was first H2 blocker to be introduced. It is a competitive inhibitor. It is well absorbed orally but due to first-
pass metabolism, the bioavailability of the drug reduces to about 60–80%. It has shorter duration of action. It acts for about
6–8 h.
 Though it has poor ability to penetrate the CNS, it crosses the placental barrier easily and is also secreted in milk.
Adverse Effects
It has antiandrogenic action and inhibits oestrogen to be metabolized in the liver. Gynaecomastia, loss of libido and impotence
are caused due to prolonged use.
Headache, dizziness, xerostomia, rashes and diarrhoea are some common effects seen with the use of cimetidine.
It crosses blood-brain barrier (BBB) and produces confusion, hallucination and delirium in some people especially geriatric
patients.
Q. 5. Ranitidine
It is well absorbed orally but due to first-pass metabolism, the bioavailability of the drug reduces to about 60–80%.
It is a competitive inhibitor, and is five times more potent than cimetidine. It has longer duration of action. It acts for about
12–24 h. It has lesser ability to penetrate the CNS than cimetidine.
Adverse effects
Headache, dizziness, xerostomia, rashes and diarrhoea are some common effects seen with the use of cimetidine.
It may also cause confusion, hallucination and delirium in some people especially geriatric patients.
Q. 6. Antacids
Antacids are basic substances, which chemically react with gastric acid to form salts and water and increase the pH of the
gastric contents above 4, thereby reducing gastric acidity immediately. Antacids do not decrease acid production and hence
the potency of an antacid is generally expressed in terms of its acid neutralizing capacity (ANC).
Mechanism of Action
Antacids do not reduce the acid production but raise the antral pH, which causes reflex gastrin release. This causes more
secretion of gastric acid. Then acid rebound occurs and the gastric motility is increased causing rapid gastric emptying.
Mechanism of action of antacids is depicted as follows:

Administration of antacid
 Increase in antral pH above 4

Reflux gastrin release

Increased gastric acid production

Increased gastric motility

Rapid gastric emptying

Gastric acidity reduced
 Most of the antacids have either magnesium hydroxide or aluminium hydroxide or calcium carbonate alone or in
combination with their main components. They are effective in relieving pain of peptic ulcer.
Antacids are potent drugs in gastroesophageal reflux
disease.
Classification
The antacids are classified into following two types:
Systemic antacids, e.g. sodium bicarbonate and sodium citrate
Nonsystemic antacids, e.g. magnesium hydroxide, aluminium hydroxide gel, calcium carbonate
Systemic Antacids
They are water soluble. They act instantaneously but duration of action is short.
They are potent neutralizers as they may rise the pH up
to above 7.
Nonsystemic Antacids
They are insoluble and poorly absorbed basic compounds and react in stomach to form corresponding chloride salt. When
this reaches the intestine, the chloride salt reacts with bicarbonate, so HCO3 is not available for absorption, hence there is no
systemic alkalosis.
Q. 7. Aluminium hydroxide
Aluminium hydroxide gel is a weak base, which chemically reacts with gastric acid to form salt and water and increase the
pH of the gastric contents above 4, thereby reducing gastric acidity immediately.
It is a weak antacid which polymerises on storing, to further form lesser reactive products. Thus the acid neutralizing
capacity of the drug decreases on prolonged storage.
Mechanism of Action
 It does not reduce the acid production but raises the antral pH, which causes reflex gastrin release. This causes more
secretion of gastric acid. Then acid rebound occurs and the gastric motility is increased causing rapid gastric emptying. It is
effective in relieving pain of peptic ulcer. It is a potent drug in gastroesophageal reflux disease.
Combining Antacids Magnesium trisilicate is a fast-acting drug and hastens gastric emptying, while aluminium hydroxide is
slow
Aluminium hydroxide gel and magnesium trisilicate are acting and delays gastric emptying. Combining the combined and
used as antacids to maximize the wanted drugs neutralizes the laxating effect of magnesium trieffects and minimize the adverse
effects. silicate and constipating effect of aluminium hydroxide.
SHORT NOTES
Cimetidine
Cimetidine was first H2 blocker and is a competitive inhibitor.
 It is well absorbed orally but due to first-pass metabolism, the bioavailability of the drug reduces to about 60–80%. Has
shorter duration of action. It acts for about 6–8 h.
Adverse Effects
It has antiandrogenic action. Headache, dizziness, xerostomia, rashes and diarrhoea
are some common effects seen with the use of cimetidine.
Q. 2. Antacids
Antacids are weak bases, which chemically react with gastric acid to form salts and water and increase the pH of the gastric
contents above 4, thereby reducing gastric acidity immediately. Most of the antacids have either magnesium hydroxide or
aluminium hydroxide or calcium carbonate alone or in combination with their main components.
Antacids do not decrease acid production and hence potency of antacid is expressed in terms of its acid neutralizing capacity.
The antacids are classified into two types as follows:
Systemic antacids, e.g. sodium bicarbonate and sodium citrate
Nonsystemic antacids, e.g. magnesium hydroxide,
aluminium hydroxide gel, calcium carbonate.
Q. 3. Omeprazole
Or, What is omeprazole? Mention its two uses.

Omeprazole is a proton pump inhibitor which inhibits final common step in gastric acid secretion.
The significant pharmacological action of omeprazole is dose-dependent suppression of gastric acid secretion. It is powerful
inhibitor of gastric acid and totally abolishes HCl secretion.
Omeprazole reduces pain rapidly. Faster healing has
been demonstrated with 40 mg/day.
Uses
 Omeprazole is more effective than H2 blockers on ulcers and in healing of oesophageal lesions. It controls hyperacidity in
Zollinger-Ellison syndrome.
Continued treatment can prevent relapse. It also controls bleeding from peptic ulcer.
Omeprazole is an integral component of anti-H. pylori
therapy.
Q. 4. Ranitidine
It is a H2 receptor antagonist, a competitive inhibitor, and is five times more potent than cimetidine.
It is well absorbed orally but due to first-pass metabolism, the bioavailability of the drug reduces to about 60–80%. Has
longer duration of action, acts for about 12–24 h.
Adverse Effects
Headache, dizziness, xerostomia, rashes and diarrhoea are some common effects seen with the use of ranitidine.
It may also cause confusion, hallucination and delirium
in some people especially geriatric patients.
Q. 5. Aluminium hydroxide
Aluminium hydroxide gel is a weak base, which chemically reacts with gastric acid to form salt and water and increase the
pH of the gastric contents above 4, thereby reducing gastric acidity immediately. It does not reduce the acid production but
raises the antral pH, which causes reflex gastrin release. This causes more secretion of gastric acid. Then acid rebound occurs
and the gastric motility is increased causing rapid gastric emptying. It is effective in relieving pain of peptic ulcer. It is a
potent drug in gastroesophageal reflux disease.
6. Cimetidine and ranitidine
Comparison between cimetidine and ranitidine is listed in Table 39.1.
TABLE 39.1 Comparison between Cimetidine and
Ranitidine
Cimetidine Ranitidine
Potent competitive H2 receptor blocker Competitive H2 receptor blocker—5 times more potent than cimetidine
Intermediate acting Long acting
Poor CNS penetration No CNS penetration—does not cross blood-brain barrier
Has antiadrenergic effects— causes loss of libido, impotence, gynaecomastia Has no antiadrenergic effects
Q.7. Ranitidine is preferred to cimetidine. Or,
Give two reasons for prescribing ranitidine over cimetidine.

Because of the following advantages, ranitidine is preferred over cimetidine:

Ranitidine is five times more potent compared to cimetidine.
It is longer acting compared to cimetidine.
Cimetidine has antiadrenergic effects while ranitidine has no antiadrenergic effects, no CNS effects as it does not cross blood-
brain barrier.
It does not inhibit microsomal enzymes.
Q. 8. Rationale of combining aluminium hydroxide gel and
magnesium trisilicate as antacids.

Aluminium hydroxide gel and magnesium trisilicate are combined and used as antacids to maximize the wanted effects and
minimize the adverse effects. Magnesium trisilicate is a fast-acting drug and hastens gastric emptying, while aluminium
hydroxide is slow acting and delays gastric emptying. Combining the drugs prolongs the action of the drug to a required level
and makes it intermediate acting.
Combining the drugs neutralizes the laxating effect of magnesium trisilicate and constipating effect of aluminium hydroxide.
Q. 9. Sucralfate
Sucralfate is an ulcer protecting drug. At the gastric pH it forms a sticky viscid gel that gets attached to the base of the
ulcer and acts as a physical barrier protecting the ulcer from contact from acid and pepsin.
 It stimulates synthesis of prostaglandins in the gastric mucosa which helps in inhibition of gastric acid secretion, increases
mucosa production and protects the cells in the mucosa. These actions help in the healing of the ulcer.
Dose: Each tablet is given 1 h before food and at bed time for 4–8 weeks. Then 1 g tablets BD are given for 6 months as a
maintenance course.
Q. 10. Proton pump inhibitors
The clinically used proton pump inhibitors are omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole.
Proton pump inhibitors act by blocking the final step in gastric acid secretion and are most powerful inhibitors of gastric acid
secretion.
The proton pump inhibitors are inactive at neutral pH and only get activated at a pH less than 5.
They get rearranged to two cationic forms—a sulphenic acid and a sulphonamide configuration. These cations inactivate the
H1K1ATPase from the -SH by reacting with it.
Q. 11. Aspirin is contraindicated in peptic ulcers.
The aspirin is contraindicated in peptic ulcers because of following reasons:
Aspirin irritates the gastric mucosa and leads to epigastric distress, nausea and vomiting.
In acidic pH of the stomach, aspirin remains in an unionized form. The drug particles get attached to the gastric mucosa and
irritate it. They also promote back diffusion of the acid in the stomach.
Apart from this they also inhibit prostaglandin synthesis which is responsible for inhibiting gastric acid secretion and increase
production of mucosa. This leads to occurrence of ulcers.
Aspirin also leads to reduced platelet aggregation and promotes bleeding in ulcers.

Emetics, Antiemetics and Other Gastrointestinal Drugs

SHORT ESSAYS
Compare promethazine and ranitidine.
 Comparison between promethazine and ranitidine is given in Table 40.1.
Most commonly used emetics are one spoon of mustard powder with water or hypertonic salt solution. They act peripherally
by irritating the stomach and are used as household emetics.

TABLE 40.1 Comparison between Promethazine and

Ranitidine
Points of
Comparison Promethazine Ranitidine
Type H1 antihistamine H2 antihistamine
Action on histamine receptors Block H1 receptors Block H2 receptors
Effects They induce effects on smooth muscles of gut, blood
vessels and triple response They act on histamine-induced gastric secretion, cardiac stimulation, uterine and bronchial
relaxation
Uses Used in blocking histamine-induced allergic reactions, antimotion sickness, sedation, parkinsonism, local anaesthetic
in higher doses Used in treatment of peptic ulcer
Adverse effects Sedation, dizziness, motor incoordination, inability to concentrate, dryness of mouth, blurred vision,
constipation, urinary retention, teratogenic Headache, dizziness, bowel upset, dry mouth, hepatic injury, haematological
changes in elder patients
Q. 2. Emetics
Drugs that produce vomiting are called emetics.
They help to produce vomiting by stimulating the vomiting centre in the medulla oblongata.
The vomiting centre has two zones of stimulation as follows:
Chemoreceptor trigger zone (CTZ) located in the postrema
Nucleus tractus solitarius
Morphine and apomorphine are centrally acting emetics; they induce vomiting by stimulating CTZ. Syrup ipecac is a safe
emetic. It has both peripheral and central actions. Emetics are indicated in certain cases of poisoning.
Some drugs used as emetics are as follows:
Apomorphine: It is derived from morphine. When given SC or IM induces vomiting within 5–10 min by stimulating the CTZ
centre.
Ipecacuanha is an alkaloid emetine that induces vomiting in 15 min. It is available as a syrup ipecac and is given even to
children.
All emetics are contraindicated in the following:
Corrosive (acid, alkali) poisoning due to risk of perforation to oesophageal mucosa.
CNS stimulant drug poisoning: Convulsions may be precipitated.
Kerosene (petroleum) poisoning: Chances of aspiration of the liquid and chemical pneumonia are high.
Unconscious patients, because they may aspirate the vomitus.
Q. 3. Metoclopramide
Metoclopramide is a prokinetic agent and an antiemetic that is chemically related to procainamide.
Actions
It acts by blocking the D2 receptors and antagonizes the dopamine thus hastening gastric emptying by increasing gastric
peristalsis. It acts on the CTZ area in the brain by acting against the dopaminergic receptors and inhibits vomiting reflex.
It increases lower oesophageal tone. It opposes gastroesophageal reflux.
Therapeutic Uses
As antiemetic: It is popular and effective drug for many types of vomiting like postoperative, drug-induced, radiation sickness,
etc. It is less effective in motion sickness.
Gastrokinetics: To accelerate gastric emptying When emergency general anaesthesia has to be given and patient had taken
food less than 4 h before
 To relieve gastric stasis associated with diabetes or
postvagotomy
To facilitate duodenal intubation
In functional gastrointestinal disorders like persistent hiccups, dyspepsia, gastroesophageal reflux disease (GERD) and during
cancer therapy
Adverse Effects
Sedation, dystonia, diarrhoea, gynecomastia, galactorrhoea and parkinsonism, increased sodium retention
Q. 4. Prokinetic agents
Prokinetic drugs are those that enhance gastroduodenal motility and gastric emptying by enhancing acetylcholine release
from the cholinergic neurons in the gut.
They act by blocking the D2 receptors and antagonize the dopamine thus hastening gastric emptying by increasing gastric
peristalsis.
 By blocking dopamine receptors in the CTZ. They act as antiemetics.
Commonly used prokinetic agents are as follows:
Metoclopramide
Domperidone
Cisapride
Mosapride
Uses
Prokinetic agents are used to hasten gastric emptying in conditions like the following:
Major surgeries in emergency situations where the time gap between food intake and the surgery is less than 4 h
To relieve gastric stasis caused due to postvagotomy or diabetes
To facilitate duodenal intubation
Adverse Effects
Metoclopramide: Sedation, drowsiness, dizziness and diarrhoea, gynecomastia, galactorrhoea and parkinsonism while dystonia
is rarely seen.
Domperidone: Headache, dryness of mouth, diarrhoea, rashes
Cisapride: Diarrhoea
Q. 5. Rationale of using domperidone as antiemetics Or,
Domperidone is preferred over metoclopramide in vomiting.

Dopamine is a prokinetic and antiemetic that acts by blocking D2 dopamine receptor. It is less potent and less efficacious
than metoclopramide. It acts on the chemoreceptor trigger zone (CTZ) to inhibit vomiting reflux. As it does not cross blood-
brain barrier, the extrapyramidal adverse effects are rare and few. It is the preferred antiemetic in children. Domperidone is
usually administered orally, but its oral bioavailability is low because of extensive first-pass effect; metabolized in the liver and
metabolites are excreted in urine. Side effects are much less than that of metoclopramide. It may cause headache, dryness of
mouth, diarrhoea and rashes.
Q. 6. Name antiemetic drugs and mention their adverse effects.

Antiemetics are drugs that inhibit the vomiting reflex by acting on the chemoreceptor trigger zone (CTZ) located in the
postrema and nucleus tractus solitaries both of which are located in the medulla oblongata.
Classification
Dopamine antagonists (prokinetics): Domperidone, metoclopramide
Antimuscarinic drugs: Hyoscine, H1-antihistamines like cyclizine, promethazine, diphenhydramine
5HT3 antagonists: Ondansetron, granisetron and dolasetron
Neuroleptics: Chlorpromazine, prochlorperazine and haloperidol
Other agents: Cisapride, corticosteroids
Adverse Effects
Metoclopramide: Sedation, dystonia, diarrhoea, gynecomastia, galactorrhoea and parkinsonism
Domperidone: Headache, dryness of mouth, diarrhoea, rashes
Cisapride: Diarrhoea
SHORT NOTES
Metronidazole
Metronidazole is a nitroimidazole that inhibits various microorganisms like Entamoeba histolytica, Trichomonas vaginalis,
Giardia lamblia and Balantidium coli.
Metronidazole is toxic to the microbial DNA and kills
the organism.
Uses
Intestinal and extraintestinal amoebiasis
Trichomonas vaginitis
Giardiasis
Helicobacter pylori infections
Q. 2. Name two drugs used to suppress vomiting.

The drugs that suppress the vomiting reflex by acting on the chemoreceptor trigger zone (CTZ) are called antiemetics.
Various drugs that are used to suppress the vomiting are as follows:
Dopamine antagonists (prokinetics): Domperidone, metoclopramide
Antimuscarinic drugs: Hyoscine, H1-antihistamines like cyclizine, promethazine, diphenhydramine
5HT3 antagonists: Ondansetron, granisetron
Neuroleptics: Chlorpromazine, prochlorperazine
Other agents: Cisapride, corticosteroids
Q. 3. Metoclopramide
Metoclopramide is a prokinetic agent and an antiemetic that is chemically related to procainamide.
It increases gastric peristalsis and helps in gastric emptying.
It acts on the CTZ area in the brain and inhibits vomiting reflex.
Therapeutic uses: As antiemetic, gastrokinetics, in gastrointestinal disorders like persistent hiccups, dyspepsia,
gastroesophageal reflux disease (GERD) and during cancer therapy
Adverse effects: Sedation, dystonia, diarrhoea, gynecomastia, galactorrhoea and parkinsonism
Q. 4. Rationale of using metoclopramide in vomiting
Metoclopramide is a prokinetic agent and an antiemetic that is chemically related to procainamide. Rationale of using
metoclopramide in vomiting is that it acts on the CTZ area in the brain by acting against the dopaminergic receptors and
inhibits vomiting reflex.
 it acts by blocking the D2 receptors and antagonizes the dopamine thus hastening gastric emptying by increasing gastric
peristalsis.
Q. 5. Rationale of using domperidone as antiemetics
Dopamine is a prokinetic and antiemetic that acts by blocking D2 dopamine receptor.
It acts on the chemoreceptor trigger zone (CTZ) located in the postrema to inhibit vomiting reflux.
As it does not cross blood brain barrier, the extrapyramidal adverse effects are rare and few. It may cause headache,
dryness of mouth, diarrhoea and
rashes.
Q. 6. Promethazine
Promethazine is a H1 antihistamine that acts on the histamine receptors and induces effects on smooth muscles of gut, blood
vessels and triple response.
Uses: Used in blocking histamine-induced allergic reac-
tions, antimotion sickness, sedation, parkinsonism, local anaesthetic in higher doses
Adverse effects: Sedation, dizziness, motor incoordina-
tion, inability to concentrate, dryness of mouth, blurred vision, constipation, urinary retention, teratogenic
Q. 7. Prokinetic drugs. Mention two prokinetic drugs and their two adverse
effects.

Prokinetic drugs are those that enhance gastroduodenal motility and gastric emptying by enhancing acetylcholine release
from the cholinergic neurons in the gut.
They act as antiemetics by blocking dopamine receptors in the CTZ.
Various prokinetic drugs and their adverse effects are as follows:
Metoclopramide: Sedation, dystonia, diarrhoea, gynecomastia, galactorrhoea and parkinsonism
Domperidone: Headache, dryness of mouth, diarrhoea, rashes
Cisapride: Diarrhoea

Drugs for Constipation and Diarrhoea

SHORT ESSAYS
Drugs used as purgatives
Purgatives are drugs that are used to promote defaecation and they are used in treatment of constipation.
Classification of Purgatives
Bulk forming purgatives: Dietary fibres like bran, ispaghula (isabgol), methyl cellulose, psyllium
Fecal softeners (stool wetting agents): Docusate sodium (DOSS), liquid paraffin
Osmotic purgatives: Magnesium sulphate, magnesium hydroxide, sodium salts, lactulose
Stimulant or irritant purgatives: Bisacodyl, phenolphthalein, senna, caster oil
Prokinetic agents: 5-HT4 agonist, tegaserod
Uses of Purgatives
Bulk forming purgatives are used in simple constipation and when straining at stools has to be avoided.
Fecal softeners such as docusates increase absorption of nonabsorbable drugs.
Liquid paraffin lubricates hard stool by coating it.
Osmotic purgatives are used to prepare bowel before surgery, food poisoning, after purge in tapeworm infestation.
Purgatives are used in flushing out antihelminthic drugs and helminthes.
Saline purgatives are used in food or drug poisoning. Q. 2. ORS
Oral rehydration solution (ORS) is used in patients with diarrhoea to replenish the lost water and maintain the electrolyte
balance.
The principle behind an ideal ORS is that it should be isotonic or a little hypotonic. The osmolarity should be around 200–
310 mOsm/L.
 The molar ratio of glucose should be equal to or higher than that of sodium, but it should not exceed 110 mM. The amount
of potassium and salts like bicarbonate and citrate lost due to diarrhoea should be replaced with the ORS.
Composition (WHO recommended standard formula)
Sodium chloride (NaCl)—3.5 g
Potassium chloride (KCl)—1.5 g
Trisodium citrate—2.9 g
Glucose—20 g
All the above components should be dissolved in 1 L of water.
Uses
ORS is used to replace the fluids and salts lost from the body during diarrhoea.
They are used to maintain hydration in patients post surgically, after burns and trauma, and in cases of heat stroke.
SHORT NOTES
 Rationale of using loperamide in diarrhoea
Loperamide is an opiate drug used in the treatment of diarrhoea. It has selective action on the gastrointestinal tract and has
antisecretory action.
It is slowly soluble in water and does not have desired effect when given parenterally. It has very few adverse effects like
nausea, vomiting and abdominal cramps.
Q. 2. Bulk purgatives
Bulk forming purgatives are hydrophilic substances like bran, methylcellulose, agar, plantago, ovata, etc. which absorb
water, swell up and increase in bulk of the stools. They cause mechanical distension, so stimulate peristalsis and promote
defaecation.
They are used in simple constipation and when straining at stools has to be avoided.
Bulk forming purgatives commonly used are as follows:
Dietary fibres like bran
Ispaghula
Methyl cellulose
Psyllium
Q. 3. Name two osmotic purgatives.

Osmotic or saline purgatives are the most powerful and rapid-acting agents. They are the salts of magnesium, sodium or
potassium.
Osmotic purgatives are used to prepare bowel before surgery, after food or drug poisoning, after purge in tapeworm
infestation.
Osmotic purgatives commonly used are as follows:
Magnesium sulphate
Magnesium hydroxide
Sodium salts
Lactulose
Q. 4. Magnesium sulphate
Magnesium sulphate is an osmotic purgative, which has strong action and results in more fluid evacuation than laxative.
Mechanism of action: It acts by increasing the water content of the faeces by increasing colonic content and makes it easily
propelled. It decreases the absorption of water and electrolytes from the intestines.
It produces 1–2 fluid evacuation within 1–3 h. It can nearly empty the bowels. It may cause slight cramping of the
stomach, and are not used in regular constipation therapy. They are used in evacuation before surgeries like colonoscopy, in
cases of food poisoning or drug overdosage and after antihelminthic (hookworm) treatment to evacuate the dead worms.
Q. 5. Loperamide
 Loperamide is an opiate drug used in the treatment of diarrhoea. It has selective action on the gastrointestinal tract and has
antisecretory action.
It is slowly soluble in water and does not have desired effect when given parenterally. It has very few adverse effects like
nausea, vomiting and
abdominal cramps.
Q. 6. Liquid paraffin

Liquid paraffin is a type of fecal softener. It lubricates hard stool by coating it and softens it.
Chemically it is an inert mineral oil which cannot be
digested.
Adverse Effects
Causes discomfort as it may leak out of the anus.
May cause paraffinomas when absorbed in the intestine.
May cause lipoid pneumonia when aspirated.
Q. 7. Anthraquinone preparations
The senna and cascara are the popular anthracene purgatives.
They are usually administered at bed time to produce their effect in the morning as they take 6–7 h to act.
They are contraindicated in lactating mothers, they are secreted in the milk. The side effects are skin rashes, black
pigmentation of
the colonic mucosa and discolouration of urine.
Q. 8. Hazards of using purgatives Regular use of purgatives may cause various gastrointestinal
disturbances like irritable bowel syndrome, loss of electrolytes, loss of salts like calcium, dehydration. Excessive
dehydration may lead to death.
Q. 9. ORS
Oral rehydration solution (ORS) is used in patients with diarrhoea to replenish the lost water and maintain the electrolyte
balance.
Composition
Sodium chloride (NaCl)—3.5 g
Potassium chloride (KCl)—1.5 g
Trisodium citrate—2.9 g
Glucose—20 g
Water—1 L
Uses
ORS is used to replace the fluids and salts lost from the body during diarrhoea.
They are used to maintain hydration in patients post surgically, after burns, and trauma, and in cases of heat stroke.
Part XII
Antimicrobial Drugs

General Considerations
LONG ESSAYS
Mention classification of antibiotics and describe the mechanism of action
and uses of two commonly used antibiotics.
Antimicrobial agents are the substances which suppress the growth of or kills other microorganisms.
CLASSIFICATION OF ANTIMICROBIAL AGENTS
I. Based on Type of Action
Bactericidal agents: Penicillin, cephalosporins, aminoglycosides, fluoroquinolones, rifampin, metronidazole
Bacteriostatic agents: Tetracyclines, chloramphenicol,
sulphonamides, erythromycin, clindamycin
II. Based on Their Spectrum of Activity
Narrow-spectrum antibiotics: Penicillin G, erythromycin, streptomycin
Broad-spectrum antibiotics: Tetracyclines, chloramphenicol
III. Based on Their Mechanism of Action
Drugs that inhibit cell wall synthesis: Penicillins, cephalosporins, cycloserine, vancomycin, bacitracin
Drugs that cause leakage from cell membranes: Poly-
peptides, polymyxins, colistin, bacitracin, polyenes, amphotericin B, nystatin, hamycin
Drugs that inhibit protein synthesis: Tetracyclines, chloramphenicol, erythromycin, clindamycin, linezolid
Drugs that cause misreading of m-RNA code and affect permeability: Aminoglycosides, streptomycin, gentamicin, etc.
Drugs that inhibit DNA gyrase: Fluoroquinolones, ciprofloxacin
Drugs that interfere with DNA function: Rifampin,
metronidazole
Drugs that interfere with DNA synthesis: Idoxuridine, acyclovir, zidovudine
Drugs that interfere with intermediary metabolism: Sulphonamides, sulfones, dapsone, PAS, trimethoprim, pyrimethamine,
ethambutol
The mechanism of action and side effects of two commonly used antibiotics are as follows:
A. PENICILLIN
Penicillin is most important of the antibiotics and belongs to a group of antibiotics called as b-lactam antibiotics.
Mechanism of Action
Penicillin and all b-lactam antibiotics interfere with the bacterial cell wall synthesis by inhibiting transpeptidase so that
synthesis and crosslinking of peptidoglycan chain does not take place. This weakens the bacterial cell wall and makes the
organisms vulnerable to damage by solutes in the surrounding medium, i.e. plasma. Penicillin is a bactericidal drug. As cell
wall synthesis occurs during growth phase, antibiotic is most effective against actively multiplying organisms. In addition
penicillins activate the bacterial, endogenous, autolytic system and initiate cell lysis and death.
Uses
The penicillin is a drug of choice for infections caused by organisms susceptible to it.
Dental infections Penicillin G is effective in most of the common infections in dentistry.
It is also used for periodontal abscess, periapical abscess, pericoronitis, ulcerative gingivitis, etc.
It can also be used prophylactically to cover dental procedures.
Medical conditions
Streptococcal infections: Pharyngitis, tonsillitis, oti-
tis media, rheumatic fever, etc.
Pneumococcal infections
Gonorrhoea
Syphilis: Benzathine penicillin is drug of choice.
Diphtheria, tetanus, anthrax, actinomycosis infections
Prophylactic use: To prevent recurrence of rheumatic
fever, surgical fever
B. FLUOROQUINOLONES
Fluoroquinolones are the synthetic fluorinated analogues of nalidixic acid. They are quinolone antimicrobials having one or
more fluorine substitutions.
Classification
First generation fluoroquinolones: Norfloxacin, ciprofloxacin, ofloxacin, pefloxacin
Second generation fluoroquinolones: Lomefloxacin,
sparfloxacin, levofloxacin, gatifloxacin, moxifloxacin
Mechanism of Action
The fluoroquinolones are bactericidal and act by inhibiting the enzyme bacterial DNA gyrase, and hence prevent the
supercoiling of DNA resulting in the inhibition of DNA synthesis which is responsible mainly for their activity against Gram-
negative bacteria. They also inhibit topoisomerase IV which contributes towards their activity against Gram-positive
bacteria.
In Gram-positive bacteria, their major target is topoisomerase IV that has similar function as that of a subunit of DNA
gyrase.
The bactericidal action probably is due to digestion of DNA by exonucleases produced on signals from damaged DNA.
Fluoroquinolones inhibit bacterial DNA gyrase enzyme
Fluoroquinolones damage bacterial DNA
Exonucleases
Digest DNA
Uses
They are generally used in bacterial infections. Ciprofloxacin is a first generation fluoroquinolone antimicrobial drug.
It is active against Gram-negative bacilli especially enterobacteriaceae and neisseria. Ciprofloxacin has rapid bactericidal
activity by digesting DNA.
Therapeutic Uses
It is used in
urinary tract infections,
bacterial gastroenteritis,
typhoid fever,
gonorrhoea and
skin, soft tissue, gynaecological infections, skeletal infections etc.
It is used in combination with other antibiotics for serious infections like Gram-negative septicaemias, meningitis, etc.
It is used as component chemotherapy against multidrug resistance TB.
During conjunctivitis topical therapy is effective of ciprofloxacin.
Q. 2. Classify antimicrobial agents based on the mechanism of action with
examples. Explain four advantages of combined use of antimicrobial
with examples.

Antimicrobial agents are the substances which suppress the growth of or kills other microorganisms.
CLASSIFICATION
Based on their mechanism of action antimicrobial agents are classified as follows:
Drugs that inhibit cell wall synthesis: Penicillins, cephalosporins, cycloserine, vancomycin, bacitracin
Drugs that cause leakage from cell membranes: Poly-
peptides, polymyxins, colistin, bacitracin, polyenes, amphotericin B, nystatin, hamycin
Drugs that inhibit protein synthesis: Tetracyclines, chloramphenicol, erythromycin, clindamycin, linezolid
Drugs that cause misreading of m-RNA code and affect
permeability: Aminoglycosides, streptomycin, gentamicin
Drugs that inhibit DNA gyrase: Fluoroquinolones, ciprofloxacin
Drugs that interfere with DNA function: Rifampin, metronidazole
Drugs that interfere with DNA synthesis: Idoxuridine, acyclovir, zidovudine
Drugs that interfere with intermediary metabolism: Sulphonamides, sulfones, dapsone, PAS, trimethoprim, pyrimethamine,
ethambutol
ADVANTAGES OF COMBINED USE OF ANTIMICROBIAL DRUGS Synergism
A combination of two or more antibacterials has either synergism, additive actions, indifference or antagonism depending on
the drugs and microorganism.
If minimum inhibitory concentration of each antibacterial is reduced to 25% or less, then the combination is synergistic.
25–50% then it is additive. more than 50% then it is antagonism.
 A synergistic drug sensitizes the organism to action of the other members of combination manifesting as more rapid lethal
action of combination than individual members alone.
Two bacteriostatic agents are often additive, sometimes synergistic. For example:
Sulphonamide and trimethoprim have supra-additive effects exerting bactericidal effect.
b-lactamase inhibitor clavulanic acid or sulbactam with amoxicillin or ampicillin for b-lactamase producing Haemophilus
influenzae, Neisseria gonorrhoeae and others.
Two bactericidal drugs are frequently additive if the organism is sensitive to both producing faster cure and reducing chances
of relapse. For example:
Penicillin or ampicillin with streptomycin or gentamicin for enterococcal SABE
Carbenicillin or ticarcillin with gentamicin for pseudomonas infection
Ceftazidime with ciprofloxacin for pseudomonas
infected orthopaedic prostheses
 Rifampicin with isoniazid in tuberculosis
Combination of a bactericidal with a bacteriostatic drug may be synergistic or antagonistic depending on the organism.
If organism is highly sensitive to the cidal drug then response is equal to static drug given alone because cidal drug primarily
acts on the rapidly multiplying bacteria while the static drug retards multiplication. For example: Penicillin with
erythromycin for group A streptococci Nalidixic acid with nitrofurantoin of E. coli
If the organism has low sensitivity to the cidal drug then synergism may be seen. Penicillin with sulphonamides for
actinomycosis Streptomycin with tetracyclines for brucellosis Streptomycin with chloramphenicol for Klebsiella
pneumoniae infection
Rifampicin with dapsone in leprosy
Reduction in Severity or Incidence of Adverse Effects
If the combination of drugs is synergistic, then dose can be reduced, reducing the severity or incidence of adverse effects
especially if the drugs have low safety margin. For example:
 Streptomycin with penicillin G for SABE due to Streptococcus faecalis
Amphotericin B with rifampicin or minocycline (latter though not antifungal enhance action of the former)
Amphotericin B with flucytosine for cryptococcal meningitis
Prevention of Emergence of Resistance
Resistance to one antibacterial substance due to mutation is independent of resistance to another. If incidence of resistance to
one drug is 1024 and of another is 1026 then chances of resistance to the other drugs is one bacilli out of 1010 bacilli.
Thus the chances of bacilli surviving the host defence and to cause relapse are minimal. This approach is valid primarily for
chemotherapy of chronic infections needing prolonged therapy like tuberculosis, leprosy, H. pylori, HIV.
It is of less value in most acute and short-lived infections, however used in Haemophilus influenzae: Sulphonamides with
streptomycin
Staphylococcus aureus: Ciprofloxacin with rifampicin
Broadened Spectrum of Antimicrobial
Action
Treatment of mixed infections: In mixed infections, two or more antibacterial agents are used to cover the pathogen. Drugs
are chosen on the basis of bacteriological diagnosis, sensitivity pattern and are employed in full doses.
To cover anaerobes, clindamycin or metronidazole are commonly used.
However, it may sometimes be possible to find a single drug effective against all the infecting organisms. Bronchiectasis,
peritonitis, certain UTIs, brain abscesses, diabetic foot infections, bedsores, gynaecological infections, etc.
Initial treatment of severe infections: In cases where the bacteriological diagnosis is unknown, the combination of drugs
covering Gram-positive and Gram-negative organisms and sometimes even anaerobes is given till the causative organism is
identified. Penicillin with streptomycin Cephalosporins or erythromycin with an aminoglycoside with metronidazole or
clindamycin
Topically: Antibacterial agents covering a broad range of Gram-positive and Gram-negative bacteria are combined for topical
applications. For example: Bacitracin, neomycin, polymyxin B
SHORT NOTES
What is superinfection? Give two examples.

Superinfection is the appearance of a new infection resulting from the use of antimicrobials. Antibacterials alter the normal
microbial flora of the intestinal, respiratory and genitourinary tracts. The normal flora contribute to the host defence
mechanism by inhibiting the colonization of pathogenic organisms, by producing antibacterial substances called bacteriocins
and by competing for nutrients. When the normal flora are destroyed by the antibacterials, there can be dangerous infections
due to various organisms especially the normal commensals.
The broader the antibacterial spectrum of a drug, the more are the chances of superinfection, as the alteration of normal flora is
greater.
Common microorganisms causing superinfection are
Candida albicans manifests as oral thrush, diarrhoea, vaginitis,
Staphylococci manifest as enteritis and

Sulphonamides, Co-trimoxazole and Quinolones

LONG ESSAYS
E. coli manifests as UTI.

Enumerate fluoroquinolones. Mention their antimicrobial spectrum, therapeutic uses and

adverse effects.
Or,
Discuss the mechanism of action, uses and adverse effects of fluoroquinolones.
Fluoroquinolones are the synthetic fluorinated analogues of nalidixic acid. They are quinolone antimicrobials having one or
more fluorine substitutions.
Classification
First generation fluoroquinolones: Norfloxacin, ciprofloxacin, ofloxacin, pefloxacin
Second generation fluoroquinolones: Lomefloxacin, sparfloxacin, levofloxacin, gatifloxacin, moxifloxacin
The first generation fluoroquinolones (FQs) that were introduced in 1980s have one fluoro substitution.
The second generation fluoroquinolones (FQs) that were introduced in 1990s have additional fluoro and other substitutions
with further extending antimicrobial activity to Gram-positive cocci and anaerobes and conferring metabolic stability (longer
t1/2).
Antibacterial Spectrum
Ciprofloxacin is highly effective against Gram-negative organisms like Escherichia coli, Enterobacter, Proteus, Klebsiella
pneumoniae, Salmonella, Shigella, Haemophilus ducreyi, Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria
meningitidis, etc.
 Moderate-to-low activity against Staphylococcus aureus, Pseudomonas aeruginosa, Chlamydia, Mycoplasma and
Mycobacterium.
Most of the anaerobes Bacteroides fragilis, Clostridium difficile, etc. are resistant to ciprofloxacin.
Newer fluoroquinolones like levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, etc. have greater activity against
streptococci and some activity against anaerobes.
Mechanism of Action
The fluoroquinolones are bactericidal and act by inhibiting the enzyme bacterial DNA gyrase, and hence prevent the
supercoiling of DNA resulting in the inhibition of DNA synthesis which is responsible mainly for their activity against Gram-
negative bacteria.
DNA gyrase consists of two subunits A and B. The A subunit nicks the DNA and reveals it. The B subunit introduces negative
supercoils. The action of DNA gyrase is important in bacterial replication as it prevents excessive positive supercoiling of the
strands when they separate to permit transcription.
The fluoroquinolones have high affinity towards A subunit of DNA gyrase and thus prevent nicking and resealing of DNA thus
interfere with DNA replication producing damaged DNAs.
They also inhibit topoisomerase IV which contributes towards their activity against Gram-positive bacteria.
In Gram-positive bacteria, their major target is topoisomerase IV that has similar function as that of A subunit of DNA gyrase.
The bactericidal action probably is due to digestion of DNA by exonucleases produced on signals from damaged DNA.
Pharmacokinetics
Ciprofloxacin is rapidly absorbed orally but its absorption is delayed by food.
The oral bioavailability is 60–80% and plasma protein binding is less (20–35%).
It has high tissue permeability thus achieving higher concentration of the drug in lung, sputum, muscle, bone, prostate and
phagocytes than plasma.
It is excreted primarily in the urine by both glomerular filtration and tubular secretion.
Uses
Because of wide-spectrum bactericidal activity, oral efficacy and good tolerability ciprofloxacin is used extensively in broad
range of infections even as blind therapy.
The usual dose is 250–750 mg BD orally and 100–200 mg IV.
i. Urinary Tract Infections Fluoroquinolones are one of the most commonly used antimicrobial agents for UTI. They are
superior to co-trimoxazole for the treatment of UTI. They are also effective for the treatment of bacterial prostatitis as they
are concentrated in the prostatic tissue.
High cure rates even in complicated cases or those with
indwelling catheters and prostatitis
ii. Gonococcal Infections (Gonorrhoea)
Single dose of 500 mg ciprofloxacin or 400 mg of ofloxacin is nearly 100% curative in cervicitis, urethritis and pelvic
inflammatory disease due to N. gonorrhoeae.
Now ceftriaxone is the first drug of choice due to increased prevalence of quinolone resistant gonococci.
 Fluoroquinolones are also effective for chlamydial infections and chancroid. Three-day treatment is excellent alternative to
co-trimoxazole in chancroid.
iii. Bacterial Gastroenteritis or Diarrhoeas Fluoroquinolones are very effective in severe cases due to E. coli, Shigella,
Salmonella and Campylobacter jejuni respond quickly. They reduce stool volume in cholera.
For travellers’ diarrhoea due to E. coli, fluoroquinolones are as effective as co-trimoxazole.
Norfloxacin, ciprofloxacin or ofloxacin therapy for 3–5 days is adequate.
iv. Typhoid Fever
Ciprofloxacin (500–700 mg BD for 10 days) is the drug of choice used to treat acute stage as well as carriers. Course of
treatment varies between 10 and 14 days.
Pefloxacin or ofloxacin can also be used. They are also effective in eliminating the chronic carrier state of Salmonella typhi
when therapy is continued for 6 weeks.
v. Bone, Soft Tissue, Gynaecological and Wound Infections High cure rates in infections caused by S. aureus and Gram-
negative bacteria.
High dose prolonged treatment is required for osteomyelitis and joint infection.
For diabetic foot infections fluoroquinolones are used along with antianaerobic agents like clindamycin or metronidazole.
vi. Respiratory Infections
Used for Mycoplasma, Legionella, H. influenzae, Branhamella catarrhalis and some Gram-negative bacilli.
Ciprofloxacin has been used to eradicate meningococci from nasopharynx thus eliminating carrier state, but the preferred
drug is rifampicin.
vii. Mycobacterial Infections
Fluoroquinolones are used in combination with other antimicrobial agents as a part of therapy of multidrug resistant
tuberculosis, MAC infections in AIDS patients and leprosy.
viii. Gram-negative Septicaemia Used parenterally along with a third generation cephalosporins or an aminoglycoside.
 Ciprofloxacin is used topically for conjunctivitis due to Gram-negative organisms.
ix. Prophylaxis of Infections in Neutropenic, Cancer or Susceptible Patients
Fluoroquinolones are often used in combination with an aminoglycoside.
Adverse Effects
Common adverse effects are related to GI tract like nausea, vomiting, bad taste, anorexia and abdominal discomfort.
CNS effects like dizziness, headache, restlessness, anxiety, insomnia, impairment of concentration, dexterity tremors and
seizures at high doses or in presence of precipitating factors.
Hypersensitivity reactions include skin rashes, pruritus, photosensitivity, urticaria, swelling of lips, etc. Tenosynovitis and
tendon rupture can occur rarely.
Q. 2. Classify sulphonamides. Discuss the mechanism of action, adverse effects and
uses of co-trimoxazole.
SULPHONAMIDES
Sulphonamides are derivatives of p-amino-benzene sulphonamides (sulphanilamide). Classification of sulphonamides
based on duration of
action is as follows:
Short-acting (4–8 h): Sulphadiazine
Intermediate-acting (8–12 h): Sulphamethoxazole
Long-acting (,7 days): Sulphadoxine, sulphamethoxypyrazine
Special purpose sulphonamides: Sulphacetamide so-
dium, sulphasalazine (topical), silver sulphadiazine
(topical), mafenide (topical)
CO-TRIMOXAZOLE
Co-trimoxazole is the fixed dose combination of trimethoprim 80 mg and sulphamethoxazole 400 mg.
Mechanism of Action
Co-trimoxazole acts by sequential blockade of folate metabolism. Trimethoprim selectively inhibits bacterial
dihydrofolate reductase whereas the sulphamethoxazole inhibits conversion of PABA to dihydrofolate. Individually both the
drugs are bacteriostatic but their combination renders co-trimoxazole bacteriocidal.
Maximum synergism is seen when the organism is sen-
sitive to both the components.
Preparation
Optimal synergy of co-trimoxazole is seen at a concentration ratio of sulphamethoxazole:trimethoprim (20:1). This ratio is
obtained in plasma when both these drugs are given in dose ratio of 5:1 because trimethoprim enters many tissues and has a
larger volume of distribution than sulphamethoxazole and attains lower plasma concentration.
Pharmacokinetics
Trimethoprim adequately crosses blood-brain barrier and placenta while sulphamethoxazole has a poorer entry.
 Trimethoprim is more rapidly absorbed than sulphamethoxazole. Trimethoprim is 40% plasma protein bound while
sulphamethoxazole is 65% bound. Trimethoprim is partly metabolized in liver and excreted in urine.
Antibacterial Spectrum
Antibacterial spectra of trimethoprim and sulphonamides overlap considerably. Additional organisms covered by the
combination are as follows:
Salmonella typhi, Serratia, Klebsiella, Enterobacter,
Yersinia enterocolitica, Pneumocystis jiroveci Sulphonamide-resistant strains of Staphylococcus aureus, Streptococcus
pyogenes, Shigella, Enteropathogenic Escherichia coli, Haemophilus influenzae, Gonococci and Meningococci
Adverse Effects
Nausea, vomiting, stomatitis, headache and rashes: usually occurring side effects
Folate deficiency (megaloblastic anaemia): infrequent Blood dyscrasias: rarely seen Neonatal haemolysis and
methamoglobinemia: if given
near term in pregnancy
Uraemia: in patients with renal disease Fever, rash and bone marrow hypoplasia: in AIDS pa-
tients with Pneumocystis carinii infection
Bone marrow toxicity: in elderly
Therapeutic Uses
i. Urinary Tract Infections Most acute uncomplicated infections respond rapidly.
Single dose therapy with four tablets of co-trimoxazole is recommended for acute cystitis. Three to ten days course for lower
and upper urinary tract infections.
It is especially valuable in chronic and recurrent cases and
in prostatitis as the trimethoprim is concentrated in prostate.
ii. Respiratory Tract Infections Both upper and lower respiratory tract infections including chronic bronchitis and
faciomaxillary infections, otitis media caused by Gram-positive cocci and H. influenzae respond well. It is drug of choice in
nocardia infection. It is also used
in whooping cough.
iii. Typhoid
Co-trimoxazole is used as an alternative in patients not tolerating fluoroquinolones. Sensitive strains respond to one
double strength tab BD for 2 weeks. Twelve-week course eradicates carrier state provided
gallbladder is not involved.
iv. Bacterial Diarrhoeas and Dysentery Co-trimoxazole is used for many severe and invasive infections by Campylobacter,
E. coli, Shigella and Yersinia enterocolitica. It is effective in ampicillin-resistant cases.
v.
vi.
 Chancroid
Cotrimoxazole (trimethoprim 800 1 sulphamethoxazole 160 mg) BD for a week days is the third drug of choice and
inexpensive alternative to ceftriaxone, erythromycin or ciprofloxacin.
Granuloma Inguinale
It is an alternative to doxycycline or erythromycin. It is an effective alternative to penicillin for protecting agranulocytosis
patients and treating respiratory and other infections in them. Intensive parenteral co-trimoxazole therapy is used
successfully in septicaemiae.
vii. Pneumocystis Jirovecii
1. Cotrimoxazole is of therapeutic as well as prophylactic value. One double strength (DS) tablet 4–6 times/day for 2–3
weeks is curative and one DS tab daily is used prophylactically.
SHORT ESSAYS
Classify sulphonamides. Write important adverse effects.
Classification of Sulphonamides
Classification of sulphonamides based on duration of action is as follows:
Short-acting (4–8 h): Sulphadiazine
Intermediate-acting (8–12 h): Sulphamethoxazole
Long-acting (,7 days): Sulphadoxine, sulphamethoxypyrazine
Special purpose sulphonamides: Sulphacetamide sodium, sulphasalazine (topical), silver sulphadiazine
(topical), mafenide (topical)
Important Adverse Effects
Usually occurring side effects are nausea, vomiting, stomatitis, headache and rashes.
Folate deficiency (megaloblastic anaemia) is infrequent.
Dose-related crystalluria, renal irritation, haematuria and anuria
Hypersensitivity reactions in form of rashes, urticaria and drug fever, arthritis, serum sickness like syndrome and polyarteritis
nodosa are infrequent.
Stevens-Johnson syndrome and exfoliative dermatitis with long-acting agents.
Rarely causes hepatitis and suppression of bone marrow.
Contact sensitization with topical use.
Haemolytic anaemia may occur in a dose-dependent manner in individuals with G-6-PD deficiency.
Causes kernicterus in premature newborns by displacement of bilirubin from plasma protein binding sites and deposition in
basal ganglion due to more permeable blood-brain barrier.
Q. 2. Sulphonamides are not very effective in the presence of pus. Explain.

Sulphonamides inhibit the conversion of PABA to dihydrofolic acid (DHF) and trimethoprim inhibits dihydrofolate reductase
(DHFR). It thus prevents the reduction of DHF to tetrahydrofolic acid (THF).
Co-trimoxazole is the combination of sulphamethoxazole and trimethoprim. Trimethoprim selectively inhibits bacterial
dihydrofolate reductase whereas the sulphamethoxazole inhibits conversion of PABA to dihydrofolate.
Individually both the drugs are bacteriostatic but their combination renders co-trimoxazole bacteriocidal.
Maximum synergism is seen when the organism is sensitive to both the components. Presence of pus, blood and tissue
breakdown products make sulphonamides ineffective as these are rich in PABA.
Q. 3. Explain the mechanism of action of co-trimoxazole.
Co-trimoxazole produces sequential blockade of folate metabolism, i.e. two drugs interfere with two successive steps in the
same metabolic pathway and produce supraadditive effect.
Sulphamethoxazole inhibits folate synthetase and hence it inhibits the conversion of PABA to dihydrofolic acid (DHF) and
trimethoprim inhibits dihydrofolate reductase (DHFR). It thus prevents the reduction of DHF to tetrahydrofolic acid (THF) as
shown:
PABA
Folate synthetase ← (-)sulphamethoxazole
Dihydrofolic acid (DHF)
Folate reductase ← (-)Trimethoprim
Tetrahydrofolic acid (THF)
3. Co-trimoxazole is the combination of sulphamethoxazole 4. Individually both the drugs are bacteriostatic
but their and trimethoprim. Trimethoprim selectively inhibits bac- combination renders co-trimoxazole bactericidal. Maxiterial
dihydrofolate reductase whereas the sulphamethox- mum synergism is seen when the organism is sensitive azole inhibits
conversion of PABA to dihydrofolate. to both the components.
SHORT NOTES
Co-trimoxazole
1. Trimethoprim selectively inhibits bacterial dihydrofo-
late reductase whereas the sulphamethoxazole inhibits
Co-trimoxazole is the fixed dose combination of trimeconversion of PABA to dihydrofolate. thoprim and sulphamethoxazole.
Individually both the drugs are bacteriostatic but their
Co-trimoxazole acts by sequential blockade of folate combination renders co-trimoxazole bactericidal. metabolism.
Maximum synergism is seen when the organism is sen-
3. Therapeutic uses sitive to both the components.
Urinary tract infections: Valuable in chronic and re-
current cases and as well as in prostatitis Q. 3. Long-acting sulphonamides
Respiratory tract infections: Both upper and lower respiratory tract infections
Typhoid: Co-trimoxazole is used as an alternative in
Sulphonamides that are long acting are patients not tolerating fluoroquinolones.
a. sulphadoxine and
Bacterial diarrhoea and dysentery
b. sulphamethoxypyrazine. e. Chancroid
They act for about 7 days.
f. Intensive parenteral co-trimoxazole therapy is used
They are generally used in chloroquine-resistant masuccessfully in septicaemiae. laria along with pyrimethamine.
Q. 2. Rationale of combination of sulphamethoxazole with trimethoprim

Beta-Lactam Antibiotics
LONG ESSAYS
Define the term antibiotics and chemotherapy. Classify penicillins. Explain their
mechanism of action, uses and adverse effects.
Or,
Classify penicillins. Write in brief the therapeutic uses of penicillin G.
Add a note on treatment of acute anaphylactic shock due to
intramuscular injection of procaine penicillin.
Or,
Define antibiotics. Classify penicillins. Explain their mechanism of actions, toxicity and
important uses of penicillins.

CHEMOTHERAPY
Chemotherapy means the treatment of infectious diseases or malignancy with drugs to destroy microorganisms or cancer cells
preferentially with minimal damage to the host tissues. The infection may be due to bacteria, virus, fungi, protozoa or
helminthes.
ANTIBIOTICS
These are substances produced by microorganisms, which suppress the growth of or kill other microorganism at very low
concentrations.
PENICILLIN
It is the most important and the first antibiotic to be used, obtained from a fungus of Penicillium notatum, but the yield was
very low. The present source of pencillin is the high-yielding Penicillium chrysogenum.
Classification
Natural penicillins: Benzyl penicillin (penicillin G)
Semisynthetic penicillins
Acid-resistant penicillins: Phenoxymethyl penicillin (penicillin V)
Penicillinase-resistant penicillins: Methicillin, oxacillin, cloxacillin, dicloxacillin
Extended-spectrum penicillins: Aminopenicillins, ampicillin, bacampicillin, amoxicillin
Carboxypenicillins: Carbenicillin, carbenicillin indanyl, carbenicillin phenyl (carfecillin), ticarcillin
Ureidopenicillins: Piperacillin, mezlocillin, mecillinam
(amdinocillin)
b-lactamase inhibitors: Clavulanic acid, sulbactam
Mechanism of Action
b-lactam antibiotics produce bactericidal effect by inhibiting cell wall synthesis. Bacterial cell wall is composed of
peptidoglycan, a highly crosslinked structure. It makes the cell wall rigid and also gives it stability.
b-lactam antibiotics inhibit the biosynthesis of peptidoglyc
Mechanism of action of penicillins can be summarized as follows:
Penicillins
Bind and inactivate penicillin binding proteins (PBPS) on the cell wall of susceptible bacteria
Inhibit transpeptidase
Prevent peptidoglycan synthesis
Cell wall deficient forms develop (spheroplasts and filamen- tous forms)
Autolysis
Cell death (bactericidal effect)
Therapeutic Uses
Penicillin G or benzyl penicillin is the drug of choice for infection caused by bacteria susceptible to it, i.e. streptococci,
pneumococci, Bacillus anthracis, Corynebacterium diphtheriae, Clostridia, Listeria, Spirochaetes and Neisseria species. a.
Streptococcal infections
Pharyngitis, otitis media, scarlet fever, rheumatic fever. 0.525 MU IV 8 hourly for 7–10 days.
Subacute bacterial endocarditis caused by Streptrococcus viridians or faecalis. 10–20 MU IV. daily with streptomycin 0.5 g IM
BD for 2–6 weeks.
Pneumococcal infections: Though not recommended but can be given if organism is sensitive. 3–6 MU IV every 6 hourly.
Meningococcal infections: Respond well to high dose
of penicillins.
Gonorrhoea
Penicillins have been taken over by fluoroquinolones or ceftriaxones as the first-line drugs. However it can be used in NPPG
infection as 4.8 MU IM single dose divided and given in both buttocks or procaine penicillin with 1g probenecid orally.
For ophthalmia neonatorum due to sensitive Neisseria gonorrhoeae. Saline irrigation 1 1 drop containing 10,000– 20,000
U/mL of sodium penicillin G in each eye every 1–2 h for 1 week.
In severe cases give 50,000 U IM BD in addition.
Syphilis: Penicillin G is the drug of choice for syphilis
Early and latent syphilis: 1.2 MU of procaine penicillin daily for 10 days or 2.4 MU of benzathine penicillin weekly for 1–3
weeks.
Late syphilis: 2.4 MU of benzathine penicillin weekly for 4 weeks or 5 MU IM of sodium penicillin G 6 hourly for 2 weeks.
Diphtheria: Penicillin treatment is of adjuvant value to antitoxin therapy and prevents carrier state. 1–2 MU of procaine
penicillin daily for 10 days.
Tetanus and gas gangrene: Penicillin is used to kill the organism and has adjuvant value to antitoxin. 6–12 MU of penicillin G
daily.
Anthrax: 4 MU of penicillin G 6 hourly for 2 weeks
Actinomycosis: 2–4 MU IV of penicillin G 6 hourly for
4 weeks
Trench mouth: Along with metronidazole, low doses of penicillin G for 7 days is effective.
Penicillin G is the drug of choice for rare infections like anthrax, actinomycosis, rat-bite fever and those caused by Listeria
monocytogenes, Pasteurella multocida.
Prophylactic Use
Rheumatic fever: Low concentration of penicillin prevents colonization by streptococci responsible for rheumatic fever. The
most convenient regimen of benzathine penicillin is 1.2 MU every 4 weeks till 18 years of age or 5 years after an attack which
ever is more.
Gonorrhoea and syphilis: 2.4 MU single dose of procaine penicillin or benzathine penicillin before or within 12 h of contact
provides protection for both these sexually transmitted diseases.
Bacterial endocarditis: Penicillin is used before dental extraction, endoscopies, catheterization and other surgical procedures to
prevent bacteremia in patients with valvular heart disease.
Agranulocytosis: Penicillin alone or in combination with an aminoglycoside.
Surgical infections: 1 MU of procaine penicillin with an aminoglycoside injected 1 M 1 h before and 8–12 h after surgery can
reduce wound infection.
Adverse Effects
Penicillin causes the following:
Hypersensitive reactions such as skin rashes, urticaria, fever, dermatitis, joint pain, serum sickness or even acute anaphylactic
reactions.
Other effects: Pain and sterile abscess at the site of IM injection
Prolonged use of IV may cause thrombophlebitis.
Acute anaphylactic reactions: The symptoms of anaphylactic shock are severe hypotension, bronchospasm and laryngeal
oedema.
Crossreactivity can occur among penicillins and also
among b-lactams.
Jarisch-Herxheimer Reaction
It is an acute exacerbation of signs and symptoms of syphilis during penicillin therapy. It is due to release of endotoxins
from the dead organisms.
 The manifestations are fever, chills, myalgia, hypotension, circulatory collapse, etc. It is treated with aspirin and
corticosteroids.
Treatment of Anaphylactic Shock
The patient is kept in reclining position, administered oxygen at high flow rate and performed cardiopulmonary resuscitation
if required.
Inject adrenaline 0.3–0.5 mg (0.3–0.5 mL of 1 in 1000 solution) IM and repeat every 5–10 min if patient does not improve. It
is the only life-saving measure.
Administer (H1 antihistaminic) diphenhydramine 50–100 mg IM or slow IV. Inj. hydrocortisone sodium succinate 100–
200 mg IV
Limitations or Drawbacks of Penicillins
Orally not very effective (acid labile) Short duration of action Narrow spectrum of antibacterial activity Destroyed by
penicillinase enzymes Possibility of anaphylaxis
Q. 2. Classify cephalosporins. Describethe antibacterial spectrum, therapeutic uses
and adverse effects of third generation cephalosporins.

Cephalosporins are a group of semisynthetic antibiotics derived from cephalosporin C, obtained from a fungus
Cephalosporium. They are chemically related to penicillins.
Classification
Cephalosporins Parental Oral
First generation Cephalothin
Cephapirin
Cefazolin
Cephaloridine Cephalexin
Cephradine
Cefadroxil
Second generation Cefoxitin Cefuroxime Cefaclor Cefuroxime axetil
Third generation Cefotaxime
Ceftizoxime
Ceftriaxone
Ceftazidime
Cefoperazone Cefixime Cefpodoxime proxetil Cefdinir
Ceftibuten
Fourth generation Cefepime Cefpirome
Third Generation Cephalosporins
Antibacterial spectrum, therapeutic uses and adverse effects of third generation cephalosporins are as follows:
 These compounds were introduced in 1980. Third generation cephalosporins have potent action against aerobic Gram-
negative as well as some Gram-positive bacteria but it is not so active on aerobes, particularly Bacteriodes fragilis,
Staphylococcus aureus and Pseudomonas aeruginosa.
They have highly augmented activity against Gramnegative enterobacteriaceae. All are highly resistant to b-lactamases from
Gram-negative bacteria.
Drugs like ceftazidime and cefoperazone are active
against pseudomonas.
Therapeutic Uses
Third generation cephalosporins are used alone or with aminoglycosides in severe Gram-negative infections. a.
Meningitis
Bacterial meningitis caused by Gram-negative bacilli especially in children caused by Haemophilus influenzae,
enterobacteriaceas. Inj. Cefotaxime or Ceftriaxone are the preferred drugs.
Dose: Cefotaxime 1–2 g (50–100 mg/kg/day in children) IM or IV 6–12 hourly. Ceftriaxone 4 g followed by 2 g IV
(children 75–100 mg/kg) once daily for 7–10 days.
Penicillinase producing N. gonorrhoeae (PPNG) infections: Single dose treatment with third generation cephalosporins is used
in infection.
Cefotaxime 19 IM 1 19 probenecid orally Ceftriaxone 250 mg IM single dose is the drug of choice.
Typhoid fever: Ceftriaxone 4 g IV daily for 2 days followed by 2 g/day till 2 days after fever subsides (children 75 mg/day) and
cefoperazone are very effective for treatment of multidrug resistant salmonella infections.
Mixed aerobic-anaerobic infection in cancer or immunocompromised patients and those undergoing colorectal surgery,
obstetric complications.
Cefotaxime 1–2 g IM or IV 6–12 hourly (children
50–100 mg/kg/day)
Infection by odd organisms or hospital infections or nosocomial infection: Infection by the organisms resistant to common
antibiotics may respond to third generation cephalosporins.
Cefotaxime 1–2 g IM or IV 6–12 hourly (children
50–100 mg/kg/day)
Ceftizoxime 0.5–1 g IM or IV 8–12 hourly
Ceftriaxone 1–2 g IM or IV/day
Ceftazidime 0.5–2 g IM or IV 8 hourly
Septicaemia caused by Gram-negative organisms: A cephalosporin may be combined with an aminoglycoside.
Prophylaxis and treatment of infections in neutropenic patients: Third generation cephalosporins may be used alone or in
combination with an aminoglycoside.
Respiratory infections like pneumonia, acute exacerba-
tions of chronic bronchitis Cefpodoxime proxetil 200 mg BD Cefdinir 300 mg BD Ceftibuten 200 mg BD
Ceferamet pivoxil 500 mg BD-TDS
Urinary infections, skin and soft tissue and gastrointestinal infections: Produced by Gram-negative organisms respond well to
third generation cephalosporins.
Adverse Effects
Cephalosporins are more toxic than penicillin but are generally well tolerated.
Pain after IM injection mainly with cephalothin and thrombophlebitis after IV injection.
GI disturbances like diarrhoea due to alteration of gut ecology or irritative effect is common with parenteral cefoperazone and
cefixime.
Hypersensitivity reactions may manifest as rashes, anaphylaxis, angioedema, asthma and urticaria. A 10% may show
crossreaction with penicillin.
Severe bleeding is seen in cefoperazone and ceftriaxone. It is produced due to hypoprothrombinemia commonly
in patients with cancer, intra-abdominal infection or renal failure. Moreover, moxalactam has a carboxyl substitution in the side
chain at position 7. This causes perturbation of platelet surface receptors prolonging the bleeding time.
Neutropenia and thrombocytopenia are reported with ceftazidime but are rare.
A disulfiram-like interaction with alcohol has been reported with moxalactam and cefoperazone.
Rise in plasma transaminases and blood urea is seen with ceftazidime.
Q. 3. Classify semisynthetic penicillins. Discuss the mechanism of action, adverse
effects and therapeutic uses of amoxicillin.

Extended spectrum penicillins are semisynthetic penicillins, which are active against a variety of Gram-negative bacilli in
addition to Gram-positive cocci.
CLASSIFICATION OF SEMISYNTHETIC
PENICILLINS
Acid-resistant alternative to penicillin G: Phenoxymethylpenicillin (penicillin V)
Penicillinase-resistant penicillins: Methicillin, oxacil-
lin, cloxacillin
Extended-spectrum penicillins
Aminopenicillins: Ampicillin, bacampicillin, amoxicillin
Carboxypenicillins: Carbenicillin, carbenicillin indanyl, carbenicillin phenyl (carfecillin), ticarcillin
Ureidopenicillins: Piperacillin, mezlocillin
Mecillinam (amdinocillin) b-lactamase inhibitors: Clavulanic acid, sulbactam
ACTION OF PENICILLINS
Penicillins
Bind and inactivate penicillin-binding proteins (PBPs) on the cell wall of susceptible bacteria
Inhibit transpeptidase
Prevent peptidoglycan synthesis
Cell wall deficient form (spheroplasts and filamen- tous forms)
Autolysis
Cell death (bactericidal effect)
ANTIBACTERIAL SPECTRUM
Gram-positive: Streptococci (including enterococci), pneumococci, Staphylococcus aureus, Bacillus anthracis,
Corynebacterium diphtheriae, Clostridia, Listeria,
Spirochaetes Gram-negative: Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae, Escherichia coli,
Protease, Salmonella and Shigella
ADVANTAGES OVER AMPICILLIN
Oral absorption is better and food does not interfere with its absorption. Thus higher and more sustained blood levels are
produced. Incidence of diarrhoea and skin rash is less. It is less active against Shigella and Haemophilus influenzae.
 It is preferred over ampicillin in typhoid, bronchitis, urinary tract infections, SABE and gonorrhoea in a dose of 0.25–1 g
TDS oral.
ADVERSE EFFECTS
Diarrhoea due to irritation to the lower intestine by the unabsorbed drug and alteration of bacterial flora but is less compared
to ampicillin.
Maculopapular skin rashes in patients with AIDS, EB
virus infections or leukaemia and concurrent administration of allopurinol
THERAPEUTIC USES
Urinary tract infections: It is the drug of choice in UTI caused by Escherichia coli, Proteus mirabilis, nonhaemolytic
streptococci and enterococci. In a dose of 250–1000 mg TDS.
Upper respiratory tract infections: It is effective for pharyngitis, sinusitis, otitis media, acute exacerbation of chronic bronchitis
caused by Streptococcus pyogenes, Streptococcus pneumoniae and Haemophilus influenzae.
Q. 4. Classify penicillins. Describethe mechanism of action, antibacterial spectrum
and the therapeutic uses of ampicillin.

The penicillins are classified as follows:

Natural penicillins: Benzyl penicillin (penicillin G)
Semisynthetic penicillins:
Acid-resistant penicillins: Phenoxymethyl penicillin (penicillin V)
Penicillinase-resistant penicillins: Methicillin, oxacillin, cloxacillin, dicloxacillin
Extended-spectrum penicillins
Aminopenicillins: Ampicillin, bacampicillin, amoxicillin
Carboxypenicillins: Carbenicillin, carbenicillin indanyl, carbenicillin phenyl (carfecillin), ticarcillin
Ureidopenicillins: Piperacillin, mezlocillin, mecillinam (amdinocillin)
b-lactamase inhibitors: Clavulanic acid, sulbactam
MECHANISM OF ACTION OF AMPICILLIN
Penicillins
Bind and inactivate penicillin binding proteins (PBPs) on the cell wall of susceptible bacteria
Inhibit transpeptidase
Prevent peptidoglycan synthesis
Cell wall deficient form
(spheroplasts and filamentous forms)
Autolysis Cell death (bactericidal effect)
ANTIBACTERIAL SPECTRUM
Ampicillin is active against all organisms sensitive to penicillin G, e.g. Gram-positive streptococci (including enterococci),
pneumococci, Staphylococcus aureus, Bacillus anthracis, Corynebacterium diphtheriae, Clostridia, Listeria, Spirochaetes. In
addition it is active against many Gram-negative bacilli like Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus
influenzae, Escherichia coli, Protease, Salmonella and Shigella.
ADVERSE EFFECTS
Diarrhoea due to irritation to the lower intestine by the unabsorbed drug and alteration of bacterial flora.
Maculopapular skin rashes in patients with AIDS, EB virus infections or leukaemia and concurrent administration of
allopurinol.
THERAPEUTIC USES
Urinary tract infections: It is the drug of choice in UTI caused by Escherichia coli, Proteus mirabilis, nonheamolytic
streptococci and enterococci. Dose: 500 mg 6 hourly for 7–10 days. But now incidence of resistance has increased and
fluoroquinolones or cotrimoxazole are now commonly used for empirical therapy.
Respiratory tract infections: Particularly mixed infections with Haemophilus influenzae and Diplococcus pneumoniae, e.g.
bronchitis, sinusitis, otitis media, etc. are best treated with ampicillin.
Meningitis: Ampicillin is the first-line drug for oral treatment of NPPG infections. Single dose 3.5 g ampicillin with 1 g
probenecid is adequate. But now as a significant number of meningococci are resistant, it is usually combined with third
generation cephalosporin or chloramphenicol for initial therapy.
Typhoid fever: Ampicillin is used to treat typhoid carrier states but ciprofloxacin is superior to it. It is infrequently used when
ciprofloxacin and other drugs cannot be given.
Bacillary dysentery: It is used in bacillary dysentery as Shigella often responds to ampicillin but now as many strains are
resistant to it, quinolones are preferred.
Subacute bacterial endocarditis: Ampicillin 2 g IV 6 hourly with concurrent administration of gentamicin is advocated.
Septicaemiae and mixed infections: Injectable ampicillins are used in combination with gentamicin or newer cephalosporins.
SHORT ESSAYS
Miscellaneous: Ampicillin is preferred to tetracycline in pregnant women and infants in management of intestinal
malabsorption and treatment of whooping cough.
 Adverse effects of penicillin
Adverse effects of penicillin are as follows: Hypersensitive reactions such as skin rashes, urticaria, fever, dermatitis, joint
pain, serum sickness or even acute anaphylactic reactions. Other effects: Pain and sterile abscess at the site of IM injection.
Prolonged use of IV may cause thrombophlebitis.
Acute anaphylactic reactions: The symptoms of anaphylactic shock are severe hypotension, bronchospasm and laryngeal
oedema.
Cross-reactivity can occur among penicillins and also
among b-lactams.
Jarisch-Herxheimer Reaction
It is an acute exacerbation of signs and symptoms of syphilis during penicillin therapy. It is due to release of endotoxins
from the dead organisms.
 The manifestations are fever, chills, myalgia, hypotension, circulatory collapse, etc. It is treated with aspirin and
corticosteroids.
Treatment of Anaphylactic Shock
The patient is kept in reclining position, administered oxygen at high flow rate and performed cardiopulmonary resuscitation
if required.
Inject adrenaline 0.3–0.5 mg (0.3–0.5 mL of 1 in 1000 solution) IM and repeat every 5–10 min if patient does not improve. It
is the only life-saving measure. Administer (H1 antihistaminic) diphenhydramine 50– 100 mg IM or slow IV. Inj.
hydrocortisone sodium succinate 100–200 mg IV
Q. 2. Uses of benzyl penicillin
THERAPEUTIC USES OF BENZYL PENICILLIN
Penicillin G or benzyl penicillin is the drug of choice for infection caused by bacteria susceptible to it, i.e. Streptococci,
Pneumococci, Bacillus anthracis, Corynebacterium diphtheriae, Clostridia, Listeria, Spirochaetes and Neisseria species.
Streptococcal infections Pharyngitis, otitis media, scarlet fever, rheumatic fever. 0.5–5 MU IV 8 hourly for 7–10 days.
Subacute bacterial endocarditis caused by Streptococcus viridians or faecalis. 10–20 MU IV daily with streptomycin 0.5 g IM
BD for 2–6 weeks.
Pneumococcal infections: Though not recommended but can be given if organism is sensitive. 3–6 MU IV every 6 hourly.
Meningococcal infections: Respond well to high dose of penicillins.
Gonorrhoea
Penicillins have been taken over by fluoroquinolones or ceftriaxones as the first-line drugs. However, it can be used in NPPG
infection as 4.8 MU IM single dose divided and given in both buttocks or procaine penicillin with Ig probenecid orally.
For ophthalmia neonatorum due to sensitive Neisseria gonorrhoeae.
Saline irrigation with 1 drop containing 10,000– 20,000 U/mL of sodium penicillin G in each eye every 1–2 h for 1 week.
In severe cases give 50,000 U IM BD in addition 5. Syphilis: Penicillin G is the drug of choice for syphilis.
Early and latent syphilis: 1.2 MU of procaine penicillin daily for 10 days or 2.4 MU of benzathine penicillin weekly for 1–3
weeks.
Late syphilis: 2.4 MU of benzathine penicillin weekly for 4 weeks or 5 MU IM of sodium penicillin G 6 hourly for 2 weeks.
Diphtheria: Penicillin treatment is of adjuvant value to antitoxin therapy and prevents carrier state. 1–2 MU of procaine
penicillin daily for 10 days.
Tetanus and gas gangrene: Penicillin is used to kill the organism and has adjuvant value to antitoxin. 6–12 MU of penicillin G
daily
Anthrax: 4 MU of penicillin G 6 hourly for 2 weeks.
Actinomycosis: 2–4 MU IV of penicillin G 6 hourly for 4 weeks
Trench mouth: Along with metronidazole, low doses of penicillin G for 7 days is effective
Penicillin G is the drug of choice for rare infections like anthrax, actinomycosis, rat-bite fever and those caused by Listeria
monocytogenes, Pasteurella multocida.
PROPHYLACTIC USE
Penicillin G or benzyl penicillin is used as prophylactic in following conditions: 1. Rheumatic fever
Gonorrhoea and syphilis
Bacterial endocarditis
Agranulocytosis
Surgical infections
Q. 3. Classification of cephalosporins
Cephalosporins are a group of semisynthetic antibiotics derived from cephalosporin C obtained from a fungus Cephalosporium.
They are chemically related to penicillins. Classification
Cephalosporins Parenteral Oral
1. First generation Cephalothin
Cephapirin
Cefazolin
Cephaloridine Cephalexin
Cephradine
Cefadroxil
2. Second generation Cefoxitin Cefuroxime Cefaclor Cefuroxime
axetil
3. Third generation Cefotaxime
Ceftizoxime
Ceftriaxone
Ceftazidime
Cefoperazone Cefixime Cefpodoxime proxetil Cefdinir
Ceftibuten
4. Fourth generation Cefepime Cefpirome
Q. 4. Classification and therapeutic uses of extendedspectrum penicillins

Extended-spectrum penicillins include the following:

Aminopenicillins: Ampicillin, bacampicillin, amoxicillin
Carboxypenicillins: Carbenicillin, carbenicillin indanyl, carbenicillin phenyl (carfecillin), ticarcillin
Ureidopenicillins: Piperacillin, mezlocillin, mecillinam
(amdinocillin)
b-Lactamase inhibitors: Clavulanic acid, sulbactam
THERAPEUTIC USES
Urinary tract infections: It is the drug of choice in UTI caused by Escherichia coli, Proteus mirabilis, nonhaemolytic
streptococci and enterococci. Dose: 500 mg 6 hourly for 7–10 days. But now incidence of resistance has increased and
fluoroquinolones or co-trimoxazole are now commonly used for empirical therapy.
Respiratory tract infections: Particularly mixed infections with Haemophilus influenzae and Diplococcus pneumoniae, e.g.
bronchitis, sinusitis, otitis media, etc. are best treated with ampicillin.
Meningitis: Ampicillin is the first-line drug for oral treatment of NPPG infections. But now as a significant number of
meningococci are resistant it is usually combined with third generation cephalosporin or chloramphenicol for initial therapy.
Typhoid fever: It is infrequently used when ciprofloxacin and other drugs cannot be given.
Bacillary dysentery: It is used in bacillary dysentery as Shigella often responds to ampicillin but now as many strains are
resistant to it, quinolones are preferred.
Subacute bacterial endocarditis: Ampicillin 2 g IV 6 hourly with concurrent administration of gentamicin is advocated.
Septicaemiae and mixed infections: Injectable ampicillins are used in combination with gentamicin or newer cephalosporins.
Miscellaneous: Ampicillin is preferred to tetracycline in pregnant women and infants in management of intestinal
malabsorption and treatment of whooping cough.
Q. 5. Penicillins act as bactericidal agent.

Penicillins act as bactericidal agent by inhibiting the synthesis of the bacterial cell wall. Mechanism of action is given as
follows:
Penicillins
Bind and inactivate penicillin binding proteins (PBPs) on the cell wall of susceptible bacteria
Inhibit transpeptidase
Prevent peptidoglycan synthesis
Cell wall deficient form
(spheroplasts and filamentous forms)
Autolysis
Cell death (bactericidal effect)

Section | IV
Penicillins act on bacterial cell wall and inhibit the enzyme transpeptidase and carboxypeptidase. Thus the crosslinking
between the N-acetyl muramic acid and N-acetyl glucosamine which is necessary for maintenance of structure of the cell wall
does not take place.
When bacteria divide in presence of penicillin, the resultant bacteria are cell wall deficient or are the L forms. As the interior
of the bacterium is hyperosmotic, these L forms swell and burst ultimately causing bacterial lysis or cell death.
They are also said to act by depressing some of the bacterial autolysins, which usually function during bacterial cell division.
 As the cell wall of a Gram-positive bacterium is almost entirely made up of peptidoglycans, the penicillins are highly
effective in Gram-positive bacterial infections. They are more lethal in the phase of rapid multiplication when the cell wall
synthesis takes place.
Q. 6. Cloxacillin and the staphylococcal infections
Cloxacillin is a penicillinase-resistant pencillin. Cloxacillin has an isoxazolyl side chain and is resistant to acid and
penicillinase. It is less active against penicillin G sensitive organisms and should not be used as a substitute. It is more active
against methicillin against penicillinase producing staphylococci, but not against MRSA. Because staphylococcal infections are
rare in the oral cavity, cloxacillin is rarely used in dentistry.
It is incompletely but dependably absorbed from oral route, especially if taken in empty stomach. It is more than 90%
plasma protein bound.
Elimination occurs primarily by kidney and partly by liver. Plasma half-life is about 1 h.
Dose: 0.25–0.5 g orally every 6 h and for severe infections 0.25–1 g IM or IV for higher blood concentration levels.
Q. 7. Name four semisynthetic penicillin preparations, their advantages and
therapeutic uses.

Extended-spectrum penicillins are semisynthetic penicillins, which are active against a variety of Gram-negative bacilli in
addition to Gram-positive cocci.
CLASSIFICATION OF SEMISYNTHETIC PENICILLINS
Acid-resistant alternative to penicillin G: Phenoxymethylpenicillin (penicillin V)
Penicillinase-resistant penicillins: Methicillin, oxacillin, cloxacillin
Extended-spectrum penicillins:
Aminopenicillins: Ampicillin, bacampicillin, amoxicillin
Carboxypenicillins: Carbenicillin, carbenicillin in-
danyl, carbenicillin phenyl (carfecillin), ticarcillin
Ureidopenicillins: Piperacillin, mezlocillin
Mecillinam (amdinocillin)
b-lactamase inhibitors: Clavulanic acid, sulbactam
ADVANTAGES OVER AMPICILLIN
Oral absorption is better and food does not interfere with its absorption. Thus higher and more sustained blood levels are
produced.
Incidence of diarrhoea and skin rash is less.
It is less active against Shigella and Haemophilus influenzae. It is preferred over ampicillin in typhoid, bronchitis, urinary
tract infections, SABE and gonorrhoea in a dose of 0.25–1 g TDS oral.
ADVERSE EFFECTS
Diarrhoea due to irritation to the lower intestine by the unabsorbed drug and alteration of bacterial flora but is less compared
to ampicillin
 Maculopapular skin rashes in patients with AIDS, EB
virus infections or leukaemia and concurrent administration of allopurinol
THERAPEUTIC USES
Urinary tract infections: It is the drug of choice in UTI caused by Escherichia coli, Proteus mirabilis, nonhaemolytic
streptococci and enterococci. In a dose of 250–1000 mg
TDS.
Upper respiratory tract infections: It is effective for pharyngitis, sinusitis, otitis media and acute exacerbation of chronic
bronchitis caused by Streptococcus pyogenes, Streptococcus pneumoniae and Haemophilus influenzae.
Q. 8. Amoxicillin and gentamicin
The comparison between amoxicillin and gentamicin is as given in Table 44.1.
TABLE 44-1 Comparison between Amoxicillin and Q. 9. Ampicillin and amoxicillin
Gentamicin
Parameters to
Be Compared Amoxicillin Gentamicin
Type Extended-spectrum penicillin (amino penicillin) Aminoglycoside
Source Synthetic Natural (obtained from Micromonospora purpurea)
Mechanism of action Interference with synthesis of bacterial cell wall Inhibition of protein synthesis
Antibacterial spectrum Most Gram-positive and few Gram- negative bacilli (streptococci, enterococci, pneumococci,
meningococci) and some Gram-negative ba-
cilli (Escherichia coli, Proteus, Salmonella) Some Gram-positive
(staphylococci and Streptococcus fecalis) and many Gram-negative bacilli (pseudomona, protem, Escherichia coli, Klebsiella,
Enterobacter,
Serratia)
Route of administration Oral or parenteral Parenteral only (not effective orally)
Adverse effects Not serious (diarrhoea and rashes may develop) Serious ototoxicity, nephrotoxicity neuromuscular
blockade
Uses Typhoid, bronchitis UTI, SABE and gonorrhoea Respiratory tract infections, burns, UTI, lung abscess,
osteomyelitis, otitis media, septicaemia, meningitis and SABE
Ampicillin Amoxicillin
Route of administration: Oral or parenteral Route of administration: Oral or parenteral
Acid stable, incompletely absorbed from GIT, hence diarrhoea is more common Acid stable, completely absorbed
from GIT, hence incidence of diarrhoea is less
Food interferes with absorption Food does not interfere with absorption
Superinfections are more
common Superinfections are less common
Uses: UTI, RTI, meningitis, gonorrhoea, typhoid, bacillary dysentery, cholecystitis, SABE, septicaemia and mixed infections
Uses: Typhoid, bronchitis UTI, SABE and gonorrhoea
Effective against Shigella and Haemophilus influenzae Less effective against Shigella and H. influenzae
Ampicillin reduces the effectiveness of oral contraceptives Amoxicillin does not reduce the effectiveness of oral
contraceptives
Dose: 250–500 mg QID Dose: 250–500 mg TID

Ampicillin and amoxicillin both are semisynthetic extendedspectrum penicillins (amino penicillins).
Both of them are bactericidal drugs and act by interfering with synthesis of bacterial cell wall.
Comparison between ampicillin and amoxicillin is given in Table 44.2.
TABLE 44-2 Comparison between Ampicillin and Amoxicillin
SHORT NOTES
 Probenecid and penicillin in chemotherapy
Probenecid competes with b-lactams (penicillins and cephalosporins) for active tubular secretion and retards their excretion,
thereby increasing the plasma concentration as well as the duration of action of b-lactams. Hence simultaneous
administration of probenecid and penicillin is useful in the treatment of bacterial endocarditis and gonococcal infections to
enhance therapeutic efficacy.
Q. 2. What is D-penicillamine? Mention its two uses.

D-penicillamine is a copper chelating agent with a gold-like action in rheumatoid arthritis, but less efficacious. It is not
favoured now because it does not offer any advantage over gold in terms of toxicity.
Loss of taste, systemic lupus erythematosus, myasthenia gravis are some major disadvantages.
Q. 3. Rationale of combining amoxicillin and clavulanic acid. Write
one indication of this combination.
 Clavulanic acid is added along with amoxicillin to reestablish the activity of the latter against b-lactamase producing
resistant Staphylococcus aureus, Haemophilus influenzae, Neisseria gonorrhoeae, Escherichia coli,
Section | IV
Proteus, Klebsiella, Salmonella, Shigella and Bacteroides fragilis.
After binding to the enzyme, clavulanic acid itself gets inactivated, hence called a suicide inhibitor. The combination of
clavulanic acid and amoxicillin (augmentin) is available for oral administration.
Augmentin is used for the treatment of skin and soft tissue, ear, respiratory and urinary tract infections caused by b-
lactamase producing strains.
Q. 4. Name few semisynthetic penicillins.

A few examples of semisynthetic penicillins are as follows:

Acid-resistant penicillin: Phenoxymethylpenicillin (penicillin V)
Penicillinase-resistant penicillins: Methicillin, oxacillin, cloxacillin
Extended-spectrum penicillins: Aminopenicillins, ampicillin, amoxicillin
Q. 5. Ampicillin
Ampicillin belongs to semisynthetic extended-spectrum penicillins (amino penicillins).
It is a bactericidal drug and acts by interfering with synthesis of bacterial cell wall. Antibacterial spectrum: Ampicillin is
active against all organisms sensitive to penicillin G, e.g. Gram-positive and in addition it is active against many Gram-
negative bacilli also.
Therapeutic uses
Urinary tract infections
Respiratory tract infections
Meningitis
Typhoid fever
Bacillary dysentery
Subacute bacterial endocarditis
Septicaemiae and mixed infections
Miscellaneous: Ampicillin is preferred to tetracycline in pregnant women and infants in management of intestinal
malabsorption and treatment of whooping cough.
Adverse Effects
Diarrhoea
Maculopapular skin rashes in patients with AIDS, EB virus infections or leukaemia
Q. 6. Name third generation cephalosporins.
Cephalosporins are a group of semisynthetic antibiotics derived from cephalosporin C obtained from a fungus Cephalosporium.
They are chemically related to penicillins. Third generation cephalosporins are as follows:
Parenteral Oral
Cefotaxime
Ceftizoxime
Ceftriaxone
Ceftazidime
Cefoperazone Cefixime
Cefpodoxime proxetil
Cefdinir
Ceftibuten
Q. 7. Why penicillin (bactericidal drugs) is not combined with
sulphonamides (bacteriostatic drugs)?

Penicillins (bactericidal drugs) are highly lethal in the phase of active multiplication because rapid cell wall synthesis occurs
when the organism are actively multiplying. Administration of sulphonamides (bacteriostatic drugs) simultaneously retards
the active multiplication of the organisms. Thus when a bactericidal drug like penicillin is combined with bacteriostatic drug
like sulphonamides, there is antagonism instead of synergism of both the drugs; hence penicillin is not combined with
sulphonamides.
Q. 8. Amoxicillin
Amoxicillin is semisynthetic extended spectrum penicillin (amino penicillin).
It is a bactericidal drug and acts by interfering with synthesis of bacterial cell wall.
Less effective against Shigella and Haemophilus
influenzae.
Normal dose: 250–500 mg TID Advantages over ampicillin are as follows:
Oral absorption is better and food does not interfere with its absorption. Thus higher and more sustained blood levels are
produced.
Incidence of diarrhoea and skin rash is less.
It is preferred over the ampicillin in typhoid, bronchitis, urinary tract infections, SABE and gonorrhoea in a dose of 0.25–1 g
TDS.
Therapeutic uses: It is a drug of choice in urinary tract infections caused by Escherichia coli, Proteus mirabilis,
nonhaemolytic streptococci and enterococci and upper respiratory infections.
Q. 9. b-lactamase inhibitors
b-lactamase inhibitors are the drugs which inhibit the enzyme b-lactamase produced by many Gram-positive and Gram-
negative bacteria. Clinically available b-lactamase inhibitors are clavulanic acid, sulbactam and tazobactam. Clavulanic
acid competitively and irreversibly inhibits b-lactamases produced by a wide range of grampositive and Gram-negative
bacteria.
After binding to the enzyme, clavulanic acid itself gets inactivated hence called a suicide inhibitor.
The combination of clavulanic acid and amoxicillin (augmentin) and with ticarcillin (timentin) is available for IV
administration. For example, augumentin is used for the treatment of skin and soft tissue, ear, respiratory and urinary tract
infections caused by b-lactamase producing strains.
Sulbactam is a semisynthetic b-lactamase inhibitor, available in combination with ampicillin. Used in the treatment of skin
soft tissue, intra-abdominal and pelvic infections by b-lactamase producing strains
Tazobactam is more potent than sulbactam and is available in combination with piperacillin. Tazobactam–piperacillin
combination is used for infections caused by b-lactamase producing strains of Escherichia coli and Bacteroides.
Q. 10. Uses of benzyl penicillin
THERAPEUTIC USES OF BENZYL PENICILLIN
Penicillin G or benzyl penicillin is the drug of choice for infections caused by bacteria susceptible to it, i.e. streptococci,
pneumococci, Bacillus anthracis, Corynebacterium diphtheriae, Clostridia, Listeria, Spirochaetes and Neisseria species.
Streptococcal infections
Pneumococcal infections
Meningococcal infections
Gonorrhoea
Syphilis
Diphtheria
Tetanus and gas gangrene
Anthrax
Actinomycosis
Trench mouth: Along with metronidazole, low doses of penicillin G for 7 days is effective.
Penicillin G is the drug of choice for rare infections like anthrax, actinomycosis, rat-bite fever and those caused by Listeria
monocytogenes, Pasteurella multocida.
PROPHYLACTIC USE
Penicillin G or benzyl penicillin is used as prophylactic in following conditions: 1. Rheumatic fever
Gonorrhoea and syphilis
Bacterial endocarditis
Agranulocytosis
Surgical infections
Q. 11. Cloxacillin in staphylococcal infection
Cloxacillin has an isoxazolyl side chain and is highly penicillinase as well as acid resistant. It is more active than
methicillin against penicillinase producing Staphylococcus. With rampant use of penicillin to treat infections, many
staphylococcal strains have started producing penicillin rendering penicillin G ineffective. Therefore, now cloxacillin is
preferred in penicillinase producing staphylococcal infection.
Q. 12. Explain the rationale for the combination of ampicillin and
probenecid in chemotherapy.

Probenecid blocks the tubular secretions of ampicillin, thus achieving higher and longer lasting plasma concentration of
ampicillin.
It also decreases the volume of distribution of ampicillin.
For these reasons probenecid is combined with ampicillin in chemotherapy of infections. It is used to prolong penicillin or
ampicillin action by increasing and sustaining their blood levels, e.g. in gonorrhoea, SABE available as Benemid or Bencid
0.5 g tab.
Section | IV
Tetracyclines and Chloramphenicol
LONG ESSAY
Enumerate tetracyclines. Write their antimicrobial spectrum and therapeutic uses. Or,
Explain broad-spectrum antibiotics. Describethe mechanism of action, therapeutic uses
and toxic effects of tetracyclines.
Or,
Describethe clinical uses and toxicity of tetracyclines. How will you treat a
case of superinfection due to tetracycline therapy?
Tetracyclines are antibiotics obtained from soil actinomycetes. They are broad-spectrum antibiotics as they are
effective against a large number of microorganisms except fungi and viruses. They are bacteriostatic and bacteriocidal.
Classification
Tetracyclines are classified into three groups as follows:
Group I (short-acting): Tetracyclines, oxytetracycline, chlortetracycline
Group II (intermediate-acting): Demeclocycline, meth-
acycline
Group III (long-acting): Doxycycline, minocycline
Mechanism of Action
They inhibit protein synthesis by binding with 30S ribosomes and block t-RNA attachment to m-RNA ribosome complex
and thus peptide chain fails to grow and results in inhibition of protein synthesis.
In the Gram-negative bacteria tetracyclines diffuse through porin channels. Lipid-soluble members enter through positive
diffusion.
Mechanism of action of tetracyclines can be depicted as follows:
Tetracyclines
Bind reversibly to 30S ribosomes in susceptible organism interferes with
Attachment of aminoacyl tRNA to the mRNA ribosome complex
Prevents
Addition of amino acid to growing peptide chain
Peptide chain fails to grow
Inhibits protein synthesis (bacteriostatic)
Uses
A. Medicinal Uses
Rickettsial infections: It is a drug of first choice in rickettsial infections like epidemic typhus, Rocky Mountain spotted fever,
scrub fever, rickettsial pox and Q fever. Chlamydial infections
Lymphogranuloma venereum: It is caused by Chlamydia trachomatis and is a sexually transmitted disease, where
doxycycline is the drug of choice. Trachoma Psittacosis
 In atypical pneumonia due to Mycoplasma pneumoniae tetracyclines are used to shorten the duration of illness. Cholera:
Single dose of tetracycline 2 g or doxycycline 300 mg is effective in adults. It reduces stool volume and eradicates the Vibrio
cholerae from the stool.
Lyme disease is successfully treated with tetracyclines. It is a drug of second choice in the following:
To penicillin or ampicillin for tetanus, anthrax, acti-
nomycosis
To penicillin or ciprofloxacin in gonorrhoea To penicillin or ceftriaxone in syphilis
B. Orodental Conditions
It is specially useful in chronic periodontitis or juvenile periodontitis.
They benefit some periodontal diseases by their antimicrobial activity and also suppress activity of collagenase by chelating
calcium and inhibition of free radicals.
Adverse Effects
Gastrointestinal: On oral administration, they cause GI irritation manifested as epigastric pain, nausea, vomiting and
diarrhoea.
oesophageal ulceration specially with doxycycline due to release of drug from capsule in the oesophagus.
Dose-related toxicity
Hepatotoxicity
Fatty infiltration of liver and jaundice
Precipitation of acute hepatic necrosis in pregnancy
Renal toxicity Prominent only in presence of existing kidney disease
All except doxycycline accumulate and enhance renal failure.
Outdated tetracyclines produce a reversible Fanconi’s syndrome due to damage to PCT by degraded products like
epitetracyclines, anhydrotetracycline, epianhydrotetracyclines.
Phototoxicity Sunburn-like or other severe skin reactions on exposed body parts especially with demeclocyclines and
doxycyclines.
Occasionally they may also produce pigmentation and distortion of nails.
Teeth and bones: Tetracyclines have chelating property and calcium tetracycline chelate gets deposited in developing bone and
teeth.
a. If given from mid pregnancy to 5 months of extrauterine life, following conditions occur: Deciduous teeth are
affected.
Brown discolouration of ill-formed teeth Teeth becomes susceptible to caries.
If given at 3 months to 6 years of age, following conditions occur: Permanent anterior dentition affected Repeated course
more damaging
Given during late pregnancy or childhood, following conditions occur: Temporary suppression of bone growth occurs.
With prolonged uses possibility of deformities
and height reduction
Antianabolic effect Reduced protein synthesis and overall catabolic effect
Induce negative nitrogen balance and increase blood urea.
Increased intracranial pressure: Noted in some infants
Diabetes insipidus: Demeclocyclines antagonize ADH action and reduces urine concentrating ability of kidney.
Vestibular toxicity: Minocyclines produce ataxia, vertigo and nystagmus which subsides on discontinuation of drug. ix.
Hypersensitivity Skin rashes, urticaria, glossitis, pruritus ani and vulvae and even exfoliative dermatitis but not
common.
Angioedema and anaphylaxis are extremely rare.
x. Superinfections Tetracyclines are most common antibiotic responsible for superinfections causing marked
suppression of the resident flora. Involves mouth, skin or vaginal flora.
Intestinal superinfection like pseudomembranous enterocolitis is most prominent.
 Higher the dose, complete suppression flora re-
sults with greater risk of superinfection.
Contraindications
SHORT ESSAYS
Renal impairment Hepatic insufficiency Pregnant and lactating mothers Children below 10 years of age
Patients on diuretics

Adverse effects of broad-spectrum antibiotics

The broad-spectrum antibiotics are tetracyclines and chloramphenicol. They are so termed as they are used against a number of
Gram-negative and Gram-positive infections.
ADVERSE EFFECTS OF BROAD-SPECTRUM ANTIBIOTICS
Irritative effects
Epigastric pain, nausea, vomiting and diarrhoea
Pain at IM injected site, thrombophlebitis of injected vein on repeated use
Dose-related toxicity
Liver damage: Fatty infiltration of liver and jaundice
Kidney damage: Prominent only in presence of existing kidney disease
Phototoxicity: Sunburn-like or other severe skin reactions on exposed body parts especially with demeclocyclines and
doxycyclines
Teeth and bones
Tetracyclines have chelating property and calcium tetracycline chelate gets deposited in developing bone and teeth.
Brown discolouration of ill-formed teeth
Antianabolic effect: Reduced protein synthesis and overall catabolic effect
Section | IV
Increased intracranial pressure: Noted in some infants
Diabetes insipidus: Demeclocyclines antagonize ADH action and reduce urine concentrating ability of kidney
Vestibular toxicity: Minocyclines produce ataxia, vertigo and nystagmus which subsides on discontinuation of drug.
Hypersensitivity reactions: Skin rashes, urticaria, glossitis, pruritus and even exfoliative dermatitis occur but not common.
Superinfections: Tetracyclines are most common antibiotics responsible for superinfections by causing marked suppression of
the resident flora.
Adverse effects especially associated with chloramphenicol are bone marrow depression, agranulocytosis, grey baby syndrome,
aplastic anaemia and hypersensitivity reactions.
Q. 2. Differences between oxytetracycline and doxycycline.
Differences between oxytetracycline and doxycycline are given in Table 45.1.
TABLE 45-1 Differences between Oxytetracycline and
Doxycycline
Parameters Oxytetracycline Doxycycline
Source Streptomyces rimosus Semisynthetic derivative
Potency Low High
Intestinal absorption Moderate Complete, no interference by food
Plasma protein binding Low High
Elimination By rapid renal excretion Primarily excreted in faeces
Plasma half-life 6–10 h 18–24 h
Dosage 250–500 mg TDS or QID 200 mg initially, followed by
100–200 mg OD
Alteration of intestinal flora Marked Least
Incidence of diarrhoea High Low
Phototoxicity Low High
Specific toxicity Less tooth discolouration Low renal toxicity
Q. 3. Tetracyclines
1. Tetracyclines are antibiotics obtained from soil actinomycetes. They are broad-spectrum antibiotics as they
are effective against a large number of microorganisms except fungi and viruses.
Classification
Tetracyclines are classified into three groups as follows:
Group I (short-acting): Tetracyclines, oxytetracycline, chlortetracycline
Group II (intermediate-acting): Demeclocycline, meth-
acycline
Group III (long-acting): Doxycycline, minocycline
Mechanism of Action
1. They inhibit protein synthesis by binding with 30S ribosomes and block t-RNA attachment to m-RNA ribosome
complex and thus peptide chain fails to grow and results in inhibition of protein synthesis.
Uses
Orodental Conditions
It is specially useful in chronic periodontitis or juvenile periodontitis and also suppress activity of collagenase by chelating
calcium and inhibition of free radicals. Medicinal Uses
It is a drug of first choice in the following diseases:
Veneral diseases like lymphogranuloma venereum
Atypical pneumonia due to Mycoplasma pneumoniae
Cholera
Plague
Rickettsial infections
It is a drug of second choice in tetanus, anthrax, actinomycosis, gonorrhoea and syphilis.
Adverse Effects
GI irritation manifested as epigastric pain, nausea, vomiting, and diarrhoea
Hepatotoxicity
Renal toxicity
Phototoxicity
Teeth and bones: Tetracyclines have chelating property and calcium tetracycline chelate gets deposited in developing bone and
teeth.
Antianabolic effect
Diabetes insipidus
Vestibular toxicity
Hypersensitivity reactions like skin rashes, urticaria, etc
Superinfections
Q. 4. Give reasons for not prescribing tetracyclines to a child of 5
years.
Or,
Tetracyclines are contraindicated during pregnancy and infancy. Explain.
Tetracyclines have chelating property and calcium tetracycline chelate gets deposited in developing bone and teeth.
If given from mid pregnancy to 5 months of extrauterine life, following conditions occur: a. Deciduous teeth are
affected
Brown discolouration of ill-formed teeth
Teeth become susceptible to caries
If given at 3 months to 6 years of age, following conditions occur:
Permanent anterior dentition affected
Repeated course more damaging
If given during late pregnancy or childhood, following conditions occur:
Temporary suppression of bone growth occurs
With prolonged uses possibility of deformities and
height reduction
Q. 5. Adverse effects of chloramphenicol
Chloramphenicol is a broad-spectrum antibiotic obtained from Streptomyces venezuelae.
It is bacteriostatic and not bactericidal.
It is effective against Gram-positive and Gram-negative organisms, Rickettsiae, Chlamydiae and Mycoplasma.
Adverse effects of chloramphenicol are as follows:
Bone marrow depression
Leukopenia
Thrombocytopenia
Agranulocytosis
Aplastic anaemia
Grey baby syndrome
SHORT NOTES
Hypersensitivity reactions

Enlist four tetracyclines.

Tetracyclines are antibiotics obtained from soil actinomycetes. They are broad-spectrum antibiotics as they are effective
against a large number of microorganisms except fungi and viruses.
Various tetracyclines are as follows:
Group I: Tetracylcine, oxytetracycline
Group II: Demeclocycline
Group III: Doxycycline, minocycline
Q. 2. Tetracycline should not be given with antacids.Explain.
Tetracyclines are not given along with calcium salts, milk, antacids or iron preparations as they have chelating
property, so when calcium is taken along with tetracycline will form insoluble complexes and reduces absorption of
tetracyclines.
Q. 3. Mention the uses of tetracyclines.

Uses of tetracyclines are as follows:

Orodental conditions: It is especially useful in chronic periodontitis or juvenile periodontitis.
It is a drug of first choice in veneral diseases like Lymphogranuloma venereum, atypical pneumonia, cholera, plague and
rickettsial infections.
It is a drug of second choice in tetanus, anthrax, actinomycosis, gonorrhoea and syphilis.
Q. 4. Doxycycline
Doxycycline is semisynthetic derivative of tetracycline.
It is a highly potent drug with a broad-spectrum of activity against Gram-positive, Gram-negative organisms, Rickettsiae,
Chlamydiae.
Its absorption is complete in the intestine and is not interfered by the presence of food.
Its plasma protein binding is high and duration of action is long.
Its plasma half-life is about 18–24 h.
Dosage: 200 mg initially, then 100–200 mg OD.
It does not cause any alteration in the intestinal flora and hence occurrence of diarrhoea is low.
It is primarily excreted in faeces as conjugate.
It has low renal toxicity but high phototoxicity.
Q. 5. Chloramphenicol
Chloramphenicol is a broad-spectrum antibiotic obtained from Streptomyces venezuelae.
It is bacteriostatic and is effective against Gram-positive and Gram-negative organisms, Rickettsiae, Chlamydiae and
Mycoplasma.
Uses
Typhoid fever
Bacterial meningitis
Anaerobic infections
Rickettsial infections
Section | IV
Parameters Tetracycline Doxycycline
Potency Low High
Intestinal absorption Moderate Complete, no interference by food
Plasma protein binding Intermediate High
Plasma half-life 6–10 h 18–24 h
Alteration of intestinal flora Marked Least
Incidence of diarrhoea High Low
Elimination By rapid renal excretion Primarily excreted in faeces
e. Eye infections
4. Adverse effects
Bone marrow depression
Leukopenia
Thrombocytopenia
Agranulocytosis
Aplastic anaemia
Grey baby syndrome
Hypersensitivity reactions
Q. 6. Enumerate two differences between tetracyclines and doxycycline.

Tetracyclines and doxycycline exhibit following differences:

Aminoglycoside Antibiotics
LONG ESSAY
 Enumerate aminoglycoside antibiotics, their mechanism of action and their adverse
effects. Write about the antimicrobial spectrum and therapeutic uses of
gentamycin.
Or,
Enumerate aminoglycoside antibiotics. Write the antimicrobial spectrum, therapeutic
uses and adverse effects of any one of them.
Or,
What are aminoglycoside antibiotics? Briefly state the pharmacological actions, adverse effects
and uses of any one of them.

AMINOGLYCOSIDE
 Aminoglycoside antibiotics are a group of natural and semisynthetic antibiotics having polybasic amino groups linked
glycosidically to two or more aminosugar residues. They are mainly used to treat Gram-negative infections.
Aminoglycosides in current therapeutic use are as
follows:
For systemic use a. Streptomycin
Gentamicin
Kanamycin
Amikacin
Tobramycin
Netilmicin
Sisomycin
For GI infections and gut sterilization
Neomycin
Paromomycin
For topical use in the eye and on the skin
Neomycin
Framycetin
Gentamicin
Mechanism of Action
The aminoglycosides are bactericidal antibiotics, acting in two main steps:
Transport of aminoglycosides through the bacterial cell wall and cytoplasmic membrane
Binding to ribosomes and resulting in inhibition of pro-
tein synthesis
Transport across the bacterial cell wall The antibiotics diffuse through the outer coat of the Gram-negative bacteria through
porin channels.
Thus penetration is dependent upon maintenance of a polarized membrane and on oxygen-dependent active processes.
These are inactivated under anaerobic conditions. Therefore, anaerobes and facultative anaerobes under deficient O2 supply
are resistant to aminoglycosides.
Penetration is also favoured by high pH. Aminoglycosides are 20 times more active in alkaline pH than in acidic medium.
Ribosomal binding and inhibition of protein synthesis:
Once inside the bacterium, the antibiotic binds to 30S and 50S subunits as well as 30S and 50S interface. They freeze
initiation of protein synthesis. The cidal action of the antibiotic is due to leaking of ions, amino acids and even proteins
through highly permeable cell membrane leading to cell death.
Both these mechanisms are attributed to the incorporation of the defective proteins into the cell membrane.
Adverse Effects
The adverse effects common to aminoglycosides are as follows:
I. Ototoxicity
It is the most important adverse effect but is dependent on dose and duration of the treatment. Ototoxicity is greater when
plasma concentration of the drug is persistently high and above threshold level. Vestibular and cochlear dysfunctions can
occur due to 8th cranial nerve damage and vestibular dysfunction is manifested as headache appearing first followed by nausea,
vomiting, dizziness, nystagmus, vertigo and ataxia.
Important risk factors for ototoxicity are as follows: a. Elderly patients
Repeated use of aminoglycosides
Persistently increased concentration of drug in plasma
Concurrent use of other ototoxic drugs like vancomy-
cin, minocycline, loop diuretics, etc.
II. Nephrotoxicity
 Aminoglycoside concentrate in the renal cortex depending on the dose.
They cause renal damage by interfering with the prostaglandin production by the kidney. This renal damage is totally
reversible if the drug is promptly discontinued.
The risk factors for nephrotoxicity are as follows:
Elderly patients
Pre-existing renal disease
Concurrent use of other nephrotoxic drugs like AMB, vancomycin, cisplatin, cyclosporine, etc.
III. Neuromuscular Blockage Apnoea and muscular paralysis have been reported.
All aminoglycosides reduce release of ACh from the motor nerve endings. Myasthenic patients are more susceptible to this
effect. Hence should be avoided.
IV. Hypersensitivity Reactions: They are rare, occasionally skin rashes, drug fever and eosinophilia may occur.
GENTAMICIN
Gentamicin is the most commonly used aminoglycoside antibiotic obtained from micromonospora purpurea.
Antibacterial Spectrum
Gentamicin has a broad antibacterial spectrum.
It is the most commonly used aminoglycoside antibiotic for aerobic Gram-negative infections due to E. coli, Klebsiella,
Proteus and Pseudomonas aeruginosa. It is also effective against Gram-positive infections like enterococci, streptococci and
staphylococci.
It inhibits many Streptococcus faecalis and some Staph-
ylococcus aureus.
Therapeutic Uses
Gentamicin is the first-line aminoglycoside but its use is restricted to serious Gram-negative bacillary infections. Dose: 3–5
mg/kg/day IM either as a single dose or divided in three 8 hourly doses.
Gentamicin may be used alone or in combination with penicillin or cephalosporins or any other antibiotic (mixed infections) or
with another aminoglycoside (nosocomial infection) depending on the sensitivity pattern in following situations:
Preventing and treating respiratory infections in critically ill patients
Patients on respirators with tracheostomy. Postoperative pneumonia Patients with implants and in ICU Gentamicin
however should be used to treat community acquired pneumonias caused by Gram-positive cocci and anaerobes.
Gentamicin’s important use alone or in combination with piperacillin or any third generation cephalosporins (serious
infections) is in Pseudomonas, Proteus or
Klebsiella infections presenting as burns,
urinary tract infection, pneumonia, lung abscess, osteomyelitis, middle ear infections and septicaemia, etc.
Meningitis caused by Gram-negative bacilli is best treated with gentamicin as follows:
3–5 mg/kg/day IM in 3–8 hourly doses with 4 mg intrathecal injection daily
Section | IV
 Combination with third generation cephalosporins e. Topical use: Gentamicin is used topically as an ointment d.
Subacute bacterial endocarditis: Gentamicin is used in (0.1%) for various skin lesions and burns and as an eye
combination with penicillin drop (0.3%) in conjunctivitis.
SHORT ESSAYS
Mention therapeutic uses and two adverse effects of neomycin.

Neomycin is obtained from Streptomyces fradiae, and is wide-spectrum aminoglycoside active against most Gram-negative
bacilli and some Gram-positive cocci.
It is highly nephrotoxic and ototoxic (mainly auditory). It is therefore not used systemically.
Therapeutic uses of neomycin are as follows:
Used topically for infections of skin and mucous membrane like ulcers, wounds and burns.
Used in combination with bacitracin or polymyxin B for infections of eye and external ear.
Used orally for the followings:
Preparation of bowel before abdominal surgery in order to reduce postoperative infections.
Hepatic coma or encephalopathy: Neomycin on oral administration reduces ammonia levels in blood by destroying colonic
bacteria. However because of toxic potential it is infrequently used for this purpose.
Adverse effects of neomycin are as follows:
Topically applied neomycin has low sensitizing potential.
Neomycin on oral administration has damaging effect on intestinal villi.
Prolonged treatment can result in malabsorption syndrome with diarrhoea and steatorrhoea.
Due to marked suppression of gut, flora superinfection by Candida can occur.
This may accumulate in patients with renal insufficiency causing kidney damage, hence is contraindicated if renal function is
impaired.
When applied to peritoneum it can cause apnoea due to muscle paralyzing action. Q. 2. Mention two
therapeutic uses and two adverse effects of gentamicin.

Therapeutic Uses
Gentamicin is the most economical and first-line aminoglycoside antibiotic, but its use is restricted to serious Gram-negative
bacillary infections.
Gentamicin’s important use alone or in combination with piperacillin or any third generation cephalosporins (serious
infections) is in Pseudomonas, Proteus or Klebsiella infections presenting as a. burns,
urinary tract infection,
pneumonia,
lung abscess,
osteomyelitis,
middle ear infections and
septicaemia, etc.
Meningitis caused by Gram-negative bacilli is best treated with gentamicin.
Subacute bacterial endocarditis: Gentamicin is used in combination with penicillin.
Topical use: Gentamicin is used topically as an ointment (0.1 %) for various skin lesions and burns and as an eye drop (0.3%)
in conjunctivitis.
Adverse Effects
Adverse effects of gentamicin are as follows:
Ototoxicity
Nephrotoxicity
Neuromuscular blockade
The aminoglycosides produce toxic effects common to all the members whereas relative propensity differs.
SHORT NOTES

Aminoglycoside antibiotics
Aminoglycoside antibiotics are a group of natural and semisynthetic antibiotics having polybasic amino groups linked
glycosidically to two or more aminosugar residues.
They are widely used in treatment in medical, gynaecological and other systemic infections but rarely in dentistry.
The aminoglycosides are bactericidal antibiotics acting by inhibition of protein synthesis.
Aminoglycosides in current therapeutic use are as follows:
For systemic use: Streptomycin, gentamicin
For GI infections and gut sterilization: Neomycin, paromomycin
For topical use in the eye and on the skin: Neomycin,
framycetin
Q. 2. Streptomycin
Obtained from Streptomyces griseus and is mainly effective against aerobic Gram-negative bacilli.
When used alone, bacteria, especially tubercle bacillus rapidly develops resistance to it.
It is the least nephrotoxic of all the aminoglycosides.
Uses
Tuberculosis
Subacute bacterial endocarditis
Plague
Tularaemia
Brucellosis
Q. 3. Gentamicin
Gentamicin is the most commonly used aminoglycoside antibiotic obtained from Micromonospora purpurea.
Gentamicin has a broad antibacterial spectrum.
Therapeutic uses of gentamicin are as follows:
Serious Gram-negative aerobic bacillary infections
Subacute bacterial endocarditis
Tuberculosis
Meningitis caused by Gram-negative bacilli is best treated with gentamicin.

Macrolide and Other Antibacterial Drugs in Treatment of Urinary Tract Infections

LONG ESSAY
Topical use: It is used topically as an ointment (0.1 %) for various skin lesions and burns and as an eye drop (0.3%) in
conjunctivitis.
 Enumerate macrolide antibiotics. Describethe antimicrobial spectrum and
therapeutic uses of erythromycin.

Macrolide antibiotics contain a many membered lactone ring with attached sugars, e.g. erythromycin, clarithromycin and
azithromycin which are bacteriostatic in low concentration and bactericidal in the large concentration.
Erythromycin is obtained from Streptomyces erythreus. Roxithromycin, clarithromycin and azithromycin are semisynthetic
macrolides.
ERYTHROMYCIN
Mechanism of Action
Erythromycin and other macrolides bind to bacterial 50S ribosomal subunit and inhibit protein synthesis. They are
bacteriostatic, but at high concentrations, they can act as bactericidal agents. They are more active in alkaline pH. These
antibiotics are used against Gram-positive organisms.
Pharmacokinetics
Erythromycin is adequately absorbed from the upper GI tract. It is destroyed by gastric acid (acid labile) and hence must be
administered as enteric-coated tablets to protect it from gastric acid.
Food may delay the absorption of erythromycin. It is widely distributed in the body and reaches therapeutic concentration in
prostatic secretions but does not cross the blood-brain barrier (BBB).
It is partly metabolized in the liver, excreted in bile and
undergoes enterohepatic cycling.
Antibacterial Spectrum and Therapeutic Uses
Erythromycin is narrow spectrum, includes mostly Grampositive and few Gram-negative organisms and overlaps considerably
with that of pencillin G.
Enterobacteriaceae, other Gram-negative bacilli and Bacteroides fragilis are not inhibited.
Erythromycin is used as a drug of first choice in the following conditions:
Section | IV
Mycoplasma pneumoniae infections: Erythromycin hastens the rate of recovery.
Diphtheria: Erythromycin is very effective for eliminating the carrier state and for the treatment of acute infection.
Pertussis (whooping cough): Erythromycin is most effective for the treatment as well as for prophylaxis of close contacts.
Chancroid: Erythromycin 2 g/day for 7 days is one of the drugs of choice.
Erythromycin is used as a second drug of choice in the following conditions:
Campylobacter enteritis: Here duration of diarrhoea and presence of organisms in stools is reduced. However fluoroquinolones
are superior.
Legionnaire’s pneumonia: Though 3 week erythromycin treatment is effective. Especially azithromycin is preferred as the drug
of choice.
Chlamydia trachomatis infections of urinogenital tract: Erythromycin base is preferred for chlamydial infections in children
and pregnant women. Erythromycin 500 mg 6 hourly for 7 days is effective, alternative to single dose of azithromycin.
Penicillin-resistant staphylococcal infections: Its value has reduced due to emergence of erythromycin resistance as well.
Erythromycin is used as an alternative drug in patients who are allergic to penicillin.
Tetanus: Administration of human tetanus antitoxin, tetanus toxoid, anticonvulsant (e.g. diazepam) and debridement of wound
are the important therapeutic measures. A course of oral erythromycin for 10 days may be given to eradicate Clostridium
tetani.
Streptococcal infections: Tonsillitis, pharyngitis, cellulitis, pneumonia, etc. respond to erythromycin.
Staphylococcal infections in mild cases.
Prophylactic uses
SHORT ESSAYS
For prophylaxis of recurrences of rheumatic fever Before surgery to prevent bacterial endocarditis in patients with
valvular lesion.
 Erythromycin
Erythromycin is a macrolide antibiotic obtained from Streptomyces erythreus.
It is bacteriostatic in low concentration and bactericidal in the large concentration.
Mechanism of action: Erythromycin binds to bacterial 50S ribosomal subunit and inhibits protein synthesis.
Erythromycin is adequately absorbed from the upper GI tract. It is destroyed by gastric acid (acid labile) and hence must be
administered as enteric-coated tablets to protect it from gastric acid.
It is partly metabolized in the liver, excreted in bile and
undergoes enterohepatic cycling.
Antibacterial Spectrum
Erythromycin is narrow spectrum, includes mostly Gram- positive and few Gram-negative organisms and overlaps
considerably with that of pencillin G. While Enterobacteriaceae, other Gram-negative bacilli and Bacteroides fragilis are not
inhibited.
Therapeutic Uses
Erythromycin is used as a drug of first choice in the following conditions:
Mycoplasma pneumoniae infection
Diphtheria
Pertussis (whooping cough)
Chancroid
Erythromycin is used as a second drug of choice in the following conditions:
Campylobacter enteritis
Legionnaire’s pneumonia
Chlamydia trachomatis infections of urinogenital
tract
Penicillin-resistant staphylococcal infections
Erythromycin is used as an alternative drug in patients who are allergic to penicillin. a. Tetanus
Streptococcal infections
Staphylococcal infections in mild cases
For prophylaxis of recurrences of rheumatic fever and before surgery to prevent bacterial endocarditis in patients with valvular
lesion.
Q. 2. Compare and contrast penicillin and erythromycin.
Comparison between contrast penicillin and erythromycin is given in Table 47.1.
Penicillin Erythromycin
Penicillin interferes with bacterial cell wall synthesis by inhibiting transpeptidase so that cell wall deficient species are
produced which swell and burst Erythromycin inhibits bacterial protein synthesis by binding with the 50S ribosomes
Penicillin is rapidly excreted in urine by active tubular secretion Renal excretion of erythromycin is minimal. It is
usually excreted in bile
Penicillins exhibit adverse effects like hypersensitivity reaction, pain at IM site, etc. Erythromycin is remarkably a safe
drug
Penicillin Erythromycin
The penicillin has a b-lactam ring in their chemical structure The erythromycin has a macrocyclic lactone ring. attached
with sugars
The penicillin is a bactericidal drug Erythromycin is a bacteriostatic at low but bactericidal at high concentration
TABLE 47-1 Comparison between Contrast Penicillin and Erythromycin
SHORT NOTES
Four therapeutic uses of erythromycin
The therapeutic uses of erythromycin are as follows:
Mycoplasma pneumoniae infections
Diphtheria and sepsis
 Whooping cough
Genital and respiratory tract infections Community acquired pneumonia
For prophylaxis of bacterial endocarditis during dental procedures in patients with valvular heart disease
Q. 2. Macrolide antibiotics
Macrolide antibiotics contain a many-membered lactone ring with attached sugars, e.g. erythromycin, clarithromycin and
azithromycin.
They are bacteriostatic in low concentration and bactericidal in the large concentration.

Antitubercular Drugs
LONG ESSAY
Erythromycin is obtained from Streptomyces erythreus. Roxithromycin, clarithromycin and azithromycin are semisynthetic
macrolides.
 Classify drugs used in tuberculosis. Write the pharmacology of any two
commonly used drugs. Or,
Enumerate the drugs used in the treatment of tuberculosis. Write the
mechanism of action and adverse effects of any one of them?
Or,
Discuss chemotherapy of pulmonary tuberculosis. Mention mechanism of action adverse
effects of three commonly used drugs?

The drugs which are given against tuberculosis are known as antitubercular drugs.
Classification of antitubercular drugs is as follows (Table 48.1):
i. First-line antitubercular drugs (standard drugs): These drugs have high antitubercular efficacy as well as low toxicity and are
used routinely. ii. Second-line antitubercular drugs (reserve drugs): These drugs have low antitubercular efficacy or high
toxicity or both and are used in special circumstances.
TABLE 48-1 Classification of Antitubercular Drugs
First-Line Drugs Second-Line Drugs Newer Drugs
Isoniazid (H) Thiacetazone Ciprofloxacin
Rifampicin (R) Paraaminosalicylic acid Moxifloxacin
Pyrazinamide (Z) Ethionamide Gatifloxacin
Ethambutol (E) Cycloserine Clarithromycin

First-Line Drugs Second-Line Drugs Newer Drugs

Streptomycin (S) Kanamycin Azithromycin
Amikacin Rifabutin
Capreomycin Rifapentine
Two of the standard drugs commonly used in treatment
of tuberculosis are a. isoniazid and
b. rifampicin.
A. ISONIAZID (INH)
Isoniazid is a highly effective and the most widely used antitubercular drug and is an essential component of all antitubercular
regimens.
Mechanism of Action
Isoniazid acts by inhibition of synthesis of mycolic acids, which are unique fatty acid components of the mycobacterium cell
wall. It targets INH-A gene which encodes fatty acid synthase enzyme.
 The sensitive mycobacterium concentrates INH and converts it to an active metabolite by a catalase-peroxidase enzyme
which interacts with the INH-A gene.
Isoniazid acts on extracellular as well as intracellular bacilli. Fast multiplying organisms are rapidly killed but quiescent ones
are only inhibited.
Adverse Effects
Peripheral neuritis, paraesthesia, numbness, mental disturbances and rarely convulsions are the most important dose-
dependent toxic effects of INH.
Peripheral neuritis: It is produced due to interference with utilization of pyridoxine and its increased excretion in urine. The
risk of peripheral neuritis is prevented by routinely giving 10 mg/day of pyridoxine along with INH. Hepatitis: It is another
major adverse effect common in older people and in alcoholics. It is due to dose-related damage to hepatocytes and is
reversible on stopping the drug. Rashes, fever, acne and arthralgia are other side effects.
B. RIFAMPICIN
It is a semisynthetic antibiotic obtained from Streptomyces mediterranei. It is a first-line antitubercular drug. It is called
sterilizing agent, as it is the only agent that can act on all types of bacillary subpopulations.
Mechanism of Action
Rifampicin affects both extracellular and intracellular organisms. It is the only drug active against persisters present in
central caseous lesion.
It acts best on slowly or intermittently dividing bacilli.
It is bactericidal to Mycobacterium tuberculosis and covers all subpopulations of TB bacilli and also atypical mycobacteria.
It acts by inhibiting bacterial DNA-dependent RNA polymerase and thereby suppressing chain initiation in RNA synthesis thus
stopping expression of bacterial genes.
Adverse Effects
Hepatitis: It is the major adverse effect and is dose dependent. It usually occurs in patients with pre-existing liver diseases.
The drug should be discontinued on the development of jaundice.
 Respiratory syndrome: It presents as breathlessness associated with shock and collapse.
Other minor reactions common with intermittent therapy are as follows:
Cutaneous syndrome: Flushing, pruritus and rash on face and scalp, redness and watering of eyes
Flu-like syndrome: Chills, fever, headache, malaise and bone pain
Abdominal syndrome: Nausea, vomiting, abdominal cramps with or without diarrhoea
C. STREPTOMYCIN
Streptomycin is an aminoglycoside antibiotic. It was the first effective drug developed for the treatment of tuberculosis. It is a
bactericidal drug and acts only against extracellular organisms due to poor penetrating power.
Mechanism of Action
It binds to the 30S ribosomes and inhibits bacterial protein synthesis. They are bactericidal.
Toxic Manifestations of Streptomycin
Streptomycin is avoided during pregnancy because if used in infants it causes fetal ototoxicity.
 It is avoided using with other ototoxic drugs like minocycline and diuretics.
It is avoided using with nephrotoxic drugs like amphotericin-B and cyclosporine.
It should not be mixed with any other drug in same syringe. Resistance develops when used alone.
Therapeutic Uses
It is used in tuberculosis, plague, tularemia, brucellosis, urinary tract infections and septicaemia.
Treatment of Tuberculosis
Tuberculosis is one of the most difficult infections to cure.
The properties of mycobacteria like slow division, development of resistance, ability to remain as persisters for years and
intracellular location of the bacilli have enhanced the problem.
The aim of treatment is to kill the dividing bacilli thus making the patient sputum negative and to destroy the persisters in
order to prevent relapse and ensure complete cure.
A combination of drugs is used in treatment of tubercu-
losis to
delay the development of resistance,
reduce toxicity and
shorten the course of treatment.
Majority of cases are sensitive to first-line drugs. Initial treatment should be intensive and include drugs that have maximum
effect.
Good patient compliance and cost of therapy should
also be considered.
Treatment Regimens for Tuberculosis
Depending upon the duration of treatment, the regimens are divided into the following:
Long-course regimens (conventional regimens): These consist of INH along with one or two bacteriostatic drugs for 18
months. This is usually not recommended now because of poor patient compliance and high failure rate.
Short-course chemotherapy: There are several shortcourse regimens of 6–9 months duration, which are convenient, highly
effective and less toxic. All regimens will have two phases as follows:
Initial intensive phase: The patient receives intensive treatment with 3–4 tuberculocidal drugs daily or thrice weekly for a
period of 2–3 months. The main objective of this phase is to render the patient noncontagious.
Continuation phase: The patient receives 2–3 drugs, usually INH and rifampicin daily or thrice weekly for a period of 4–6
months. This phase helps to eliminate persisters and prevents relapse.
WHO Guidelines for Treatment of Tuberculosis
There are two treatment regimens sharing the common criteria of classification as follows:
Category-wise alternative treatment regimens recommended by WHO in 1997
Revised National Tuberculosis Control Programme (RNTCP) 1997 of India, recommended and followed in India.
Under Revised National Tuberculosis Control Programme DOTS (directly observed treatment short-course) is being
implemented (Tables 48.2 and 48.3).
The standard code is explained below:
TABLE 48-2 Category-wise Alternative Treatment Regimens for Tuberculosis (WHO 1997)
Category
of TB Type of Patient Initial Phase
(Daily/3 3
Per Week) Continuation Phase Total
Duration
I New sputum
positive Seriously ill sputum negative Seriously ill
extrapulmonary 2HRZE (S) 4HR/4H3R3
or
6HE 6 months
8 months
II Sputum positive relapse
Sputum positive failure
Sputum positive treatment after default 2HRZES 1
1HRZE 5HRE or
5H3R3E3 8 months
8 months
III Sputum negative not seriously ill
Extrapulmonary not seriously ill 2HRZ 4HR/4H3R3 or 6HE 6 months
8 months
IV Chronic or suspected
MDR-TB cases For H resistance For H 1 R resistance RZE for 12 months
 ZE 1 S/Etm 1 Cipro/ofl
TABLE 48-3 Treatment Regimes Followed in India Under the Revised National Tuberculosis Control Programme
(RNTCP 1997)
Category of TB Initial Phase Continuation Phase Total
Duration
I 2H3R3Z3E3 4H3R3 6 months
II 2H3R3Z3E3S3 1 1H3R3Z3E3 5H3R3E3 8 months
III 2H3R3Z3 4H3R3 6 months
Each antitubercular drug is given standard abbreviations: Isoniazid (H) Rifampicin (R) Pyrazinamide (Z)
Ethambutol(E) Streptomycin (S) Ethionamide (Etm)
The number before a phase is the duration of that phase in months. The number in the subscript is the number of doses of
that drug per week. If there is no subscript number the drug is given daily.
SHORT ESSAYS
Mention four adverse effects of rifampicin. Or,
Mention two important uses of rifampicin and its two adverse effects.

Rifampicin is a semisynthetic antibiotic obtained from Streptomyces mediterranei. It is a first-line antitubercular drug. It is
called sterilizing agent, as it is the only agent that can act on all types of bacillary subpopulations.
Mechanism of Action
Rifampicin affects both extracellular and intracellular organisms. It is the only drug active against persisters present in
central caseous lesion. It acts best on slowly or intermittently dividing bacilli.
It is bactericidal to Mycobacterium tuberculosis and covers all subpopulations of TB bacilli and also atypical mycobacteria.
It acts by inhibiting bacterial DNA-dependent RNA polymerase and thereby suppressing chain initiation in RNA synthesis thus
stopping expression of bacterial genes.
Adverse Effects
Hepatitis: It is the major adverse effect and is dose dependent. It usually occurs in patients with pre-existing liver diseases.
The drug should be discontinued on the development of jaundice.
Respiratory syndrome: It presents as breathlessness associated with shock and collapse.
Other minor reactions common with intermittent therapy are as follows:
Cutaneous syndrome: Flushing, pruritus and rash on face and scalp, redness and watering of eyes
Flu-like syndrome: Chills, fever, headache, malaise and bone pain
Abdominal syndrome: Nausea, vomiting, abdominal cramps with or without diarrhoea
Q. 2. One use and mechanism of action of isonicotinic acid hydrazide
(INH)
Isoniazid (INH) is a highly effective and the most widely used antitubercular drug and is an essential component of all
antitubercular regimens.
Mechanism of Action
Isoniazid acts by inhibition of synthesis of mycolic acids, which are unique fatty acid components of the mycobacterium cell
wall. It targets INH-A gene which encodes fatty acid synthase enzyme.
The sensitive mycobacterium concentrates INH and converts it to an active metabolite by a catalase-peroxidase enzyme
which interacts with the INH-A gene.
Isoniazid acts on extracellular as well as intracellular bacilli. Fast multiplying organisms are rapidly killed but quiescent ones
are only inhibited.
Adverse Effects
Peripheral neuritis, paresthesia, numbness, mental disturbances, and rarely convulsions are the most important dose-
dependent toxic effects of isoniazid (INH). Peripheral neuritis It is produced due to interference with utilization of
pyridoxine and its increased excretion in urine.
The risk of peripheral neuritis is prevented by routinely
giving 10 mg/day of pyridoxine along with INH. Hepatitis It is another major adverse effect common in older people and
in alcoholics.
It is due to dose-related damage to hepatocytes and is reversible on stopping the drug. Rashes, fever, acne and arthralgia
are other side effects.
Q. 3. DOTS in chemotherapy of TB Direct observed treatment short-course (DOTS) therapy is
a community-based tuberculosis treatment and care strategy under the revised National Tuberculosis Control Programme.
Under this strategy, the antitubercular drugs during the intensive phase are administered under direct supervision of peripheral
health staff such as MPWs or through voluntary workers such as teachers, anganwadi workers, dias, ex-patients and social
workers.
This strategy has ensured high cure rate through its
three components as follows: Appropriate medical treatment Supervision and motivation by health and nonhealth
workers
 Monitoring of disease status by health services
Q. 4. Mention the six drugs used in tuberculosis.

The drugs which are given against tuberculosis are known as antitubercular drugs.
Classification of antitubercular drugs is as follows (Table 48.4):
First-line antitubercular drugs (standard drugs): These drugs have high antitubercular efficacy as well as low toxicity and are
used routinely.
Second-line antitubercular drugs (reserve drugs): These drugs have low antitubercular efficacy or high toxicity or both and are
used in special circumstances.
Q. 5. Explain why multidrug therapy is used in the treatment of
tuberculosis?
Tuberculosis is one of the most difficult infections to cure.
First-Line Drugs Second-Line Drugs Newer Drugs
Isoniazid (H) Thiacetazone Ciprofloxacin
Rifampicin (R) Paraaminosalicylic acid Moxifloxacin
Pyrazinamide (Z) Ethionamide Gatifloxacin
Ethambutol (E) Cycloserine Clarithromycin
Streptomycin (S) Kanamycin Azithromycin
Amikacin Rifabutin
Capreomycin Rifapentine
TABLE 48.4 Classification of Antitubercular Drugs The aim of treatment is to kill the dividing bacilli thus making the
patient sputum negative and to destroy the persisters in order to prevent relapse and ensure complete cure. A combination of
drugs is used in tuberculosis to delay the development of resistance, reduce toxicity and shorten the course of treatment.
 Majority of cases are sensitive to first-line drugs. Initial treatment should be intensive and include drugs that have maximum
effect.
Good patient compliance and cost of therapy should also be considered.
SHORT NOTES
The properties of mycobacteria like slow division, development of resistance, ability to remain as persisters for years and
intracellular location of the bacilli have enhanced the problem.

Pyridoxine should be administered with INH. Or,

Rationale of combining INH (isonicotinic acid and hydrazide) with pyridoxine
in the treatment of tuberculosis.
INH causes peripheral neuritis and neurological manifestations due to interference with utilization of pyridoxine and its
rapid excretion through urine.
 This can be prevented by adding 10 mg/day of pyridoxine or is treated by 100 mg/day of pyridoxine.
Therefore, INH is combined with pyridoxine in the treatment of tuberculosis to reduce the risk of peripheral neuritis.
Q. 2. Isonicotinic acid (INH)
Isoniazid (INH) is a highly effective and the most widely used antitubercular drug and is an essential component of all
antitubercular regimens.
Mechanism of action: Isoniazid acts by inhibition of synthesis of mycolic acids, which are unique fatty acid components of
the mycobacterium cell wall.
Isoniazid acts on extracellular as well as intracellular bacilli.
Adverse effects
Peripheral neuritis, paraesthesia, numbness, mental disturbances, and rarely convulsions are the most important dose-
dependent toxic effects of isoniazid (INH). Hepatitis is another major adverse effect common in older people and in
alcoholics. Rashes, fever, acne and arthralgia are other side
effects.
Q. 3. Rifampicin
Rifampicin is a semisynthetic derivative of rifamycin B obtained from Streptomyces mediterranei.
Rifampicin affects both extracellular and intracellular organisms. It acts best on slowly or intermittently dividing bacilli.
It is bactericidal to Mycobacterium tuberculosis and covers all subpopulations of TB bacilli and also atypical mycobacteria.
It acts by inhibiting DNA-dependent RNA synthesis, thus stopping expression of bacterial genes.
Adverse effects: Hepatitis, other minor reactions common with intermittent therapy include cutaneous syndrome, flu-like
syndrome and abdominal syndrome.
Q. 4. DOTS in chemotherapy of tuberculosis
Direct observed treatment short-course (DOTS) is a community-based tuberculosis treatment and care strategy under the
revised National Tuberculosis Control Programme.
 Under this strategy, the antitubercular drugs during the intensive phase are administered under direct supervision of
peripheral health staff such as MPWs or through voluntary workers such as teachers, anganwadi workers, dias, ex-patients and
social workers. Through its three components this strategy has ensured
high cure rate.
Appropriate medical treatment Supervision and motivation by health and nonhealth
workers
Monitoring of disease status by health services
Q. 5. Pyrazinamide
Pyrazinamide is a tuberculocidal drug that is more active in acidic pH. It is effective against intracellular bacteria.
It is well-absorbed and achieves good concentration in CSF.
Adverse effects Cannot be used alone as resistance develops. Hepatotoxicity is the most common adverse effect.
Hyperuricaemia due to decreased excretion of uric
acid
Arthralgia Anorexia, vomiting and rashes
Q. 6. Four adverse effects of rifampicin
Rifampicin is a semisynthetic derivative of rifamycin B obtained from Streptomyces mediterranei. Adverse effects of
rifampicin are as follows:
Hepatitis is the major adverse effect and is dose dependent.
It usually occurs in patients with pre-existing liver diseases.
The drug should be discontinued on the development of jaundice.
Respiratory syndrome: It presents as breathlessness as-
sociated with shock and collapse.
Purpura, haemolysis, shock and renal failure Other minor reactions common with intermittent therapy are as follows:
Cutaneous syndrome: Flushing, pruritus with rash on face and scalp, redness and watering of eyes
 Flu syndrome: Chills, fever, headache, malaise and bone pain
Abdominal syndrome: Nausea, vomiting, abdominal

Antileprotic Drugs
SHORT ESSAYS
cramps with or without diarrhoea

Dapsone
1. Dapsone or diaminodiphenyl sulfone is the oldest, cheapest, most active and most commonly used agent for treatment
of leprosy even today.
Mechanism of Action
Dapsone is chemically related to sulphonamide and has the same mechanism of action.
Dapsone is structural analogue of PABA and hence competitively inhibits bacterial folate synthetase which is involved in the
conversion of PABA to folic acid. This causes folic acid deficiency resulting in injury to the bacterial cell.
It also competitively inhibits the union of PABA with pteridine residue to form dihydropteroic acid which conjugates with the
glutamic acid to produce dihydrofolic acid.
It also gets incorporated to form an altered folate which is metabolically injurious.
Thus dapsone produces leprostatic effect as shown:
PABA skin smear negativity is attained or not and 6 months for
paucibacillary leprosy.
(-)Folate synthetase 4. Treatment schedules of leprosy are listed in Table 49.1.
Dapsone→↓ DHFA
TABLE 49.1 Treatment Schedule of Leprosy
Dihydrofolate reductase

THFA
Pharmacokinetics
Dapsone is given orally and is almost completely absorbed from the gut. 70% is plasma protein bound.
Widely distributed in the body and mainly concentrated in the infected skin, muscle, liver and kidney.
It is partly secreted in bile and undergoes enterohepatic cycling.
Metabolized by acetylation and excreted in urine.
Adverse Effects
The common adverse effects are dose-related haemolytic anaemia and methaemoglobinaemia, particularly in patients with
G6PD deficiency.
Gastric intolerance like anorexia, nausea, vomiting, headache, drug fever, paraesthesia and mental symptoms.
Cutaneous reactions include allergic rashes, fixed drug reaction, hypermelanosis, phototoxicity and rarely exfoliative
dermatitis.
Hepatitis and agranulocytosis rarely occur.
Lepra reaction
Therapeutic Uses
1. Leprosy
Main indication: 100 mg daily self-administered for 6 months in paucibacillary and 24 months in multibacillary leprosy.
Used in chloroquine-resistant malaria combined with pyrimethamine.
Q. 2. Schedule for treatment of leprosy or multidrug therapy in
leprosy
Leprosy is treated by multidrug therapy (MDT) regime introduced by WHO in 1981 and implemented under National Leprosy
Eradication Programme.
The drugs used are dapsone, rifampicin and clofazimine. All these drugs are administered orally.
The WHO recommended the following standard MDT regimen in 1994 as fixed duration therapy of 2 years for multibacillary
leprosy, whether disease inactivity or
Drugs Used Multibacillary
Leprosy (24 months) Paucibacillary
Leprosy (6 Months)
Rifampicin 600 mg once a month supervised 600 mg once a month supervised
Dapsone 100 mg daily self- administered 100 mg daily self- administered
Clofazimine 300 mg once a month supervised or 50 mg daily self- administered
Alternative regimens are as follows:
Clofazimine 50 mg with any two newer drugs (ofloxacin, minocycline, clarithromycin, etc) daily for 6 months followed by
clofazimine 50 mg with any one new drug daily for another 18 months.
In case of single lesion paucibacillary leprosy: (ROM regimen)
Ofloxacin 400 mgMinoRifampicin 600 mgcycline 100 mg  as a single dose
Q. 3. Explain briefly about lepra reactions.

1. Lepra reactions are immunologically-mediated reactions that occur during the course of the disease. Aetiology is
unknown and precipitated by infection, trauma, mental stress, etc. There are two types of reactions:
Lepra reaction (erythema nodosum leprosum)
Reversal reaction
Lepra Reaction
Occurs in lepromatous leprosy (LL) usually with institution of chemotherapy or intercurrent infection.
It is arthus type or type III hypersensitivity reaction due to release of antigens from the killed bacilli.
It may be mild, severe or life threatening (erythema nodosum leprosum).
Lepra reaction is of abrupt onset, existing lesions enlarge, become red, swollen and painful. Several new lesions may appear.
It is characterized by tender, inflamed subcutaneous nodules with fever, lymphadenopathy, arthritis, nerve pain, orchitis, etc.
Treatment
Temporary discontinuation of dapsone is recommended only in severe cases. The severe forms are treated with thalidomide but
pregnancy is absolute contraindication.
Other drugs used are analgesics, antipyretics, antibiotics, etc.
Clofazimine 200 mg daily is highly effective in controlling the reaction except the most severe ones.
Corticosteroids should be used only in severe cases.
Reversal Reaction
It is delayed type of hypersensitivity seen in borderline categories of leprosy and is common in tuberculoid type of leprosy
(TT).
Even after completion of therapy, cutaneous ulcerations, multiple nerve involvement with pain and tenderness occur suddenly.
SHORT NOTES
It is treated with clofazimine or corticosteroids.

Mention the drugs used in lepra reactions. Or,

Treatment of lepra reactions
The drugs used in lepra reactions are as follows:
Type 1 lepra reactions or reversal reactions are treated with oral prednisolone, i.e. corticosteroids or clofazimine.
Type 2 lepra reactions: The severe forms are treated with thalidomide but pregnancy is absolute contraindication. Other drugs
used are aspirin, clofazimine, chloroquine and prednisolone.
Q. 2. DDS
Dapsone or diaminodiphenyl sulfone (DDS) is the oldest, cheapest, most active and most commonly used agent for treatment
of leprosy even today.
Dapsone produces leprostatic effect by causing folic acid deficiency resulting in injury to the bacterial cell.
Therapeutic uses of dapsone are as follows:
Main indication is treatment of leprosy.
Used in chloroquine-resistant malaria combined
with pyrimethamine
Adverse effects
Dose-related haemolytic anaemia and methaemoglo-
binaemia
Gastric intolerance like anorexia, nausea, vomiting, headache, fever, paraesthesia and mental symptoms
Cutaneous reactions include allergic rashes, fixed drug
reaction, hypermelanosis, phototoxicity and rarely exfoliative dermatitis
Lepra reaction
Q. 3. Enlist three drugs for leprosy.
The drugs used in treatment of leprosy are called as antileprotic drugs. The treatment of leprosy is done by multidrug
therapy.
Various drugs used for leprosy treatment are as follows:
Sulfone
Dapsone
DADDS
Phenazine derivatives
Clofazimine
Antitubercular drugs
Rifampicin
Ethionamide
Prothionamide
Other antibiotics
Ofloxacin
Minocycline
Clarithromycin

Antifungal Drugs
SHORT ESSAYS
Amphotericin B 2. Amphotericin B (AMB) is active against a wide range
of fungi and yeast like Candida albicans, Histoplasma
capsulatum, Cryptococcus neoformans, Blastomyces der-
1. Amphotericin B is a broad-spectrum antifungal agent matitidis, Coccidiodes rhodotorula, Aspergillus, Sporoobtained
from Streptomyces nodosus. thrix and fungi causing mucormycosis.
To deal with dapsone-resistant strains of Mycobacterium leprae, MDT with rifampicin, dapsone and clofazimine was
introduced by WHO.
Mechanism of Action
Amphotericin binds to ergosterol present
in fungal cell membrane

Forms pores and channels in the cell membrane

Permeability of the membrane increases

Leakage of intracellular contents occurs leading to
Death of fungi (fungicidal)
Pharmacokinetics
Amphotericin B is poorly absorbed from gut hence is not suitable orally and so it is given IV.
Formulations
AMB is poorly water soluble, hence IV and intrathecal preparation are made with deoxycholate—AMB colloidal deoxycholate
complex (AMB—DOC).
ABCD (AMB colloidal dispersion), ABLC (AMB lipid complex) and liposomal AMB are the lipid based new formulations of
AMB. They are developed mainly to reduce its toxicity, improve tolerability and produce site specific delivery of the drug.
Uses
It is used intravenously for all life-threatening deep mycotic infections.
AMB is the drug of choice for severe deep mycosis in immunocompromized individuals.
Topical AMB is used for cutaneous candidiasis.
It is used as an alternative in the treatment of kala-azar and mucocutaneous leishmaniasis.
Adverse Effects
AMB is the most toxic of all the antifungal agents.
IV infusion of amphotericin B causes fever, chills, muscle spasms, vomiting, headache, and hypotension.
Anaemia and electrolyte disturbances are commonly seen.
It also causes bone marrow depression which leads to anaemia and renal impairment.
Q. 2. Antifungal drugs
Or,
Name four drugs used in fungal infections.
Fungal infections may be systemic or superficial. Antifungal drugs are used in the treatment of fungal infections.
Antifungal drugs are classified as follows:
Antifungal antibiotics
Polyenes: Amphotericin-B, nystatin, hamycin and
natamycin (pimaricin)
Heterocyclic benzofuran: Griseofulvin
Antimetabolites: Flucytosine (5-FC)
Azoles
Imidazoles (topical): Ketoconazole, miconazole, clotrimazole and econazole
Triazoles (systemic): Fluconazole and itraconazole
Allylamine: Terbinafine
Other topical agents: Tolnaftate, undecylenic acid, benzoic acid, salicylic acid, selenium sulphide, ciclopirox olamine, sodium
thiosulphate
Uses
Antifungal drugs are used against a large variety of fungi and yeasts like Candida albicans, Histoplasma capsulatum,
Cryptococcus neoformans, Blastomyces dermatitidis, Coccidiodes immitis, Torulopsis, Rhodotorula, Aspergillus, Sporothrix,
deep mycoses, Epidermophyton, Trichophyton, Microsporum.
Q. 3. Griseofulvin
Griseofulvin is a heterocyclic benzofuran, derived from Penicillium griseofulvum. It is an antibiotic antifungal agent.
It is a fungistatic and not a fungicidal agent.
Spectrum of Activity
Griseofulvin is active against most of the dermatophytic species of fungi like Epidermophyton, Trichophyton, Microsporum. It
is not active against species like Candida.
Mechanism of Action
Griseofulvin gets deposited in the keratin forming cells in the skin, nails and hair.
 Griseofulvin

Interacts with polymerized microtubules

Disrupts the mitotic spindles

Spindle poison
Thus griseofulvin inhibits fungal mitosis (fungistatic).
Adverse Effects Uses
Though toxicity due to griseofulvin is low, GI distur- 1. Griseofulvin is used in treatment of dermatophytic inbances,
peripheral neuritis, CNS symptoms, headache fections. The duration of treatment depends on the site are common complaints.
of lesion and thickness of infected keratin layer.
Discontinuation of the drug is advised in case of rashes 2. It is reserved for cases involving nail, hair, or large
body and photoallergy. surface involvement.
It is used in cases of Athlete’s foot.
SHORT NOTES
Name two broad-spectrum antifungal antibiotics.
Broad-spectrum antifungal drugs are used against a large variety of fungi and yeasts like Candida albicans,
Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidiodes immitis, Torulopsis, Rhodotorula,
Aspergillus, Sporothrix, deep mycoses, Epidermophyton, Trichophyton, Microsporum.
Antifungal Antibiotics
Polyenes: Amphotericin-B, nystatin, hamycin and natamycin (pimaricin)
Heterocyclic benzofuran: Griseofulvin
Q. 2. Nystatin
Nystatin is a polyene antibiotic obtained from Streptomyces noursei.
It is used only topically in candida infections as it is poorly absorbed from the skin and mucous membranes and has high
systemic toxicity.
Therapeutic Uses
Nystatin can be used orally in case of monilial diarrhoea due to superinfection or otherwise in dose of 5 lakh units TDS.
It is effective in monilial vaginitis: As vaginal suppositories 1 lakh units tablet inserted twice daily.
Nystatin can be used topically for oral, pharyngeal, corneal, conjunctivitis, and cutaneous candidiasis.
It can also be combined with tetracycline to prevent superinfection.
Side Effects
Gastrointestinal disturbances, nausea and bad taste can occur on oral administration.
Q. 3. Ketoconazole
Ketoconazole is a broad-spectrum antifungal that is used in superficial candidal infections, dermatophytosis, and deep mycosis.
It is effective orally as well as topically for various fungal infections.
It is the most toxic among azoles, hence used commonly by topical route for candida and dermatophytic infections.
Adverse effects: Ketoconazole is less toxic than amphotericin B, but it causes gastric irritation, headache, allergic reactions,
gynaecomastia and sometimes hepatotoxicity.
Uses
Used in the treatment of dandruff with ketoconazole shampoo.
It is used in the treatment of dermatophytosis of large body surface, tinea of nails, dermal leishmaniasis and kala-azar.

Antiviral Drugs
SHORT ESSAY
Classify antiviral drugs.
Viruses are intracellular parasites and depend on host cells for food, growth and multiplication.
Antiviral drugs interfere with the steps of viral reproduction cycle within host cell.

As it reduces the levels of corticosteroid production, it is used in the treatment of Cushing’s syndrome.
CLASSIFICATION OF ANTIVIRAL AGENTS
Drugs used against herpetic infection (antiherpes agents): Acyclovir, valacyclovir, ganciclovir, idoxuridine, vidarabine,
foscarnet
Drugs used against HIV infection (antiretroviral agents)
Nucleoside reverse transcriptase inhibitors: Zidovudine, didanosine, zalcitabine, stavudine, and lamivudine
Nonnucleoside reverse transcriptase inhibitors:
Nevirapine, delaviridine and efavirenz
Protease inhibitors: Saquinavir, indinavir, ritonavir and lopinavir
Fusion inhibitor: Enfuvirtide
Anti-influenza virus agents: Amantadine, rimantadine, and oseltamivir
SHORT NOTES
Other antiviral agents: Ribavirin and interferons

Acyclovir
Acyclovir is an antiherpes virus agent.
It is effective against the following viruses:
Herpes simplex virus type I and type II
Varicella zoster virus
Epstein Barr virus
Mechanism of Action
Acyclovir
HSV thymidine kinase

Acyclovir monophosphate

cellular enzymes
Acyclovir diphosphate
cellular enzymes

Acyclovir triphosphate
Inhibits DNA synthesis and viral replication.
1. Acyclovir acts by inhibiting viral DNA synthesis by causing DNA chain termination. Acyclovir is a welltolerated drug
available for oral, topical and intravenous administration.
Uses
HSV type-I infections of face, mouth, skin, oesophagus or brain and type-II infections of genitals, rectum, skin, hands or
meninges
Herpes zoster infections
Chicken pox
Adverse Effects
Common ill effects include nausea, diarrhoea, headache, rashes. Topical application can cause burning, irritation.
Given IV it can cause renal and neurotoxicity.
Q. 2. Zidovudine
Zidovudine is a thymidine analogue, active against HIV infections and other retroviruses. It is the first antiretroviral drug
approved for treatment of HIV infection.
Mechanism of Action
1. Zidovudine is converted to its triphosphate derivative which inhibits reverse transcriptase.
Adverse Effects
Bone marrow depression, headache, nausea, vomiting, and insomnia can occur.
High doses can cause myopathy and neurotoxicity.
Uses
Zidovudine is the drug of choice in HIV infections.
Given during pregnancy and continued in newborns for up to 6 weeks, it reduces the risk of transmission to the baby.
Antimalarial Drugs
LONG ESSAY
Classify the drugs used in malaria and briefly outline mechanism of action,
clinical uses and toxicity of chloroquine.

Malaria is a major public health problem in most of the developing countries like India. It is caused by four species of
protozoan parasite Plasmodium.
CLASSIFICATION OF ANTIMALARIAL
DRUGS
4-Aminoquinolones: Chloroquine, amodiaquine Quinolone–methanol: Mefloquine Acridine: Quinacrine (Mepacrine,
Atabrine) Cinchona alkaloid: Quinine
 Biguanides: Proguanil (Chloroguanide) Diaminopyrimidines: Pyrimethamine vii. 8-Aminoquinoline:
Primaquine, bulaquine viii. Sulphonamides and sulphone: Sulphadoxine, sulphamethopyrazine, dapsone
Tetracyclines: Tetracycline, doxycycline
Sesquiterpine lactones: Artesunate, artemether, arteether
Phenanthrene methanol: Halofantrine xii. Naphthoquinone: Atovaquone
Antimalarial drugs can be classified according to stage of use as follows:
Casual prophylactics (primaquine, pyrimethamine): These destroy the tissue forms of the parasite in liver cells and prevent
invasion of the erythrocytes. They are also called primary tissue schizontocides.
Blood schizontocides (suppressives like chloroquine, quinine, mefloquine, halofantrine, pyrimethamine, chloroguanide and
artemisinin): Suppressives destroy erythrocytic forms and terminate clinical attacks of malaria.
Tissue schizontocides used to prevent relapse (primaquine): They act on hepatic forms of P. vivax, P. ovale, that produce
relapses. Given with a blood schizontocide, they bring about radical cure and eradicate the parasite from the body in these
relapsing malarial infections.
Gametocidal drugs (primaquine, chloroquine, quinine): These destroy gametocytes and prevent the transmission of malaria.
CHLOROQUINE
It is a synthetic 4-aminoquinoline. It is a rapidly acting erythrocytic schizontocide with activity against all the four species of
plasmodia.
It also destroys gametocytes of P. vivax, P. ovale, P. malaria and completely cures falciparum malaria. Patients become
afebrile in 1–2 days. Chloroquine is safe in pregnancy. It also has anti-
inflammatory properties.
Mechanism of Action of Chloroquine
Mechanism of action of chloroquine is not completely known.
 It is actively concentrated by sensitive intraerythrocytic plasmodia, higher concentration is found in infected RBCs.
Chloroquine is a base. It concentrates in acidic food vacuoles of the parasite and interferes with the degradation of
haemoglobin by parasitic lysosomes.
Polymerization of toxic haeme to nontoxic parasite pigment haemozoin is inhibited by formation of chloroquine–haeme
complex. Haeme itself or its complex with chloroquine then damages the plasmodial membranes.
Clumping of pigment and changes in parasite mem-
branes follow.
Adverse Effects
Toxicity of chloroquine is low but side effects are frequent and unpleasant: Nausea, vomiting, pruritus, headache, visual
disturbances, insomnia and skin rashes may occur.
Parenteral administration can cause hypotension, cardiac depression, arrhythmias and CNS toxicity including convulsions.
Prolonged treatment with high doses can cause irreversible retinopathy.
 High doses can also cause cardiomyopathy and psychi-
atric problems.
Uses
Chloroquine is the drug of choice for clinical cure and suppressive prophylaxis of all types of malaria. Chloroquine is
highly effective in the treatment of malaria due to sensitive strains of all four species (600 mg base stat, 300 mg after 6 h and
300 mg
for the next 2 days). It is also used for prophy- Photogenic reactions
laxis—300 mg/week.
Extraintestinal amoebiasis Rheumatoid arthritis Lepra reactions vii. Discoid lupus
erythematosus—very effective. viii. Infectious mononucleosis—affords symptomatic relief.
SHORT NOTES
Emetine
Emetine is derived from Ipecac (Brazil root). Directly affects the trophozoites but not the cysts.
As oral absorption is improper, they are given parenterally.
They can be used only in severe amoebiasis but not preferred due to toxicity.
Adverse effects:
Pain at the injection site
Thrombophlebitis
Nausea, vomiting, diarrhoea
Cardiotoxicity
Q. 2. Chloroquine
It is a synthetic 4-aminoquinoline. It is a rapidly acting erythrocytic schizontocide with activity against all the
It also destroys gametocytes of P. vivax, P. ovale, P. malaria and completely cures falciparum malaria. Patients become afebrile
in 1–2 days.
Chloroquine is safe in pregnancy. It also has antiinflammatory properties.
Chloroquine attains high concentration in the liver, is directly toxic against trophozoites and is therefore useful in hepatic
amoebiasis.
Uses
Chloroquine is the drug of choice for clinical cure and suppressive prophylaxis of all types of malaria.
Extraintestinal amoebiasis
Rheumatoid arthritis
Photogenic reactions and lepra reactions.
four species of plasmodia.

Antiamoebic and Other Antiprotozoal Drugs

LONG ESSAY
Infectious mononucleosis—affords symptomatic relief.

Define chemotherapy. Classify the drugs used in treatment of amoebiasis and

malaria.

Chemotherapy can be defined as the use of chemicals in infectious diseases to destroy microorganisms with damaging the
host tissues. Paul Ehrlich, the father of modern chemotherapy, coined the term chemotherapy. He showed that certain dyes
can destroy microbes and demonstrated methylene blue can be used in malaria. He also synthesized some arsenical compounds
for treatment of syphilis and sleeping sickness.
ANTIAMOEBIC DRUGS
Amoebiasis caused by the protozoan Entamoeba histolytica is a tropical disease common in developing countries.
It spreads through fecal contamination of food and water.
Antiamoebic drugs can be classified as follows:
Tissue amoebicides
Drugs effective in both intestinal and extraintestinal amoebiasis. For example:
Nitroimidazoles: Metronidazole, tinidazole, sec-
nidazole, ornidazole, satranidazole
Alkaloids: Emetine, dehydroemetine
Drugs effective only in extraintestinal amoebiasis: Chloroquine
Luminal amoebicides: Drugs effective only in intestinal amoebiasis. For example:
Amide: Diloxanide furoate
8-Hydroxyquinolones: Quiniodochlor, diiodohy-
droxyquin (iodoquinol)
Antibiotics: Tetracyclines
CLASSIFICATION OF ANTIMALARIAL
DRUGS
4-Aminoquinolones: Chloroquine, amodiaquine Quinolone–methanol: Mefloquine Acridine: Quinacrine (Mepacrine,
Atabrine) Cinchona alkaloid: Quinine
Biguanides: Proguanil (Chloroguanide) Diaminopyrimidines: Pyrimethamine vii. 8-Aminoquinoline:
Primaquine, Bulaquine viii. Sulphonamides and sulphone: Sulphadoxine, sulphametopyrazine, dapsone
Tetracyclines: Tetracycline, doxycycline
Sesquiterpine lactones: Artesunate, artemether, arteether xi. Phenanthrene methanol: Halofantrine xii.
Naphthoquinone: Atovaquone
Antimalarial drugs can be classified as follows:
Casual prophylactics—Primaquine, pyrimethamine These destroy the tissue forms of the parasite in liver cells and prevent
invasion of the erythrocytes. They are also called primary tissue schizontocides.
Blood schizontocides—Suppressives like chloroquine,
quinine, mefloquine, halofantrine, pyrimethamine, chloroguanide and artemisinin
Suppressives destroy erythrocytic forms and terminate clinical attacks of malaria. Tissue schizontocides used to
prevent relapse—Primaquine
They act on hepatic forms of P. vivax, P. ovale that produce relapses. Given with a blood schizontocide, they bring about
radical cure and eradicate the parasite from the body in these relapsing malarial infections.
SHORT ESSAYS
Gametocidal drugs—Primaquine, chloroquine, quinine These destroy gametocytes and prevent the transmission of malaria.

Therapeutic uses of metronidazole in dentistry

Metronidazole is a powerful amoebicide. Apart from this it also inhibits Trichomonas vaginalis and Balantidium coli.
Anaerobic bacteria are also sensitive.
The uses of metronidazole are as follows:
Amoebiasis—Metronidazole is the drug of choice in all forms of amoebiasis in the dose of 400–800 mg TDS for 3 days.
It is highly effective in a dose of 200 mg TDS for 7 days in giardiasis. A shorter course of 3 days with 2 g/day is equally
effective.
Trichomonas vaginitis: Metronidazole 400 mg TDS for 7 days is the drug of choice, achieves 100% cure.
H. pylori infections in peptic ulcer patients can be treated with a combination of metronidazole, clarithromycin and
omeprazole/ranitidine.
Metronidazole is effective drug in anaerobic bacterial infections which occur mostly after colorectal or pelvic surgery,
appendectomy, etc.
Oral metronidazole 800 mg TDS is more effective, more convenient, less toxic and is preferred over vancomycin.
Uses in dentistry
Metronidazole is used in anaerobic infections like pericoronal abscess or periodontal abscess in combination with
ampicillin/ciprofloxacin.
Metronidazole is used in treatment of acute ulcerative gingivitis as an alternative to penicillin G.
Q. 2. Mention three uses and three adverse effects of metronidazole.

Uses
Metronidazole is a powerful amoebicide.
The uses of metronidazole are as follows:
Amoebiasis: Metronidazole is the drug of choice in all forms of amoebiasis in the dose of 400–800 mg TDS for 3 days.
It is highly effective in giardiasis.
Trichomonas vaginitis: Metronidazole 400 mg TDS for 7 days is the drug of choice.
H. pylori infections in peptic ulcer patients can be treated with a combination of metronidazole, clarithromycin and
omeprazole/ranitidine.
Uses in dentistry
Metronidazole is used in anaerobic infections like pericoronal abscess or periodontal abscess in combination with
ampicillin/ciprofloxacin.
Metronidazole is used in treatment of acute ulcer-
ative gingivitis as an alternative to penicillin G.
Adverse Effects
Side effects to metronidazole are relatively frequent but mostly nonserious.
Gastrointestinal effects like anorexia, nausea, abdominal pain, metallic taste in the mouth are the most common. Looseness of
stool is occasional.
Less frequent side effects are headache, glossitis, stomatitis, dryness of mouth and transient neutropenia.
CNS effects like dizziness, peripheral neuropathy, insomnia, high doses can cause convulsions.
SHORT NOTES
Metronidazole
Metronidazole is a powerful amoebicide. Apart from this it also inhibits Trichomonas vaginalis and Balantidium coli.
Anaerobic bacteria are also sensitive.
Mechanism of action: In the microorganisms, metronidazole is reduced to a derivative which is toxic to the DNA. It is well
absorbed and reaches adequate concentrations in the CSF.
Metronidazole is the drug of choice in all forms of amoebiasis in the dose of 400–800 mg TDS for 3 days.
Uses in dentistry
Metronidazole is used in anaerobic infections like pericoronal abscess or periodontal abscess in combination with
ampicillin/ciprofloxacin.
Anthelmintics
SHORT ESSAY
Metronidazole is used in treatment of acute ulcerative gingivitis as an alternative to penicillin G.

Treatment of hookworm infestation

Hookworm infections are more common in the developing countries. It is seen in people with poor hygiene.
Ancylostoma duodenale and Necator americanus are some common hookworms that infest.
Anthelmintics are deworming agents. A vermicide kills while a vermifuge promotes expulsion of worms.
Hook worm infections can be treated with mebendazole and albendazole.
MEBENDAZOLE
It is a benzimidazole introduced in 1972. It is a broadspectrum antihelmintic cures roundworm, hookworm, pinworm and
strongyloides infestations.
Mechanism of action
It blocks the glucose uptake in the parasite and causes depletion of its glucose stores. The eggs and larvae are also destroyed
along with the worms.
The site of action of mebendazole appears to be microtubular protein b-tubulin of the parasite. It binds to b-tubulin of
susceptible worms with high affinity and inhibits its polymerization. Hatching of nematode eggs and their larvae are also
inhibited. Ascaris ova are killed.
It is given orally 100 mg twice a day for 3 days.
It is well tolerated.
Large doses may cause headache, dizziness, loss of hair and granulocytopenia.
It may rarely provoke abnormal migration of the roundworms which may come out through the mouth or nose.
Uses
Mebendazole is used in the treatment of roundworm, hookworm, pinworm, tapeworm, trichuriasis and hydatid disease. It is of
special value in multiple worm infestations.
ALBENDAZOLE
It is a congener of mebendazole, has actions similar to mebendazole but is better tolerated and it has the advantage of a single
dose administration in many cases.
Adverse effects are similar to mebendazole but milder.
Uses
Albendazole is the drug of choice in roundworm, hookworm, pinworm, trichuriasis infestations in a single 400 mg dose. Dose
to be repeated after 2 weeks in pinworm infestation to prevent reinfection from ova that have matured later.
Trichinosis, tapeworms and strongyloidiasis require 3 days treatment.
Neurocysticercosis: Albendazole is the drug of choice.
Hydatid disease: Albendazole is the drug of choice given for 4 weeks.
SHORT NOTES
Piperazine citrate 3. Flaccid paralysis results and the worms are expelled.
4. Adverse effects are mild, gastrointestinal symptoms, headache and dizziness are seen occasionally. Pipera-
Piperazine citrate is effective in roundworm and pin- zine citrate for roundworm and pinworm infestations. It worm
infestations. is also safe in pregnancy.
It competitively blocks the action of acetylcholine there by contractions in the worms.
Part XIII
Chemotherapy of Neoplastic Diseases

General Considerations
SHORT ESSAYS
List toxic effects of alkylating agents.
Alkylating agents are cell cycle nonspecific or phase nonspecific anticancer drugs. They exert cytotoxic, immunosuppressant
and radiomimetic action.
Alkylating agents used in cancer therapy are as follows:
Nitrogen mustards: Mechlorethamine, cyclophosphamide, melphalan, chlorambucil
Alkyl sulfonate: Busulfan
Nitrosureas: Carmustine, lomustine, streptozocin
Platinum containing compounds: Cisplatin, carboplatin
General toxic effects of alkylating agents include the following:
Bone marrow suppression: It manifests as leukopenia, agranulocytosis, thrombocytopenia, and in higher doses— aplastic
anaemia. In such persons infections and bleeding are common.
Immunosuppression: Decreased lymphocytes result in immunosuppression. Such patients are prone to opportunistic infections
with fungi, bacteria and viruses.
Skin and hair: Alopecia (loss of hair) occurs due to damage to hair follicles. Dermatitis and skin rashes also can occur.
GIT: Nausea and vomiting occur with most of the cytotoxic drugs due to central action. Stomatitis, diarrhoea,
GI bleeding and ulcers are due to necrosis of rapidly dividing epithelial cells of gut mucosa.
Gonads: Reduced spermatogenesis in men and amenorrhoea and infertility in women.
Fetus: Teratogenicity is common with administration of cytotoxic drugs during pregnancy. They cause multiple defects in the
fetus and may also cause fetal death.
Hyperuricaemia: Gout and urate stones in urinary tract are due to excessive cell destruction.
Carcinogenicity (secondary malignancy) and mutagenicity.
Specific Toxicity
Haemorrhagic cystitis especially caused by cyclophosphamide
Pulmonary fibrosis caused by busulfan
Nephrotoxicity with cisplatin
Q. 2. Vinca alkaloids
Vinca alkaloids are the antineoplastic drugs. They are isolated from periwinkle plant (Vinca rosea, Catharanthus roseus). They
are cell cycle specific (CCS) agents and act during M phase of cell cycle.
The clinically used vinca alkaloids are
vincristine (oncovin) and
vinblastine.
Mechanism of Action
They act by inhibiting mitosis as follows:
Vincristine and vinblastine
Binds to microtubular protein, β-tubulin

Prevents the formation of mitotic spindle and polymerization and assembly of microtubules

The chromosomes fail to move apart during mitosis

Metaphase arrest occurs

Cell division is inhibited

Pharmacokinetics
Vinca alkaloids are not well absorbed orally. They are administered through freely running IV infusion because they are
irritants. They are primarily excreted by the liver through bile.
Vincristine
It is a rapidly acting drug.
Therapeutic uses
Vincristine is very useful for inducing remission in childhood acute leukaemia.
Other indications are childhood tumours like neuroblastoma, Hodgkin’s disease, Wilms tumour, Ewing’s sarcoma. Toxicity
Neurotoxicity manifesting as cranial nerve palsies, peripheral neuritis with paraesthesia and constipation. It has marrow sparing
effect.
Vinblastine
It is the most commonly employed drug.
Therapeutic Uses
It is primarily used in Hodgkin’s disease and testicular tumours and carcinoma of breast.
Toxic effects
Bone marrow suppression, nausea, anorexia, vomiting and diarrhoea
Q. 3. Name two antimetabolites used in cancer therapy.
Antimetabolites are analogues related to normal components of DNA or of coenzyme involved in nucleic acid synthesis. They
are used in treatment of malignancies.
They competitively inhibit utilization of normal substrate or get themselves incorporated forming dysfunctional
macromolecules.
The antimetabolites used in therapy are as follows:
Folate antagonist: Methotrexate
Purine antagonists: 6-MP, 6-thioguanine (6-TG)
Pyramidine antagonists: 5-FU, cytarabine
Therapeutic Uses
a. Folate Antagonists
i. Methotrexate (Mtx)
It is one of the most commonly used anticancer drugs.
Methotrexate is curative in choriocarcinoma. It is also used for maintaining remission in children with acute leukaemiae.
It is used to manage difficult neoplasms in higher doses. 250–1000 mg/m2 body surface area of methotrexate infused IV over 6
h followed by 3–15 mg IV calcium leucovorin within 3 h repeated as required. It is also useful in other malignancies,
rheumatoid arthritis, psoriasis and as immunosuppressant.
b. Purine Antagonists
6-Mercaptopurine (6-MP): 2.5 mg/kg/day and 1.2 mg/kg/ day for maintenance.
6-Thioguanine (6-TG): It is also used for maintenance.
c. Pyrimidine Antagonists
5-Fluorouracil (5-FU): Solid tumours of breast, colon, urinary bladder, liver, etc. (1 g orally on alternate days (6 doses) then 1 g
weekly or 12 mg/kg/day IV for 4 days followed by 6 mg/kg IV on alternate days) 1% topical solution for cutaneous basal cell
carcinoma.
Cytarabine (cytosine arabinoside): To induce remission in acute leukaemia in children and adults. 1.5–3 mg/kg IV BD for 5–10
days. Used in Hodgkin’s disease and non-Hodgkin’s lymphoma also.
Q. 4. Methods to ameliorate the toxicity of anticancer drugs.

Various methods to ameliorate the general and specific toxic effects of anticancer drugs are as follows:
Bone marrow suppression can be ameliorated or reduced by the following: a. Platelet transfusion
Granulocyte colony stimulating factor (G-CSF)
Erythropoietin
Bone marrow transplantation
Using bone marrow sparing drugs
Hyperuricaemia can be prevented by good hydration, allopurinol and corticosteroids.
Haemorrhagic cystitis especially caused by cyclophosphamide is ameliorated by administering mesna systemically and
acetylcysteine locally.
Megaloblastic anaemia with methotrexate can be ameliorated by folinic acid or leucovorin or citrovorum factor.
SHORT NOTE
Saline infusion and mannitol reduces the incidence of nephrotoxicity.

Nitrogen mustard
The nitrogen mustards are alkylating agents which include the following: a. Mechlorethamin
Cyclophosphamide
Melphalan
Chlorambucil
Cyclophosphamide is the most commonly used alkylating agent used in combination with other anticancer agents in the
treatment of Hodgkin’s disease, Burkitt’s lymphoma, lymphatic leukaemia, etc.
It also has powerful immunosuppressant effect, hence is useful in rheumatoid arthritis, nephritic syndrome and to prevent as
well as to treat graft rejection during organ transplantation.
Chlorambucil (leukeran) is a slow-acting and least toxic nitrogen mustard. It was the standard treatment for chronic lymphatic
leukaemia (CLL).
Melphalan is highly effective in multiple myeloma.
Q. 2. Name two antibiotics used in cancer therapy.
The commonly used antibiotics used in cancer therapy are as follows:
Actinomycin D (dactinomycin)
Doxorubicin
Daunorubicin (rubidomycin)
Bleomycin
Mitomycin C
Mithramycin (plicamycin)
Q. 3. Antimetabolites
Commonly used antimetabolites are as follows:
Folate antagonists
Methotrexate (Mtx)
Purine antagonists
6-Mercaptopurine (6-MP) 6-Thioguanine (6-TG) Azathioprine
Pyrimidine antagonist
5-Fluorouracil (5-FU) Cytarabine (cytosine arabinoside)
Antimetabolites are analogues related to normal components of DNA or of coenzyme involved in nucleic acid synthesis.
They competitively inhibit utilization of normal substrate or get themselves incorporated forming dysfunctional
macromolecules.
They are used in treatment of malignancies.
Q. 4. Methotrexate
Methotrexate (Mtx) is one of the most commonly used anticancer drugs.
Methotrexate is curative in choriocarcinoma. It is also used for maintaining remission in children with acute leukaemiae.
It is used to manage difficult neoplasms in higher doses.
It is also useful in other malignancies, rheumatoid arthritis, psoriasis and as immunosuppressant.
Q.5. Name vinca alkaloids.

Vinca alkaloids are the antineoplastic drugs. They are isolated from periwinkle plant (Vinca rosea, Catharanthus roseus).
The clinically used vinca alkaloids are (a) vincristine (oncovin) and (b) vinblastine.
Vincristine is very useful for inducing remission in childhood acute leukaemia but is not good for maintenance therapy. Other
indications are lymphosarcoma, Hodgkin’s disease, Wilms tumour, Ewing’s sarcoma and carcinoma lung.
Vinblastine is primarily used in Hodgkin’s disease and testicular carcinoma with other antineoplastic drugs.
Q. 6. Cyclophosphamide
Cyclophosphamide is most commonly used alkylating agent.
It is a prodrug and is active in liver by CYP450 system. The final active metabolites derived are phosphoramide mustard and
acrolein.
It is usually administered orally and also through IM or IV routes and metabolites are excreted mainly in urine.
Cyclophosphamides are used in the treatment of Hodgkin’s lymphoma, leukaemiae in children and as an immunosuppressant.
Part XIV
Miscellaneous
Immunosuppressants, Gene Therapy and Drugs Acting on Skin and Mucous Membranes
SHORT ESSAYS
Common adverse effects include haemorrhagic cystitis, alopecia, bone marrow depression, stomatitis, vomiting, amenorrhoea
and teratogenicity.

Uses of astringents in dental practice

Astringents are the substances which precipitate superficial proteins without penetrating the cells when applied to skin or
mucous membrane. They form a protective coating and harden the surface.
Astringents check minor haemorrhages, arrest capillary oozing as they promote clotting and precipitate proteins on the bleeding
surface.
Astringents are mainly used as obtundents, styptics and mummifying agents.
Types of astringents
Vegetable astringents: Tanic acid and tannins
Metallic or mineral astringents: Alum, salts of zinc,
copper, iron, aluminium and silver
Miscellaneous: Alcohol
Uses
Astringents are used as follows:
Mouthwashes
Paints
Lotions and dentifrices in aphthous ulcers, stomatitis and gingivitis
Local haemostatics
Q. 2. Counter irritants
Certain irritants produce remote effect which tends to relieve pain and inflammation in deeper organs are called counter
irritants.
The mechanism of counterirritation is that when the counterirritant is applied to the area of skin supplied by nerves from the
same segment as the deeper organs from which pain impulses are coming, the cutaneous impulses obscure the deeper
sensations.
They are generally massaged to relieve headache, muscular pain, joint pain, pleural or peritoneal pain, colics, etc.
Drugs commonly used are volatile oils like turpentine oil, clove oil, eucalyptus oil, mustard seeds, capsicum, methyl salicylate
and alcohol.
For example:
Vicks VapoRub: Contains menthol 2.8%, camphor
5.25%, thymol 0.1%, turpentine oil 5.5% ointment
Amruthanjan: Contains eucalyptus oil 17%, camphor 10%, thymol 1%, menthol 4.5%, methyl salicylate 7% ointment
Iodex: Contains methyl salicylate 5%, iodine 4%
nonstaining ointment
SHORT NOTES
Tannicacid and tannins
Astringents are agents which precipitate superficial proteins when applied to skin or mucous membrane. They form a
protective coating and harden the surface.
Tannic acid is a vegetable astringent obtained from many plants but is generally obtained from the nutgalls of oak.
Tannins are found in tea, catechu, nutmeg, areca nut (betel nut), etc. They denature the proteins forming protein tannate.
The uses are as follows:
Bleeding gums—as glycerine of tannic acid
Bleeding piles—as tannic acid suppository
Alkaloidal poisoning—precipitates ingested alkaloids as tannates
Q. 2. Clove oil
Clove oil is a type of obtundent. It is an agent that diminishes sensitivity. It is used to make the excavation painless.
Its mechanism of action is that it paralyses the sensory nerves where it causes initial irritation followed by numbness.
The disadvantage of clove oil is that it may stain the dentine yellow.
Q. 3. Astringents
Astringents are agents which precipitate superficial proteins when applied to skin or mucous membrane.
They form a protective coating and harden the surface.
Astringents check minor haemorrhages—arrest capillary oozing as they promote clotting and precipitate proteins on the
bleeding surface.

Antiseptics, Disinfectants and Ectoparasiticides

LONG ESSAY
Astringents are used as obtundents, styptics and mummifying agents. For example: Tannic acid, galls of oak, alcohol, alum,
salts of zinc, copper, iron, aluminium and silver

Define and classify antiseptics. Mention about mechanism of action and properties
of antiseptics, different preparations and uses of phenol.

Antiseptic is an agent that destroys microorganisms on contact and can be used on living tissues.
The term germicide covers both antiseptics and disinfectants. Germicides are widely used in domestic products like soaps,
toothpastes and aftershave lotions.
Classification
Acids: Boric acid, benzoic acid Alcohols: Ethanol, isopropyl alcohol Aldehydes: Formaldehyde, glutaraldehyde
Surfactants: Soaps, benzalkonium, cetrimide, cetylpyridinium chloride, dequalinium chloride
Phenol derivatives: Phenol, cresol, resorcinol, chlorhexidine, chloroxylenol, hexachlorophene
Halogens: Iodine, iodophores, chlorine, chloramines vii. Oxidizing agents: Hydrogen peroxide, potassium permanganate,
benzoyl peroxide
Dyes: Gentian violet, methylene blue, brilliant green, acriflavine, proflavin
Metallic salts: Mercurial compounds, silver nitrate, zinc compounds
Mechanism of Action
Mechanism of action of germicides may be grouped into the following:
Oxidation of bacterial protoplasm
Denaturation of bacterial proteins
Detergent-like action
Competition with essential substrates for the important
enzymes in the bacterial cell
Properties
An ideal germicide should have following properties: a. A wide antibacterial spectrum
Should be chemically stable.
Should have rapid action.
Nonirritating to the tissues
Do not interfere with the wound healing activity even in the presence of pus, exudates and the tissue degradation products.
It should not be absorbed into systemic circulation.
Phenol Derivatives Phenol
It is one of the earliest antiseptics introduced by Lord Lister in 1867. It is bactericidal and fungicidal but has poor action
against viruses and spores. It acts by denaturing the bacterial proteins. It also has a mild local anaesthetic action. Phenol
rapidly penetrates even intact skin and mucous membrane.
It is a protoplasmic poison. Phenol is extremely irritant to exposed tissues (corrosive)— when swallowed, it burns buccal,
oesophageal and gastric mucous membrane.
Uses
Phenol is used to disinfect urine, faeces, sputum of patients and is sometimes used as antipruritic because of its local
anaesthetic action.
Cresol
It is a methylphenol, which is as toxic as phenol but is more active.
It is used as a disinfectant for utensils and excreta and for washing hands. For example: Lysol is 50% soapy emulsion of
cresol. It has higher antiseptic activity and is a useful disinfectant for hospital and domestic use.
Chloroxylenol (Dettol)
It is a less toxic-chlorinated phenol, effective against Gram-positive and Gram-negative organisms.
It has phenol coefficient of 70 and is noncorrosive and nonirritating to intact skin.
 Surgical dettol contains 1.4% of chloroxylenol for skin, 6.25% for instruments and 1–3% in antiseptic cream.
Hexachlorophene
This is chlorinated phenol acts by inhibiting bacterial enzymes and causing lysis. It is effective mainly against Gram-
positive organisms and has weak action against Gram-negative organisms.
It is odourless and nonirritating to use on skin. It is used in soaps for surgical scrubbing, for cleaning the skin in obstetrics,
carbuncles and seborrhoeic dermatitis. It may cause allergic reactions. It also reduces body odour by preventing bacterial
decomposition of organic material and thus used as deodorant.
Chlorhexidine (Hibitane)
Effective against Gram-positive and Gram-negative organisms and fungi.
SHORT ESSAY
It is rapid acting and nonirritating, e.g. Savlon (chlorhexidine 1 cetrimide).
 Potassium permanganate
Potassium permanganate is an oxidizing agent and an astringent. The purple crystals are water soluble.
It acts by liberating oxygen which oxidizes bacterial protoplasm.
Organic matter reduces its activity and the solution gets decolourized.
It promotes rusting; concentrated solution is caustic and causes burns and blistering.
1:4000–1:10 000 solution of potassium permanganate is used for gargling, irrigating cavities, urethra and wounds.
For stomach washing in alkaloidal poisoning (except atropine and cocaine as they are not efficiently oxidized).
1% solution in mycotic infections like athlete’s foot.
5% solution as styptic.
Topically to oxidize venom in case of snake and scorpion bite
To purify well water
To disinfect vegetables and fruits
5. Uses
SHORT NOTES

Acriflavine
Acriflavine is an orange-yellow acridine dye active against Gram-positive bacteria and gonococci.
It is nonirritant, efficacy is unaffected by organic matter but it is enhanced in alkaline medium.
1:1000 solution is used in infected wounds and burns, 2% pessary in vaginitis and cervicitis.
Solutions lose efficacy on exposure to light and hence are stored in amber bottles. For example: Acrinol 0.1% acriflavine
cream.
Q. 2. Chlorhexidine
Chlorhexidine (Hibitane) is a powerful nonirritating antiseptic that disrupts bacterial cell membrane.
It is relatively more active against Gram-positive bacteria though Gram-negative organisms and fungi.
It is rapid acting and nonirritating, e.g. Savlon (chlorhexidine 1 cetrimide).
Q. 3. Uses of antiseptics in dentistry
Thymol is used as an antiseptic and a deodorant in mouthwashes and gargles.
Eugenol has the odour of clove and is also a local anaesthetic commonly used for dental filling.
Q. 4. Bleaching agents
Bleaching agents are used to remove pigmentation of the teeth. Oxidizing agents like sodium peroxide and perhydrol, reducing
agents like sodium thiosulphate and other agents like chlorides, hydrogen peroxide and ultraviolet rays have been used as
bleaching agents. Hypochlorites remove silver and iron stains; sodium thiosulphate removes iodine stains while chlorinated
lime is used to remove stains by aniline dyes.
Q. 5. Commonly used antiseptics in dentistry
Antiseptics commonly used in dentistry are thymol, menthol, eugenol, benzoic acid, boric acid, calcium and manganese
peroxide.
Thymol is a powerful antiseptic and a deodorant in mouthwashes and gargles.

Chelating Agents
SHORT ESSAY
Eugenol has the odour of cloves and is also a local anaesthetic commonly used for dental filling.

Name four chelating agents.

The clinically useful chelating agents are

calcium disodium edetate (CaNa2EDTA),
dimercaprol, 3. D-penicillamine and 4. desferrioxamine.
Calcium Disodium Edetate (CaNa2EDTA)
The calcium sodium and the disodium salts of EDTA form stable and highly water-soluble complexes with many divalent and
trivalent metallic ions and owe their therapeutic application to this chelating property.
It chelates many divalent and trivalent metals like zinc, manganese, iron, lead deposits in the bone and are mobilized, chelated
and excreted through kidneys.
Adverse effects include nephrotoxicity, fatigue, fever, myalgia and dermatitis.
CaNa2EDTA is mainly used in lead poisoning. It can be also used in zinc, manganese and iron poisoning. Sodium edetate is
used in severe hypercalcaemia.
Dimercaprol
Dimercaprol or British anti-Lewisite (BAL) is a colourless oily liquid synthesized by Stocken and Thompson during World
War II as an antidote to Lewisite—an arsenical war gas. Hence it is also called British lewisite gas or BAL.
Dimercaprol chelates arsenic, mercury, lead and other heavy metals. It is given IM; appropriate plasma concentrations should
be maintained.
Adverse effects are dose related and include hypertension, tachycardia, vomiting, sweating, burning sensation in the lips and
the mouth and headache.
D-penicillamine
This is a monothiol compound prepared by alkaline hydrolysis of benzene penicillin.
It forms water-soluble complexes with copper, mercury and lead ions thus facilitating their excretion in urine.
Therapeutic uses: Hepatolenticular degeneration (Wilson’s disease), rheumatoid arthritis and is of some value in treating acute
lead and mercury poisoning.
Desferrioxamine
It is obtained from Streptomyces pilosus; is a potent and specific chelator of iron.
Therapeutic uses: Acute iron intoxication, haemochromatosis
SHORT NOTES
The drug is contraindicated in patients with severe renal disease or anuria and in pregnant women.

Dimercaprol
Dimercaprol is a colourless oily liquid developed by the British during World War II as an antidote to lewisite— an arsenical
war gas. Hence it is also called British lewisite gas (BAL).
Dimercaprol chelates arsenic, mercury, lead and other heavy metals. It is given IM; appropriate plasma concentrations should
be maintained.
Adverse effects are dose related and include hypertension, tachycardia, vomiting, sweating, burning sensation in the lips and
the mouth and headache.
Q. 2. Chelating agents
Chelating agents or heavy metal antagonists bind the heavy metal ions and make them nontoxic, the chemical complex formed
is called a chelate. The process of complex formation is known as chelation.
The complex so-formed is water-soluble and is eliminated by the kidneys.
The clinically useful chelating agents are CaNa2EDTA, dimercaprol, d-penicillamine and desferrioxamine.
Chelating agents are more effective in preventing the utilization of ligands than in reactivating them; hence, the earlier they are
given, the better.
Q. 3. EDTA
The calcium sodium and the disodium salts of EDTA form stable and highly water-soluble complexes with many divalent and
trivalent metallic ions and owe their therapeutic application to this chelating property.
It chelates many divalent and trivalent metals like zinc, manganese, iron, lead deposits in the bone and are mobilized, chelated
and excreted through kidneys.
Adverse effects include nephrotoxicity, fatigue, fever, myalgia and dermatitis.
CaNa2 EDTA is mainly used in lead poisoning. It can be also used in zinc, manganese and iron poisoning. Sodium edetate is
used in severe hypercalcaemia.
Q. 4. Dimercaprol used in arsenic poisoning
Dimercaprol or British anti-Lewisite (BAL) is a colourless oily liquid synthesized by Stocken and Thompson during World
War II.
Dimercaprol chelates arsenic, mercury, lead and other heavy metals.
Adverse effects are dose related and include hypertension, tachycardia, vomiting, sweating, burning sensation in the lips and
the mouth and headache.

Vitamins
SHORT ESSAYS
Pyridoxine
Vitamin B6 is also known as pyridoxine.
Sources: Liver, meat, eggs, soya bean, cereals, legumes and milk
Physiological functions of pyridoxine: Pyridoxal phosphate is a coenzyme involved in the synthesis of several amino acids,
biogenic amines and other compounds like GABA.
Symptoms of deficiency
Seborrhoeic dermatitis
Glossitis
Peripheral neuritis
Anaemia
Mental confusion
Lowered seizure threshold due to decreased GABA
levels in the brain
Uses
Prophylaxis and treatment of pyridoxine deficiency.
INH-induced peripheral neuritis: Pyridoxine is used both for prophylaxis and treatment.
Convulsions in infants and children due to pyridoxine deficiency
‘Morning sickness’ in pregnancy: Pyridoxine may reduce vomiting by unknown mechanism.
To treat mental symptoms in women on oral contra-
ceptives (50 mg daily)
Q. 2. Vitamin C
Or, Ascorbic acid
Vitamin C is also known as ascorbic acid.
Sources: Citrus fruits, tomatoes, gooseberry, vegetables, and potatoes are rich in vitamin C.
Physiological role and actions of vitamin C are as follows:
Ascorbic acid is involved in several metabolic reactions including oxidation and reduction reactions and in cellular respiration.
It is essential for the integrity of connective tissue, for the development of cartilage, bone, and teeth and for wound healing.
Essential for biosynthesis of adrenal steroids, catecholamines, oxytocin, and ADH, and metabolism of cyclic nucleotides and
prostaglandins.
Symptoms of deficiency: Vitamin C deficiency results in
scurvy characterized by connective tissue defects resulting in haemorrhages in subcutaneous tissue petechiae, ecchymoses,
impaired wound healing, tender bleeding gums,
deformed teeth,
brittle bones,
anaemia and
growth retardation.
Therapeutic uses:
Prevention of ascorbic acid or vitamin C deficiency
in individuals at risk: 50–100 mg/day.
In treatment of scurvy: 500–1000 mg/day
Large doses (0.5–1.5 g) of vitamin C has been tried as prophylactic against common cold with controversial benefits.
To acidify urine: 1 g TDS in urinary tract infections
Anaemia of scurvy is corrected by ascorbic acid, but
no adjuvant value in other anaemias.
Q. 3. Thiamine deficiency
Vitamin B1 is essential for as a coenzyme in carbohydrate metabolism: Decarboxylation of keto acids, hexose monophosphate
shunt
Daily requirement: 1–2 mg
Deficiency symptoms of vitamin B1 are as follows:
a. The syndrome of thiamine deficiency produces beriberi seen in dry and wet forms.
Dry beriberi: Neurological symptoms are prominent. Polyneuritis with numbness, tingling, hyperaesthesia, muscular
weakness and atrophy resulting in wrist drop, foot drop, paralysis of whole limb, mental changes, sluggishness, poor memory,
loss of appetite, and constipation. Wet beriberi: Cardiovascular system is primarily affected. The characteristic features are
dependent oedema and high output cardiac failure. Protein deficiency is commonly associated and adds to the generally
anasarca due to chronic heart failure (CHF). Wernicke encephalopathy and Korsakoff psychosis are also thought to be due to
thiamine deficiency.
Q. 4. Name two fat-soluble vitamins and mention two uses of them.

Fat-soluble vitamins are those that are soluble in lipids or fats and get excreted out of the body through them. There are four
fat-soluble vitamins. They are vitamin A, vitamin D, vitamin E and vitamin K.
Vitamin A
Uses
In the prophylaxis and treatment of vitamin A deficiency (prophylaxis of vitamin A deficiency during infancy, pregnancy,
lactation, hepatobiliary diseases, steatorrhoea): 3000–5000 IU/day in presence of increased requirement.
Treatment of established vitamin A deficiency: 50,000– 100,000 IU IM or orally for 1–3 days followed by intermittent oral
supplemental doses.
In skin diseases like acne, psoriasis, ichthyosis retinoic acid or synthetic analogues of vitamin A like tretinoin or isotretinoin
are used.
Vitamin K
Uses
1. Prophylaxis and treatment of bleeding due to deficiency of clotting factors in the following:
Dietary deficiency of vitamin K: 5–10 mg/day orally
Prolonged antimicrobial therapy: 5–10 mg/day orally
Obstructive jaundice or malabsorption syndrome:
10 mg/day IM or orally
Liver diseases: 10 mg/day IM or orally
Newborns: 1 mg IM soon after birth or 5–10 mg IM to mother 4–12 h before delivery
To reverse the effects of overdose of oral anticoagu-
SHORT NOTES
lants: 10 mg IM followed by 5 mg 4 hourly

Ascorbic acid Or, Vitamin C

Vitamin C is also known as ascorbic acid.
Sources: Citrus fruits, tomatoes, gooseberry, vegetables, and potatoes are rich in vitamin C.
Physiological role and actions of vitamin C are as follows:
Ascorbic acid is involved in several metabolic reactions.
It is essential for the integrity of connective tissue, for the development of cartilage, bone and teeth and for wound healing.
Symptoms of deficiency: Vitamin C deficiency results in scurvy, impaired wound healing, tender bleeding gums, deformed
teeth, brittle bones, anaemia and growth retardation.
Therapeutic uses
Prevention of ascorbic acid or vitamin C deficiency
in individuals at risk: 50–100 mg daily
In treatment of scurvy: 500–1000 mg/day
To acidify urine: 1 gm TDS in urinary tract infections
Q. 2. Vitamin B6
Vitamin B6 is also known as pyridoxine.
Sources: Cereals, legumes, liver, milk, meat and eggs.
Physiological functions: Pyridoxal phosphate is a coenzyme involved in the synthesis of several amino acids, biogenic amines
and other compounds like GABA
Symptoms of deficiency: Glossitis, peripheral neuritis, anaemia, dermatitis, and low seizure threshold
6. Uses: Prophylaxis in the treatment of pyridoxine deficiency, INH-induced peripheral neuritis and convulsions in
infants due to pyridoxine deficiency.
Q. 3. Vitamin B12 Or, Cyanocobalamin
Synthesized by microorganisms.
Sources: Liver, fish, egg yolk, meat, cheese and pulses.
Physiological functions: Acts as coenzyme for several vital metabolic reactions, essential for DNA synthesis.
Symptoms of deficiency: Addisonian anaemia due to deficiency of intrinsic factor, due to destruction of parietal cells, and
resulting in failure of B12 absorption.
Other causes: Gastrectomy, chronic gastritis, malabsorption, and fish tapeworm infestation (consumes vitamin B12).
Uses
Multivitamins for oral use
B12 deficiency: Prophylaxis and treatment of mega-
loblastic anaemia (3–10 mg daily)
B12 neuropathies

Vaccines and Sera

SHORT ESSAY
What procedure will be adapted so that tetanus does not result from your
treatment? How will you treat a case of tetanus?
Tetanus is a wound infection. It is caused by the bacterium Clostridium tetani, an anaerobic spore forming bacterium that enters
the wound, multiplies and produces powerful toxins which produce the disease. It produces two toxins tetanospasmin
(neurotoxin) and tetanolysin (haemolysin).
Tetanus may occur due to wounds caused due to piercing of earlobes, injury with rusted nails, as a complication to road traffic
accident, as infection acquired in operation theatre, in neonates when the umbilical cord is treated with cow dung.
Prophylaxis during treatment:
Pregnant women can be administered two tetanus toxoid injections, 1 mL IM in the third trimester of pregnancy.
Immunized individuals can be given booster dose to achieve active immunity.
Tetanus antitoxin can be used for penetrating wounds of head and face, and wounds of devitalized and contused tissues.
Treatment of Established Cases
1. General Management
1. Admission and isolation in a quiet room, to avoid minor stimuli which precipitate spasms. Wound care
includes drainage of pus, excision of necrosed tissue, removal of foreign body and proper dressing.
Inj. tetanus toxoid 0.5 mL IM
Antitetanus serum (ATS) 50,000 units intravenous, given after a test dose in the subcutaneous tissue.
Instead of ATS, human antitetanus globulin 3000– 4000 units can be administered to prevent anaphylaxis.
Inj. crystalline penicillin 10 lakh units every 6 hourly for a period of 7–10 days.
2. Specific Management
Mild cases: There is only tonic rigidity without spasms or dysphagia. Patient can be managed by heavy sedation using a
combination of chlorpromazine, phenobarbitone and diazepam.
Seriously ill cases: They have dysphagia and reflex spasms. A nasogastric tube is introduced for feeding purpose and to
administer drugs. Tracheostomy if breathing is difficult.
Dangerously ill cases: Patient have major cyanotic convulsion. In addition to continuing sedatives, patients are paralysed with
muscle relaxants (neuromuscular blocking agents) and positive pressure ventilation is given till they recover. Adequate
nutrition, care of urinary bladder, care of bowel, frequent change of position to avoid bedsores have to be taken care of.
SHORT NOTE

Posterior pituitary extract given by IV drip before delivery only.

Oxytocin is an octapeptide secreted by the posterior pituitary gland.

It increases the force and the frequency of uterine contractions. With low doses full relaxation occurs between contractions.
It is used before delivery to induce labour in case of postmaturity or to augment it in case of uterine inertia.
It is also used to control postpartum haemorrhage as an alternative to ergometrine.
Improper administration or overdosage causes too strong contractions forcing the presenting part through incompletely dilated
birth canal, causing maternal and fetal soft tissue injury, rupture of uterus, fetus asphyxia and death.

Dental Pharmacology
LONG ESSAYS
Discuss fluoride pharmacology in relation to its utility as an anticaries
agent. What are the different formulations in which fluoride is used for
this purpose? Give a short account of fluoride toxicology.
Fluoride is a halogen and is a highly reactive and most electronegative of all elements.
Mechanism of Action
The composition of apatite is affected by the ionic composition of the fluid with which it is in contact and there is exchange
of ions between the apatite crystals and the oral fluid by the surface reaction.
 There is heteroionic substitution of OH2 by F2 ions as F2 enters the hydration shell surrounding the apatite crystals and gets
incorporated into the crystal surface.
Initially a friable layer of calcium fluoride is formed on the surface leaving underlying enamel intact.
This fluoride rich surface layer then undergoes slow exchange with F2 getting incorporated in the crystal lattice forming
fluoroapatite. Fluoroapatite makes tooth resistant to bacterial enzymes
and acids.
Pharmacological Actions
Fluorides alter the physiochemical properties of the teeth as follows:
Fluorides inhibit the bacterial enzymes which produce acids and therefore, prevent decalcification of the teeth.
Fluorides convert the hydroxyapatite of enamel and dentine to fluoroapatite which is more resistant to destruction by acids
thus making the outer layers of enamel harder and more resistant to demineralization.
Fluorides also stimulate remineralization of the enamel.
Therefore fluorides are used in caries.
Fluoride Formulations
Dentifrices: Several commercial dentifrices contain fol-
lowing fluoride salts: a. Sodium fluoride
Sodium monofluorophosphate
Stannous fluoride
These dentifrices should be used twice a day regularly.
b. Mouth rinses: 0.2% solution of sodium fluoride containing 900 ppm of fluoride is to be retained in mouth for a minute
and this procedure should be done twice a week.
Fluoride Toxicity
Usually results from consumption of water with fluoride content above
2 ppm and accidental or suicidal consumption of fluoride contain-
ing rat poisons.
Manifestations Acute Toxicity
Nausea, vomiting, diarrhoea Hypotension Hypocalcaemia, hypomagnesaemia Cardiac arrhythmias Acidosis
Chronic Toxicity
Mottling of enamel Brownish-black discolouration of teeth Joint pain and stiffness Osteosclerosis of the spine and
pelvis Thickening of cortex of long bones and bony exostoses (crippling fluorosis)
Treatment of fluoride toxicity
Induce vomiting or gastric lavage with calcium contain-
ing fluid
Treat cardiac arrhythmias Correct the acid base imbalance Alkaline diuresis to enhance fluoride excretion
Q. 2. Classify disinfectants and antiseptics used in dental practice with suitable
examples. Describetheir general uses in dentistry. What are the specific
uses of clove oil and eugenol?

Disinfectants are chemical agents which are used on inanimate objects to inhibit or kill microbes on contact.

Section | IV
Antiseptics are chemical disinfectants which can be safely applied to skin or mucous membrane and are used to prevent
infection by inhibiting the growth of bacteria.
Classification of disinfectants and antiseptics used in dental practice:
Phenol derivatives
Phenol Cresol Resorcinol Hexylresorcinol Chloroxylenol Hexachlorophene
Oxidizing agents
Potassium permanganate Hydrogen peroxide Benzoyl peroxide
Halogens Iodine Iodophores Chlorine Chlorophores Biguanides Chlorhexidine
Quaternary ammonium compounds
Cetrimide Cetylpyridinium chloride Benzalkonium chloride (Zephiran) Dequalinium chloride
Soaps of sodium and potassium
Alcohols
Ethanol Isopropanol
Aldehydes
Formaldehyde Glutaraldehyde
Acids
Boric acid Acetic acid
Metallic salts
Ammoniated mercury
Phenyl mercuric nitrate
Merbromin
Sliver nitrate Silver sulphadiazine Mild silver protein Zinc sulphate Calamine Zinc oxide
Dyes
Gentian violet Brilliant green Acriflavine Proflavine
Furan derivatives Nitrofurazone
Uses in Dentistry
As a component of mouthwashes (chloroxylenol, chlorhex-
idine, cetylpyridinium chloride)
 For gargling (potassium permanganate) For root canal therapy (sodium hypochlorite solution) As gum paints
(dequalinium chloride)
Specific uses of clove oil and eugenol are as follows:
Clove oil and eugenol are useful for its disinfecting properties, relieving of pain, especially toothache, arthritis and
rheumatism. Clove oil is effective when used for complaints of the digestion system. It is also of use for skin problems
especially for skin sores and leg ulcers. Clove oil can be useful for bronchitis and dizziness and to help lift depression, while
strengthening memory and fighting weakness and lethargy. Clove oil can be used in a blended massage oil to assist with
diarrhoea, bronchitis, chills, colds, muscular numbness, spasms, rheumatism and arthritis. For toothache the outer jaw can be
massaged with this oil. When used in a cream or lotion, it helps to sort out leg ulcers and skin sores.
SHORT ESSAYS
Describe briefly obtundents. 2. Commonly used obtundents are phenol, thymol, menthol, clove oil,
camphor, silver nitrate, zinc chloride, parafor
maldehyde, absolute alcohol, benzyl alcohol, etc.
1. Obtundents are the agents which diminish dentine sen- 3. The mechanism of action, advantages and
disadvansitivity. tages of few of them are listed in Table 61.1.
Clove oil can be included at a low rate as part of a mouthwash for toothache.
TABLE 61.1 Obtundents
Obtundents Mechanism of Action Advantage Disadvantage
Phenol Protoplasmic poison which paralyses nerves followed by numbness Rapid in action. Infected Does not stain
dentine is healthy dentine.darkened Penetrability can Poor be increased by penetrability
combining with KOH and glycerin
Menthol, clove oil,
camphor Paralyses Rapid action
sensory nerves followed by numbness Yellow staining of dentine by clove oil
Silver nitrate Precipitates Rapid action superficial protein by astringent action Black staining of dentine Poor
penetrability
Paraformaldehyde Precipitation Painless, of protein by nonstaining formaldehyde released Slow action
Inflammation of pulp by formaldehyde
Absolute alcohol, benzyl alcohol Destruction of nervous tissue Paralyses sensory nerves followed by numbness
Therapeutic Uses
Previously they were used to make the excavation painless but now uses of local anaesthetics have made them outdated.
Q. 2. Dentifrices
Dentifrices are the agents which are used for cleaning the teeth with the help of a toothbrush. They are available as powders,
liquids or pastes.
They are used to clean the teeth but in addition they also have other benefits due to their contents.
An ideal dentifrice is one pleasant in taste, odour and consistency and does not damage the gums or the teeth.
Ingredients of a dentifrice are as follows:
Abrasives
Dental abrasives are fine powdered substances which assist the scouring action of toothbrush.
They are inorganic salts of low solubility and are available in the form of powder or paste but the powdered form is more
powerful. For example: Prepared chalk, calcium phosphate, calcium and magnesium carbonates, magnesium oxide, ferric
oxide, charcoal, silicates powder pumice and kaolin.
Detergents
Detergents are the cleaning agents which act by lowering the surface tension, dissolving fatty substances and mucous plaques,
foaming on scrubbing the teeth and acting as lubricants, loosening the debris adhering to the teeth and few act by liberating
oxygen and acting as antiseptic. For example: Sodium lauryl sulphate—a pale yellow powder effective in both acid and
alkaline medium and in hard water.
Antiseptics
They are used to keep the commensal bacterial flora of the oral cavity in check. For example: Thymol, menthol, eugenol,
benzoic acid, boric acid, calcium and magnesium peroxide.
Sweetening Agents
These are used to enhance palatability of the toothpaste. The preferred sweetening agent is saccharine.
Colouring Agents
These do not serve any pharmacological purpose but are used only for commercial reasons making the toothpaste attractive.
For example: Commonly used colouring agents are liquor rubri (red) and methylene blue (blue).
Other Agents
(a) Binding agents like mucilage of tragacanth, gum acacia, and bentonite, (b) humectants like glycerine and sorbitol and (c)
antacids like sodium bicarbonate.
Q. 3. Disclosing agents
Disclosing agents are certain dyes which are used to make the relatively invisible supragingival plaques visible.
Methods of Application
Painting the teeth with cotton swab, rinsing the mouth and as a tablet or wafer to be chewed dissolving it in saliva followed by
rinsing with water.
For example:
Erythrosin is most widely used disclosing agent. Erythrosin tablets are dissolved into a solution or chewed to be dissolved in
mouth. Stains the plaque area red.
Fluorescein dye: Stains the plaque yellow and it does not stain gingival tissues. Its disadvantage is that special light is required
to see stained plaque and is expensive.
Iodine-containing solutions: Matured plaques are stained blue while new plaques are stained red. Its disadvantage is that it
causes high incidence of allergic reactions and it has unacceptable taste.
Section | IV
Q. 4. Bleaching agents 3. Others: Chlorides, hydrogen peroxide, ultraviolet rays
 Bleaching agents are the chemical substances used to
remove the pigmentation of the teeth. Therapeutic Uses
Classification They are used to remove stains from the teeth like hypo-chlorites remove silver and iron stains, sodium
thiosulphate
1. Oxidizing agents: Sodium peroxide, perhydrol removes iodine stains while chlorinated lime is used to re 2.
Reducing agents: Sodium thiosulphate move stains by aniline dyes.
SHORT NOTES
Fluorides in dentistry
Fluorides are multipurpose substances used in dentistry. Fluoride is a halogen and is highly reactive and most
electronegative of all elements.
Therapeutic Uses
Caries
Fluoride is used topically for prophylaxis of caries.
It is used in the form of dentifrices or mouth rinses.
Dental plaque: Stannous fluoride mouth rinses or gels are effective in plaque control.
Desensitizing agent: High doses of fluorides act as dental desensitizing agent by occluding dentinal tubules and hardening the
dentine surface.
Q. 2. Sialagogues
Sialagogues are the drugs which increase the flow of saliva. For example: Ginger and calomel, sugar-free gum, tobacco,
organic acids such as ascorbic, citric or malic
Therapeutic uses: Xerostomia
Q. 3. Mummifying agents
Mummifying agents (Table 61.2) are the substances used to harden and dry the pulp tissues. This hardening makes the tissue
resistant to infection.
Commonly used astringents are a combination of astrin-
TABLE 61.2 Mummifying Agents
Mummifying Agents Mechanism of Action Used in
Combination with
Liquid formaldehyde Precipitation of protein Zinc oxide and glycerin
Iodoform Liberating iodine Eugenol, phenol
Tannic acid Precipitation of protein Tannic acid and glycerol
gents and antiseptics in form of paste.
Q. 4. Mouthwashes
Mouthwashes are solutions containing active ingredients meant for cleansing and deodorizing the oral cavity like astringents,
antiseptics and obtundents, flavouring and sweetening agents.
Various types of mouth washes are as follows:
Antiseptic and astringent mouthwashes for soreness under dentures
Obtundent mouthwashes for sensitive oral lesions
Detergent mouthwashes for cleaning and deodorizing action. For example: Chlorhexidine, povidone iodine
Prolonged use of concentrated solution may cause
adverse effects like staining the teeth.
Therapeutic uses
15–30 mL of diluted solution are used for gargling
and rinsing the mouth in soreness under dentures
Sensitive oral lesions
Postoperative and other bedridden patients for deodorizing the oral cavity and to maintain oral hygiene
Halitosis and stomatitis
Q. 5. Use of fluoridesin caries
Fluorides inhibit bacterial enzymes which produce acids and therefore prevent decalcification of the teeth.
Fluorides convert the hydroxyapatite of enamel and dentine to fluorapatite which is more resistant to destruction by the acids
thus making the outer layers of the enamel harder and more resistant to demineralization.
Fluorides also stimulate remineralization of the enamel; therefore fluorides are used in caries.
Q. 6. Chlorhexidine
Chlorhexidine is a biguanide compound which is a powerful, rapid acting antiseptic acting against a wide range
of Gram-positive and Gram-negative organisms and against fungi at pH 5–8.
Bacterial spores are prevented from germinating but are not killed.
It acts by disrupting the bacterial cell membrane and is effective even in the presence of blood or pus.
It is nonirritating and has low potential for producing contact dermatitis and photosensitivity.
5. Available as 5% aqueous concentrate and 1% water miscible cream.
6. Uses: It is used extensively for surgical scrub, neonatal bath, mouthwash, obstetrics and as general skin antiseptic.
 
 
 
 
 
 

Self-Assessment Questions 
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