PHARMACOLOGY NOTES FOR OLL.

Definition: Pharmacology is the science that deals with drugs.

It is the study of substances that interact with living systems through chemical processes such as
binding to regulatory molecules and activating or inhibiting normal body processes.

These substances are given to achieve a beneficial therapeutic effect on some body processes in the
patient or for their effects on processes in parasites or microbes affecting man.

The word pharmacology is derived from Greek words pharmacon – drug and logus (a discourse or
treatise).

Medical pharmacology is the science of substances used top prevent, Diagnose and treat disease

The word drug is derived from the French word drogue – a dry herb.

A drug is any substance that brings about change in biologic function of the body through its
chemical action.

It is the single active chemical entity in a medicine that is used for diagnosis, prevention, treatment,
relief or cure of a disease in man and animals.

WHO defines a drug as any substance or product used or intended to be used to modify or explore
physiological systems or pathological states for the benefit of the recipient.

Therapeutics:Means to cure for, to tend to or to nurse.

It is a branch of medicine concerned with the cure of disease or relief of symptoms.

It includes drug treatment.

Pharmacotherapeutics: This is application of pharmacological information together with

knowledge of the disease for its prevention, mitigation or cure.

Branches of pharmacology:

• Pharmacy

• Pharmacovigilance

• Posology

• Pharmacognosy

• Toxicology

• Pharmacopoeia
Pharmacy: is the art and science of identification, selection, preservation, standardization
compounding and dispensing of medicinal substances.

Pharmacognosy: Pharmacognosy is the science of identification of drugs.

Pharmacopoeia is an official code containing a selected list of the established drugs and medicinal
preparations with descriptions of their physical properties and tests for their identity, purity and
potency.

Pharmacovigilance: Is the science and activities relating to the detection, assessment,

understanding and prevention of adverse effects of drugs

DRUGS: A drug is any substance that brings about chance in biologic function through its chemical
actions.

The drug usually interacts with specific molecules called receptors in the biologic system which plays
a regulatory role.

In order for a drug to interact chemically with its receptor its molecule must have

• the appropriate size,

• electrical charge,

• shape and

• atomic composition.

Because drugs are often administered at locations distant from their intended sites of action, they
must have appropriate properties to facilitate transportation from the site of absorption to the site
of action.

Drugs should be inactivated or excreted from the body at reasonable rate so as to attain an
appropriate duration of action

Physical Properties: A drug may be solid, liquid or gaseous at room temperature.

This determines the route of administration.

Drug size: The molecular weight of drugs varies hence a drug must be sufficiently unique in shape,
charge and size so as to bind to the specific receptors.

Drug Shape: The shape of a drug molecule should be such that it allows binding of the drug to its
receptor site.

The drug shape should be complementary to that of the receptor site (key and lock).
DRUG-BODY INTERACTIONS: The interactions between a drug and the body occur through
pharmacokinetic and pharmacodynamic processes.

Pharmacodynamic: The processes involve the actions of the drug on the body.

Pharmacodynamics (Pharmacon – drug; dynamics – power) is the quantitative study of the

biological and therapeutic effects of drugs on the body systems

Pharmacokinetic: processes involve the actions of the body on the drug.

Pharmacokinetics (Pharmacon – drug; kinesis – movement) is the study the absorption, distribution,
metabolism and excretion of drugs and their relationship to pharmacologic response (what the body
does to the drug).

Priniciples of Drug Action: Generally drugs do not bring about new functions to the body cells or
systems but only alter the pace of ongoing cellular activities.

Priniciples of Drug Action: Generally drugs do not bring about new functions to the body cells or
systems but only alter the pace of ongoing cellular activities.

Generally drugs do not bring about new functions to the body cells or systems but only alter the
pace of ongoing cellular activities.

Stimulation: Selective enhancement of activity of specialized cells e.g. adrenaline stimulates the
heart.

Depression: Selective diminution of activity of specialized cells e.g. barbiturates depress the CNS
and quinidine depresses the heart.

Replacement: This is use of natural metabolites, hormones or synthetic preparations in deficiency

states e.g.

levadopa in Parkinsonism,

insulin in diabetes mellitus

iron in anaemia.

Cytotoxic action: some drugs are administered so as to destroy some cells such as cells harbouring
parasites or caner cells e.g. chloroquine on malaria infected cells, penicillins and mebendazole.

Normally body functions are mediated through systems involving

chemotransmitters or local hormones,

receptors,
carrier molecules

specialized macromolecules such as DNA.

Many drugs act by altering the body’s control systems by binding to specific sites on cells altering its
function and subsequently the physiological or pathological system it contributes to.

This is the reason why drugs have to be structurally specific.

Receptors mediate the actions of both pharmacologic agonists and antagonists.

Drugs such as hormones and neurotransmitters regulate the function of receptor macromolecules as
agonist by activating the receptors to signal as a direct result of binding it.

Other drugs function as antagonists by binding to the receptors without activating generation of a
signal hence they interfere with the ability of an agonist to activate the receptor.

Metabolic processes

Drugs act on the metabolic process within the cell by: -

Enzyme inhibition e.g. platelet cyclo-oxygenase is inhibited by aspirin, xanthine oxidse is inhibited
by allopurinol, cholinesterase is inhibited by neostigmine

Inhibition of transport processes that carry substances across cells e.g. probenecid blocks transport
of anions in the renal tubule cell hence can be used to delay excretion of penicillin and enhance
elimination of urates.

Extracellular:Drugs act outside the cell by: -

Direct chemical interaction e.g. chelating agents, antacids. Drugs that chelate metals can be used to
hasten the removal of those metals from the body e.g. calcium sodium edentate chelates many
divalent and trivalent metals and is useful in treatment of lead poisoning.

MECHANISMS OF DRUG ACTION

The activity of a drug depends upon the concentration of the drug in the body fluids and tissues.

This is influenced by absorption, first pass metabolism, biotransformation (metabolism), excretion,

tissue affinity and condition of the internal environment.

A drug may act outside the cell (extracellular), on the cell surface or inside the cell (intracellular).

A drug may act outside the cell (extracellular), on the cell surface or inside the cell (intracellular).
PHYSICAL PROPERTIES

Physical properties of a drug can influence its action in a number of ways for instance

Colour: A pleasant colour may exert a psychological effect on how the patients perceive the drugs to
act.

For example many of the rural folks in Kenya rate coloured tablets higher that the white ones, pink
coloured antacid is more preferred by many patients compared to white antacid.

Physical mass: Compounds such as bulk laxatives (bran) and psyllium seeds absorb water when
administered orally and swell in size initiating peristalsis in the GIT and exerting a laxative effect.
ANTIBIOTICS

Anti-infective and chemotherapeutic agents:

 Beta-lactam antibiotics
 Tetracycline
 Macrolides
 Amino glycosides
 Sulphonamides and Sulphoamide combinations
 Anti TB drugs
 Antifungal agents
 Antiviral agents
 Antiprotozoal
 Antihelminthics
 Others-Chloramphenicol,Clindamycin
ANTIMICROBIAL THERAPY

INTRODUCTION

Infection is the invasion and multiplication of microorganisms in body tissues.

Infectious diseases comprise a wide spectrum of illnesses caused by a wide range of microorganisms;
e.g. bacteria, viruses, rickettsiae and chlamydiae, fungi and protozoa. Infectious diseases have featured
prominently in human history e.g. Middle Ages – pandemic of bubonic plaque; Early 20 th – yellow fever
interrupted the completion of Panama Canal; 1940s and 50s – polio crippled thousands in USA and
Europe. The classification of Antimicrobials is based on: microorganism affected; mechanism of action
and spectrum of activity. The clinicians need to use Antimicrobial therapy judiciously and optimally to
achieve therapeutic goals, avoid adverse reactions and therapeutic failure. To achieve this, the following
basic principles need to be considered: Identification of infecting organism, Sensitivity/resistance to
microorganisms, Role of host defense mechanisms and dosage/duration of therapy.
ANTIBIOTICS/ANTIBACTERIAL DRUGS

These are antibacterial substances derived from fungi and bacteria e.g. penicillin from fungi. There are
different antibacterials available and the clinician select them based on the principles discussed earlier
in the introduction. There are different groups of antibacterials based on molecular structure. Members
of each group have the same pharmacokinetics, pharmacodynamics and the same range of adverse
effects. Examples of classes of antibiotics includes: Beta-lactam antibiotics, tetracycline,
aminoglycocides, macrolides, quinolones, Azoles, Antimycobacterial agents, Sulphonamides and other
unclassified antibiotics like chloramphenical and Spectinomycin.

BETA-LACTAM ANTIBIOTICS

They all posses the beta - lactam ring as a basic chemical structure

Subclasses:

1. Penicillin
2. Cephalosporin and Cephamycins
3. Others: - carbapenenerns, monobactams

PENINCILLINS

These are the first antibiotics to be discovered in 1929. Produced by growing one o f the penicillium
moulds in deep tanks. According to the variety of fungus and the composition of the medium, either
benzyl penicillin (penicillin G) or phenoxymethyl penicillin (penicillin V) results. Different semi-synthetic
penicillins haves been made by adding various chains to the basic penicillin nucleus (6-aminopenicillanic
acid).

Penicillins have different anti bacterial spectrums:

-Narrow spectrums (natural peninillins) e.g. Benzyl penicillin, phenoxymethylpenicllin, Phenethicilin.

-Antistaphylloccoccal penicillins (Beta-lactamase resistant penicillins or penicillinase-resistant

penicillins): e.g. Cloxacillin, flucloxacillin, Methicillin.
-Broad spectrum: e.g. Ampicilin, amoxicillin, baccampicilin, pivampicillin, talampicilin, mezlocillin.

-Antipseudomonal (Extended spectrum penicillin)-e.g. Carbecillin, Carfecillin, Ticarcillin, Temocillin,

Aziocillin, Piperacillin.

Pharmacodynamics

Inhibit Tran peptidase enzyme that cross links peptide chains thereby inhibiting synthesis of the
peptidoglycan layer of cell wall which protects the bacterium from its environment.

The cell weak wall becomes incapable of withstanding the osmotic gradient between its interior and its
environment so that it swells and explodes. Thus penicillin are bactericidal. Effective against multiplying
bacteria (dividing cells) as resting bacteria is not making new cell wall. Some bacteria can produce Beta-
lactamase enzyme which opens the beta-lactam ring of penicillin and inactive them.

Pharmacokinetics

Benzyl penicillin. – destroyed by Gastric acid hence is parentrally administered.

Phenoxymethylpenicillin –Can be orally given as it resists gastric acid.

Half life of penicillins is less than 2hrs.Have poor lipid solubility hence doesn’t cross BBB insignificant
amounts. Distributed into body waters and enter into cerebral spinal fluid if meninges inflamed.
Metabolism takes place in the liver and elimination in the kidney – glomerular filtration and active
tubular secretion .Elimination can be delayed by concurrently giving probenecid which competes
successfully for the transport mechanism e.g. when high plasma concentrations are required.

Prototypes

Narrow spectrum Penicillins

Benzyl penicillin (penicillin G)

Penicillin G is gastric Acid – unstable .Used where high plasma concentrations are required. Maximum
blood concentrations reached after 15 minutes. Half life is 0.5 hr hence reasonably spaced doses have to
be large to maintain a therapeutic concentration.
High doses can be maintained by use of probenecid which reduces renal secretion of penicillin G.

Indications:

Actinomycosis, gonococcus infections, throat infection, Otitis media, streptococcal endocarditis,

meningococcal meningitis, Pneumonia meningitis

Dosage

By IM or slow iv injection or by infusion

Adult: 1.2g daily in 4 divided doses increased to 2.4 daily if necessary. i.e. 300-600 mg Q.I.D. Child I
month – 12 yrs- 00 mg/kg daily in 4 divided doses

Penicillinase (Beta lactamase resistant penicillins, anti staphylococcal penicillins)

Most staphylococci are resistant to pen. G because of ß - lactamase which inactivates penicillins.
Examples include: Cloxaxillin, flucloxacillin, methicillin, temocillin.

Are gastric acid stable but food interferes with absorption.

Prototype

Cloxacillin

Half life is 30 minutes. Indicated for infections due to penicillinase – producing staphylococci especially
skin infections soft tissue infections eg Cellulitis, otitis externa, impetigo etc.

Dosage

Adults- by mouth 500g Q.i.d i.e. every 6 hrs at least 30 minutes b4 food because food decreases
absorption. By 1M 250mg every 4-6 hrs, IV injection or infusion 500 every 4-6hrs. Dose may be increased
in severe infections. Child less than 2 yrs, any route – quarter adult dose. Children 2-10 yrs - ½ adult
doses.
BROAD SPECTRUM PENICILLINS

Their activity extends beyond gram positive and gram negative cocci (susceptible to pen G) to include
many gram –ve bacilli. But do not resist ß – lactamases- producing organisms. Less potent than pen G
against gram +ve cocci.

Prototype

Ampicillin

Gastric acid stable. Half life is one hr. moderately (50%) absorbed orally and food interferes with
absorption. Drug is concentrated in bile and it undergoes enterohepatic recycling. Approximately 1/3
the dose appears in urine unchanged. Almost all staphylococcal aureus, 50% E. coli 15% of haemophillus
influenza are now resistant.

Indications: Urinary tract infections, Otitis media, sinusitis, chronic bronchitis, invasive salmonellosis and
gonorrhea.

Unwanted effects

-Diarrhea quite common with ampicillins, Macular rashes resembling measles/rubella rashes-
discontinue treatment, nausea

Dosage: Adult oral 0.25 – 1gm 6 hrly at least 30min before food. Gonorrhea- 2-3.5g as a single dose with
probenecid. UTI: 500mg every 8 hrs. By 1M or IV injection or infusion

500mg 4-6 hrly higher doses in meningitis. Child under 10 yrs: Any route: half adult dose.

Talampicillin, Pivampicillin, Bacampicillin

These are esters of ampicillin. Their absorption little affected by food hence higher plasma
concentrations can be achieved. Less incidence of diarrhea (by ½) than ampicillin. Are pro-drugs
(inactive) forms of ampicillin. They are de-esterified in the gut or liver to release ampicillin to systemic
circulation.
Amoxicillin

Derivative from ampicillin and differs by only one hydroxyl group (OH). Have similar antibacterial
spectrum as ampicilin.When given orally its better absorbed than ampicillin.

Absorption not affected by presence of food in the stomach. Half life is 1 hrs.Diarrhea less frequent with
amoxicillin than ampicillin by 12%.

Indications: see under ampicilin.

Dosage: Adult dose by mouth is 250mg every 8 hrs; can be doubled in severe infections.

Child up to 10 yrs: 125mg 8 hrly; doubled in severe infections. In severe or recurrent purulent
respiratory infections 3g every 24 hrs. By 1M 500mg 8 hrly- adult; Child 50-100 mg/kg daily in divided
doses. By iv or infusion 500mg every 8 hrs- adult, increased to 1gm every 6 hrs.Child-50- 100mg/kg daily
in divided doses. Amoxicillin (250Mg) can be combined with clavulanic acid(125mg).Clavulanic acid itself
has no significant antibacterial activity but binds to beta lactamase and thereby competitively protects
the penicillin, so potentiating it against bacteria which owe their resistant to production of beta
lactamase. The combination forms co-amoxiclav (augmentin). Active against beta lactamase producing
bacteria that are resistant to amoxyllin which include: Staph aureus (most strains), 50 % of E-coli
strains, 15% if H.influenzae strains, Bacteriocides, klebsiella spp,

Dosage for Augmentin:- one tablet 8hrly–adult i.e. 250 mg 8 hrly. Double dose in severe infections.Child
6-12 hrs: 5mls every 8hrs; doubled in severe infections.2-6 yrs (13-21 kg) ;2.5 mls times 2 daily;2 months
-2 yrs;0.5ml/kg times 2 daily.

Unwanted effects of Penicillins.

Main hazard of penicillin is allergic reactions – occur up to 10 % of pts – due to its metabolite (penicilloic
acid) combines with proteins to make hapten which acts as allergen.manifested as;-itching , rashes
(azematous or urticarial), drug fever, augioneurotic oedema. Rarely- anaphylactic shock which can be
fatal.

There is cross- allergy between various forms of penicillin due to their common structure in part to
degradation product (penicilloyl group).Hence, a history of allergy to pen, is vital. Other adverse effects:
Diarrhea, Neutropenia and convulsions if doses are high and for over 10 days use. Penicillins given as
Na+ or K+ salts hence caution for renal or cardiac patientss due to extra some of Na+ K+ ions.
Diarrhoea, especially with poorly absorbed penicillins eg ampicillin,platelet dysfunction.

CEPHALOSPORINS

Have wider spectrum than penicillins.Hence , more expensive than penicilins. All have similar
antibacterial spectrum although individual agents have differing activity against certain organisms.

Pharmacokinetics

Usually given parenterally, though few may be given orally eg cephalexin, cephradine and
cefadroxil.Have wide distribution and excreted unchanged in urine especially by tubular
secretion.Dosage reduced for patients with renal impairement.Active secretion in the kidney can is
blocked by probenecid.Metabolism in the liver. Half life is 1-4 hrs. Resistance is occurring due to
chromosomal beta lactamase (ESP gram –ve bacteria) and mutations of binding sites proteins.

CLASSIFICATION OF CEPHALOSPORINS

1st generations e.g. cephalothin, cephapirin, cephalexin, cefadroxil, Cephradine, cefazolin.Generally

active against gram +ve bacteria. Moderate activity against gram–ve organisms.

2nd generations eg: Cefactor, Cefuroxime, Cephamandole/Cefamandole, Cefotetan, Cefonicid, cefprozil,

cefoxitin-cephamycin, ceforanide, carbacephem.

NB: Better than 3rd generation cephalosporin against gram+ve bacteria esp. staphylococcus. Generally
active against gram –ve but also to some extent gram+ve

E.g. Haemophilus influenza and Neisseria gonorrhea, E. coli, Shigella.

Moderate –gram +ve organisms e.g. clostridium, staphylococcus, streptococcus, pneumoccal.

3rd generation: e.g. Cefotaxime, ceftazidine, cefodizime, ceftriaxone, cefixime, ceftizone, moxalactam,
cefperazone.Generally active against gram +ve and gram –ve bacteria. Especially better than 2 nd
generation in gram –ve bacteria
Pharmacodynamics

Mechanism of action of cephalosporin is similar to penicillin i.e. impair cell wall synthesis hence
bactericidal. Some resist attack by beta lactamase though not all.

Indications:eg Septicemia, pneumonia, meningitis,biliary tract infections, peritonitis, urinary tract

infections, sinusitis.

Unwanted effects

-Most common –hypersensitivity, 10% of patients who are sensitive to penicillin are also sensitive to
cephalosporin i.e. cross-allergy involving about 10% of patients. Hemorrhage due to interference with
blood clotting factors. Use of cephalosporin for more than two weeks causes: thrombocytopenia,
neutropenia, interstitial nephritis, abnormal liver tests.

Interactions

Latamoxef, cefradine and other cephalosporin reacts with alcohol to produce Disulfiram- like effects.

Prototype

Ceftriaxone (Rocephin)

3rd generation

Indications

Has longer half life than other cephalosporins hence need O.D administration.Used for such conditions
as serious infections e.g. septicemia, pneumonia, meningitis, UTI, RTI, skin and soft tissue
infections .Also used for surgical prophylaxis

Contraindicaton/Caution

Penicillin sensitivity, renal impairment calcium ceftriaxone may appear as precipitate in urine or as gall
stones. Contra-indications in infant under 6 weeks

Dosage: Deep 1M or IV injection over 2-4 minutes or by intravenous injection 1g daily as a single dose;2-
4g daily in severe infections;Chil;d over 6 wks
20-50mg /kg daily as a single dose, up to 80mg/kg as a single dose in severe infections

Cefluroxine (zinacef)

Is in 2nd generation)

Indications – see ceftriaxone above; more active against haemophilus influenza and neisseria
gonorrhea.More widely used. Half life 1-5 hours

Caution, contraindication –sere ceftriaxone

Dosage By mouth –usually as pro-drug: Adult 250mg 82 daily in most infections e.g. RTI e.g. bronchitis.
Doubled in severe lower RT infections e.g. pneumonia, haemophilus influenza infection. Very good
against Neisseria gonorrhea-1g as a single dose.

-Child over 3yrs- 125mg 82/day if necessary can be doubled.By 1m, IV or infusion

750 mg every 6 hrly.1.5g every 6 hrs in severe infections. Child usual dose: 60mg /kg daily in divided
doses

Cefradoxil

1st generation

Indications:-infections due to sensitive gram +ve and gram-ve bacteria e.g. UTI, RTI, skin and soft tissue
infections

Contraindications /Caution

Penicillin-sensitivity, renal impairment, Cephalosporin hypersensitivity, Porphyria.

Dosage – cefadroxil,Patient over 40kg 0.5/kg BD daily;Child under 1 yr 25 mg/kg daily in divided doses;1-
6 yrs -250mg BD daily;Over 6 yrs 500mg BD daily.

Learning activity.

Read more on Carbapenems and monobactams

NURSING MANAGEMENT IN CEPHALOSPORIN THERAPY.

Sensitivity to penicillin, cephalosporin-contra

Bleeding disorder (may cause hypoprothrombinemia). Monitor bleeding time and prothrombin time.
Bowel inflammatory diseases history-increased danger of pseudo membranous colitis. Clients with
Diabetes melitus who are using copper sulfate urine glucose tests (clinitest) may have false –positive
result while taking cephalosporins.Enzymatic tests erg clinistix and ketodiastix can be used.

Alcoholic beverages and alcohol-containing medications should be avoided.

TETRACYCLINES

Broad spectrum antibiotics.-Value has decreased due to bacterial resistant. 1 st isolated in 1948-
chlortetracycline.Isolated from strains of streptomyces fungi.

Pharmacokinetics

All undergo entero hepatic circulation. Partially (50%) absorbed but-minocycline & doxycycline – a good
absorption. Absorption increased in the absence of food.Cross placental barrier. Excreted unchanged in
urine (glomerular filtration) –avoid in renal impairment except for doxycycline and minocycline -
excreted via GIT (feces-bile).

(Go- side effectsa0

Pharmacodynamics

All have basically similar antibacterial spectrum. Minocycline slightly broader.

Bind to 30s ribosomal submit of bacteria ribosome –hence inhibit protein synthesis.

Do so by blocking attachment of changed aminoacyl t-RNA to A site .Ribosome have 3 sites for
attachment for tRNA i.e. A, P, and E tRNA brings individual Amino acids into Ribosomes.Tetracycline
enter bacterial cell by energy dependent process..
Bacteriostatic. AA into ribosome. Ribosomes has 3 binding sites for tRNA-A,P,E.

Interactions

Antacids and iron preparation reduce absorption by chelation to calcium, aluminum and iron.
EXAMPLES:Tetracycline,Doxycycline, Minocycline,Oxytetracycline,Lymecycline, Demecloycline
hydrochloride,ethacycline,hlortetracycline,dimethyl chlortetracycline, -reverinNB: Democloxycyline-
also used to chronic hyponatraemia due increased ADH e.g. in malignant lung tumors.

Indications

Spectrum – gram +ve and gram –ve

Though there is an increased bacterial resistant to tetracycline, it’s still used for treatment of some
infections psittacosis, Salpingitis, Urethritis, Lymphogranuloma venerum. Mycoplasma
pneumonia,Brucellosis,Shigellosis,Helicobacter Pylori infection,-Rickettsial diseases e.g. Q. fever,
typhus.cholera ,Borrelia ( lyme disease -choice, relapsing fever ),-Acne,Amoebic dysentery,
Spirochetes’,Protozoa-Bacillary dysentery ,Chlamydia spp

Unwanted Effects

-GIT disturbance –most vital-nausea and vomiting, Vit B complex deficiency,Super infection since grossly
interfere with flora – antibiotic –related colitis.eg by Candida ulbicans.Proteus Vulgaris, Aspergillus
fumigates;Possible hepatotoxity –especially with high dose and /or renal impairment ;Dental hypoplasia
and bone deformities;Retarded bone growth and teeth discoloration

NB: Tetracycline are deposited in growing bone and teeth (being bound to calcium) causing staining
(coloring –brown/yellow) occasionally dental hypoplasia (defective development of any tissue) hence
shouldn’t be given to; children under 7yrs or 12 yrs. pregnant mothers (from 4 th month);breast feeding
women. They are deposited in dentine and enamel of unerupted teeth causing pitting, cusp
malformation, yellow or brown pigmentation and increased susceptibility to caries. Discoloring of
permanent teeth occurs if taken between (4 yrs -6 yrs).

NB: prolonged tetracycline use can stain fingernails at all ages.

Contraindications : After 4th month of pregnancy, Renal failure.

Prototype
Tetracycline – sustamycin, tetrachel, achromycin

Dosage

By mouths :

250mg -500mg every 6 hrs. increase dose in severe infections to 500mg every 6-8 hrly.

IM -100mg 6-8 hrly. By IV infusion 500mg every 12 hrs to a max of 2g daily

For 1-2 or latent syphilis 500mg every 6hrs; Non gonococcus arthritis 500mg every 6hrs for 7-14 days

AMINOGLYCOSIDES

This is a group of antibiotic that has broad spectrum.

They include such drugs as: Streptomycin, Karamycin, Neomycin, Netilmycin, Tobramycin, Gentamicin-
most active and commonly used; Amikacin, Framycetin

Learning activity: Read more on Spectinomycin –related to these drugs and good for treatment of
gonorrhea for penicillin allergic patients.

Pharmacokinetics

Water soluble –highly polar. Not absorbed through gut hence given IV or IM. Do not cross BBB. Half life
2-5 hrs.Excretion usually through kidney – usually unchanged –caution in renal impairment.

Pharmacodynamics

-Binding to 30s ribosomal subunit leading to formation of non- functional initiation complex which leads
to inhibition of bacterial protein synthesis + misreading the genetic code such that incorrect acids
sequence are entered into peptide chain . Abnormal proteins are formed which result are fatality of the
microbe.Under aerobic conditions are rapidly bactericidal – penetrate cell wall thro active and passive
processes. Active process-02 dependent –polyamine carrier system. Bactericidal effects enhanced by
beta lactam antibiotics. Some are bacteriostatic.
Indications: septicemia, pelvic and abdominal sepsis, brucellosis, bacterial endocarditis

Pneumania, meningitis.Neomycin –gut sterization for surgery- 1gm 4 hrly

NB: Amikacin –widest spectrum together with netilmcin can be used for organisms resistance to
gentamicin and tobramycin; Neomycin and framycetin are too toxic for systemic use hence used
typically for ear, eyes and skin infections.

NB: serious and dose related

Unwanted effects

Dose –related and reaction shouldn’t exceed 7- 10 days.Nausea, vomiting, diarrhea, headache, lethargy

NB: Aminoglycocides require plasma concentration monitoring especially t in infants, elderly, obesity,
high doses being given and if reaction exceeds 7 days renal impairment states. Hypersensitivity,GIT
affects e.g. nausea, vomiting, diarrhea;Headache,lethargy.

Nephrotoxicity- reversible but may be serious if there is renal impairment.

Containdications

Pregnancy - 8th nerve [Auditory nerve (vestibulo- cochlear nerve)] toxicity-ototoxicity (especially during
development of nerve)

Cochlear parts affected by- Kanamycin, amikacin ,neomycin while vestibular parts are affected by-
tobramycin, gentamycin , streptomycin

NB: netilmicin less ototoxic –good for long use.

-Myasthenia gravis-cause neuromuscular blockade (if given concurrently with NM blocking agents. Due
to inhibition of ca2+ uptake necessary for exocytotic release of Ach.). Hence cause myasthenia gravis-
like effects, especially for patients who are on muscle relaxants

Interactions

Greater chances of ototoxicityif given together with other ototoxic drugs eg diuretics-ethacrynic acid
and capreomycin(antiTB)

Prototype.
Gentamicin

Most active aminoglycosidic antibiotics.-gentamicin, Cidomycin/Genticin

-Pnuemonia

NB: can given together with penicillin and metronidazole

Contraindications/Caution

-Renal impairment

-Infants and elderly

-Plasma gentamycin concentration should be monitored. In all patients especially in extremes of age.

-Pregnancy –cross placenta-cause fetal 8th nerve damage.

-Myasthenia gravis – worsens the condition.

Dosage: IM or by slow IV injection /infusion over at least 3 minutes

2-5 mg/kg daily 8hrly.Reduce dose in renal impairment and elderly. For 7 days

I.e. 80gm/60mg BD with benzyl pen in elderly.Child ups to 2 wks.-3mg/kg every 12 hrs

2 wks- 12 yrs -2 mg/kg every 8 hrs.By intrathecal route 1mg daily –increased if necessary to 5 mg
daily.1m injection.2-4 mg/daily in divided doses every 8 hrs.

NB: 1. Reaction shouldn’t exceed 7 days.

2. For best RX Gentamicin can be combined with beta lactam antibiotics – potentiating /synergistic
antibiotics effect( expands spectrum of antibiotics and prevent emergence of resistance).

Amikacin

Indications

Serious gram negative infections resistant to Gentamicin.

NB: rationale
Stable to 8 of the 9 classified aminoglycocide inactivating enzymes whereas gentamicin is inactivated by
5 (Gentamicin stable to only 4 of the inactive enzyme).

S/E, caution, contraindication- see gentamicin

Dosage

By IM or slow IV injection or Infusion 15mg/kg daily in 2 dividend doses.

Neomycin sulfate (mycifradin, Nivemycin)

Too toxic for parenteral administration.

-Used for infections on –skin and- Mucus membrane

Reduce colonic bacterial content prior to bowel surgery or in hepatic failure.

Caution, contraindication, side effects

See Gentamicin

-Avoid in intestinal obstruction and renal impairment

Dose

By mouth for bowel sterilization 1gm every 4 hrs.

4-QUINOLONES/FLUOROQUINOLONES

These include broad spectrum antibiotics

Nalidixic acid was the first widely used quinolone.

Though widely used for UTI, has little system activity.

Other newer quinolones include;Norfloxacin,Ciprofloxacin,Ofloxacin,Levofloxacin-Acrosoxacin-
acrosoxacin,pefloxacin

Narrow spectrum

-cinaxacin

-Nalidixicin acid (not fluorinated)

Mode of action

-complex but inhibits DNA gyrase(topoisomerase 11) , the enzyme that maintains the helical twists in
DNA.

-Mostly bacteriocidal but some are bacteriostatic – gram-ve organisms and gram +ve organisms.

-not effective against anaerobes.

(topoisomerase 11 /DNA Gyrase produce a –ve supercoil in DNA & thus permit transcription
/replication).

-well absorbedfrom the gut-widely distributed in body tissues

-eliminated by renal excretion, hepatic metabolism, biliary secretion.

-norfloxacin and ciprofloxacin t1/2 -3 hrs oflo-5 hrs, perfloxacin 10 hrs-concentration in lungs, kidneys,
prostate and phagocytes,

-doesn’t cross BBB except perflox and oflox (40% and 90% respectively of their serum concentration).

-Aluminum and Mg+ antacids –interfere with absorption.

-may inhibit P45 hence interact with other drugs at metabolism e.g. hteophylline used asthmatics
(bronchilator).

Theophy has narrow thetap index –toxicity –sysrhythmia, seizure (children), nausea/ vomiting, tremor,
anxiety.

Adverse effects

-GIT upset
-CNS effects – dizziness, headache, confussion, convulsions etc

Allergic reactions- skin rashes

-Liver enzyme inhibitors- impairment.* of some other drugs e.g theoophline, caffeine, warfarin effect
increased.

-Cause arthropathy in immature animals hence avoid in children growing and adolescents- hence not
recommended unless the benefit outweigh the risk.

NB: theo give aminophylline (theo +ethylenediamine-20 times soluble that theophy)

Aminophylline ehtylenediamine)

Indications:complicated UTI,pseudomonas aemginosa resp. infection in patients with cystic fibrosis,

Invasive external otiti-by p. aemginis,Chronic gram –ve bacilliary, osteomuelitis, slamonella tupi – carrier
state ,Gonorrhea – oflo and norflo,bacteria prostatitis (norflo)

-cervities (oflo)

-Anthrax.

Prototype

Ciprofloxacin (aproxin) t1/2- 3 hrs

NB Effective against gram negative bacteria (mostly) e.g.

-salmonella ,-shigella,-campylabacter,-psendomonas,-Enterobacteriaceae (negative baathi)

Less effective against gram the bacteria eg,-strept pneumoniae,-strept. Faocahis,-active aginist
dhlamydia and some mycobacteria

Therefore, indicated for:

.UTI

.gut infections
Dosage: By mouth 250-750gm *2 daily: By IV infusion (over 30-60 minutes) 200-400mg twice daily.

NB: Not recommended for children and adolescents unless benefit out weigh risks, hence.

E. MACROLIDES

These are antimicoobials like

Enythromycim(mostly importants)

dirithromycin

Azithromycin

Spiramycin

Darc thromycin.

Pharmacodynamics

Inhibit protein bacteria synthesis by irreversibly binding to ribosomal 50s subunit of the sensitive
micro-organisms hence, Bacteriaostatic

But sometimes can be bacteriocidal especially if dosage is high eg Azithro-bcidal against streprogenes,
spneumoniae,Holufluezwa

Pharmacokinetics

NB: Binding sites (50s) same as dindamycin and chloramphenicol, hence can complete of given
concurrentl ( should not)

Antibacterial specturum is similar that of penicillin, hence an alternative in penicillin-allergic pts

-of the microlides, Enythromyicn is the most important, hence

Erythromycin-Erymax, Erythroped -Inactivated by gastric acid hence administered as protected tabs

(enteric coated tabs)-estolate (ester)-form erythro.by hydrolyses (1 st phase met. of estolate–active
erythromycin released. Dissolved and absorbed in s.intensive.Half life is 1/2 aprox-2hrs (dose
dependent).undergone enterohepatic circulation.

Elimination exclusively via bile feaces esters e.g. stearate, Enthylsuccine and estolate-resist acid and
better absorbed.

Indications:

-campylobacter enteritis,-pneumonia,-legionnaires disease (legionella pneumophila)

-Chronic prostalities,-acne vulgaries,-Diphtheria – eliminate diphtheria carrier state

-Relapsing UTI – due to L-forms of bacteria e.g. E.coli protens, Mirabilis

-Whooping cough,-mycoplasma pneumonia,t1/2-gomin (erythromycin)

NB: an effective alternative in penicillin –allergic patients infected with staph. Pyogenes, strep-
pnuemoniae or and treponema.

Pharmacokinetics

Distribution: good: concentrates in spleen and liver placenta, breast milk, inflamed
meninges.Metabolism liver. Ecxel feaces and small urine.

Resistance: plasmid – controlled alteration of the eryth. Binding site on bacterial ribosome.

Unwanted effects

Estolate –can cause cholestatic hepatitis it’s an allergic reaction /direct toxicity –abd, pains,
hepmegullus, jaundice, and fever.

-GIT disturbance e.g. diarrhea (major) abd. Discomfort, cramping, nausea, vomit

- Headache, dizziness

-enzyme inhibitor and interferes with metabolism of drugs like warfarin, carbamazepine, theophylline-
increasing their effect.
 -may cause hepatotoxicity in 10% pregnant women hence not recommended in pregnancy.

-hearing disturbance (transient).

Dosage

By mouth (adult and child over 8 yrs)

250-500mg every 6 hrs /day.Maximum dose -4g in severe infections.

Child up to 2yrs – 125 mg 6 hrly.By IV infusion 25-50mg/kg daily as continuous or 6 hrly divided doses

CLIDAMYCIN –

Mechanism of action like erythromycin – bacteriostatic and some bactericidal.

Read more.

AZOLES

(a) Metronidazole and tinidazole (anti bacteria and anti protozoal) which are described here.
(b) Fluconazole, itraconazole, clotrimazole, econazole, ketoconazole, isocazole and miconazole – anti
fungal drugs.
(c) Mebendazole,thiabendazole which are described under anti helimimthic drugs
Nimorazole which is used for trichomonias.

Prototype

Metronidazole

Very active against anaerobic and protozoa

Pharmacodynamics

Connected to an active form by reduction of its nitro group this binds to DNA and prevents nucleic
acid formation. Hence to bacteristatic.

Pharmacokinetics
 Well absorbed after oral or rectal administration.

Distributions well to eradicate infens in urine partly un charged and partly as metabolite. Half life is 8
hrs.

Indications

Active against anaerobic bacteria and protozoa. Treatment of sepsis to which organism e.g.
Bactericides spp. anaerobic cocci.

Intra-abdominal infection and sephicaemia, wounds and pelvic infers osteomyhits, of brain /lungs.

Prevention of posperactive infers especially after bowel surgery.

Antbotic related coliths eg pseudomembraneous coliths.

The chomowaris of urogenital tracts in both sexs.

Amoebiasis (entamoeba histolythca)

Whether symptomless carries or cysts or intensive and extra-intestinal infers.

Giardias(Giardia lamblia)

Acute ulcers gingivitis and dental infers

(fusobacterium spp).

Aerobic vaginosis(Gardneralla vaginalis)

Dosage

Established Aerobic infers usuallyRX for 7 days.

By mouth

800gm initially 3 days then 400gm every 4 days or 500gm every8 hours or just 400gms 8 hrs for 7 days
By rectum

1gm every 8hours for 3 days, then 1gm 12 hours. By iv infusion 500gm every 8 hours.Child (any
route) 7.5mg, 1kg every 8 hours.Surgical prophylaxis

By mouth

400mg every 8 hrs started 24 hrs before surgery then continued postoperative by iv infusion by
rectum until oral administration can be resumed for 2 days.

Unwanted Effects

Vomiting and nausea, Diarrhea, Furred tongue, unpleasant metallic taste in the mouth, Headache,
dizziness and ataxic,-Rashes, urticania, angiodema, peripheral neuropathy is RX prolonged.,
Epileptiform seizure if the dose is high,Disulfiram-like effect occurs without alcohol metronidazole
inhibit aldeldehyde dehydrogenase which metabolism alcohol.

These effects can be lethal-e.g. tachycardia –diaphoresis, vomiting and BP nausea etc.

Tinidazole

Similar to metrondazole but has a longer t1/2(13)hrs

DOSAGE

-2gm as a single dose can be as effective as a course of metronidazole or an aerobic

By mouth

2gm initially followed by 1gm daily or 500gm*27 days usually for 56 days

For bacterial vaginosis and acute ulcerative gingivitis –a single dose of 2gm

Prophylaxis before surgery –a single dose of 2gm approximately 12 hours before surgery.
SULPHONAMIDESAND SULPHONAMIDES COMBINATIONS

Among the first antibacterial to be discovered (1935)

Pharmacodynamics

Acts by inhibiting formation of folic acid for bacterial metabolism hence are bacteriostatic.

Sulphonamides are usually given in combination with trimethoprim which potentiates its action.Assists
in inhibit successive steps in the synthesis of DNA and RNA. Much Resistance has developed against
them –not very popular.

Examples of sulphonamide:

Sulfadiazine, sulphadiazine, Sulfadiazine, sulphadimidine, Sulfisoxazole, sulphadimidine

Sulfasazine, sulfametopyrazine, Sulphaloxate.

Pharmacokinetics

Good Gut absorption except some like sulphadiazine and sulphadimine are well absorbed in the
gut.Other like calcium sulphadiazine and sulfasalazine are poorly absorbed, hence has been used for
pre-operative bowel preparation. A wide distributed e.g. BBB, placenta.

Some have been used for topical applications for prophylaxis/RX of Burns; legs ulcers pressure sores etc
because of wide antibacterial spectums.Pyrimetha(antimalirial) and related chemically to
trimethoprim .Sulphamethoxazole plus trimoxazole (septrine 80gms).They are well absorbed from
gut .half life is 1/2 10hours.-80 percent excreted by kidney hence reduce dosage is renal impairement.-
Has replaced use of sulphonamides alone.

Indications

Pneumonia due to pneumoniacystis carionii,-toxoplasmosis

Nocardiasis nocardiasteroides.-UTI, Sometimes chronic bronchitis.

Trimethoprime

Resemble the pytiridine moiety of folate reductase, hence synthesis of nucleotide (DNA/RNA).
Dose

By mouth -960gm or 2 tabs 12 hours for most infections

-dosage could be increased to 1.4gm in severe infers

Pharmacodynamic of sulphanamide/trimethoprim combination

PABA

Sulfinamides dihydropteroate synthetase

Bacterial folate

Trimethophim Dihydrofolate reductase

Bacterialtetrahydrofolate etc.
 Sythesis of thymidylate etc

Dosage

Children 6weeks - 5 month 120mg 12hours

From 6 months to 5 years -240mg 10 hours.

From 6 to 12 years -480mg 12hrs.

ANTI TB DRUGS/ANTIMYCOBACTERAIL AGENTS

TB kills approximately 2m persons per year

WHO estimate: 1b to be infected by 2000 to 2020.without 35m deaths?

In Africa: 15% of HIV associated death causes by TB.

TB out of control in many parts of the world –world’s leading causes of death from a single agent
first line drugs :-isoniazid ,-rifampin,rifabutin , -ethambutol,pyrazinamide

Second Line
-Capreomycim,-cycloserine,-streptomycine,-clarithromycin,-ciprofloxacin

To decreased possibility of emergence therapy is employed,involving the folling:

First initial phase 2 month:three days used concomitantly .

Rifater 1sunmiazid, rimpician ,pyranamide (plus ethambitol of organism subpected to be resisance)

Reduce bacterial population rapidly

Contimatian phase, of four month: two days .Isonias and rifampian.

NB Longer – term requirement needed for PTS without meruifits, bone joint involvement or rimactazid.

NB

: Based on research studies in specific countries, other anidelines may be shiplihthy

variable.

ISONIAZID

Pharmacodynamics

-Bacteriaostatic against resting organism

-can kill dividing bacteria.

-pass into mammalian cells, hence effective against intracellular organism.

Not –clear

Postulate

Inhibit synthean of mycobic acid, important constituents of cell wall and pectuliar to mycobic.
Also repoed to combine with enzyme that is uniquely found in isoniazid –sensitive strains of
mycobacteria –this result in disorganization of metabolism of the cell.

Resistance

Due to reduced penetration in the cell.

Pharmacokinetics

-Good gut distribution

-Wide distribution

NB

Penetrates well into casesus” tuberculous lesion that is (necrotic lesions, with a cheese like
constisitency) Metabolism –usually acetylator- depending on genetic factors.

T1/2 in slow in activator –three hours

T1/2 rapid in activator –one hour

Excessive urine –partly unchanged and partly acetylated fun.

 Unwanted Effects

-Dose dependent

-occur in 5% ph

-Allergy skin emptical- commonest

Other

-Fever

-hepatotoxity

-haemato lotical changes

-arthritic symptoms

-vasculitis.

Haemolylic anemia- in glucose

-phosphate dehydrogenase,deficiency

Metabolism of –antiepilephic agents –eg phanytoin, ethosyximide carbamazipe-plasma concentration

and foxity eg these drugs.
-peripheral / central CNS effects due to pyridoxine deficiency in malnuushed persons.

Pyridoxal- hydrazone formation occurs in slow acetylators.

Rifampicin (rifampin)

-One of most active ant TB known

-Also active against gramitive and negative bacteria

-Enter phargocytic cells and kill intra cellular micro organism e.g tubercle bacillio.

Pharmacodynamics

Inhibit DNA –dependent RNA polymerase in eukaryotic cells.

Resistance

Due to:-

One to chromosomal mutation leading to chemical modification of microbial DNA dependent RNA
polymerase.

Pharmacokinetic .

Orally

Wide distribution –

Give orange tiny to saliva, sputum, tears and sweat.

Incase of reach 10 to 40% of IB same concentration

Excreted – urine, bile undergoes heterohepatic recycling.

Metabolic hers antbact, activity but reduces during Rumens since it induces microsomal enzymes.

Unwanted Effects

Infrequent:

Commonest –skin emption, fever

GTI disturbances

Liver damage –fatal with small eg parts.

Asses liver function before Remits

Induce enzyme, affect bet of:

-warfare

-glucose conicoids, narcolics, oral antidiatetics dapsone, estrunfens(eg oral contrasephinem failure)
Ethambutol

Pharmacodynamics

Effective only on mycobacterium

-Mechanism of action unknown but inhibits their growth on 24huors.

Arabinogalation

Resistance emerges rapidly on used by its own.

Phamacokinetics

-Good absorption

-peak plasma within Four hours.

-taken up by any through out and slowly released.

-t1/2 three to four (3 to 4) hours

-Excrete urine.

-can reach therapy concentrated with CFS for tuber.memiyiths.

Unwanted Effects

Are common

-Vital –optic neuritis –dose –related especially if renal function decrease

Leading to visual disturbance .red green color blindness followed by decrease in visual activity.

Monitor color vision in long RXments.

Pyrazinamide

Pharmacodynamics

-Inactive at neural PH.

-Tuberculostastic at acid PH.

Effective against intracellular organisms are kept

Phargocytosis, in which PH is low.

Pharmacokinetics:

-Gut absorption good

-wide distribution BBB.

-Excretion through kidneys.

Unwanted effects:

-Gout
-Git upsets

-Malaise

-Fever

Hepatic damage

-some high doses.

Asses liver functions before treatment.

Capreomycm

Pharmacodynamic

Mechanism of action is not known

-peptide antbiotic

Pharmacokinetic

-Im given

-Has cross reaction with aminioglycoside kanamycim

Unwanted effects

-kidney damage

-damage to 8th cramid hence deay and ataxia.

NB

Do not give together with streptomycin or other drugs that may damage the 8 th cranial nerve.
Cyclosine

-Broad spectum antibiotic

-Inhibit bacteria growth –colforms mycobacteria.

-water soluble

-destroyed by acid PH.

Pharmacodynamics

Compelitive inhibit cell wall synthesis by preventing formativeof by:

D:Alamine

D –Ala-D-Ala dipeptride that is added to the initial tripeptide.

Side chain on N-acety /muramic acid.

That is prevent completion of major building block of peptidoglycan.

Pharmacokinetics

-good oral absoption.

-peak PH concentrate after Four hours.

-Good composition distribution,plus CSF –same concentration as blood.

-Elimination – urine active form mostly.

Unwanted effect

-Headache

-Inifability
-depression

-convulsions

-polychotic

Drugs Used To Treat Leprosy.

Approximate 11million in world have leprosy

Usually in Africa, Asia, and parts of South America.

Approximately 600,000 to 700,000 defected each.

Who (1982)-started multidiny treatment

Paucibacillary leprosy –leprosy with few baallis but with tubercoloid in nature.

RX dapsche and nfampicin for six months.

Multibaallary leprosy –leprosy with numerous (lepromatons wtype) bacilli.

RX for at least two years with Rifampin, daspone, clofazimine.

Daspsone

Pharmacodynamics

Chemically related to sulfonamide

It action antagonized by PABA –inhibit folate syntheses (probably)

Resistance increasing hence combined with.

Pharmacokinetics
-Oral good absorption

-t1/2 24-48

-Under ground interohepatic recycling –feacese excreted

Also used in dermatitis lerpetiformis (chronic blistering skin conditions associated with disease)

Unwanted effects

-haemolysis of red blood cells most secure to cause frank anemia

-methaemoglobinaemia

-Anorera

-nausea and vomiting

-fever

-allergic dermatitis

-neuropathy

-lepra reaction-exacerbation of lepramatous lesion can occur and syndrome resembling infections
monomumicleosis-can be fatal.

ANTI-FUNGAL DRUGS

Introduction

Many fungi –commerisal or present in the environment.

-serious super ficial injection and systemic infections were uncommon esp in cool and temperate zones

-since 1970s incidence has increased due to eg

*increased use of broad-spectum antboths which decrease eliminate non pathogenic bactirio population
that complete with fungi.
* increased use of people with low decreased immune response due to

*immune syppresat /cancer

Chemotherapy –increase opportunistic infers that is infection with fungi that rarely cause disease in
healthy individuals.

ANTIFUNGAL DRUGS

Incidence of fungal infers has increased because of –

-AIDS

-Immumosuppresant use of transplantations

-Born marrow and organ transplantations

-Increased use of b –spectum antibiotics.-

-chemotherapy in cancer

-sevinty varies

Superficial ---------sys temic/disseminated.

Mycoses Superficial infers –by 1%candidaspecists dermatophytes any fungi causing parasitic skin dx

Candoda-oral, esophangeal, ut and skin infers

Drmatophyte-skin, hair, nails.

Superficial infers one to trichophyton spp,microsporny hydrax caused by fungus epidermophyton spp.

Systemic/dissenuhated mycoses causes difficulties to RX eg

-candidiasis affect deep tissues /organs

-Aspergillosis eg pulmopnery mycosis anydx

-cryptococcosis

-coccidioidomycosis/coccidomycosin

NB

Not always possible to make a definitive diafuosis of a fungal infers.

Insuch a situation, clients with fever of unknown cause becomes candidates for ant fungal treatment
when antibacterial therapy has prone inadequately

*Characteristic features

Superficial mycosis

Superficial candidiasis caused by candida albicans(yeast) normally found in skin, mouth,gut,vaginal tract
.when there is over growth .e.g clotrimazole nystain

Other superficial infers caused by fungal parasite –dermazole:infers called tinea infers e.g

-ringworms

-tineacapitis(scalp)
-tinea baarbae (beard)

-tinea unguium (nail)

-Tinea pedis

-tinea cruris (groin)

-tinea corpora’s (skin,body ringworms)

-tinea vesicular (dermal,skin layer)

RX-tropical agents but systemic a coles or friseofulvin may be used in serious infections.

SYSTEMICN MYCOSIS

Could be 1% or secondary (opportunistic)

Could involve lungs, liver, speen, kidney, born, joint and skin, CNS.

-Examples of 1% Infers

-Histoplasmosis (Histoplasma capsulatum)

-coccidiomysis(coccidioides immitis)

-blastomycosis(Blastomyces dermatitidis)

Paracoccidomycosis
Example of 2% (opport) inferns

*Candidiasis

*Aspergillosis(Aspergillus spp)

*Cryptococcisis( Cryptococcus neoformans)

NB

Common in:

Immumosuppresed parts (AIDS)

-On immumosuppresed. Therapy

-On TPN (introduce them)

-Diabetes

-Pregnat women
-Burn victims

Pharmacodynamic Mechamism of Major Antifungal Drugs

ACT BY:

*Inhibiting cell wall synthesis or disrupts all membrane eg fluconazole inhibit synthesis of ergosterol in
fugal cell membrane.

Also cell membrane permeability may be altered eg by amphoterian Band Nystatin

*Inhibit synthesis of DNA and RNA eg flucytosine.

*Other inhibits folic acid and peptide.

*inhibit mitosis at the ribsomes.

NB:

One drug may have more one MOA.

Classes of Antifungal Agent s

-Polyenes eg nystatin, Aphoterian B(only) in clinical use.

-Fluorinated pyramiding –only one drug here fluorinanated (Ancobon)

Rarely used alone because of resistace hence used commonly with amphoterican B synergistic.
AZOLES

Have two sub types

-Imidazoles

-Triazoles} slight difference in pharmacokinetic and phardynamics

NB:

But all share most of characteristic eg MOA, s/e,etc

MOA: ergosterol synthesis inhibited – hence weak cell membrane

Timidazoles

-dotrimazole

-Econazole

-fenticonazole

-sulconazole

-ketoconazole

-miconazole

Indication:
Local RXment of vasinal candidiasis and dermatophyte inferns

Triazoles

Fl uconazole

Straconazole

Variconazoles

OTHERS

Caspofunguin

Active against Aspergillus SPP given by for invasive inferns.

Griseofulvin

For widespread /intractable (resisted other drugs)

Dermatophyte inferns

We ll tolerated and be used in children duration of RX may processed for months depending on site of
inferns.

Also good for ringworms.

POLYENE. PROTOTPE

Available for use middle -1950s used for treatment of systemic fungal infections.

Mode of action

Antibiotic that binds to ergosterol, a major component of fungal cell membranes

Bewered to form “amphoterian pores” that alter membrane stability and allow leakage of cellular
content eg intracellular.

Bacterial are not susceptible because they lack ergosterol.

Amphoterian B blind to mammalin cholesterols with less affirity, but this action may explain some
adverse effects.

Ergosterol (fungal membrane sterol)

Cholesterol (sterol in plasma membrane of animal cell)

Sterol –large subfp of steroid containing an OH up at position 3 and branched aliphatic side chain of
eight or more carbon atoms at position, 17.

Pharmacologic Properties

Poorly absorbed in gut

Effective via gut in fungal infections of gut

Usually administered intravenously.

Complexed with sodium ions deoxycholate.

Also intrathecal

Poor penetration into CNS.

-

90% bound to plasma proteins.

-Elimination – pseudominantly via biliary route (slowly excreted over a period of days)

-can be detected in urine weeks after cessation of the therapy.

THERAPEUTIC USES

Treats most severe fungal infections e.g. those caused by

*Candida –candidiasis.

*Histoplasma capsulation-Histoplasma.

*Cyptococus neoformums –crptococcosis

*coccidiodes immitis –coccidiodonycosis

*blastomyces dermatitidis- blastomy cosis

*Aspergillus spp –Aspergillosis

*Sporothix schenckii.

These occur especially in low immune parts.

Drugs of choice for major systemic infections

Liposome –encapsulated amphoterian Bis under irrestijstion and appear to be less toxic.

RESISTANCE

Usually due to decrease membrane eigosterol content or from a change in membrane structure that
reduces amphoteric binding.
Combination therapy with flucytosine can be used eg RXof candida infection, crptococcal merungitis and
systemic candidiasis. By mouth 100 to 200mg in 6 hours Child 100mg dairy

ANTIPARASITIC DRUGS
Parasites include:-

 Protozoa/ single-celled organism

 Nematoda (round worms)
 Platyhelminthes (flatworms)

Parasites live on or in the human body during some part o their lifecycle and depend on the human
host for shelter and sustenance.

Helminhths include:-
 Nematodes (round worms)
 Trematodes (flukes) blood flukes – schistoma
 Cestodes (tapeworms)

Infections by helminthes usually located in small intestines, lungs, cecum, eyes, muscles, lymphatics,
liver, urinary tract, blood vessels of gut of skin.

Parasitic infections
Many environmental conditions favour their existence e.g. hot/ humid climatic conditions, poor
sanitation, over crowding etc.
Symptoms of parasitic infections depends on the area in which infestation develops e.g.

Protozoan infestation of gut – diarrhea, cramping and abdominal pain.

Infestation of blood – fever, chills, rigor.

Helminths
Nematodes (Round worms) e.g.

 Trichris trichura
 Wuchereria bancrofti
 Trichimella spiralis
 Enterobius vermicularis
 Askaris Lumbricoides
 Ancylostoma duodenale
 Stronglyloides stercoralis
 Onchocerca volvulus

Trematodes
 Fasciola hepatica
 Schistosoma haematobium
 Schistosoma japonicum
 Schistosoma mansoni

Cestodes (Tapeworms)

Taemia saginata – Beef tapeworm

Taemia solium – pork tapeworm

Echinococcus granulosus – hydatidlyst

Diphyllobothium latum (fish tapeworm)

 Protozoa
Entamoeba histolytiza – amoebic dysentery

Plasmodium spp – malaria

Leishmania spp – kala-azar, cutreos & mucocutaneous leishmaniasis

Trypasosoma spp

T. cruzi – changes dx

T. brucei – African sleeping sickness

Texoplasma gondii – Toxoplasmosis

Pneumocystsis carimi – pneumonitis

Giardia lamblia – Epidermic diarrhoea

Trichomonas vafinalis – Trichomonoasis (vafinitis)

ECTOPARASITES
Pediculus humanus

Var. corporis – Body louse

Var. capitis – Head louse

Pediculus pubis – Public

Scarcoptes scabiei – scabies

Var. hominis
Maggots (larvae of)

Dipterous flies myiasis

Cliggers (mites)

Ticks – skin

ANTIMALARIALS
Classified as:

Blood schizonticides

e.g. chloroquine, quinine

mefloquine, proquaril

pyrimethamine/ sulfadoxine (single or separat) dapsone & Tetracyclines, doxy & mimocy.

Tissue schizonticide
 Proguarid
 Tetracycline
 Doxycycline
 Minocycline
 Primaquine
 Other drugs
- artemether – lumefantrine
- corteamisp
- coartem
Blood schizonticodes

Rapidly reduce erythrocytic stage.

Tissue schizonticides eradical primary (p. falciparum & p. vivax) and secondary p (vivax & p. ovale)
exoerythrocytic forms and destroy all gametocytes. Forms.

NB: P. falciparum is now resistant to chloroquine in many parts of the world.

Quinine
An alkaloid derived from the bark of the cincona tree.

MOA
- Binds to plasmodial DNA to prevent protein synthesis but its exact mode of action
remains uncertain.
- Used to treat p. falciparum malaria in areas of multiple drug – resistant.
- Well absorbed in GUT – delayed by antacids
- t½ 14 hours
- metabolism – liver
- excretion – kidney acidification of urine increases clearance
- used to Rx chloroquine – resistant P. falciparum often is combination & pyrimethamine/
sulfadoxine (Fansidar)
- Has a low therapeutic index
- Produces curare like effects on skeletal muscle and can cause.
 GIT imitant
 CNS disturbances
 Renal damages
 Rare hemolytic anaemia
 Associated with “black water” fever in previously sensitized pts.
Black water fever has a fatality rate of 25% due to intravascular coagulation and
renal failure.
 -

Antibacterial agents

Sulfanicides & sulfones vital for prophylaxis

Tetracyclines (doxycycline)
Sometimes used in combination with quinine against acute attack caused by multi-resistant strains of
plasmodia. Usually combined with pyrimethamined sulfadoxine.

Agents against Amoebiasis

Causative organism Entamoeba histolytica ingested in cyst form, divides in the colon and can invade the
intestinal wall to cause severe dysentery.

Entamoeba histolytica is excreted in the feces as cysts by assumptomatic carriers or as the less mature
tryphozoites by individuals with diarrhoea.

Infection may also be asymptomatic or present as a milder form of intestinal injection or as an extra-
intestinal injection.

Available drugs are active against trophozoites but generally not active against cysts.

Tissue amebicides

e.g. emetine

chloroquine

metronidazole
Active against organisms in the

- Intestinal wall
- Liver & others intestinal tissues
Not active against organisms in the intestinal lumen.

Luminal amebicids

- diloxanide
- iodoquinol
- tinidazole
They act primarily in intestinal lumen.

Prototype

Metronidazole (flagyl)
- As 5-nitronidazole that after nitro reduction reacts with intracellular macromolecules of
anaerobes may also inhibit DNA synthesis and after DNA repair.
- Well absorbed in GIT
- t½ 8 hours
- Metabolism by liver & metabolites partially active
- Elimination by renal system.
- Not very good for luminal injections but usually used for intestinal amebiasis, amebic
liver abscesses.
- Can be combined with iodoquinol or dilaxamide furoate to eradicate luminal disease.
- Metronidazole also active against Griadia Intestinalis (formerly G. Iamblia Trachoma
Vaginalis)

NB:
Metronidazole shows activity against many anaerobic bacteria to include Bacteroides & clostridia.
S/E
 Reversible CNS disturbances
 Discolouration of urine
 Disulfiram – like effects with alcohol

NB:
Avoid in the 1st trimester of pregnancy.

AGENTS ACTIVE AGAINST LEISHMANIASIS

 Stibogluconate Sodium (Pentostam)
 Pentamidine (pentam)
 Amphoteriari B
Active against L. braziliensis & L. mexicana.

Also used when antimonial is contra-indicated/ ineffective.

 Allopurinol

AGENTS AGAINST TRYPANOSOMIASIS

 Nifurtimox (lampit)
MOA – causes DNA damage

Rx South American Trypanosomiasis caused by Trypasosoma cruzi (chaga’z disease).

 Suramin
 Eflornithine hydrochloride
 Melarsoprol
 Pentmidine
Drugs for other protozoal infections

 Giardiasis
- Quinacrine
- Metronidazole
 Pneumocystis carinii
- Trimethoprime/ sulfamethoxazole
- Pentamidine isethionate
- Oerosol pentamidine
 Trichomoniasis
- Metronidazole
 Toxoplasmosis
- Pyrimethamine
- Trisulfapyrinuidines – a mixture of sulfadiazine, sulfamerazine & sulfamethazine.

ANTI-HELMINTICS
Against Nematoe (round worms) injections

- Mebendazole (vermox) and Albendazole (zental).

Both are benzimidazole carbamates that bind to parasite free tubulin to inhibit its polymerization and
microtubule assembly.

Irreversibly inhibit glucose uptake by nematodes. This results to glycogen depletion and decreased ATP
production which immobilizes the intestinal nematodes later cleared by the GIT in faeces.

 Poorly absorbed but fatty meals enhances absorption.

Oral administration – intestinal but not tissue parasite.

Indications
Roundworm infections caused by:-

 Ascaris lumbricoides
 Capilaria philipinensis
  Enterobius vermicularis (pinworm)
 Necator americanus (hookworm)
 Trichuris trichiura (whipworm)
Also for cestodes injens e.g.

- Echinococcus granulosus
- E. multilocularis
- Thiabendazole (mintezol)
- Pyrantel pamoate (antiminth)
- Piperazine citrate
- Diethylcarbamazine (Hetrazan)
- Ivermectin

AGENTS AGAINST CESTODE (TAPEWORM AND TREMATODE (FULKE

INFECTIONS)
Praziquantel (Biltricide)

MOA not known but thought to cause musle contraction with paralysis of the worm. Also causes
tegmental damage.

 Well absorbed in GIT

 First pass – metabolism in liver –
Bioavailability

Half life in hepatic dx & by inducers of cytochrome P-450 e.g. Carbamezepine & by inhibitors e.g.
Cimetidine.

Most effective drug against all flukes injections i.e.

 Blood fluke – schitosomiasis

 Intestinal paragonimiasis
 Liver
Also – Tapeworm infections
Contraindication

Ocular cysticercosis

Niclosanide (Niclocide)

Bithionol – for Fasciola hepatica (sheep liver fluke injection).

ANTIVIRAL DRUGS
 Antiviral agents most active when viruses are replicating. Hence the earlier the treatment the
better.
 Major problem is that substantial amount of viral multiplication has often taken place before
symptoms occur.
 Viruses also develop resistance just like Bacteria.
 If host immune system is compromised, the illness is very severe.
Otherwise most viral infections resolve spontaneously in immunocompetent subjects.

Herpes simplex and varicella-zoster

 Aciclovir
 Famciclovir – product of penciclovir
 Valaciclovir (ester of aciclovir)
 Idoxuridine

Human Immunodeficiency Virus

 No cure for HIV

 Drugs halt or slow dx progression
 HIV drugs are toxic but life expectancy
NB: Should be used carefully to reduce the chance of S/E
 Pxment aimed at reducing viral load as much as possible and for as long as possible.
 Should be started before the immune is irreversibly damaged.
 Strict compliance is vital
 Refimen chosen should take into account points convenience & tolerance.
 Development of drug resistance reduced by using a combination of drugs – which should have
synergistic or additive activity while ensuring that their toxicity is not additive.
 Testing for resistance to antiviral particularly in therapeutic failure should be considered.
 Optimum time for initiating treatment will depend on:-
- CD4 count (T-lymphocyte count) <200cells/mm3
- Plasma viral load – plasma HIV RNA
- Clinical symptoms
- Total blood count, urea & electrolyte & liver test
i. Initiating treatment with a combination of drugs
ii. Nucleoside reverse transcriptase
Inhibitors with EITHER

A non-nucleoside reverse transcripatse inhibitor.

OR

1 or 2 protease inhibitors

Anti retroviral profile

The gold standard of anti-retroviral therapy is HEART i.e. Highly Sctive Anti-retroviral Therapy which is a
combination of three or more antiretroviral drugs in treatment of HIV injection.

These antiretroviral drugs fall in three different classes and work at different sites on the HIV virus.

1. Nucleoside analogue Reverse Transriptase Inhibitors (NRTIS

MOA
Incorporates themselves inot DNA of virus hence stopping the building process.

The resulting DNA is incomplete.

Examples

Zidovdine (AZT

Didanosine (ddi

Lamivudine (3TC)

Stavudine (d4T

Zalcitabine (ddc)

Abacavir (ABC)

2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

MOA
Binds directly into reverse trancriptase preventing the conversion of RNA to DNA – hence prevent HIV
production.

NB Called Non-nucleoside though they work at same stage as nucleoside analogues but act in a
complete different way.

Examples
 Efavirenz (EFZ) 600mg UD
 Nevirapine (NVP) 200mg BD
 Delavirdine (DLV) 600mg BD

3. Protease Inhibitors

Work at the last stage of HIV virus reproduction cycle.

Examples

Saquinavir hard gel (SQV) 600mg TID

Saquinavir soft gel (SQV) 1200mg TID

Ritonavir (RTV) 600mg Bd

Indinavir (IDV) 800mg TID

ANALGESICS

Drugs used to treat pain:

 Non-Narcotic analgesics
 Narcotic analgesics
 Drugs to treat headache

DRUGS USED FOR THE TREATMENT OF PAIN

INTRODUCTION

Unpleasant sensory or emotional experience usually associated with tissue damage eg inury,
inflammation or cancer.Other pains arise for no obvous reason eg trigeminal neuralgia and phantom
limb pain. Neuropathic pain due to damaged neural tissue. Can be produced by neurological disease
which affects the sensory pathway.Its a severe chronic pain which is unrelated to peripheral tissue
damage.It could be due to cardiovascular accident,multiple sclerosis.diabetic neuropathy,herpes zoster
infection(shingles).Pain araising from brain or nerve injuries may not respond to conventional analgesics
like Narcotic analgesics, NSAIDS, but may respond to other drugs like antidepressants.neuroleptics, and
antiepileptics.Here pain is seen as a disordered neuronal response like mania schizophrenia not just as
“normal “ response to inury.Hence pain can be:

 Peripheral nociceptive afferent neuron activated by noxious stimuli

 Central mechanism by which the afferent inputs generates a pain sensation
NB: Prostanladins (PGDS) are required for inflammation which usually accompanies pain.PGDS do not
cause pain by themselves but they enhance pain producing effect of other agents eg bradykinin,
cytokines, serotonin.They stimulate /sensitise pain receptors (niciceptors) to chemical mechanical
stimulation. Most common presenting symptom of all patients.Pain has a lot of emotional (affective)
implications – pts perception of pain affected by emotional state of the patient.Hence there is need for
adequate rapport when dealing patients with emotional distress.

Other names used for Narcotic analgesics include opiods or opiates.However these terms have some
differences:

Opioids:

Any substance, whether endogenous or sy thetic that produce morphine like effects that are blocked by
antagonists like naloxone.

Opioates:

Restricted to synthetic morphine like drugs with non-peptide structures.

A related term is opium which an extract of Poppy papaver somniferum and contains many alkaloids
related to morphine.

Brain & spinal cord produce their own pain killers known as endorphins and enkephalins in response to
pain.Endorphins are natural chemicals that resemble morphine and act as highly effective pain relievers’
for a short period hence less effective for chronic pain.Dynorphins also pay some part in the pain
sensation.Endophins act on pain endorphin receptors which are also acted upon by opiates.

Thus: Kappa, delta, sigma and mu receptors.There exist subtypes of these receptors and are all coupled
to G-proteins.

These receptors mediate different effects of opiates eg Kappa mediates such effects as depression of
appetite, analgesic effect, sedation, miosis; Mu receptors mediate physical dependence, analgesic effect
euphoria respiratory depression.It is important to note that mu receptors mediate most of the narcotics
action for both wanted and and unwanted narcotic analgesics effects.Narcotic can be either pure
agonist, partial agonist or pure antagonist to these receptors. Drugs like morphine & pethidine are pure
agonists to these receptors.Pentazo and narlorphine are partial agoniste .Others likenaloxone and
naltrexone is pure antagonist which can be used to treat opioid poisoning.

Examples of opiates/ opioids:

Morphine ,Codeine ,Heroine ,Pethidine (synthetic-meperidine) ,Fentanyl (synthetic),Dextroprophene +

paracetamol= distalgesic – less irritant to gut,Methadone ,Diamorphine (heroine) ,Pentazolines,
cyclazocine,Levorphanol ,Tramadol – less constipation,respiratory depression and addition potential;
Dextropropoxyphene;Semisynthetic thebaine derivatives eg Etorphine, buprenorphine;Loperamide –
though not used for pain since it does not enter brain it enhances peristalsis hence used for diarrhea.

PHARMACODYNAMICS
The mechanism of action of narcotic analgesic is variable.Only two will be discussed here;

Cellular action

Opiates recetors are coupled withto G-proteins.Binding to these receptors leads to inhibition of
adenylate cyclase which leads to decrease in intacellular CAMP.This leads to increased opening of K+
channels and inhibits opening of Ca++ channels.This leads to Hyperpolarisation of neurons which
decreases neuronal activity.

Nociceptor pathway
Nociceptor afferent neurons ie C fibers (slow) and AB, (fast) are affected.narcotic analgesics inhibit
transmission of nociceptor impulses.

PROTOTYPE

MORPHINE

Pharmacokinetics
Can be administered in different routes eg oral,sustained release,injection and intrathecal route.Oral
route is preferable in chronic pain while these other route rae good in acute pain.Half life is 3-6
hours.Metabolism is in liver through conjugation with glucuronide.Two typesd of metabolite result ie
morphine 6-glucuronide which has better analgesic effect than morphine and morphine 3-glucuronide
which has an antagonist eefect to morphine.Excretion is exclusively in urine therefore the dosage should
be reduced in renal impairent.Morphine undergoes enterohepatic circulation.

Indications

Pain relieves especially in chronic illness where it confers a state of euphoria and mental detachment
which reduces effective component of pain. Act on limbic system. Anxiety & agitation involved in painful
stimulus. Not all produce euphoria e.g. codeine, pentazocine.

Other narcotics like codeine and dextramethorphan can be used as cough suppresants because it
decreases cough/tussal reflex.

Dosage
Acute pain – by subcutaneous injection (not suitable for edematous pts) or by im injection. 10mg every 4
hours if necessary 15mg (20mg) for heavier well-muscled patients.10-30mg/day is the usual dose.

Child upto 1 month: 150 micrograms/kg; 1 – 12 months: 200 micrograms/kg

1-5yrs: 2.5 – 5mg; 6-12 yrs: 5 – 10mg; by slow IV injection: ¼ - ½ corresponding intramuscular dose.Do
not use in neonates, instead you can use pethidine.

Give opiates to patients who actually require them because of potential for dependence except
for terminally ill patients where dependence is of no concern.Some substances are used along
analgesics in the management of pain. These are called Adjuvant drugs e.g. caffeine,
antihistamine, amphetamines, antidepressants which are particularly good for neuropathic pain
eg postherpetic neuralgia.They enhance the effect of opioids.
NB:Morphine poisoning
Patient will be in coma and the pupils will be characteristically constricted.Treat morphine poisoning
with naloxone 0.4ml IV stat

Repeat in 20-30min duration (Naloxone is a pure antagonist of morphine).Naloxone can also be used for
diagnosing morphine poisoning.
Contraindications

 Severe respiratory diseases

 Constipation

Unwanted effects

 Depress respiration (u receptors)

o Opioids increases threshold at medullary respiratory center for carbon dioxide i.e. the
level of carbon dioxide at which respiratory center responds increases due to increased
threshold.
 Decrease cough reflex i.e. depress tussal reflex especially codeine, dextramethophan.
 Causes histamine release hence cause itching
 Sedation
 Mysosis/ miosis
o Very important symptom for someone addicted to morphine i.e. pin-pointed
(contriction) pupils.
NB: Pethidine doesn’t have the above effect.

NB: No tolerance to this miosis.

 GIT effects like decreased acetylcholine release at GIT and hence reduced peristaltic
movements, increased segmented tone, increase tone of anal sphincter and other sphincters,
Nausea & vomiting-affects 40% of patients .These effects cause constipation in which there is no
tolerance.Avoid morphine in gallstones.
 Physical (abstinebce syndrome) and psychological dependence (craving)
 Administration of a drug should be continued to avoid withdrawal symptoms.
 Immunosuppressant effect – if used for long term use.
NB: Tolerance: Tends to develop rapidly ie in less than 12-14 hours.It develops to the following
effects: Euphoria, analgesic, emesis, and respirstory depression.Tolerancee doesnot develop
tomiosis and constipation
Pethidine (meperidine)
Synthetic narcotic analgesic that is widely used than morphine.Acts like morphine but doesn’t constrict
pupils.Has 10% analgesic potency that of morphine.Tends to constrict cerebral vessels, subsequently
increasing CSF pressure hence headache.Very addictive and also causes constipation .Half life is 3 hrs.

Indications
- Moderate to severe pain of any kind,Obstetric analgesia,Peri – operative analgesia
Cautions, contra indications, Side effects –see morphine

Dose
By mouth for adult: 50-150mg every 4hrs; child 0.5 – 2mg/kg

By SC or IM: 25mg – 100mg 4hrly; child im – 0.5 – 2mg/kg

By IV injection: 25-50mg repeated after 4 hrs:

NON-NARCOTIC ANALGESICS

INTRODUCTION

These can be classified into two classes

 Non-steroidal anti-inflammatpry drugs (NSAIDS)

 Paramonophenol derivatives

Non-steroidal anti-inflammatpry drugs (NSAIDS)

These analgesics are widely used os both prescription and over-the -counter drugs.they are called non-
steroidal because just like steroids they can be used for treating inflammatory conditions

Classification

They can fall under different subclasses;

 Propionic Acid Derivatives egFenbufen,Ibuprofen,Ketoprofen,Naproxen and Fenoprofen

 Salicylates and their related substances eg Aspirin,diflunisal
 Indoleacetic acid derivatives eg Indomethacin, Sulindac, Etodolac, Tolmetin, Diclofenac,
Ketorolac
 Anthranilic acid/Fenamic acid derivatives eg Mefenamic acid, flufenamic acid/meclofenamate
 Oxicams eg piroxicam,Tenoxicam,Meloxicam
  Pyrozolones eg Azapropazone,Phenylbutazone,Oxyphenbutazone
PHARMACODYNAMICS

NSAIDS act peripherally by inhibiting the enzyme arachidonate cyclo-oxygenase thereby inhibiting
prostagladin and thromboxane A2 synthesis.Note that both thromboxane synthetase and prostaglandin
sythetase are inhibited by NSAIDS.

Phospholipid (in cell lipid)

Phospholipase A2

Arachidonic acid

Hydroperoxy

Acids

Cyclic Endoperoxides

(Prostagladins)

Leukotrienes
 Prostacyclin Thromboxanes A2 Others

(Platelet) (Endothelium) PGE2

PGF2∞

Thromboxane A2 is important for vasoconstriction and platelet aggregation whereas prostacyclin

is a vasodilator that inhibits platelet aggregation.There are two types of cyclo-oxygease ie COX
1 and COX 2. COX 1 is involved in tissue homeostasis eg platelets and GIT whereas COX2 is
invivoved in the functioning of inflammatory cytokines like interleukin-1,tumor necrosis factor-
alpha,prostanoids etc.The anti-inflammatory effect of NSAIDS is related to inhibiton of COX 2
and subsequently inhibition of COX1 causes unwanted effects .Unfortunately,most of the
available NSAIDS are not selective for COX2.Hence,most of them have unwanted
effect,especially among the elderly.However,Celecoxib and Rofecoxib have recently introduced
as COX2-inhibitors,though they are not available locally.
General indications of NSAIDS
The major indications of NSAIDS include
 Anti-inflammatory effect-reduce those components of inflammatory activity and immune
response e.g. Vasodilation, Oedema, Pain, fever
 Analgesic effect.PGDs production that sensitize nociceptors to inflammatory mediators
e.g. bradykinin, serotonin.Headache relieve due to decreased prostaglandin- mediated
vasodilation.
 Antipyretic effect.Bacterial endotoxins cause relaease of pyrogen interleikin 1 which
stimulate hypothalamus to produce PGE2 which cause increase in temperature
 Prolong labor.Inhibits prostaglandins which are involved in labor
 Cardiovascular conditions eg transient ischaemic attacks,angina pectoris and coronary artery
bypass graft.Due to antiplatelet aggregation effect as thomboxane A2 is inhibited
 Dysmenorrhea-Inhibits PGDS involved in contractions
 Rheumatoid arthritis and juvenile arthritis

General Unwanted effects of NSAIDS

1. Gastrointestinal effects

Is the commonest due to inhibition of COX-1 which is necessary for production of Prostaglandins which
inhibit gastric acid secretion,and ensure intergrity of mucosa, Such GIT effects include dyspepsia
diarrhoea, nausea, constipation, gastric bleeding/ ulceration.PGD analogue, misoprostol reduces this
damage.Selective COX-2 have minimal GIT effects

2. Skin eruptions – 2nd commonest e.g. rashes, urticaria, photosensitivity rxns e.g.

Mefanamic acidcause 10-15%, sulindac 5-10% frequency

3. Adverse renal effects:

 Renal effects-Due to inhibition of biosynthesis of prostanoids which are involved in

maintenance of renal blood flow dynamics .Chronic NSAID use may cause, chronic nephriti,
renal papillary necrosis .
 Bronchospasms in Aspirin – sensitive asthmatics
 Bone marrow depression, liver disorder.
 Analgesic neuropathy

NSAIDS SUBDIVISIONS

Salicylaters & related substances

Examples of drugs in this class: Salicyclic acid, diflunisal, Benorylate( Apririn + paracetamol)

Prototype

Acetyl salicylic acid-Aspirin

Aspirin is a derivative of salicylic acid which is too toxic (eg very irritative) to be used.Therefore its
derivative ie Acetyl salicylic Acid (Aspirin) is ussualy used.

Pharmacokinetics

Aspirin can be given orally in many preparations .Rapidly absorbed from GIT-stomach & ileum.In
blood, aspirin is broken down by esterase enzyme into acetic acid & salicyclic acid.Half life is 15-50
Indications: Anti-inflammatory effect,Analgesic, Antipyretic, Antiplatelet effects.Therefore can be used
in such conditions as rheumatoid arthritis,juvenile arthritis,cardiovascular problems like transient
ischaemic attack,Angina pectoris , deep venous thrombosis and heart attacks.

Dosage is 0.3g-4g/day for adults.Its not recommended for childen and adolescents because of pontetial
for Reyes syndrome.

Contraindications

 Children and adolescent below the age of 16 years unless specifically indicated like in Kawasaki
disease and juvenile arthritis.
 Prevoius or actve peptic ulceration
 Haemophilia
 Hypersensitivity to aspirin or any other NSAID
 Gout
Unwanted effects

 Gastric irritation especially at high doses and eldely

 Salicylism especially at high doses which is manifested as tinnitus & hearing difficulty, dizziness,
headache, confusion.
 Gastrointestinal effects: Abdominal pains, nausea and vomiting
 Hypersensitivity may occur: respiratory rhinitis/ asthma, wheezing, urticaria, angioedema,
shock.
 May provoke gout
 Eyes Syndrome (‘wet brain and fatty liver’) in children and adolescent below 16 years
 May worsen bleeding
 Hepatotoxicity
 Cardovascular system- toxic doses amounts may depress heart function and dilates pleripheral
vessels.
NB: Benorylate is an ester of ASA + paracetamol (acetaminophren) which has anti-inflamatory analgesic
& antipyretic effect.It acts longer than ASA and is less likely to cause bleeding and GIT irritation.

Drug interactions
  Aspirin displaces many drugs from albumin binding sites e.g. warfarin, tolbutamide, phenytoin,
probenecid
 Potentiate the effect of anticoagulant e.g. Warfarin, heparin.

Indoleacetic Acid derivatives

Examples: diclofenac, Indomethacin, Ketorolac, Sulindac, Tolmentin, Etodolac

Prototype

Indomethacin (Indocid)

Most powerful inhibitor of prostagladins.Half life is 2-10 hours. Average is 3 hours. Highly protein
bound-90%

Indications

Gout, Patent ductus arteriosus, rheumatoid arthritis, Myocardial infarction

Dosage: 50mg-200mg daily in divided doses.Because of its toxic effect, you should start with the
minimum dose and then increase as the patient can tolerate.

Unwanted effects
 Gastric irritation with ulcer formation, bleeding and perforation may occur.
 Severe headache similar to migraine due to cerebral oedema.
 Vomiting, dizziness, ataxia (staggering)
 Can aggravate existing renal disease
 Allergic reactions – portray cross-allergy with aspirin has been reported
 Fluid & salt retention which reduces the effectiveness of diuretic drugs.
 May cause confusion, hallucination.
 Not recommended for pregnant women and children unless the benefit outweighs the potential
harm.

Propionic acid derivatives

Examples includes: Fenbufen, Ibuprofen, Ketoprofen, Naproxen, Fenoprofen
Prototype

Ibuprofen (Brufen)

Well absorbed in the GIT.Half life 2 hous.Has less incidence of GIT adverse effect compared to aspirin.Its
indicated for moderate pain

Unwanted effects: Epigastric discomfort, activation of peptic ulcer and bleeding may occur, headache,
dizziness, fever & rashes may also occur.

Dosage: For adult start initially with 1.2-1.8g daily in 3-4 divided doses.Preferably after
food.Increased to maximum of 2.4g daily individed doses.For a child 20mg/kg daily in divided
doses for juvenile anthritis/still’s disease.Not recommended for children under 7kg.
Anthranilic Acids/ Fenamic acid derivatives

Examples: mefenamic acid, flufenamic acid/meclofenamate

Prototype

Mefanamic acid (ponstan)

Half life of 4hrs.Slowly absorbed from gut.Eliminated in urine & faeces

Indications
Mild to moderate pain in rheumatoid arthritis (including juvenile arthritis), osteoarthritis,
Dysmenonhea, Menorrhagia
Dosage: 500mg TDS preferably after food.Child over 6yrs: 25mg/kg daily in divided doses. For
not longer than 7days except in juvenile arthritis
Unwanted effects: haemolytic anaemia, upper abdominal discomfort, peptic ulcer & diarrhea
Oxicams derivatives
Examples: Tenoxicam, Piroxicam, Meloxicam

Prototype

Piroxicam (feldene)

Well absorbed in the GIT and has anti-inflamatory effect equal to indomethacin
Has half life of 45 hrs partly due to enterohepatic recycling which helps maintain plasma
concentrations .Other oxicams may have a half life of up to 60 hous.

Indications: Rheumatoid disease, Musculo-skeletol disorders, Gout

Dosage: Adult dose by mouth for rheumatic disease give 20mg daily as a single dose or divided
doses.Child over 6yrs by mouth in juvenile arthritis 5mg daily
Pyrazolone derivatives

Examples: Azapropazone, phenylbutazone, oxyphenbutazone.

Prototype

Phenylbutazone

Has anti-inflammatory, analgesic, antipyretic and uricosuric effects.Well absorbed from the gut .Mainly
excreted unchanged in urine .Half life is 20 hours

Indications
Rheumatoid disease

Musculo-skeletal disorders e.g. osteoathritis, ankylosing spondylitis

Dosage
Initially start with 400-500mg daily then 200-400mg daily in meals.

Not recommended for children under 14yrs.

Drug interactions

Inhibits metabolism of phenytoin and therefore increases its effect.

SIMPLE ANALGESIC/ PARAMINOPHENOL DERIVATIVE

Derivatives of paraminophenol include:-

- Paracetamol,Phenacetin
Phenacetin
Usually not used because of its seroius toxic effects e.g. hepatic necrosis. May also cause skin rash,
fever, renal disease can be worsened.
Paracetamol
Pharmacodynamics

Similar to aspirin in efficacy but has weak inhibitory effect on cyclo-oxygenase hence has no
demonstrable anti-inflammatory effect. Inhibits Prostagladins in the brain not peripherally.

Pharmacokinetics

Better absorbed at night because rate of absorption is related to gastric emptying (slower at night).High
carbohydrate decreases absorption.Slightly bound in plasma proteins.Half life is 2 hrs .The peak plasma
concentration is reached after 30-60min.Analgesic effect is gotten within 20 minutes.It undergoes
extensive liver metabolism through glucuridation to produce a toxic metabolite called N-acetyl-P-
benzoquinone imine.Exretion is in urine within 24 hours.

Indications
Mild to moderate pain and pyrexia in: - tension headache, postoperative pain, Post immunization
pyrexia, Dysmenorrhea, Myalgias, neuralgias and postpartum pain

It has some advantages over aspirin:

 Has no blood coagulation and antiplatelet effects

 Does not irritate the GIT hence good for the elderly
 Not associated with Reyes syndrome, hence appropriate for children and adolescents
Paracetamol may be combined with other analgesics e.g.Paracetamol + Dextropropoxyphene (opioid) =
Distalgesic (Co-proxamol).

Aspirin + paracetamol = Benorilate (Benorylate) which is a ester

Dosage: For adults by mouth 0.5-1g every 4-6 hrs and a maximum of 4g daily
Children: Under 2m :5mg/kg daily; 2m-1yr:60-120mg/kg daily; 1-5 yr:120-250mg/kg daily; 6-
12yr:250-500mg/kg
Unwanted effect: Rashes, blood disorders

Caution and contraindication: hepatic or renal impairement.

Drug interactions
High carbohydrate decreases absorption.Cimetidine hepatic metabolism of paracetamol.

Paracetamol toxicity
10-15g (20-30tabs) or 150mg/kg taken within 24 hrs can cause severe hepatocellular necrosis and
possible tabular necrosis.Maximal liver damage occur in 3-4 days which is featured by
encephalopathy,haemorrhage,hypoglycaemia,cerebral oedema & possible death .Therefore, despite
lack of early clinical features, those who have taken overdose should be referred to the hospital.

Treatement

Activated charcoal of 150mg/kg or 12grams whichever is smaller.Taken over period of one hr.
Acetylsteine & methiomine protects the liver if given within 8-12hrs of paractamol
ingestion.Acetylcysteine provides sulfhydryl (glutathione) group for conjugation of the
metabolite.Acetycysteine is effective up to and possibly beyond 24hrs.Cimetidne is being tested as
possible antidote against paracetamol poisoning.

Those at risk of liver damage should have plasma-paracetamol concentration measurement e.g.
alcoholics.

Mechanism of liver damage

Glutathione is produced by liver in limited amounts. It conjugates paracetamol metabolite, N-acetyl-P-
benzoquinone imine.So in excessive paracetamol metabolite the thiol (SH -) groups of key liver enzymes
are oxidized.This causes death of hepatocytes since no metabolism takes place.

NB: NSAIDS are also available for topical use on skin for elief of symptoms caused by soft
tissue trauma eg diclofenac, ibuprofen, piroxicam and oxyphenbutazone .They occur in form of
gels, cream, ointment etc

WHO GUIDELINES ON THE HEIRARCHICAL USE OF ANALGESICS

These guidelines are based on the intensity of pain.Therefore; objective assessment of pain is
important.Thus:
Mild pain: Non-narcotic analgesics – NSAIDs/ paracetamol
Moderate: Narcotics of low efficacy e.g. codeine, dextropropoxyphen, pentazocin or combined
therapy of NSAID + low efficacy opiod.

Severe pain: High efficacy opiods e.g. Morphine, pethidine, diamorphine

If there is tissue injury you need to include NSAID in the theapy.

Overwhelming pain: High efficacy opiods plus sedatives or anxiolytics eg diazepam or

phenothiazides e.g. chlorpromazine (largactil)
DRUGS TO TREAT HEADACHE
International headache society has identified 129 types.The most common types’ nclude chronic
tension, Migraine and cluster headaches

Common drugs used for the treatment of headache

 NSAIDS , Paracetamol/ acetamicophen; Lidocaine hydrochloride – particularly good for cluster
headache (nose drops); Ergot derivatives – dihydroergotamine
General mechanism of action

Have agonist/ antagonist activity for alpha adrenergic, serotonin & dipaminergic receptors.Firing of
serotoninegic neurons is reduced.

Prophylaxis: Antidepressants e.g. Amitriptyline; Beta adrenergic blockers, Ca2+ channel

blocker, Lithium.

CRITICAL ☺? THINKING ACTIVITY

1. Mr Kariuki, age 80, has osteoarthritis, which causes pain in his back, hips, and knees.His physician
prescribes ibuprofen 400mg PO qid.Why would the physician prescribe ibuprofen rather than a low dose
opiod analgesic? Given his age, what adverse effects of NSAID therapy is Mr Kariuki most at risk for?

2. Mr omondi, age 38, comes to the emergengy department after a fall .A diagnosisi of a sprained ankle
is made.he healthcare provider wraps the ankle with an elastic bandage and advices him to elevate the
ankle and keep it at rest.Aspirin 650mg PO 4 hourly PRN for pain is prescribed.Before instructing Mr
Omondi regarding his Aspirin therapy, your review his health history.What data would you be looking
for which might contraindicate the use of aspirin for Mr Omondi?

DRUGS ACTING ON THE GASTROINTESTINAL SYSTEM

There are different subclasses of drugs used in the above system.

Drugs affecting the gastrointestinal system:

 Ulcer healing drugs

 Laxatives and antidiarrheals
 Anti emetics
 Drugs for gallbladder and pancreatic diseases

ULCER – HEALING DRUGS

There are many classes of ulcer-healing drugs

 H2 – receptor antagonist
 Proton pump inhibitors
 Selective antimuscarinics
 Chelates and complexes
 Prostangladin analogues
We shall now look at some of these commonly used classes

H2 – receptor antagonist
H2 – receptor antagonist are basically found in the gut and mediate gastric acid secretion while H 1
receptors found in the vessels, respiratory tract skin and vomiting center where they mediate different
functions.

Examples of drugs under this class include: Cimetidine, Famotidine, Ranitidine, and Nizatidine
Pharmacodynamics
The production of HCL is mediated histamine, gastrin hormone & Acetylcholine .Histamine is necessary
for the action of gastrin & acetycholine in the production of hydrochloric acid.H 2 – receptor antagonist
heal gastric & duodenal ulcers by reducing gastric acid output as a result of H 2 – receptor blockade. The
parietal cell have H2 – receptors which are blocked, hence no secretion of hydrochloric acid.

Indications
Gastric & duodenal ulcerations ,stomal ulcers,reflux oesophangitis,zollinger – ellison syndrome ;other
conditions where gastric acid reduction is necessary e.g. chronic pancreatic insufficiency e.g chronic
pancreatitis-oral enzyme supplement – may fail to reach the duodenum in sufficient amounts since they
are destroyed by the acid of the stomach .

Unwanted effects:
Well tolerated, dizziness, somnolence or fatigue, rash, headache, Sometimes hypersensitivity
Prototype

Cimetidine (tagamet)

Pharmacokinetics

Ready absorbed from upper GIT. 60% of dose excreted in urine unchanged.Half life is 2 hours

Pharmacodynamics

H2 antagonist.Cimetidine reduces acid secretion by approximately 70% for 4-5 hours.

Indications
 Gastric & duodenal ulcerations ,Stomal ulcers,Reflux oesophangitis,Zollinger – ellison syndrome
 Other conditions where gastric acid reduction is necessary e.g.
 Chronic pancreatic insufficiency
 Oral enzyme supplement – may fail to reach the duodenum in sufficient amounts
since they are destroyed by the acid of the stomach hence used in chronic
pancreatitis.
Dosage

By mouth: 400mg x 2 daily i.e. breakfast and at night.

Depends on when condition is most serious (determined by the type of ulcer).

You can also give 800mg as single dose at bedtime may be good for duodenal ulcers that normally have
high nocturnal acid secretion. Maximum dose: 2.4g daily in divided doses

Infant under one year: 20mg/ kg daily in divided doses; child over 1 year: 25 – 30mg/kg daily in divided
doses.

Unwanted effects
Mild GIT upset, headache, mental confusion.These are common in the elderly

The major adverse effects in thrombocytopenia.Cimetidine also acts as an androgen – receptor

antagonist and can induce gynecomastia , impotence and loss of libido.This sexual effect are particular
for cimetidine and not other H2 antagonists.

Drug Interactions
Cimetidine is a competitive inhibitor of the cytochrome P-450 mixed function oxidase. Hence can
increase the half-life of drugs metabolized by this system e.g. warfarin, theophylline, phenytoin,
benzodiazepine.Cimetidine decreases the absorption of ketoconzole and Itraconozole.The absorption of
cimetidine is decreased by antacids.

NB: Remember the role of Helicobacter pyloric in pathophysiology of peptic ulcer

disease.Hence the use of dual therapy & triple therapy
NB: Parietal cells secrete intrinsic factor as well as hydrogen ions but in normal doses,
cimetidine doesn’t have a sufficient effect on vitamin B turnover to lead to hematological or
neurological complications.
NB: Symptoms of gastric carcinoma can be relieved by cimetidine, so that apparently successful
treatment delays the correct diagnosis.
Proton – pump Inhibitors
Example of drugs in this class: Omeprazole, Lansoprazole, pantoprazole, esomeprazole, rabeprazole.

Pharmacokinetics
Given orally as enteric coated tablet because its gastric acid unstable.Half life is 1hour.Duration of action
is 2-3 days because it accumulates in canaliculi of parientals.

Pharmacodynamics
Irreversible inhibitor of the H-, K+ - ATpase proton pump (hydrogen- potassium adenosine triphosphatase
enzyme system) of the gastric parietal cells.

They block the transport of acid from the cell into the lumen. Omeprazole reduces both stimulated and
basal acid secretion.Usually used for short term treatment ie 4wks-8wks

Indications

 Omeprazole reduces gastric damage induced by NSAIDS.

 Zollinger – Ellison syndrome ,Reflux esophangitis and Peptic ulcers
Dosage: Omeprazole tablets 20mg BD or 40mg OD x 7/7.Child >2 years 0.7 – 1.4mg/kg daily 4-12wks.
Exclude gastric malignancy before starting treatment.

NB: Usually used with antibiotics e.g. amoxycillin or clarithromycin so that Helicobacter pylori which is
usually involved in pepetic ulcer disease can be eliminated. If using:

Clarithromycin 250mg BD, Metronidazole/ trinidazole BD 400mg, Amoxycilin 500mg TDS.Use

these drugs cautiously in liver disease, pregnancy, breastfeeding, gastric malignancy

Unwanted effects
Headache, rashes, pruritus, diarrhoea, dizziness, Nausea & vomiting, Blurred vision, constipation,
flatulences, abdominal pain, mental confusion, gynecomastia, joint and muscle pains, impotence,
somnolence. Reduction of acid may permit bacterial overgrowth and subsequent infections.Omeprazole
has produced hypertrophy of antral gastrin – producing cells with long term use in animals. More
research necessary to see if the same happens in humans.

Chelates & Complex

Chelated bismuth (Bismuth Chelate) e.g. tripotassium dicitratobismuthate can be used in the refinery.

Pharmacodynamics
This chelate act in different ways: direct toxic effect to bacteria, stimulates mucosal prostangladins and
bicarbonate secretion, absorbs pepsin ,coats ulcer base and inhibits H.pylori proteolytic
enzymes.Dosage: 240mg BD x 28/7 (2 tabs BD)

0r 10mls BD (120mg/5mls), or 5mls QID x 28/7 .The treatement may be extended for further 28 days .

Unwanted effects: Blacken feaces, nausea and vomiting, darken tongue

Contra indications: Renal impairment, Pregnancy
Cholinergic antagonist – Antimuscarinics

Examples: propantheline, isopropamide & scopolamine.

Pharmacodynamic
Decrease acetycholine – stimulated secretion and motitlity of the gastrointestinal tract Hence the
reduce the acid secretion by the parietal cells.Required doses produce systematic anticholinergic
effects .These drugs are often used together with H2 antagonists.

Student learning activity: Read more on these drugs

Prostaglandin Analogue
These refer to prostaglandin E1 analogue .They are exogenous prostaglandins.
Pharmacodynamics
Acts on parietal cells to inhibit basal and stimulated gastric acid secretion and stimulate bicarbonate and
mucus production.Bicarbonate and mucusis very important for the maintenance of gastric mucosal
barrier intergrity.

Prototype

Misoprostol

Synthetic prostaglandin E1 analogue .Has antisecretory and cytoprotective properties

Indications
NSAIDS associated peptic ulcer disease.If someone is on NSAIDS for a long time eg for rheumatism ,you
require to give them for prophylaxis.
Dosage: Give 800 micrograms daily is 2-4 doses in Breakfast or main meal. Treatment goes for
4-8 wks .Proplylaxis for NSAID induced gastric & duodenal ulcer: 20micrograms 2-4 doses
daily. Taken with NSAIDs
Unwanted effects
 Diarrhea may be serious to withdrawal drugs
 Others: Abdominal pain, Dyspensia, Flatulences, Nausea and vomiting, abnormal vaginal
bleeding.
Contra indications
Pregnancy or those planning pregnancy .Generally, contraindicated in women of childbearing age unless
patient require NSAID or is at risk of developing NSAID induce- peptic ulcer.Otherwise the patient
should take effective contraceptive measures.

Mosoprostol may increase uterine tone and therefore increase the chances of abortion.

LAXATIVES
Other terms used are purgatives; carthartic, aperient & evacuant.These are medicines that promote
defeacation. Therefore, they are used in constipation. Costipation is passage of stools less frequently
than the person’s own normal pattern .

Types
 Bulk – forming laxatives
 Stimulant laxatives
 Faecal softeners
 Osmotic

Bulk forming laxatives

Examples
 Unprocessed wheat bran – taken with food or fruit juice is the most effective bulk forming
preparation.
 Methylcellulose,Ispaghula,Sterculia
These last three are especially useful for those persons who cannot tolerate bran.

Pharmacodynamics

Relieve constipation by increasing the faecal mass which stimulates peristalsis.

Full effect takes days to develop & patient should be informed of this fact.

Indications: Colostomy, ileostomy, haemorrhoids, anal fissure, chronic diarrhea associated with
diverticular disease; Irritable bowel syndrome.

Stimulant laxative
Examples of substances in this group: Bisacodyl, Anthraquinone group, Senna; dantron/danthron-
indications limited because of potential carcinogenicity/ genotoxicicty.

NB: Castor oil & cascara are obsolete stimulants.

Pharmacodynamics
They increase intestinal motility and often cause abdominal cramps. Avoid in intestinal
obstruction.Prolonged use may cause an atomic non-functioning colon & hypokalaemia.

Faecal softeners

Examples: Liquid paraffin, Bulk laxatives have faecal softening properties;

Arachis oil (ground nut/ peanut oil)

Indications: Impacted faeces, Anal fissure, haemorrhoids

Osmotic laxatives

Examples and indications:

 Magnessium hydrochloride,
 Magnesium salts
 Sodium salts – But may increase Na+ & H2O retention in susceptible individuals.
 Phosphate enemas – useful in bomel clearance before radiology, endoscopy & surgery.
  Lactulose: - Semisynthetic disaccharide which is not absorbed from gastro-intestinal tract.
Produces an osmotic diarrhea of low faecal pH and discourages the proliferation of ammonia –
producing organisms hence useful in the treatment of hepatic encephalopathy.
Pharmacodynamics

Increases the amount of water in the large bowel, either by drawing fluid from the body into the bowel
or by retaining the fluid they were administered with.

ANTIDIARRHEALS:

Introduction

They are drugs used to arrest diarrhea. Diarrhea can be acute whereby it lasts 3days-3 weeks and has a
sudden onset in a previously healthy individual. Chronic diarrhea lasts 3-4 weeks with recurring passage
of diarrhea stools, fever, anorexia, nausea, vomiting, weight reduction and chronic weakness.

Subdivisions

Opioid related drugs

These reduce the tone of small/large intestine which slows the transit of material. Peristalsis inhibited
but segmental activity (circular contractions) that mix intestinal contents. Examples: Opium tincture,
Codeine, difenoxin, Diphenoxylate

However, these drugs may delay elimination of poisons, injection agents or bacterial toxins hence make
condition worse.

Adsorbent antidiarrheal agents

Pharmacodynamics

These drugs act by coating the walls of the gut, adsorbing the bacteria or toxins causing the diarrhea and
passing them out with the stools. They are taken after each loose bowel movement until the diarrhea
has been controlled. Example, activated charcoal.

It is indicated for the prevention and relief of intestinal gas, diarrhea & gastrointestinal distress
associated with indigestion. It acts as an adsorbent and detoxicant irritants. It may also adsorb
medication, nutrients and enzymes.
Dosage: 2 capsules every 30-60 minutes as needed up to 8 doses for treatment of diarrhea symptoms.
Tablets may be chewed or dissolved in the mouth and followed by water.

Kaolin with pectin

This is a apple or citrus fruit extract.Kaolin is a natural hydrated aluminum silicate that is relatively inert
but carries the danger of obstruction; stools appear to be more formed with this agent. Pectin causes a
decrease in the intestinal pH, which destroys bacterial growth because of the unfavorable acid medium.

Dosage: 45-90ml after each loose bowel movement. Kaopectate tablets contain 600mg attapulgite per
tablet; the dose is 2 tablets after each bowel movement.

Others: Bismuth salts e.g. Bismuth subsalicylate – control travelers diarrhea

Indications

Diarrhea araising from whatever cause

Unwanted effects

 Decrease the number, consistency and fluidity of the stool.

 Decrease the levels of vitamins A, D and K. Thus supplemental vitamins should be added to the
diet.
 May interfere with the absorption of medications given concurrently e.g. digoxin, clindamycin,
lincomycin & quinidine
Note the following on the use of antidiarrheals
Before using them be sure that the patient is constipated & constipation is not secondary to an
underlying undiagnosed complaint.

Misconceptions about bowel habits have led to excessive laxative use: - which may lead to
hypokalaemia and an atomic non-functioning colon. Hence laxatives should generally be avoided except
where straining will exacerbate a condition e.g. Angina, worsen haemorrhoids .Laxatives are generally
used for

 Drug induced constipation for the expulsion of parasites after anthelmic treatment
 Clear GIT before surgery or radiological procedure.
NB: Prolonged treatment of constipation is unnecessary except sometimes in elderly
Children
Laxatives use discouraged in children. Infrequent defaecation may be normal in breast-fed babies or in
response to poor intake of fluid and fiber. Delay for more than 3 days may cause hard stools, cause pain
in passing stools, cause anal fissure.

Children can tolerate:

 osmotic laxatives e.g. lactulose or

 Bulk – forming laxatives e.g. methyl cellulose.
Enemas and suppositories may be given to clear the mass. This may be done under heavy sedation or
anesthesia (for manual evacuation).

NB: Prolonged treatment of constipation is unnecessary except sometimes in elderly.

ANTIEMETIC DRUGS
Introduction

These are drugs which are used in the controlling of nausea and reduction of vomiting.

Vomiting is a complex reflex and protective mechanism that promotes the rejection of ingested toxins
but may be stimulated by other factors including like fear, pain, movement, pregnancy and drugs
therefore, these may not serve any useful purpose.There are 4 receptors that have been identified as
being involved in mediating the emetic response namely: D2 – Depamine; H1 – Histamine; 5HT3 –
Serotonin; M1 – muscarinic Anti emetic drugs available may act on these different receptors.

Classes of antiemetic agents

 Acetylcholine receptor antagonist
 Dopamine receptor antagonists
 Antihistamines
 5HT receptor antagonist

Acetylcholine receptor antagonist

Examples: Scopolamine, hyoscine

Pharmacodynamic
Blockages of muscarimic type one receptors in the vestibular system.

Pharmacokinetics
Well absorbed in the GIT.Crosses the blood brain barrier.half life is 15-30 minutes.Metabolism in the
liver and excretion in urine

Indications
Prophylactic treatment for motion sickness

Preanaestetic agent (depress salvation and respiratory secretions).

Dosage – 0.5mg over 72 hours

Unwanted effects: Blurred vision, decreased sweating, constipation, dry mouth

Contra Indications: Patients with cardiac diseases, children and elderly adults, lactating
mothers
Antihistaminic antihemetics

Examples: Cyclizine, Promethazine, Mechizine, Hydroxyzine, Buclizine

Pharmacokinetics
Excreted in urine within 24 hours .Should be taken 30 minutes before travel.

Pharmacodynamics

Antihistamines block the action of histamine on H1 receptors. Most antihistamines group of drugs are
not specific and also blocks acetylcholine receptors. This makes them effective anti emetics

Indications: Motion sickness, Post -operations, Labyrithine disorders

Unwanted effects: Drowsiness, dry mouth
Drug Interaction
 Anticholinergic effect enhanced if concurrently administered.
 Cause additive depression with concurrent use with CNS depressants

Dopamine receptor antagonist

Examples: chloropromazine, domperidone, Metoclopromide, Haloperidol, Levomepromazine
Pharmacokinetics
Given orally or parenteraly. Metabolized in the liver and excreted in urine

Pharmacodynamics

Blocks the effect of dopamine on the chemoreceptor trigger zone (Dupamine antagonist)

Indications

 Reduce vomiting from caused by cancer chemotherapy and radiation therapy

 Control of post operative vomiting
NB; do not prevent motion sickness

Unwanted effects

Extrapyramidal effects

Serotonin (5HT3) Receptor antagonist.

Examples include: Granisetron, Ondansetron, Tropisetron, dolasetron

Pharmacodynamics

Blocks the 5HT receptors associated with the central connections of the vagus nerve in the
brainstem in close proximity to the CTZ.

Indication

Used in parents receiving caner chemotherapy

DRUGS FOR PANCREATIC DISEASES

Introduction

The pancreas produces four digestive enzymes: Lipase, amylase, chymotrypsin and trypsin. These
enzymes are secreted into the duodenum, where they help digest fats, carbohydrates, and proteins.
Deficiency of pancreatic enzymes can compromise digestion especially of fats. Causes of deficiency
include: Pancreatectomy. Cystic fibrosis, pancreatitis, and obstruction of the pancreatic duct; in these
conditions replacement therapy is needed.
Examples

Pancreatic enzymes are available as two basic preparations:Pancreatin and Pancrelipase

PANCREATIN

Pharmacokinetics

It is inactivated by gastric juice; therefore it is enterically coated to increase absorption.

H2 receptor antagonists have been used to decrease this inactivation.Excretion is through the through
feces.No absorption & distribution because it acts locally.

Pharmacodynamics

Replaces endogenous exocrine pancreatic enzymes and aids digestion of starches, fats and proteins.

Indications

 Used as replacement therapy in the symptomatic treatment of malabsorption syndrome

caused by established pancreatic insufficiency.
 Cystic fibrosis of the pancreas
 Chronic pancreatitis
Dosage: Adults and children – dosage varies with condition being treated.

Usual initial dose – 8000 – 24,000u of lipase activity orally before or with each meal or snack.Total daily
dose may also be given in divided doses at 1-2 hr interval throughout the day.

Unwanted effects

 GIT disturbances
 Diarrhoea with high doses
 Increased serum uric acid levels
 Allergic reactions
Contra indications

 Hypersensitivity to drug
 Acute pancreatitis
NB: Patient teachings on diet and drug are very important.

PANCRELIPASE

Pharmacokinetics

Taken orallyas enteric coated microspheres. It’s given together with Antacids and histamine2 receptor
blockers to reduce gastric pH thereby protecting the enzymes from inactivation.

Indications

 Exocrine pancreatic secretion insufficiency

 Cystic fibrosis in adults and children
 Steatorrhea and other disorders of fat metabolism secondary to insufficient pancreatic enzymes.
Dosage

Adults and children who are 12 years old and above: 4000 – 48,000u of Lipase with each meal.Children
7-12 years; 4000 – 12,000u with each meal.1-6 years: 4000 – 8000u

6 months: 1 year – 2000u

Pharmacodynamics

Replaces endogenous exocrine pancreatic enzymes and aids in digestion of starches, fats and proteins.

Unwanted effects

 Nausea, cramping, diarrhoea with high doses

 Increased serum uric acid levels, hence use cautiously in gout.
 Allergic reactions
DRUGS USED FOR GAL BLADDER DISORDERS

Introduction

The gall bladder serves as a repository for bile, a fluid composed of cholesterol, bile acids and other
substances. The acids present in bile facilitate the absorption of fats, while bile acids help solubilize
cholesterol.The most important condition affecting the gallbladder is cholelithiasis (formation of gall
stones)
Examples: Chenodiol, Ursodiol, Monoctanoin

Prototype

CHENODIOL

Pharmacokinetics

Well absorbed in GIT – in small intestines because it is insoluble at gastric pH. Metabolized in liver and
undergoes enterohepatic circulation.Distribution – most of the total body concentration of chenoidiol at
steady – state is present in enterohepatic circulation, therefore minimal amounts of the drug are
available for distribution into other body fluids and tissues.It crosses the placental barrier. When given
intravenously t½ is 3.1 hour.When given orally 60-80% of the drug is cleared on first pass through the
liver.Excreted in feces principally as unmetabolized chenodiol.

Pharmacodynamics

Chenodiol is a naturally occurring bile acid that reduces hepatic production of cholesterol. This facilitates
the gradual dissolution of cholesterol gallstones.

Chenodiol may also increase the amount of bile acid in bile, an effect that may enhance cholesterol
solubility.

Indications

A. Gallstones – for the dissolution of radiolucent cholesterol gallstones in patients with

radiographically well-visualised gall bladder who require cholecystectomy but are at increased
surgical risk from systemic disease.
B. Hypertriglyceridemia
Dosage: Administered orally, Adults – 250mgs twice daily for the first 2 weeks increasing by 250mgs at
weekly intervals until the recommended dosage of 13-16/kg daily is reached or intolerance
occurs.Children above 12 years: 15 mg/kg daily.

Unwanted effects

 Dose related diarrhoea – 30-40% of patients.

 Dose related hepatoxicity – liver function tests are important.
  Nausea, vomiting, anorexia, epigastric distress
 Leukopenia.
Contra indications

 Pregnant women
 Patients with known hepatocellular dysfunctions
Drug interactions

 Aluminium containing antacids interfere absorption.

 Oral contraceptives
 Anticoagulants – prolong prothrombin time

CRITICAL ☺? THINKING ACTIVITY

1. Alice, age 27, is diagnosed with severe diarrhea of 3 days duration.What criteria should be considered
in the selection of an antidiarrheal agent

2. Why is important to establish the underlying cause of vomiting before administering any antiemetic?

3. What life-style teaching would be important to be supportive of H2 receptor antagonist therapy?

CHAPTER FOUR
DRUGS FOR RESPIRATORY SYSTEM
Introduction

Mechanisms that control functioning of the brochioles

Adrenergic mechanism controlling Bronchioles

No direct sympathetic innervation to bronchioles.
Symphathetic nerve terminals in pulmonary blood vessels release norepinephrine which bind to beta 2
receptors but this stimulation is not strong.Beta 2 receptors well stimulated by epirephine from adrenal
medulla.Beta 2 adrenergic system activation result to the following:Adenylate cyclase activation which
result ot increased cyclic-AMP(2rd messenger) which subsequently result to:

 Relax bronchiole smooth muscles

 Inhibit most cell degranulation
 Stimulate ciliary apparatus to remove secretions
Hence, the following drugs can be used as the act through manipulation of the above system:

 B2 adrenergic agonists – acts through C-AMP

 Phosphodiesterase inhibitors -inhibit breakdown of C-AMP
 Xanthine compounds – bronchodilator effect by inhibiting phosphodiesterase.
Cholinergic mechanism controlling bronchioles
Acetylcholine act on muscarinic receptors (M1, M2, M3) to cause bronchoconstriction through 2 nd
messenger cyclic guanosine monophosphate (C-GMP).Increased formation of C-GMP stimulate most cell
degranulation.Intrinsic asthma thought to arise from stimulation of guanylate-cyclase which synthesis C-
GMP .Noxions gases can stimulate this enzyme.

Drugs for Asthma treatment

A. Asthma control

1. Corticosterids

Prevent and inhibit inflammatory phase of the disease.Example of drug here include: Beclomethasone
dipropionate, triamcinolone, fluticasone propionate

Mechanism of action: Inhibitor phospholipase A2 hence reduce capillary permeability and mucosal
oedema.

2. Inhaled Non-steroidal antiallergy Agents.

Cromolyn sodium, Nedocromil

Mechanism of action: Inhibit mast cell degranulation; hence bronchoconstriction.

3. Leukotriene modifiers eg Montelukast, Zafir lukast, Zileuton

Mechanism of action: Blocks leukotriene receptors in the smooth muscles hence smooth muscles relax

4. Anticholinergics (antimuscarinic)

The most important agent hee is Ipratropium

Mechanism of action: Block the muscarinic receptor hence block vagal nerve impulse to bronchioles.

B.Bronchodilators
These drugs are usually used for actual teatment of asthma

1. B2 Andrenergic receptors Agonists

Example of drugs in this cla include: Albuterol ,Bitolterol ,ephedrine sulfate,terbutaline

sulfate ,Salmeterol,salbutamol,fenoterol,Isoproterenol sulfate.These can be metered aerosol,Nebulized,
oral and Parenteral

2. Xanthines

Example of xanthine include theobromine, caffeine and theophylline.Theophylline is the is usually used
clinically in form of aminophylline.Theophylline (1, 3 dimethyl xanthine) plus
ethylenediamine=Aminophylline which is 85% theophylline. Oxtriphylline is 64% theophylline.

Mechanism of action

Increase cellular c-AMP which relaxes Smooth muscles (bronchodilator effect) & inhibits most cell
degranulation.Also inhibits phosphodiesterase which usually degrades c-AMP.

Theophylline
Pharmacokinetics

Given IV as aminophylline to treatment bronchospasms in status Asthmaticus

It can also be given orally to control bronchospasms in mild, moderate, severe asthma

Its poorly water soluble, hence it’s made in many forms to make it water soluble.
Aminophylline is the most common soluble form of theophylline and is the only one administered iv.Half
life is 3-12 hrs; it might be prolonged in extremes of age and liver disease.In smokers half life is shorter
while in non-smokers its 6hrs.This is because it cigarette smoke induces live enzymes that metabolises
theophylline.It has a very narrow therapeutic index.hence should be admnistred cautiously.

Indications

 Treatment & prophylaxis of asthma

 Cheyne – strokes respiration in which medullary sensitivity to hypoxia is reduced
 Stimulates respiration in newborns who do not breathe well
Dosage: Therapeutic concentration 10-20 micrograms/ml

NB – Stimulates medulary centers of respiration hence the benefit for hypoxic patients.

Unwanted effects

 GIT disturbances eg epigastric pain/ nausea

 Headache, dizziness, nervousness
 Mild diuresis
 Dilation of blood vessels
 Inceased hydrochloric acid secretion
Theophylline toxicity

Toxicity may manifest with the following sign and symptoms if the concentration inceases to 20-30
ug/ml: agitation, exaggerated reflexes, fasciculation (mild muscle tremors), seizures, and cardiac
arrhythmias

Drug interactions

 Cigarette and marijuana induces metabolism of theophylline, hence dosage increased in

smokers by 50-100%
 Cimetidine, erythromycin, fluconazole, oral contraceptives,c++blockers inhibit enzyme
cytochrome p-450 hence metabplism of theophylline reduced which increases its concentration
in plasma
 Rifampicin, phenytoin, carbamazepine induce cytochrome P-450 which reduces theophylline
plasma concentrations.
 Drugs used to control bronchial secretions

These drugs include:

i. Expectorants
ii. Musolytics
iii. Antihistamines
iv. Antitussives
v. Mucosal /nasal decongestants
1. Expectorants
Examples of drugs in this class include
 Glycerylguaiacolate(guaifenesin)
 Ammonium chloride
 Terpin hydrate
Pharmacodynamics

Expectorants render the cough more productive by stimulating the flow and reducing the viscosity of
respiratory tract secretions.Stimulate brochial glands to produce respiratory tract fluid through vagal
reflex.Less viscous fiuids are easily removed by coughing.

Prototype

Glycerylguaiacolate

Pharmacokinetics
 Well absorbed from GIT; Metabolized in the liver;Excreted in the urine.
Indications

Used for the symptomatic relief of respiratory conditions characterized by dry cough, non-productive
cough.

Dosage: Adults and children above 12 years 100-400mg QID

Children 100-200mg QID.The drugs should not be used for more than 7 days.
Contra indication
In persistent cough like those occurring with smoking, asthma, or emphysema, or if cough is
accompanied by excessive secretions.

Pharmacodynamics
Reduce the adhesiveness and surface tension allowing the removal of viscous mucus.

Unwanted effects
 Nausea and vomiting may occur in overdose.
 Dizziness ,headache ,rashes may occur
Drug Interactions
 May increase renal clearance for urate lowering the serum uric acid levels.
 It may increase urinary 5-hydroxyindoleacetic acid and interfere with the interpretation of its
testing for the diagnosis of carcinoid syndrome.

Mucolytics
Pharmacodynamics

They act on disulfide bonds hence liquefying tenacious secretions/mucus by making secretions easy to
be secreted..Water given by inhalation or orally is perhaps the most useful agent in eliminating
secretions.

Prototype

Acetylcysteine

Pharmacokinetics

 Absorbed from pulmonary epithelium following inhataion.

 Readily absorbed from the GUT
 Metabolized in the liver.
Indications

 Treatment for abnormally viscid mucous secretions present in clients with acute and chronic
bronchopulmonary disease or pulmonary complications of cystic fibrosis.
 Used as part of tracheostomy care.
  Treatment of acetaminophan overdose
Pharmacodynamics
It reduces the viscosity of pulmonary secretions through the above mechanism and facilitates their
removal by coughing, postural drainage and mechanical means

Unwanted effects

 Bronchospasm occurring rarely – If it occurs, it is delivered by use of bronchodilators.

 Stomatitis (Redness of mucous membrane, dry mouth, burning of oral mucosa).
 Rhinorrhea
 Nausea and vomiting
Contra indications and precautions
 Clients with bronchial asthma.
 Elderly and clients with severe respiratory insufficiency.
Drug interactions
 After exposure to air, solution should be refrigerated and used within 96 hours.
 Avoid contact with iron, copper or rubber.

Antitussives
Pharmacodynamics

Are drugs used to suppress cough.Act either on the central or peripheral nervous system or on mucosa
locally?

Centrally acting antitusives

 Suppress the cough center in medulla of the brain.
 Divided into two:Narcotics (opiates),Non-narcotics (Non-opiates)

Narcotics
 Codeine ,Morphine ,hydromorphine
Prototype codeine

For cough suppression. Taken orally, though parental administration is possible.

Dosage

Adult’s 15-60mg 4-6hrly: Children 0.5mg/kg 4-6hrly

NB

 Dosage for cough suppressants is lower than for pain.

 Dose of 15-30mg causes drowsiness, thickening of sputum and constipation.

Non-Narcotic antitusives
Effective like narcotics .Given orally, and may cause amophine- like side effects.

Examples: Dextromethorphan hydrobromide, Levopropoxyphen, Carbetapentane

Prototype
Dextromethorphan hydrobromide

Pharmacokinetics
Absorbed readily from GIT, distribution unknown.Metabolized extensively by liver.

Excretion 7-10% excreted in feces. Most excreted through the urine.Half life 11 hours

Pharmacodynamic

It is chemical analog of codeine but does not have analgesic or addictive properties.

Indications

Non-productive cough

Dosage: Adults and children above 12 years – maximum of 120mg daily in divided doses.Children
maximum of 60mg daily in divided doses.Children age 2 to 5 years maximum of 30mg daily in divided
doses.Below two years must be individualized

Contra indications and precautions

In patients taking MAO inhibitors or within 2 weeks of stopping an MAO inhibitors.Cautiously used in
sedated patients.Patients with aspirin sensitivity

Unwanted effects
Drowsiness, dizziness, nausea and vomiting, stomach pains

Peripherally acting antitussives

Used for the symptomatic relief of cough
Prototype

Benzonatate

Pharmacokinetics

The onset of action is 20 minutes. Effects last 3-8 hours.Have no inhibitory effects in the respiratory
center.

Pharmacodynamics
Anesthetizes the stretch receptors in the respiratory passages, reducing cough production.

Dosage: Adults and children above 10 years 100mg tid

Unwanted effects

Drowsiness, chilliness, headache, GIT upsets, constipation and sensation of burning in the eyes.

Drug interaction
CNS effects occur when used with CNS depressants, including alcohol.

4. Antihistamines

These drugs have been discussed later and can be used to control the bronchial secretions.

5. Mucosal decongestants

Pharmacodynamic

Causes r nasal and bronchial decongestion in allergic rhinitis, hay fever, common cold, sinusitis by the
process of vasoconstriction to prevent obstruction of Eustachian tubes.

Available as oral preparations and nasal drops-Ephedrine 0.5%, Phenylehrine 1-2%, xylometazoline
0.05%-0.1%, Oxymetazoline 0.025%.

Prototype

Ephedrine 0.5%

Pharmacokinetics
Absorption is unknown .Distribution widely distributed..Metabolized in the liver

Excretion rate is accelerated with acidic urine.

Indications and dosage

 Bronchodilation, nasal decongestion

 Adults and adolescents 25-50mg P.O. to maximum of 150mg in 24 hours used as bronchodilator.
 Nasal decongestant, 0.5% solution applied as nasal drops to nasal mucosa. Instill no more often
than 4 hourly.
Contra indications and precautions
Patients taking MAO inhibitors, severe hypertension, Cardiac disease, Diabetes, Nursing mothers

Unwanted effects: Anxiety, Tremor, dizziness, headache, Anorexia, nausea, vomiting and dry
mouth, difficulty in urinating
Dosage: Adults and adolescents age 12 and older. Maximum dose of 240mg daily in divided
doses.Children ages 6-11 years maximum dose of 120mg daily.Children ages 2-5yesr maximum
dose 60mg daily in divided doses.
ANTIHISTAMINES

Classes

They are divided into:

 The first generation drugs have strong sedatives effects than 2nd generation drugs.
 The second generation drugs have less sedation due to their less distribution into CNS.
Pharmacokinetics

Agents are rapidly absorbed following oral administration.Peak concentrations occur 1-2 hours after
administration.Are widely distributed with 1st generation entering CNS.

Metabolism – occurs in the liver – its by microsomal systems.Most 2 nd generation drugs are metabolized
by the CYP3A4 system thus are subject to interactions with drugs like ketoconazole (it inhibits the
subtype of P450 enzymes).They have an effective duration of action of 4-6 hours following single
dose.Medicine and most 2nd generation agents are longer acting (12-24 hrs).The newer drugs (2 nd
generation) are less lipid soluble and enter CNS with difficulty.Astemizole ebastine, hydroxyzine,
loratadine and terfenadine have active metabolites.The active metabolics of hydroxyzine and
terfenadine are available as drugs (cetirizine and texofenadine)

Pharmacodynamics
H1 receptor antagonist blocks the actions of histamine by reversible competitive antagonist of the H1
receptor.

Indications
Type 1 hypersensitivity receptors, Alleraic rhinitis, Urticaria, Angiooedema, Motion sickness
(promethazine & piperazines), Rhinorrhoea.

Unwanted effects

Sedation (1st generation), excitation & convulsions in children, postural hypotension, allergic rxn after
topical use, Cardiac arrhythmics

Drug interactions

 Cardiac toxicity & QT prolonation & lethal arrythmics in patients taking terfenadine or
astemizole combined with ketoconazole, Itiraconazole or macrolide antibiotics e.g.
erethromycin.
 Antimicrobiol drugs cause increase in blood concentration of antihistamines.
 Grape fruit juice inhibits CYP3A4 thereby increasing tentenadines blood levels.
FIRST GENERATION H1 ANTAGONIST

Sub-classes
a. Ethanolamines e.g.

- Carbinoxamine, Dimenhydrinace (Benadryl),Diphenhydramine,Doxylamine

b. Ethylenediamines

- Pyrilamine (New aweragen),Tripelennamine (PB2)

c. Piperazine derivatives
- Hydroxyzin (atarax),Cyclizine (Marezine),Medizine (Benine)
d. Alkylamines
- Brompheniramine (Dimetane),Chlorpheniramine (Chlor-Trimeton),
e. Phenothiazine
- Promethazine (Phenergan)
Second generation antihistamic
- Piperidines ,Astemizole (Hismanal),Fexotenadine (Allegra),Terfenadine (Seldane)
Miscellaneous
- Lorated (clarifin),Cetirizine (zyrtec)
CHLORPHENIRAMINE MALEATE

Pharmacokinetics

Well absorbed after oral administration .Peek plasma levels occur within 2-6 hours.

Has rapid and extensive distribution.Half life 12-43 hrs.Metabolism is in the GIT and has first pass
metabolism through the liver after oral administration.Excretion is in urine.

Pharmacodynamics
It binds competitively with histamine at H1 receptor. The binding is reversible. It antagonizes the effects
of histamine at the receptor sites.It crosses the blood brain barrier causing CNS effects.

Indications

Seasonal & perennial allergic rhinitis .Common cold

Pharmaceutics
May be administered orally, S.C, im injection or IV infusion. Dose 4-8mg

Unwanted effects
Sedation, Drowsiness, Dry mouth, Hypertension, Blurred vision

Contra indications/ Precautions

Narrow angle glaucoma, Prostatic hypertrophy, Stenosing peptic ulcer, Pylorodinodenal
obstruction.Bladder neck obstruction
DRUG INTERACTIONS
Interacts with hyoscine, anticholinesterases CNS depressants, Corticosteroids, Phomethezine.Caffeine
counteracts its sedative effects .Photosensitivity reactions occurs with sunlight exposure.

PROMETHAZINE

Pharmacokinetics
Absorbed from GIT.Duration of action ≥12 hours .Well distributed in tissues.

76-93% is protein bound.it crosses placental barriel but distribution in breast milk is not
established.Metabolized in the liver.Excreted in urine and faeces.Half life – unknown.

Indications: Used to treat motion sickness, nausea and allergic rhimitis.

Also used as sedative.Dosage: Can be given orally, retail, im or IV Dose 10-25mg

Pharmacodynamics
As with chlorpheniramine above.

Unwanted effects

Sedation, Confusion, Disorientation

Contra indication
Similar to chlopheniramine

Caution
Cardio-vascular disease, Impaired liver function, Sleep apnea and seizure disorders, pregnacy

Drug interactions
Promethazine interacts with: - anticholinesterases, hyoscine, CNS depressants, corticosteroids, antacids,
anticonvulsants, antihypertensives, oral antidiabetic drugs, thiazide diuretics and ototoxic drugs.
TERFENADINE
Pharmacokinetics
It’s 70% absorbed in GIT after oral administration.Reach peak concentrations in 3-6 hours & lasts 12
hours or more.Distribution properties not known.Its 97% plasma protein bound

Undergoes first – pass metabolism in the liver and GIT

Its excecrated in faeces through biliary elimination

Pharmacodynamics
It binds slowly the H1 receptors and also dissociates from receptors slowly. It is lipophobic and does not
cross blood brain barrier.Instead; it binds selectively to peripheral nervous system receptors.

Indications

Allergic rhinitis.Oronasopharyngeal irritation, Itching, Rhinorrhoea

Dosage: Adults and children above 12 years 60mg BD.

Efficacy in children < years not established.

Pharmacodynamics
It binds slowly the H1 receptors and also dissociates from receptors slowly. It is lipophobic .Instead it
binds selectively to peripheral nervous system receptors.

Should be administered with food or milk to minimize GI irritation

Unwanted effects

Drowsiness, sedation. Headache, nausea, vomiting, abdominal pain, dry mouth.

Arryhythmias & tachycardia

Contra indications/ precautions

Patient with significant liver dysfunctions.Conditions that prolong at intervals

Patients taking erethromycin, ketoconazole or itraconazole.

Drug interactions
Interacts with erythromycin, ketoconazole and itraconazole. The combination prolongs QT interval
producing tachycardua.Exposure to sunlight causes photosensitivity.

CRITICAL THINKING ACTIVITY

1. Mr. Jacob, age 70 was admitted to the hospital with symptoms of fatigue, weakness, dyspnea,
malaise, and a persistent nonproductive cough. He was diagnosed as having a viral upper respiratory
tract infection. Would a mucolytic drug be appropriate for this client? Why or why not?

2. What nursing intervention would be considered appropriate for the nursing management of a client
receiving a bronchodilating agent?

3. There are many clinically useful antiasthmatic drugs. Discuss factors that influence their use in
different clients

PSYCHOTROPIC DRUGS/ PSYCHO-NEUROLOGIC SYSTEM

HYPNOTICS AND ANXIOLYTICS

Introduction

Anxiety, fatigue and insomnia are among the most common pt complaints. Sleep is a circadian,
physiological depression of consciousness. Normal sleep is of two kinds ie NREM (non-rapid eye
movement sleep), also called orthodox or slow-wave EEG sleeps.

Its features are BP & Resp steady or decreased, Muscle relaxed, and Growth hormone minimal; Sleep is
restful, Heart rate steady or decreased. A second type is REM-(Rapid Eye Movement) or paradoxical or
fast wave EEG steep. Its Featured by BP & respiration reduced. Heart rate decrease, Cerebral blood flow,
Penis erect (unless there is dream anxiety), Skeletal muscles relaxed. A normal night begins with a sleep
latency period as the subject passes from wakefulness into NREM sleep.Initial hour of NREM sleep is
followed by about 20min of REM sleep.Then normal cycles is NREM (90min) vs REM (20min) ie about
4cycles for whole night

NB: Hypnotics disrupt normal sleep patterns – suppress REM sleep.

Abrupt withdrawal of drug that has suppressed REM sleep causes a rebound increase as though the
body requires recover what has been lost. Nightmares occur with serious rebound. Abnormal sleep
patterns may persist for weeks which cause emotional disturbance.Hence hypnoptics should be used
when necessary.

Hypnotics – produce/promote sleep.Actual mechanisms of hypnotics is not clear. But thought that they
interfere with nerve impulse transmission in the reticular activating system (RAS).This area contols sleep
and arousal mechanisms.Anxiotytics – antagonize and relieve anxiety through depression of the
CNS.Anxiolytics & Hypnotics cause dependence and tolerance ,hence use them very rarely (acute cases)
and for the shortest period possible & as infrequently as possible. Benzodiazepines are most commonly
used anxiolytics/hypnotics.Barbiturates are obsoltete as anxiolytics/hypnotics but used in
anesthesia.This is because of causing many unwanted effects.

Benzodiazepines

Classification

These drugs are classified according to half life which ranges from 5hours to 24hrs.

 Short-acting e.g. midazolam, triazolam have half life of 5hrs

 Intermediate e.g. lorazepam, Oxazepam clonazepam have a half life of 5-24 hours
 Long-acting e.g. diazepam,Chlordiazepoxide (librium),Prazepam have half life of above 24 hours
Pharmacological effects of Benzodiazepines include anxiolytic, amnestic, sedative, anticonvulsant
(muscle relaxant), hypnotic effect, pre-anesthestic agents

The above classess of drugs has similar basic therapeutic actions but differ slightly in

Lipid solubility, metabolism, elimination and half lives, hence selected for specific therapeutic uses.Good
absorption & distribution because they are highly lipid soluble. Can be given by different
routes.Extensively protein bound to the extent of 80-95%.When given repeatedly they tend to
accumulate especially in obese people or people whose fat-to-lean body mass is increased e.g.
elderly.Metabolism and excretion in liver and urine respectively.

Pharmacodynamics
GABA is a neurotransmitter that mediates inhibitory synaptic transmission in the central nervous
system.Benzodiazepines facilitates Gamma – aminobutyric acid (GABA) mediated inhibition of the
neuronal activity. Particularly in the limbic and cortical areas of CNS.They bind to benzodiazepine
receptors that are part of but distinct from the pentameric GABA-receptor- chloride -channel complex.

This allosterically increase GABA affinity and frequency of GABA stimulated chloride channel opening,
chloride conductance and neuronal hyperpolarization. Also inhibits depolarization by excitatory
neurotransmitter ie anxiolytic effect.

Benzodiazepines have effects onn many parts of the brain:

 Mental confusion & amnesia due to effect on hippocampus & cortical association areas.
 Sleep promotion – effect on sleep wakefulness clock
 Mood altering & emotional effects due to decreased neuronal activity on the limbic system
(hippocampus and amygdala)
NB: Allosteric Sites: sites other than the active site

NB: These drugs have no action in the absence of GABA.

NB: Certain B-carbodines and other ligands called “inverse agonist” some of which may be
endogenous, bind with high affinity to the benzodiazepines receptors (allosteric sites) and can
cause anxiety & induce seizures.
Indications:
 Generalized anxiety disorder,
 Situational anxiety e.g. during dental procedure
 Panic disorders & agoraphobiaAlpazolam – drug of choice here because of its high specificity
 Insomnia – difficult in falling, staying asleep. Triazolam acts first hence used to initiate sleep.
Flurazepam & temazepam acts longer hence used to sustain sleep.
 Seizures – Benzodiazepines elevate the seizure threshold.Used initially for status epilepticus.
 Pre-anesthetic and intraoperative medication – used for their anxiolytic, sedative, amnestic
actionswhich are required in operations eg Lorazepam, diazepam, midazolam.
 Muscle relaxation – muscle spasms,spasticity of cerebral palsy and spasms associated with
endoscopy eg diazepam.
Unwanted effects
Daytime drowsiness ,Ataxia,Rebound insomnia – on withdrawal ;Elderly – confusion, blurred vision,
tremors, constipation, anterograde amnesia;Depress respiration e.g. worsen COPD ;Decrease BP & heart
rate ;Paradoxical effects – hostility, aggression, talkativeness, excitement, antisocial behavour;Enhance
CNS depression when taken in combination with alcohol.

Tolerance: Develops to sedative, hypnotic, anticunvulsant effect but not anxiolytic effect.Cross -
tolerance exist with other sedative/ hypnoptic agent – barbiturates/alcohol

Also causes dependence.

Benzodiazepine withdrawal syndrome: Develops any time upto 3 weeks after stopping long acting
benzodiazepines or within few hours after stopping shortactingbenzodiazepines. It is characterised by
anxiety, insomnia, GIT disturbances, tinnitus, perceptual disturbances, lack of appetite,
perspiration.Flumazenil (Romazicon) can be used to treat this poisoning .It competitively antagonises
benzodiazepine receptors.Used to prevent or reverse the CNS effects from benzodiazepine overdose.

NB1: Chlormethiazole/ clomethiazole

Useful hypnotic in elderly because of its freedom from hangover.Dependence can develop .Short term
use in younger adults to attenuate alcohol withdrawal symptoms

A good hypnotic in elderly

NB 2: Alcohol: Alcohol is poor hypnoptic because its diuretic action interferes with sleep during the
latter part of the night with chronic use, alcohol disturbs sleep patterns and cause insomnia.

NB3: Buspirone (Buspar)

Non- benzodiazepine that relieves anxiety without sedation, hypnosis, general CNS depression or high
dependence potential.Has no other benzodiazepine like activities.

Partial agonist at serotonin (5HTIA) receptors .Response to Rx takes upto 1-2wks.

Good for chronic generalized anxiety especially in elderly who are susceptible to CNS depressant action
of benzodiazepines.May cause tachycardia or GIT distress.

Contraindications

 Epilepsy
  Severe hepatic impairement
 Renal impairment
Dose

Initially 5mg BD or TDS: Increase as necessary in 2-3days.

Usual range 15-30mg daily in divided doses max 45mg daily.

Child – not recommended

Benzodiazepines prototype

Diazepam

Pharmacokinetics

Good GIT absorption.80-90% protein bound.High lipid solubility, hence wide distribution.Onset of action
within 15-45min & diminishes in 3-4hrs. May last for 6hrs.Metabolism liver by conjugation and
oxidation.Has two active metabolites hence long halfl life of 20-100hrs.Excreted in urine .

Pharmacodynamics

Discussed before-see above

Indications

Sedation, Relaxation, Muscle relaxant, Symptomatic anxiety (anxiolytic), Alcohol withdrawal (acute)
syndrome. Induction of GA

Dose: Adult: By mouth 15-30mg/day in divided doses .Child with night temors & somnambulism: 1-5mg
at bedtime .By IM/IV (5mg/min) give 10mg repeat in 4 hrs (PRN) for acute panic attacks and alcohol
withdrawal.By rectum (rectal solution) give 500microfilms/kg OD as required

Unwanted effects

Drowsiness & light headedness following day, Confusion & ataxia (esp. elderly), Dependence, Amnesia,
Paradoxical increase in aggression

Contra indications
Resp. depression, acute pulmonary insufficiency, severe hepatic impairement, Sleep apnoea

PSYCHOTROPIC DRUGS

Introduction

Mentally insane were treated with somatic therapies before advent of psychotropics in 1950s .Such
cruel methods used include Seclusion, Physical restraints, Hydrotherapy

, Psychosurgery .In 1950s reserpine and chlorpromazine were invented and this changed the treatment
of mental illness.In late 1950s monoamine oxidase inhibitors were discoverded while TCAs were
discovered in 1960s. Psychopharmacology has grown greatly over the last few decades.

Neurotransmitter theory/Biochemical theory of mental illness

Behaviour is influenced by chemicals and structural parts (eg limbic system and frontal lobe) of the
CNS .Any alteration leads to behavioural changes. Examples of changes that lead to behavioral
impairements:

 Decrease acetylcholine – cognitive changes may occur

 Dopamine – Hyperdoparminergic activity leads to psychotic symptoms e.g. delusions
hallucinations, agitation etc.
 5HT – secreted – Alterations in levels associated with behaviour & mood changes e.g.
depression or mania/ hypnomania.
 Norep – low Norepinerphrine has been reported in suicidal patients.

Classification of psychotropics

1. Antipsychotics (neuroleptic) drugs-based on chemical structure

I. Butyrophenones
II. Phenothiazines
NB: Based on severity of unwanted effects

I. Typical/classical neuroleptics-More unwanted efects

II. Atypical neuroleptics-less unwanted effects comprared to I above
2. Antidepressants

I. Tricyclic Antideppressants
II. Monoamine oxidase inhibitors
III. Selective serotonin reuptake inhibitors
3. Anxiolytics (formerly called minor trangullizers)

I. Benzodiazepines
II. Azopirones
4. Psychostimulants eg amphetamine

5. Moods stabilizers eg

I. lithium
II. carbamazepine
ANTIPSYCHOTICS /NEUROLEPTICS

PHENOTHIAZINES& BUTYROPHENONES

Examples

Butyrophenones e.g Haloperidol, bendroperidol, fluperidol, benperidol, droperidol

Phenothiazines e.g Chlorpromazine, fluphemazine,-triflupromazines, promethazine, metocloproninde

Pharmacodynamics

Antanagonist activity in mesolimbic and mesocortical areas of the CNS at postjunctional dopamine D2
receptors where dopamine normally intribits adenyly cyclase activity.Also may be antagonist at others
recently discovered dopamines receptor or subtypes (D3-d5) & at serotonin 5HT2 receptors

Pharmacokinetics

Highly lipophilic. Highly bound to plasma protein ie 78%. Metabolised in the liver by oxidation and
conjugation
Chlorpromazine, a prototype of phenothiazines is erratically absorbed>Can also be given by IM and as
depot.Half life of most antipsychotics is 15-30 hrs.When given orally the onset of actions is ½ - 1hr while
IM acts within ½ hr.Elimination is in kidneys.Duration of action 6-24hrs depending on dosage &
frequency of administration.

Indications

Schizophremia,mania,tourette’s syndrome-tics execessive,ballismus,Severe nausea& vomiting e.g use

promethazine,metoclopramide- these drugs block dopamine D2 receptor mediated stimulation of the
chemoreceptor trigger zone (CTZ).

Antipsych are effective for treatment of schizophrenia only in 70% of patients,the rest seems to resit
treatment.The also seem to poorly control negative symptoms e.g. flat effect, social isolation,
ahedonia.Positive symptoms like delusions , hallucination, thought disorder are well controlled.

Unwanted effects

Remember: cholinergic and dopaminergic system is important in the control of movement.Cholinergic

system is excitatory while dopaminergic system is inhibitory.Since the two systems are in state of
equilibrium, any disturbance in either of them causes different impairements

Antipsychotics are not selective therefore; they bind to receptors like muscarinic andrenergic and
histamine H1 receptors.Binding to dopamine receptors causes both wanted and unwanted effects eg

A.Extrapyramidal syndrome/side effects

Due to dopamine –receptor blockade at basal ganglia & elsewhere in the CNS. These CNS effect may
lead to non-compliance. Common with high potency classical antipsychotic i.e. piperazine
phenothiazines like chloropromazine, piperazine thioxanthenes eg Chlorprothixene, flupenthixol
thiothixene &butyrophenones like haloperidol.Not very common with low potency Neuroleptics e.g.
piperidine phenothiazines, aliphatic thioxanthenes.May remit spontaneously

Examples of extra pyramidal side effects

 Acute dystonia – tonic constractions of muscles of the neck, mouth, tongue.Treat with
benztropine
 Akathisia :restlessness, pacing, inability to sit still or rest.treat with propranolol
  Parkinsonian like-syndrome: featured by muscle rigidity, shuffling or propulsive gait stooped
posture, flat facial affect, tremors and bradykinesia. Occur within 1month or few mouths of
use.
 Tardive dyskinesia – irreversible involuntary movements of jaw,mouth,legs Such movement
include tongue protrudes(fly-catcher sign);Puffing of cheeks or tongue ia a cheek(bonbon
sign);chewing movements involuntary movements of the extremities and the trunk.Ussually
occur after many years of drug use though can be precipated by withdrawal even within
six months of use .Are usually irreversible .Tardive dyskinesias occur in 10-20% of patients
affected.
The solution for tardive dyskinesia is discontinuation of the treatment for some time

NB: Clozapine doesn’t induce T-dyskinesias since it’s selective for D4 receptors and nonselective for
D1&D2 receptors hence minimal extraptramidal effects.

B.Neuroleptic malignant syndrome

This is characterized by autonomic instability, muscle rigidity, diaphoresis, profound hyperthermia &
myoglobinenia.It occurs in 1% of the patients. This is managed by discontinuation of therapy &
supportive treatment e.g. bromosciptine to overcome dopamine receptor blockade

C.Autonomic unwanted effects

Adrenoceptor blockade may cause orthostatic hypotension, impotence & inhibits

ejaculation.Antimusacrinic effects may include dry mouth,blurred vision,delayed
micturition,constipation et c

D.Other unwanted effects

 Decrease BP – caused by alpha adrenergic blockade

 Tachycardia-due to anticholinergic effect
 Electrocardiographic alterations
 Myocardial depressant effects
NB: Discontinue antipsychotics gradually over 2-3 weeks, otherwise nausea, vomiting dizziness, tremors,
dyskinesia will occur.

Learning activity-Read on the following prototypes

Chloropromazine (lagarctil) and Clozapine

ANTIDEPRESSANTS

Inroduction

Monoamine theory proposed by Shildkrant in 1965 states that an increase in monoamine transmitters
causes depression while a decrese causes mania

Tricyclic antidepressants

Examples in this class inlude Amitriptyline, Imipramine, Nortriptyline, Clonipramine, desipramine

Pharmacodynamic

Block reuptake of amines e.g. 5HT, Dopamine, Norepinephrine at the synaptic nerve endings, hence
accumulation at the synapse.

Pharmacokinetics

When given oral, they are rapidly absorbed.Its 90-95% protein bound

Binds to extravascular tissues hence has a large distribution volume and low rates of elimination.Half life
is 10-20 hrs .Metabolism is in the liver

Indications

Depression, neuropathic pain or any other state that the client has depressive symptoms .

Dosage:

Unwanted effects

TCAs tend to have affinity for muscarinic, H1 receptors and adrenergic receptors hence the cause many
unwanted effects eg sedation due to H1 effecte, Anticholinergic (antimuscarinic)/atropine- like effects-
dry mouth, constipation. Blurred vision and urinary retention.Postural hypotension, Seizures, impotence

Drug interactions
Antispychotics and steroids may inhibit TCAs elimination.Asprin is phenylbutazone may displace TCAs
from binding sites.TCAs and alcohol pontetiate the effect of each other hence death has been reported
due to severe respiratory depression.

Learning activity: Read about amitriptyline as a prototype

Selective serotonin reuptake inhibitors (SSRIs)

Examples of drugs include Fluoxetine, Paroxetine, Sertraline, and Citalopram Pharmacodynamic

Inhibit reuptake of only serotonin.This explains why these drugs are have lesser unwanted effect
compared to TCAs

Pharmacokinetics

Well absorbed orally.Half life is 15-24hours but fluoxetine has half life of 24-96 hours

Achieve their effects on 2 –4 weeks.Paroxetine and fluoxetine are not used with TCAs since inhibit TCA
hepatic metaboliism

Unwanted effects

Nausea and vomiting, Diarrhoae, Agitation, Insommia, Anorgasmia, priapism

Drug interactions

MAOI plus SSRIS may result to o serotomin syndrome which is characterized by tremors hyperthermia,
CVS collapse, increased aggression and violence.This syndrome is a psychiatric emergency.

Monoamine oxidase inhibitors (MAOI)

Examples of dugs in this class include: Phenelzine, Isocarboxazid, Tranylcypromine, selegiline,

moclobemide, and pargyline

Pharmacodynamics
Inhibit MAO type A and MAO type B.Most drugs inhibit both enzymes but others inhibit one of them eg
selegiline inhibits MAO-B while Moclobemide inhibit MAO-A.This enzyme is responsible for degradation
of norepinephrine & 5HT (MOA-A) and MAO-B- is responsible for degradation of dopamine.

Unwanted effects

Have many unwanted effects since they inhibit many enzyme systems eg decrease BP,tremors,
excitement, lnsommia,weight gain due to increase in appetite, atropine -like effectsie antimuscarinic
effects, hepatotoxicity might also occur

Drug interactions

May interact with tyramine containing foods like Aged cheese, beef ,Chicken liver, Broad bean pods ,
and aged chicken to cause ‘cheese- reaction’.Tyramine cause increased adrenaline production.This
results to increased sympathomimetic effect causing increased blood pressure,headache,intracranial
heamorrhage(hypertensive crisis)

Central nervous system Stimulants/ psychostimulants

Central nervous system is medically acceptable for:-

 Narcolepsy
 AD hyperactivity disorder
 Obesity

Drugs used for Narcolepsy & Attention deficit disorder

Amphetamine e.g. dextroamphetamine, methamphetamine, methylphenidate, pemoline.

Pharmacodynamics

Amphetamines increase effectiveness of catecholamines e.g. increase release during normal CNS activity
.May also block reuptake (amine- pump)at presynaptic membranes hence postsynaptic nerves gets
increase stimulation.Regions usually affected by above drugs:-Reticular activating system (RAS) which
controls level of arousal. Amphetamines stimulate RAS; hence increase alertness & sensitivity to stimuli;
Reward center Actions affecting dopamine at this site are thought to be source of the addictive potential
of amphetamines.
Pharmacokinetics

Given orally and has goodabsorption.Half life is 4-30hrs .Has good distribution and cross bloob brain
barrier.Excretion in the kidneys which is increased by acidifying urine.

Unwanted effects

Stimulate adrenergic system hence cause insomnia, Irritability, Restfulness, Irregular heartbeat, Growth
retardation in children – give during holidays

Caution: cardiovascular disease, Glaucoma, Hyperthyroidism, Psychoses e.g. Schizophrenia, DIP

Learning activity: Read about methylphenidate as a prototype

Drugs for Obesity – anorexiants

These drugs are called anorexiants/ appetite suppressants e.g. Benzphetamine, Diethylpropion,
Mazindol, Phendimetrazine, Phentermine, Phenylpropranolamine, Sibutramine

Pharmacodynamics

Many CNS stimulants suppress appetite by effects on the hypothalamus while stimulating other parts of
the brain.Amphetamines were used initially, but because of addiction, they are not used
currently.Tolerance develops for anorexiants .Therefore, their use is basically in the initial stages of
weight reduction programme.

Pharmacokinetics

Absorb in GIT is good .Anorexiant effect last for 4-15 hrs depending on specific agent

Metabolism is in the liver .Elimination in kidney

Have potential for addiction, hence do not use in patients with history of drug/ alcohol abuse.These
drugs not used in children since there is scanty information but may harm them.

Contraindications

Because of their sympathomimetic effect, avoid in Psychosis, Agitated states, Hyperthyroidism,

Glaucoma, Increased BP
Drugs used for Respiratory depression/ Analeptics

Examples of drug here include: Methylxanthines e.g. caffeine, aminophylline & theophylline

Pharmacodynamic

Block destruction of cyclic adenosine monophosphate (CAMP) the compound that mediates the effects
of B2 adrenergic stimulation.Increase responsiveness to external stimuli & stimulate respiration

MOOD STABILIZERS

Prototype

LITHIUM

Mood stabilizer indicated for manic – episodes in Bipolar disorders.

Pharmacokinetics

Rapidly absorbed in Gut.Sustained – release formulations are available .Has a wide distribution .Lithium
is an element related in atomic form to Na + & K+. Hence not is metabolized but excreted by mechanisms
similar to Na+ & K+. Approximately 80% filtered is reabsorbed at proximal tubule (same site as Na+) and
20% excreted. NB: Intake of Na+ & H2O is the principle determinants of lithium elimination.The more the
intake of Na+ & H2O the higher the elimination & vice-versa.Hence, diuretic may reduce lithium
elimination & lead to toxicity.

Toxicity can be treated with sodium chloride & H2O.Half life is 24 hrs .May increases to

36 hrs in adult (older), hence decreased dose.Lithium has a very narrow therapeutic index

Pharmacodynamics

Not exactly clear but thought to act in different ways: Inhibit 5HT & NE; Affects 2rd messenger
pathways; Cyclic Amp.The net effect is reduced noradrenergic transmission.

Indications

 Mania phase in MDP

 Prophylaxis for recurrent mania
  Don’t use for more than 3-5yrs because of renal toxicity.Plasma level conc. Monitor is vital.
Dosage: Therapeutic range 0.6 – 1.2mEq/L or 0.2-2g/day

Unwanted effects

 Early pregnancy – congenital malformation-Contraindicated.

 Hypothyroidism because it inhibits thyroxine secretion
 Nephrogenic diabetes inspidus – distal renal tubule become refractory to antidiuretic
hormone..Renal damage for long term use – monitor renal functions continuously 3-5yrs
Lithium toxicity

Toxic dose is 1.5-2mEq/L, hence hasd a very narrow thera peutic index

Toxic effects depend on plasma conc. e.g.

At 1.5-2 – vomit, diarrhea, muscle weakness, ataxia, slurred speech.

At – 3 – myoclonic twitches/movements, urinary/fecal incontinence, choreoathetoid movements

Treatment for this toxicity

Nacl + H2O, Osmotic diuretic – urea, mannitol; Aminophylline & acetazolamide which increase
elimination; Dialysis – penitoneal /Hemodydialysis in severe cases

CRITICAL ☺? THINKING ACTIVITY

1. What factors would need to be included in an education plan for a client taking benzodizepines? if the
client were a young married woman? an elderly client? a child?

2. What nonpharmacological nursing measures should accompany the administration of a sleep

medication?

3. Describe the role of anorexiant therapy in the overall weight reduction program?

4. Compare and contrast the clinical utility of tricyclic antidepressants, MAOIs, and SSRIs.
DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM
There are many classes of drugs acting on the above system

Diuretics, antihypertensives, antihypotensives, antianginals/vasodilators, antiarrhythmic agents, fluids

and electrolytes and cardiac glycosides

ANTIHYPERTENSIVES

Introduction
Catecholamines (Dopamine, Norepinephrine, and Epinephrine) metabolism occurs through the following
process:

Tyrosine – dopa – dopamine –nor adrenaline

- Dopadecaboxylase

Norepinephrine is sympathetic postganglionic neurotransmitter while epinephrine is a neurohormone

from adrenal medulla.

CLASSIFICATION OF ANTIHYPERTENSIVES/ HYPOTENSIVES AGENTS

1. Sympathetic nervous system inhibitors.
A.Centrally Acting

Pharmacodynamics
Activation of the Alpha 2 in the CNS-- suppresses sympathetic activity. E.g.

i. Methyldopa
ii. Clonidine
iii. Guanfacine
iv. Guanabenz
B. Adrenergic receptor blockers

B1 or B2 adrenoceptors- some non-selective, others selective.

C.Cardioselective
Examples: Atenolol, Betaxolol, Metoprolol, Nadolol, Oxprenolol, Sotalol, Acebutolol, Practolol.These
specifically act on the heart.

Pharmacodynamics

Decrease cardiac output by blocking B1, decrease rennin activity – preferred for patients with angina or
after heart attack. They decrease Ht rate, force of contraction, and coronary resistance.

C.B1 & B2 (non selective)

Examples: Penbutolol, Propranolol, Pindolol, Timolol, Carteolol

D.Alpha and beta blockers

Labetalol

E.Alpha 1 and Alpha 2 (usually non-selective)

Examples: Prazosin, Pentolamine, Phenoxybenzamine, Thymoxamine, Terazosin, Doxazosin

2. Direct vasodilators

Pharmacodynamics

Act directly on vascular smooth muscle – Arterioles & venous dilation- hence decrease peripheral
resistance. Not recommended in the presence of other cardio vascular diseases.

Alpha blockers, Ca++ channel blockers and ACE inhibitors are vasodilators are vasodilators.

3. Calcium channels blockers

Examples of drug in this class: Amlodipine, Diltiazem, Felodipine, Isradipine, Nicardipine, Nifedipine,
Verapamil, Nisoldipine

Pharmacodynamics

Blocks inward movement of Ca++ ion across cell membranes resulting in smooth muscle relaxation
(vasodilatation

4. Angiotensin Converting Enzyme Inhibitors

Examples of drugs in this class: Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, quinapril,
Trandolapril

Pharmacodynamics

Rennin is an enzyme produced by kidney in response to factors like Na + depletion, adrenergic B1.These
drugs inhibit ACE/kinase two, and hence there is reduced formation of angiotensin two which leads to
vasodilation and reduced water retention

5. Diuretics
To be covered later
6. Inhibiting synthesis of noradrenalin
Eg Pargyline.
7. Angiotension II Antagonists e.g. Irsesartan, Losartan, Valsastan

Pharmacodynamic: Vasoconstriction prevented.

Some prototypes in each class are discussed here.

Hydralazine

- Direct vasodilator
- Act by:-
Causing arteriole & venous dilatation by interfering with Ca++ release hence decrease of peripheral
resistance.

- Potent drug when used with a beta blocker or a thiazide.

- Absorbed in GIT
- Metabolism in the liver & excreted in urine.
- Since large dose are required for good effect which causes adverse effects its used in low dose
but in combination with a beta blocker + thiazides.
Dose: for treatment of BP
Orally 25mg BD daily.

Increase to a maximum of 50mg BD daily.

Slow IV. Injection 5-20mg over 20min.

Repeat same dosage after 20-30 minutes if necessary.

For treatment of hypertensive- emergencies e.g. Pre-edampsia.

20mg by IV. Infusion and repeat every 4-6 hrs if necessary.

Adverse effects
Tachy cardiac, dizziness, fluid retention, nausea & vomiting, induced lupus erythematosus when used for
a long time; nasal congestion, lachrymation, par aesthesia, muscle cramp, tremor.

Contra indication
- Patients with tachycardia
- Use cautiously in patients with history of coronary disease & renal impairment
Propranolol
A non-selective Beta blocker i.e. blocks beta receptors and reduce cardiac output and heart rate.
Hypertensive effect due to:

- decreased cardiac output

- inhibition of rennin production
- Fall in peripheral resistance.
- Usually used in conjunction with a thiazide diuretics for treatment of hypertension.
- Full benefit of its effects may not be evident for 6-8 wks.
Adverse effects
Tiredness, depression, masks hypoglycemia, Brady cardia.

Contra indication
- Heart failure
- Asthma
Dosage
Initially 80mg BD daily orally

Increasing at weekly intervals as required.

Recommended maintenance dose is between 160 – 320mg daily.

Methyldopa (Aldomet)

Tyrosine – dopa – dopamine – nor adrenaline.

Dopa decarboxylase

- Dopa decarboxylase is involved in synthesis of noradrenaline.

- Alpha methyldopa can compete successfully with dopa for dopa decaboxylase.
This leads to alpha methylnoradrenaline formation instead of nor adrenaline.

Now stimulation of sympathetic nerve releases alpha methyl noradrenaline which acts as a false
transmitter.

- Sympathomimetic action of this neurotransmitter is much less than noradrenaline.

- INCNS the false transmitter inhibits sympathetic outflow so there is a reduction in vascular tone
and BP decrease.
- Peripheral resistance falls.
- Inhibition of decarboxylation of 5-hydroxytryptophan (5HT) leads to fall in 5HT in brain causing
depression.
- Methyldopa reduces the concentration of catecholamine – dopamine, noradrenaline, &
serotonin.
- Onset of action when orally given 2 hrs maximum effect reach in 6-8 hrs
- ½ dose administered orally is absorbed.
- Metabolism – liver
- Excretion- urine as metabolite (75%) and unchanged fraction.
Indications
- Treatment moderate to serve BP + diuretic
- Hypertensive crices good response e.g. MAO I & tyramine containing food.
Dosage
Orally increase BP 250mg TDS daily.Gradually increase to maximum 3g daily.By iv. Infusion methyldopa
hydrochloride 250 – 500mg repeated after 6 hrs if required.
Adverse effects
- Dry mouth, sedation, depression, drowsiness, diarrhea, fluid retention, failure of ejaculation,
liver damage lupus erythematosus like syndrome tare.
- 20% of patients taking methyldopa (especially in direct combination test but very few develop
haemolysis.
- The antibody does not react with the methyldopa but with the red blood cells antigens of the
Rhesus negative system.
- The presence of a +ve combs’ test reactions doesn’t indicate that methyldopa needs to be
discontinued.
Contra indication
Patients with History of depression active liver disease and phaeochromacytoma (paraganglioma –
tumor of adrenal medulla, or of structurally similar tissues associated with the sympathetic chain)
symptoms due to excess of these substances.

[Combs’ test
Highly sensitive test designed to detect antibodies to red blood cells.

The direct method – detects those bound to RBCS. Indirect method detects those circulating unbound in
serum. Direct method is especially useful in the diagnosis of haemolytic syndromes]

Captoril
- An angiotensin – Converting Enzyme inhibitor.
- Prevents formation of angiotensin II, eliminating its vasoconstrictor effects and also decreasing
aldosterone production & fluid retention.
- ACE also breaks down some inflammatory peptides such as bradykinin, and the potentiation of
these may contribute to its antihypertensive.
- Captopril potentiates the effects of Bradykinin.
- Given orally. Metabolized in liver. Excreted by kidney.
Therapeutic uses
- All grades of essential hypertension
- Adjunct treatment in heart failure.
- Very useful in treatment of hypertension in diabetes as it delays the onset of albuminuria.
Adverse effects
Cough (due to potentiation of bradykinin-import for secretion production), hyperkalaemia (potassium
reduction effect of aldosterone are blocked.)

Angiodema also loss of taste, stomatosis, abdominal pain, rash.

Sometimes, protenuria, granulocytosis, nitropenia.

Contra indications
- Pregnancy
- Use cautiously in renal treatment

Drug interactions
When given together with potassium- sparing diuretic or potassium – can produce dangerous
hyperkalaemia.

NB
Combination of drugs is used in 30-40% of patients who do not respond adequately to one drug.

Combination therapy minimizes adverse effects because the drugs are taken in low doses.

These combinations may include:-

- thiazide + beta blocker

- thiazide + ACE inhibitor
- Beta blocker + calcium – channel blocker.
Dietary management of hypertension
Supplementary to drug therapy patients should embark on:

- Weight reduction of overweight

- Restrict sodium intake
- Restrict consumption of caffeine – containing beverages
- Smoking & alcohol may also negatively influence increased BP.

DIURETICS
 - Increase urine flow by acting on the kidney.
- Most agents affect water balance indirectly by altering electrolyte re-absorption or secretion.
- Osmotic agents affect water balance directly.
- Diuretics produce diuresis associated with increased sodium excretion, which results in a
concomitant loss of water and a reduction of extracellular volume.
Therapeutic uses
- Congestive heart failure (CHF)
- Abnormalities in body fluid distribution e.g. edema & glaucoma & reducing plasma volume in
hypertensive patients.
- Common side effects are related to electrolyte imbalance e.g. hypokalaemia, hyponatremia,
hypochloremic alkalosis.

Classes of Diuretics
- Thiazides and related diuretics.
- Loop diuretics
- Potassium – sparing diuretics
- Osmotic diuretics
- Mercurial diuretics
- Carbonic anhydrase inhibitors

Thiazides and related diuretics

Moderately potent diuretics

Pharmacodynamics
Inhibit sodium re-absorption at the beginning of the distal convoluted tubule and ascending loop of
Henle by interfering with Na+cl co-transporter.

Pharmacokinetics

Absorbed from GIT .Produce diuresis within 1-2 hrs of oral administration & last for 12-24 hrs.Results in
net excretion of Na+ and accompanying volume of water. No action on thick ascending loop of
Henle.Excretion of Cl-, K+, Mg++, is also increased.There is increased absorption of ca ++ .At high doses will
lead to excretion of bicarbonate (HCO 3-).Decreased excretion of uric acid & ca ++ .Usually administered
early in the day so that diuresis doesn’t interfere with sleep.Extra renal effects – vasodilatation,
hyperglycemia .Excreted by tubular secretion

Unwanted effects
- Serious ones are relatively rare
- Main – hypokalaemia
- Metabolic alkalosis
- Increase plasma uric acid – increase chances of gout
- Hyperglycemia – Inhibit insulin secretion by pancreatic islets cells
- Increase plasma cholesterol – long term use
- Male impotence
- Hypersensitivity reactions

Examples
- Bendroflumethiazide (bendrofluazide),Chlorothiazide,Hydrochlorothiazide
- Clopamide ,Benzthiazide,Cyclopenthiazide,Hydroflumethiazide
- Xipamide,Indapamide,Chlortalidone
Related substances
- Chlortalidone (chlorthalidone) & metolazone are Quinazlinones.
- Indolines e.g. indapamide and Xipamide.
Bendrofluazide

Indications

- Hypertension – alone in mild high BP. Combined in severe High BP

- Edema, especially in heart failure
- Diabetes insipidus (Nephrogenic diabetes)
- Prevent stone formation idiopathic hypercalciuria
CAUTION

- Aggravates diabetes & gout

- May exacerbate systemic lupus erythematosus
- Elderly
 - Pregnancy & breastfeeding
- Hepatic & renal impairment
- Hypokalaemia
Dose

Edema

Initially 5-10mg in the morning daily or alternate days.

Maintenance 5-10mg 1-3 times weekly

Hypertension
2.5mg in the morning

Higher dose rarely necessary

Higher dose than this may cause biochemical disturbance e.g. plasma K +, uric acid, glucose, lipids with no
advantage in blood pressure control.

Loop Diuretics
- Good GIT absorption
- Eliminated by filtration and tubular secretion.
- Some elimination occurs via the hepatic biliary route.
o Administration -Oral ,Parenteral
- Diuresis occurs within 5min of IV admin. Or 30 min of oral administration.
Pharmacodynamics
Inhibit active Nacl- reabsorption in the thick ascending limb of the loop of Henle. Inhibits carrier system.

Because of the high capacity for Nacl reabsorption in this segment, agents active at this site markedly
increase water and electrolyte excretion – hence called high ceiling diuretics – hence potential over
medication. “Torrential urine flow” is possible.

Increase excretion of Ca2+, Mg2+, and K+ as they reduce reabsoption of Na+ & cl-

Act within one hr (oral) & within ½ hr (IV)

t½ 90 minutes. Duration of action 3-6hrs.

Examples
Furosemide (Frusemide), Bumetamide ,Torasemide,Ethacrynic acid/ etacrynic
acid ,Torsemide,Piretanide – derivative of frusemide

Therapeutic uses
- CHF – reduce acute pulmonary edema.
- Diuretic resistant oedema can be treated with loop diuretic combined with thiazide diuretic-
synergistic effect.
- Hypertension especially in individuals with diminished renal function.
- Acute hypercalcemia and
- Halide poisoning
- Renal failure
- Nephrotic syndrome
- Treatment of hypocalcaemia
Contra Indications A/E
- Hypotension
- Hypokalaemia (K+ lost)
- Metabolic alkalosis due to H- secretion
- Mg2+ wasting may occur. Ca++ loss also common.
NB
Therapy instituted gradually to minimize electrolyte imbalance & volume depletions

Elderly – hypovolaemia/ decrease BP due to sudden fluid loss.

May cause dose – related ototoxicity especially in individuals with renal impairment, especially
ethacryynic acid than with furosemide.

Administer cautiously in renal impairment and other ototoxic agents e.g. amino glycosides.

Hypersensitivity is possible

Ethacrymic acid can cause GIT disturbances.

Frusemide (LasixR)
 - High efficacy loop diuretic
- Acts on thick potion of ascending limp of the loop of Henle.
- Apart from potassium loss, magnesium & calcium loss also occurs.
- The effect on calcium is utilized in the emergency management of hypercalcaemia.
- Well absorbed from gut
- Highly bound to plasma proteins
- t½ 2 hrs can rise to 10hrs in renal failure.
Indications
- Oedema
- Oliguria due to renal failure
- When given orally, acts within one hour and diuresis last for 6 hrs.
- Over treatment may lead to hypovolcaemia & circulatory collapse because its very effective/
powerful diuretic.
Unwanted effects
- Hyponatraemia, hypokalaemia & hypomagnesaemia.
- Increased calcium excretion
- GIT disturbance
Contra indications
- Comatose state associated with liver cirrhosis
- Renal failure with anuria.
Dose

By mouth

Oedema

Initially 40mg in the morning, maintenance dose 20mg daily or 40mg on alternate days.

May be increased to 50mg in severe cases. Range 20-120mg/day.

Child
1-3mg/kg daily

Potassium sparing diuretics

- Amiloride
 - Triamterene
- Spironolactone
- Cause retention of potassium hence an alternative to potassium supplements with thiazide or
loop diuretics.
Spironolactone –
Aldosterone antagonist hence causes sodium loss & potassium retention. Inhibit Na + retaining action of
Aldosterone

Can be combined with thiazides & loop diuretics so that K+ is conserved in oedema associated with

- Heart failure
- Hepatic cirrhosis
- Ascites
- Relatively weak diuretic hence the need for combination with the above.
Indications
- Oedema associated with hepatic cirrhosis, Ascites, heart failure, Nephrotic syndrome.
- Hyperaldosteronism
- Refractory oedema associated with 20 aldosteronism
Pharmacokinetics
- Good GIT absorption
- t½ 10min but its metabolite, canrenone – 16 hrs

NB
Action of spiranolactone believed to be partly due to canrenone.

Onset of action – slowly (days)

Clinical use

With K+ losing diuretics e.g. loop thiazide especially why hypoki is harzadous e.g. in Patients on difoxin or
amiodarone.

Heart failure

10 hyperaldosteronism (conn syndrome)

20 hyperaldosteronism complicated by ascites

ANTI ANGINAL DRUGS AND OTHER VASODILATORS

Introduction

The drugs effective in the treatment of angina pectoris act by dilating the coronary arteries and/or
reducing the cardiac workload by reducing pre- and after load.

Examples of subdivisions include:

 Organic nutrites and nitrates

 Beta – adrenergic blocking agents
 Calcium channel blockers
 Potassium channel activators
ORGANIC NITRATES
Pharmacodynamic

They reduce preload and after load.Dilate the main coronary arteries rather than the arterioles

Subclasses

 Rapid onset, short acting eg Glyceryl trinitrate (nitroglycerine),Amyl nitrate

 Slow onset, long acting :Isosorbide dinitrate ,Isosorbide mononitrate Pentaerythritol tetranitrate
, Erythrityl tetrarutrate
Glyceryl trinitrate
Oily liquid prepared as tablets mixing with an absorbent base.Half life is 3 min.

Mode of action – Denitration in the smooth muscle cell releases nitric oxide which is a vasodilator.

Route: Sublingually, absorbed from the mucous membrane of the mouth or IV in severe cases.
Dose
Upto 6mg daily acting for 10-45 minutes

Pharmacokinetics

Lipid soluble, well absorbed in GIT

Undergoes first metabolism and is ineffective orally (rapidly metabolized by denitration)

Side effects – feeling of fullness in the head

Adverse effects
- flushing
- headaches
- palpitations
- fall in BP especially with long acting preparations
- Rarely causes methaemoglobinaemias leadiung to cyanotic appearnce.
Tolerance
Occurs with long acting preparations

Contra indications
Severe anaemia, acute myocardial in infection.

BETA ADRENAL BLOCKING AGENTS

Occupy 2nd position to nitrates.

Pharmacodynamics

Reduce myocardial contractivity, slow heart rate, Increase coronary artery spasms in variant angina.

Examples

Propranol, Artenolol, Bisoprolol, Nebivolol, Metroprolol

Propranolol
Indications – Moderate to severe angina (stable)

Mode of action – cause redistribution of coronatry blood flow to ischaemic myocardium.

Dosage: 20-50mg orally tid

Pharmacokinetics
Well absorbed in GIT.undergoes first pass effect. Half - 3 hrs

Adverse effects
 Sudden hypotension
  Pronounced bradycardia leading to cardiac asystole.
 CNS toxicity – fatigue, muscle cramps, lethargy and rarely mental depression and
hallucinations.Excessive bradycardia countered by IV atropine.
Contra indications
 Hypersensitivity
 Cardiogenie shock
 Bradycardia
CALCIUM CHANNEL BLOCKERS
Calcium channel blockers inhibit the passage of calcium through the voltage dependant L-class
membrane channels in cardiac muscle, reduce available intracellular calcium and cause muscle to relax.

Pharmacodynamics
Reduce cardiac contractility, dilate coronary arteries, and reduce after load.

Classfication

 Dihydropyridines (most import e.g. Nifedipine)

 Phenylalkylamines (verapamil)
 Benzothiazepines (Diltiazem)
Examples of calcium blockers
Nifedipine, Amlodipine, Verapamul, Diltiazem, Isradipine, Nicardipine, Nimodipine

DIHYDROPYRIDINES

Nifedipine (Adalat, Depin, Calcigard)

Pharmacodynamics

Binds to alpha –1- subunit of L- channel but at distinct sites. Block channels effectively when ca +
channels are more active.Inhibit platelet aggregation

Pharmacokinetics
Well absorbed from GIT.Half life is 2 hours.Given sublingualy and orally

Undergo metabolism by cytochrom P-450 Cy 3A which is a source of interaction with other drugs.Dosage
is 30mg-90mg OD
Unwanted effects
Headache, Tachycardia, Dizziness, Fatigue, Orthostatic hypotension, Leg cramps, Skin rashes.
Contra indications – Hypertensive emergency

POTASSIUM CHANNEL ACTIVATORS

Pharmacodynamics

Open K+ channels, leaking K+ out of the cells membrane of vascular smooth muscle causing
relaxation.this hyperpolarizes the cell and switches off voltage-dependent calcium channels.

Examples

Diazoxide, Minoxidil, Nicorandil, Pinacidil

NICORANDIL (Zynicor)

Action – Vasodilation (K+ channel activator)

Preferably – on venous side reducing preload but also on arterioles in angina of effort.

Dosage: 10-20mg BD, route – orally

Unwanted effects

Headaches, Dizziness hypotension, same as those of nitrates

OTHER VASODILATORS
Minoxidil, Sodium nitroprusside, Diazoxide, Hydralazine, Papaverine, Alprostadil

HYDRALAZINE
Pharmacodynamics – lowers BP by direct relaxation of the arteriolar wall.

Pharmacokinetics
Well absorbed after oral iv.Elimination complete within 24 hrs.Less than 5% of oral dose is excreted in
urine .half life is one hour. Dosage 5-20mg IV over 20 minutes.Can be given orally 50-100mg daily

Adverse effects
Nausea, vomiting, gastric hypersecretion anorexia diarrhoea.Headache, palpitations, tarchicardia.
Hypersensitivity
Fever, Skin rash, Polynauritis

ANTIDYSRHTHMIC DRUGS

Introduction

Summary of ionic movements (phases of action potential)

Phase O

Rapid depolarization of the cell membrane associated with fast inflow of sodium ions through channels
that are selectively pearmeable to these ions.

Phase 1
Partial repolarisation brought about mainly by an outflow of potassium ions.Sodium channels
inactivated.

Phase 2
It’s the plateau phase.Period when there is delay in repolarisation caused by slow movement of ca ++ions
from the exterior into the cell through channels that are selectively permeable to these ions.Potassium
still exiting the cell.Sodium entering slowly.

Phase 3
Second phase of rapid repolarisation during which potassium ions move out of the cell. Calcium ions
inactivated.

Phase 4

Fully repolarised state during which potassium ions move back into the cell and sodium and calcium ions
move out of the cell.

During this phase, the interior of the cells that discharge automatically becomes gradually less negative
until a potential is reached (threshold) which allows rapid depolarization (phase O) to occur and the
cycle is repeated.Cells that do not discharge spontaneously rely on the arrival of an action potential from
another cell to initiate depolarization .
Cardiac arrythmias are disorders of cardiac function that occur when there is disturbance in Rate,
Rhythm, Impulse generation or Impulse conduction within the heart.This disturbance may be
caused by hypoxia,electrolyte imbalance,trauma,inflammation and drugs.Dysrhythmias may
cause palpitations and cerebral hypoperfussion
Major types of arrhythmias
1. Abnormal Rates of sinus rhythm (SA)

 Sinus tachycardia – abnormally fast rate > 100 beats/ min

 Sinus bradycardia-heartrate below 60 beats/min
 Sinus arrythmia – variability in heart rate associated with autonomic influences and respiratory
dynamics.
 Asystole: Absence of impulse initiation in the heart.
2. Abnormal site of impulse initiation.

Initiation of cardiac impulse at a site other than SA node is by either escape rythms or ectopic
beats.Escape rhythms represent a take over by a slower pacemaker e.g. Junctional escape rhythm –
originates in AV node; rate of 40-60 beats/ min; normal QRS configuration; Ventricular escape rhythm:
originates in purkinje fibers: rate 15-40 beats/ min: Abnormally wide QRS complex.

3. Premature or ectopic Beats

 Premature atrial complexes originate in atria but not at SA node.
 Paroxysmal atrial tachycardia: burst in atrial complexes: regular rhythm, rate 160-220
beats/min; differences in P. wave configuration usually appear.
 Atrial flutter: rapid atrial rate 220-350 beats/min
 Atrial fibrillation: Completely disorganized and irregular atrial rhythm, irregular
ventricular rhythm.
 Premature ventricular compelexes arise from cells located in ventricular mycardium.
 Ventricular tachycardia-Three or more ventricular complexes: rate > 100b/min.
 Ventricular fibrillation: Rapid, uncoordinated cardiac rhythm resulting in myocardial
quivering and lack of effective contraction
4. Conducting pathway disturbance

Atrioventricular block: disturbance in conduction between sinus impulse and ventricular response. Could
be:
  First degree block: prolong PR intervals: regular rhythm.
 Second degree block: some atrial impulses not conducted to ventricles: types I and type
II second degree block.
 Third degree block: complete heart block; no association between atrial & ventricular
conduction.
Electrocardiogram of one cardiac cycle

Description

P wave: Arises when the impulse from the SA node sweeps over the atria.

QRS Compex – represents the very rapid spread of the impulse from the AV node through the AV bundle
and purnkinje fibres and the electrical activity of the ventricular muscle.

T. wave: Represents the relaxation of the ventricular muscle.

The above is a normal ECG which originates from SA node and is known as sinus rhythm.

DRUGS TO CONTROL CARDIAC ANYHTMIAS

Classification of antiarrhythmic drugs

There are four basic classes based on their effect & action on cardiac electrical properties ie on their
electrophysiological effects.
CLASS I
Block voltage –sensitive sodium channels hence they are membrane stabilizers .Drug in this class affect
sodium channels differently in their resting,refractory and open states hence subdivided into:-

Class 1a: Depress phase O, Prolong action potential duration e.g. quinidine, procainamide,
disopyramide.

Pharmacodynamic

Block the rapid inward flux of Na + ion, hence membrane responsiveness is reduced and rapid
depolarization is slowed. Depress phase O, prolong potential duration.

Indication: Ventricular arrhythmias and supraventricular arrythmias.

Unwanted effects: GIT disturbance, dry month and throat, Anorexia and abdominal pain and cramps

Class Ib: e.g. Lidocaine, tocainide, mexiletine.

Pharmacodynamics

Block activated (open) & inactivated (at refractory state) Na + channels.Action on inactivated Na+
channels means they have affinity for diseased cardiac tissue.

Hence they control ventricular arrythimias and decrease ventricular conduction automatiticity ie
spontaneous depolarisaton depressed.Depress phase 0 without involving the autonomic nervous
system.

Indication: Ventricular arrythmias after myocardial infarction

Unwanted effects: dizziness, anorexia, nausea and vomiting, paresthesias and diaphoresis

Class 1 C: eg flecainide, lorcainide, propanfenone, encainide.

Pharmacodynamics

Decraease myocardial membrane responsesveness to sodium,slowing condiction velocity ie they

depress phase 0 markedly hence slowing conduction
Class II
Beta adrenergic blockers e.g. propranolol, acebutolol, esmolol atenolol, metoprolol

Pharmacodynamics

Block B-adrenergic receptors reducing or antagonizing actions of endogenous, catecholamines eg

epinephrine.At high concentration block sodium channels and depress membrane responsiveness –
both automaticity and conduction of cardiac impulses.

Decrease heartrate & produce vasodilation – this decrease BP & reduce myocardial O2 requirements.

Indications

 Supraventricular dysrhthmias
 Ventricular dysrhthimias
Not all class II drugs are specific for B1 receptors hence may bind to B2 receptors & cause adverse effects.

Unwanted effects: Anorexia, headache, vomiting, constipation and nausea

CLASS III
E.g. bretylium, amiodarone, sotalol

Pharmacodynamics
Mechanism of action is not clear but thought to increase/ prolong refractory period and action potential
duration by blocking potassium channels without affecting conduction time or depressing cardiac
contractility.

Hence used to control supraventricular & ventricular arrhythmias

Bretylium:

Inhibits neuronal release of catecholamines. Have some properties of class II.

Prolongs ventricular action potential & not a trial action potential.

Amiodarone
Structurally related to thyroxine. Increase refractoriness & depress sinus node automatically & slow
conduction.
All drugs that prolong action pontential ie prolong QT interval can paradoxically cause arrhythmias
(ventricular tachycardia called “torsade de pointes”.May occur in patients especially in patients taking
other drugs that prolong QT e.g neuroleptics.

Unwanted effects: Anorexia, nausea, vomiting and headache

CLASS IV
Examples: verapamil, diltiazem etc

Pharmacodynamics

Inhibit inward passage of Ca++ ions across cardiac membrane.They depress phase 4 of
depolarization.They also lengthen phase 1 and 2.

Indications

Supraventricular tachyarrhythmias

Learning activity
Read more on pharmacokinetics and dosages of the the above classes of drugs
DRUGS TO CONTROL CONGESTIVE HEART FAILURE
Introduction

Ability to pump blood into arteries depends on strength of ventricular contraction and the resistance
against which the heart works (afterload).After load determined by the blood volme and pressure.

Frank – starling law

Volume of blood that the heart delivers to the arteries depends on stress, exertion and other
factors.How the heart regulates its output to meet these variable demands is determined by the above
law. It states that the force of muscular contraction is directly related to the strengths of the muscle; the
more a muscle is stretched (within mechanical limits), the stronger its subsequent contraction.This
means that when ventricles are filled with larger than normal volume of blood, they contract with larger
than normal force to deliver their entire contents to the arteries.

NB: If cardiac muscle is stretched beyond their mechanical limits, the strenhths of the contraction
decreases and cardiac output falls. CHF results from conditions that increase: Preload, Afterload
Reduced myocardial contraction.This leads to arterial & cardiac output decrease. Compensatory
mechanism result:-

- Increase sympathetic adrenergic activity

- Activation of the rennin – angiotension – aldosterone system.
- Ventricular hypertrophy.
- These mechanisms attempts to maintain cardiac output by affecting preload, afterload &
myocardial contractility.
- These mechanisms fail after short while & cardiac decompesation occurs e.g. urine output
decrease, diaphoresis, CO2 increase, oxygen decrease aerially etc.
- NB:Cardiac output falls below venous return = CHF
- Excessive venous pressure stretch cardiac muscle fibers beyond their limit & strength of
contraction falls further.
- Systematic vasoconstriction results from chronic stimulation of the sympathetic system. This
limits renal flow and causes Na+ & H2O retention and further worsens CHF.
Drugs used for heart failure

1. ACE Inhibitors

Pharmacodynamic

Decrease Angio II (vasoconstrictor) – prevent harmful adaptations that lead to symptoms of congestive
heart failure.

 Causes vasodilation decrease systemic/ pulmonary resistance co improves as workload

improves.
 Also prevent increase collagen deposition & fibrosis in the heart (which lead to hypertrophy)
 May also improve coronary artery blood flow by effects on bradykinin.
Are first line drugs for treatment of CHF

2. Diuretics

Control pulmonary oedema that accompanies heart failure.May be used with ACEI for synergetic
effects.Contractility improves since no excessive stretching of heart muscles.
3. Vasodilators
Persistent vasoconstriction results from long term compensatory sympathetic nervous system
stimulation.This due to chronic cardiac heart failure. Sympathetic stimulation constricts vessels hence
increase worload of heart and decrease cardiac output.

Pharmacodynamics:

Decrease afterload hence increase Cardiac output and decrease wokloadof the heart.

Examples: Nitroprusside, Hydralazine, Isosorbide

4. Adrenergic receptor blockers

Block alpha receptors and cause vasodilation but negative inotropic effect is inappropriate.

5. Inotrophic agents
CARDIAC GLYCOSIDES/ DIGITALIS GLYCOSIDES
Naturally occurring compounds obtained from leaves of Digitalis purpurea (purple foxglove) & Digitalis
lanata (white foxglove).

Indications

- CHF
- Atrial fibrillation or flutter
- Paroxysmal atrial and tachycardia
Pharmacokinetics

Cardiac glycosides are the most common inotropic agents used.The different c.glycosides have different
water and lipid solubility hence specific differences between these agents eg Digotoxin is better
absorbed than digoxin.Are effective in very low doses and effects are dose related.Have very narrow
therapeutic index.Digitoxin is not commonly used because of its long half life of 5-7 days which may
cause toxicity even after discontinuing treatment

Protoypype

Digoxin

Pharmacodynamics
By inhibition of sodium – potassium ATpase (Na + K+ ATphase) pump which normally regulate the Na + - K+
concentration differences across the cell membrane.

Pump inhibition increases intracellular sodium which inhibits further entry of Na + and activate Na+- Ca++
exchange mechanism .calcium accumulates in the cardiac cell hence heart able to contract with
increased force- better output.This causes:

 Positive inotropiv effect ie increased contractility

 Increased cardiac output and perfusion of kidneys and periphery/this leads to better excretion
of fluid by the kidneys
 Increased coronary perfusion
 Have both negative chronotropic (rate) and dromotropic (impulse) effect on the heart.This is an
electrical effect.
Pharmacokinetics
Less lipid soluble than most other C. glycosides.Hence, GIT absorption is 60 – 80%.

High fiber diet may reduce absorption .About 20-25% bound to plasma proteins.

Concentrates in body tissues e.g. heart, skeletol muscle, erythrocytes, kidney, liver, intestines and
pancrease.These extracardial binding accounts for several drug interactions that occur with individuals
receiving digoxin.Also explains the long have life-36-48 hours.Digitoxin has half life of average 6
days.Distribution on space correlates with lean body not fatty tissue.Digoxin crosses Blood brain barrier
& placental barrier also in breast milk.Onset of action is within 30min – 2 hrs – oral .Peak effects
achieved in 2-6 hrs .Onset of action for iv 15-30 minutes.Peak achieved within 1-4 hours.Metabolism
occurs in liver & GIT through normal flora – small amount is excreted through this route.The rest(75%-
85%) is excreted unchanged ,hence caution taken in renal impairement.Digoxin has a narrow
therapeutic index hence plasma concentration monitoring is required ,ECG monitoring,k+ level
monitoring are very critical.

ECG effect of digoxin may include PR prolonged,QT shortened.ST depressed and T depressed

Unwanted effects
Note that digoxin has a very narrow therapeutic index.Some of the unwanted effect include: Rashes,
Glynecomastia
Digitalis toxicity

Usually due to overdose (relative) e.g. in renal impairment. It may cause many miniferstations:

Non- Cardiac unwanted effects

GIT: Anorexia, nausea, vomiting

Neurological: Confusion, Visual disturbance, Fatigue & weakness/ fainting, Dimness of vision, Double
vision (headache), Blind spots (drowsiness), Flashing lights (diarrhea)

Altered colour vision – green, yellow, purple.

Psychological: Psychological disturbance e.g. mood alteration, hallucinations & psychoses, depression.

Cardiac unwanted effects

Most serious & common

- Brandy cardia
- Arrythmias e.g. extra systoles, sinus arrhythmias, paroxysmal atrial & ventricular tachycardiac,
atrial flutter, ventricular fibrillation. All detected by E.C.G.
Management toxicity
Aims

- Discontinue treatment
- Correct hypokalaemia if needed
- If needed e.g.in life threatening situation, give digoxin – specific antibody fragment – digoxin
immune fab (ovine) (Digibind)
How to neutralize the drug
The antidote is composed of digoxin – binding fragments derived from ovine antidigoxin antibodies.The
drug attaches itself to unbound digoxin. As active extracellular digoxin levels fall as a result of the
binding process, digoxin is released from its receptor sites on cells.The newly released digoxin is also
bound to the antibody.Toxicity treatment takes 30 minutes but complete resolution takes 3-4
hrs.Digoxin fab excreted in urine and has half life of 9-10 hrs. Total elimination may take 15 hrs – 1wk
depending on renal function.Redigitalization done after 2-3 days when fab is completely cleared.If not
given when ovine is cleared it may form complexes that are eliminated in urine.
Contra indications
Second degree Av block, Supraventricular anhythmias caused by wolf-parkinson – white syndrome
(disorder of AV conduction characterized by two AV conduction pathways) Hypertrophic obstructive
cardiomyopathy.

Caution
Caution should be exercised in the following conditions: recent myocardial infarction, Sick sinus
syndrome, thyroid disease, Reduce in elderly & renal impairement, Pregnancy, Avoid in hypokalaemia,
Avoid rapid IV administration.

Dose: By mouth

Rapid digitalization 1-1.5mg in divided doses/day

Less urgent digitalization: 250-500 micrograms daily; Elderly 125 mg/day; Usual range 125-
250micrograms .Children: 1month – 2 years -Oral 0.035 – 0.06mg/ kg/day in divided doses; IV 0.03 –
0.05mg/kg/day in divided doses.

NB: Dosage is highly individualized and depends on: Age, Renal function, Lean body weight.
Drug interactions

Toxicity of cardiac glycosides is increased by potassium depleting diuretics eg thiazides and loop
diuretics because low intracellulars K+ which increases the likelyhood of arrhythimias.Patassium
depletion increases sensitivity of cardiac muscles to the effects of cardiac glycosides and reduce renal
tubular secretion of glycosides.Note that steroids,laxatives when used for a long time can also cause
depletion of potassium.

6. Phosphodiesterase Inhibitors
Examples: Amrinone, milrinone

Pharmacodynamics
Inhibits phosphodiesterase III, which degrades cyclic AMP. Hence cAMP accumulates and increases
myocardial contractility and promotes vasodilation.They have positvive inotropic effect and vasodilation
of peripheral vessels

Unwanted effect
Major risk of these drugs is cardiac arrhythimias

DRUGS USED IN HYPOTENSION AND SHOCK

Introduction

These are adrenergic drugs that b9ind to Alpha and Beta receptors

CLASSIFICATION
i. Catecholamines
ii. Non catecholamines
1. CATECHOLAMINES

These are compounds containing a catechol nucleus (ie a benzene ring within two adjacent OH groups
and an amine group containing side chain.

a. Those used to raising arterial blood pressure

Noradrenaline, Adrenaline (epinephrine), Metaraminol, Phenylephrine

b. Those acting on heart muscle

Dopamine, Dobustamine, Isoprenaline

c. Central stimulants
Amphetamine, Dextroamphetamine, Methylphenidate

d. Smooth muscle relaxants

Isoprenaline, Sulbutamol, Terbutaline, Isoxsupine

e. Those used for allergic reactions

Ephedrine, Adrenaline

f. Local vasocontrictors
Phenylaphrine ,Xylometazoline

2. NON-CATECHOLAMINES DRUGS

Introduction
These drugs increase blood pressure either by increasing the total peripheral resistance or by
augmenting cardiac output or by combination of both

Examples: Propranol, Mephentermine, Methoxamine, Metaraminol, Metaproterenol, Oraprenaline,

Dopamine Hcl, Metoprol, Phenoxybenzamine, Atenolol

These are different types of schock and each type is managed according to its cause.

Pharmacodynamics of antihypotensive drugs

Catecholamines bind to alpha and Beta receptors on cell membrane.They either increase or decrease
tissue activity.Non catecholamines inhibit the reuptake of neurotransmitters such as Dopamine,
noradrenaline and serotonin by membrane transporters hence relaxation.

Pharmacokinetics

Catecholamines are inactive orally, hence given through parenteral route.Do not cross the blood brain
barrier.Non -catecholimes some of them are given orally. They are lipid soluble.and and are well
absorbed.Some across blood brain barrier e.g. dexamophetamine and Ephedrine.Excretion is through
the kidneys .Adrenergic drugs are metabolized in the liver.

Indications

Allergic disorders, Cardiac conditions to increase blood pressure, vascular conditions, Bronchial asthma,
premature labour, peripheral vascular disease, Nasal congestion

Metabolic condition e.g. hypoglycaemia. CNS conditions (amphetamine like drugs)

Unwanted effects

i. Cardio vascular system: ventricular arrhythmias, tachycardia, palpitations, myocardial infarction

ii. CNS: Anxiety, restlessness, headache, insomnia

Prototype

EPINEPHRINE (Adrenaline)

Pharmacological class: Adrenergic

Indication and Dosage
Bronchospasms, Hypersensitivity reactions, Anaphylaxis

Dosage: Adult 0.1 to 0.5ml (S.C.), repeated in 10-15 mins or 0.25mg IV in dilution with
saline.Children 0.01ml (sc) ,Repeated in 20min to hrs.
Unwanted effects

CNS: Nervousness, tremors euphoria, anxiety, cold limbs, headache, disorientation, agitation etc.CVS:
Palpitations, hypertension, ventricular fabrillation, shock, anginal pain.GIT: Nausea and
Vomiting.Metabolic: Hyperglycaemia, glycosura.Respiratory – dyspnea.

Drug interaction

When epinephrine is administered with antihistamines, thyroid hormones, antidepressants it may

severe cardiac effects.When given with beta brokers – may cause vasoconstriction & reflex
brandycardia.When given with levodopa – enhance risk of cardiac arrhythmias

When given together with MAO inhibitors they incease the risk of increase risk of hypertensive crisis.

Pharmacokinetics
Well absorbed after S.C. or IM injection.Rapidly absorbed after inhalation.

Metabolized at symphathetic nerve endings, liver, and others tissues to inactive metabolites.Distributed
widely thoughout the body.

Pharmacodynamics

Binds and stimulates alpha and beta adrenergic recxeptors in sympathetic Nervous system.

Contra indications
Celebral arterosclerosis, Coronary insuffieciency, in general anaethesia .Labour,

Organic brain damage

Nursing considerations
Use with caution in patients with Respiratory diseases, heart dieases.Asthma

Heart artythmias, Elderly pts with Diabetes melitus, Hypertension, Benign prostatic hypertrophy
FLUID AND ELECTROLYTE IMBALANCE

FLUIDS

Water comprises of 45% to 75% of total body weight. Infants and young children have more water per
until unit body weight than adults. The importance of body water is highlighted by the fact that:-

i. It is the medium in which all metabolic reactions occur, and

ii. Precise regulation of volume and composition of body fluid is essential to health.

Drugs used to correct abnormal states of hydration

i. Sodium chloride use

Sodium chloride injection is a 0.g% solution containing 154 meq of sodium and 154 meq of chloride per
litre. It is administered intravenously. It is used in treatment of dehydration.

ii. Dextrose 5% in water

Dextrose solution is almost isotonic with blood. It replaces water losses where there is minimal loss of
electrolytes. Hypertonic solutions of dextrose are preferably administered via central vein. If
administered via peripheral vein, it should be done slowly at a rate of about 3ml per minute.

Side effects
- Local pain
- Mombophlebeitis
- Oedema and water intoxication in case of excess administration

iii. Balanced electrolyte injection

After dehydration has been corrected and the serum sodium level is normal, the extra cellular fluid is
further increased by the injection of a balanced electrolyte solution which approaches that of normal
plasma. This solution contains K10meq of sodium, 5meq of potassium 3meq of magnesium 98 meq of
chloride, 27mg of acetetle and 23 mEq of glyconate.

iv. Single salt solutions

- Ammonium chloride solution

- Calcium glyconate
- Potassium chloride injection
- Sodium bicarbonate
- Sodium lactate injection.

Electrolytes

1. Hypokalemia

Hypokalemia is treated by replacing potassium orally or parenterally. A hazard of parenteral correction

of potassium deficit is the production of potassium poisoning, or hyperkalemia. Administration of
potassium salts intravenously must be done with caution to avoid reaching a concentration that can
cause a systole or carchial arreast.

Potassium salts are contraindicated in severe renal impairement, untreated Addison’s disease, acute
dehydration and hyperkalemia. They must be used with caution in cardiac patients.

Preparations dosage and administration of potassium salts

Potassium chloride injection, U.S.P. available in sterile solutions of 10, 20, 30, 40, 60, and 100 mEq of K +
and cl- for injection.

Potassium chloride oral solution contains 20mEq of potassium per 15ml.

Potassium acetate available in 30ml vials containing 3 and 4 mEq of K+ , and as a powder.

Potassium phosphate, diabasic – available as powder.

2. Hyperkalemia
Hyperkalemia is treated by withholding potassium and administering sodium polysterine sulfonate and a
cation exchange resin. The drug is usually given orally or by stomach tube.

Side effects of sodium polysterine sulfonate treatments include anorexia, nausea, vomiting,
hypokalemia, hypocalcemia, constipation and fecal impaction.

Oral dosage for adults is 15g upto 4 times daily by month in 50-200ml of water.

3. Hypocalcemia

Hypocalcemia causes increased excitability of the nerve and neuromuscular junction, which leads to
muscle cramps, muscle twitching and teltany. Numbness and lingling of the fingers, toes and up occur.
The hypertonicity of muscle may cause tonic contractions.

Regardless of underlying cause, hypocalcemia is treated initially with intravenous administration of

calcium ion.

Calcium chloride is a salt of calcium commonly used. Calcium chloride may be given orally.

Contra indications
Hypercalcemia, ventricular fibrillation

Side effects
Peripheral vasodilation and local burning tension. Hypotension, other salts that are used in treatment of
hypocalcemia include:

- Calcium gluconate
- Calcium lactate
- Calcium gluceplate
Hypocalcemia
Treatment is variable and aimed at controlling the underlying disease.

Phosphate salts
Potassium phosphate may be used to treat mild to moderate hypercalcemia. The salts dcrease levels of
calcium through mechanism of action is still unknown. Oral administration for adults consists of 24ml of
molar diabasic sodium phosphate or a mixture salt solution four times daily to supply 3g of
phosphorous. Oral doses may cause nausea and vomiting.

Intravenous dose of 1 litre of a 0.1 molar solution of phosphate salts (0.081 mole of diabasic sodium
phosphate)

Hypomagnesemia
Hypomagnesemia is treated with intravenous fluids containing magnesium 10 to 40 mEq per day for
severe deficit followed by 10 mEq per day for maintenance.

Hypermagnesemia
An excess of Mg2+ may require dialysis. Since ca 2+ acts as an antagonist to Mg 2+, calcium salts may be
given parenterally.

HYPERNATREMIA
Increased concentration of extra cellular sodium may be caused by water loss without equivalent
sodium loss, excessive sodium administration or intake without adequate water intake, or retention of
sodium because of heart failure, cirrhosis of the liver, or nephrosis.

Treatment must be based on serum levels of sodium. If hypernatremia is the result of water
deficit, treatment consists of replenishing body water either orally or by giving dextrose and
water intravenously. Administration of drugs containing sodium may also be withheld and parent
may be placed on sodium restricted diet. Nutrietic diuretics may be administered to increase
sodium excretion.
HYPONATREMIA
Decreased concentration of sodium may result from loss of sodium, which can occur with vigorous
diuretic therapy, prolonged or excessive sweating, renal insuffieciency, addisoris disease and loss of
gastro intestinal fluid. This type of hyponatremia may be treated with 0.9% sodium chloride or Ringers
solution. If sodium deficit is severe, a 37% or 57% sodium chloride solution may be administered.

Sodium chloride in 3% or 5% solution

These solutions are recommended for treatment of severe sodium deficit. The 3% solution contains 513
mEq of sodium per litre. These solutions must be used with caution because of the danger of increased
venous pressure, which may lead to pulmonary oedema. Extreme caution is required if administered to
parents with cardio vascular or renal disease. These solutions should be administered slowly and in small
volumes (200 to 400ml). The patient’s venous pressure should be monitored closely.

CRITICAL ☺? THINKING ACTIVITY

1. What electrolyte imbalance affects the development of digitalis glycoside toxicity? Describe the
mechanism of this effect.

2. How would the differences in the groupings of antidysrhythmic agents affect the management of
client’s care?

3. Joseph,age 50,has mild hypertension,for which reserpine 0.1mg PO daily has been prescribed .As part
of a drug history to be taken before Mr Joseph begins his reserpine therapy,what past medical
conditions would the nurse specifically ask about?

4. Tom, age 58, has angina for which nifedipine 10mg PO tds has been prescribed.What laboratory
values should the nurse monitor during the nifedipine therapy?

5. Mr peter has been on sublingual nitroglycerin for years.The physician has now prescribed a
transdermal patch for him.How will Mr Peter have to modify his therapeutic regimen?

6. What conditions will place clients receiving diuretics at at higher risk for Hypokalemia? What
observations by the nurse would be particularly important for these clients?

DRUGS MODIFYING THE BLOOD

Agent affecting blood coagulation

There are many drugs that affect blood :Anticoagulant and antiplatelet drug,Thrombolytic
drugs,Systemic hemostatic drugs,Local absorbable hemostatic drugs ,Hemostatic drug for replacement
of hemophilia,Drug to lower blood lipid levels ,Drug to lower blood cholesterol
 STAGES OF BLOOD CLOTTING (COAGULATION)

Thromboplastin released by Platelets adhere to damaged blood

damaged tissue cells enters the vessel lining
blood

Intrinsic pathway
Extrinsic pathway

Pronthrombin activator

pronthrombi thrombin
Final
n
common
path way

fibrinogen Loose fibrin

threads

Stabalised
fibrin clot
FIBRINOLYSIS PATHWAY

ACTIVATORS

PLASMINOGEN PLASMIN

FABRIN BREAKDOWN
PRODUCTS
Anticoagulant and Antiplatelate drug

Introduction.Aanticoagulant drug prevent clot formation and do not affect

existing clot

Classification: Heparin and Oral anticoagulant

Antiplatelates on the other hand inhibits the aggregation of platelate and

coagulation in arterial system

Prototypes

Heparin
Is an anticoagulant and naturally occurring .Extracted from pig intestine & bovin
lungs

Pharmacodynamics
Form a complex with a plasma protein called antithrombin III which neutralizes
factor xa, the factor activating the conversion of prothrombin – thrombin .Note
that antithrombin III can also directly neutralize thrombin .However, inhibition of
F-xa, rather than the inhibition of thrombin, appears to be primarily responsible
for the effective anticoagulation action of Heparin.Heparin is also an antiplatelate
agent.In ultro, heparin stimulate platelet aggregation .In vivo, heparin appears to
coat the endothelial lining of the vessels, because heparin is a highly negatively
charged polymer. It adds –ve change to the endothelium that keeps platelets
from attaching and forming a thrombus.
Pharmacokinetics
Administered IV or deep SC.May lead to painful hematomas.Half life is 1-2hrs.

Small amounts l taken by mast cell.Large doses excreted in urine.

Indication
I. Differ with dose and route of administration.For anticoagulation given in
large doses.
II. Prevent post- operative thromboelism –give in small l doses
III. Prevent coagulation of laboratory sample and stored in blood vitro.
Unwanted effects
Allergy reactions may occur – symptom chills, fever, utricamia

Toxicity
May result to hemorrhage.This can be treated using protamine sulfate is given
before it is highly positively charged molecule .It also bind platelet and cause
platelet aggregation – that lead to thrombocytopenia and cause
thromboembolism in 5% patients.

Platelet count should be done daily after therapy due to thrombocytopenia

Oral anticoagulants
Examples; Dicumarol, Warfarin, Anisidione

Dicumarol & warfarin belongs to coumarin class .Coumarin are well tolerated but
two distinct factor

Pharmacodynamics
Cloating factor II, VII, and IX and X synthesized in liver with vitamin K as necessary
co-factor.Coumarins act by interfering with regeneration of active vitamin K in the
liver leading to vitamin K deficiency

Pharmacokinetics
Warfarin is widely used.Administer IM or IV.Well absorbed orally.Peak effect
occur within 36-72 hrs after administration .Dicumarol is longer acting than
Warfarin

Half life is long because of tight bonds with plasma protein which decrease the
effect of the drug.If the drug is displaced it may lead to increased concentration.

Indication
 Prophylaxis or treatment for DVT or pulmonary thrombosis
 Can be used during surgery to reduce thrombus formation
Unwanted effects
Hemorrhage can be caused by oral anticoagulant.Manifested in gingival
bleeding, blood in urine & stool. Drug should discontinue and if the case is severe
you give plasma to replace cloating factors and 50mg vitamin K to overcome
coumarins effect.

Drug interactions
Many drugs alter the effectiveness of dicumarol & warfarin

Anticoagulation action enhanced by drug. Decrease platelet adhesion e.g. ASA,

clofibraty, dextran, dipyridamole, hydrokychloroguin, ibuprofen.Anticoagulation
action of coumarin enhanced by drug inhibiting coumarin degradation e.g.
clofibrate, disulfiran, metronidazole, oxyphenbutazone, trimethoprin.Drugs that
displace bound – anticoagulant :Chloralhydrate, oxyphenbutazone,
phenylbutazone.These enhance its action.There those drugs that interact by
unknown mechanism eg anabolic steroid, climitdin, D-thyroxin, glucagon.Action
of comarin is diminished by drugs that accelerate its degradation eg barbiturates,
griseofolvin and rifampin. Cholestyramine decrease GIT absorption of coumarin.
Dicumarol enhances the action of phenytoin.

Anti platelet drugs

Introduction

When there is break in endothelial lining platelets readily attach to collagen in

exposed tissue. This attachment and aggregate of platelets forms a plug that stop
bleeding and aid the formation of thrombus.

Pharmacodynamic

Some drugs called antiplatelet interfere with this process .Atttachment of platelet
lead to increased synthesis of thromboxane A 2, (ADP) which stimulates further
aggregation of platelets.Drugs like aspirin, dipyridamole, clopidogrel & Ticlopidine
interfere with activation with activation of thromboxane A2.

Indication
 Patient at risk for developing arterial clots eg those who have already had a
myocardial infarction or stroke.
 Heart valve prosthesis, disorder and stunts
Thrombolytic therapy

Introduction
Plasma contain enzyme plasmin which degrades the fibrin network of a clot into
small, soluble fragments.Plasmininogen is activated to plasmin by tissue
plasminogen activator which originates in the blood vessels.Degradation products
of fibrin act as anticoagulant to limit further clot formation.
Pharmacodynamic

Drugs to speed the clot dissolution process are widely used.

Indication

Treatment of choice for an acute myocardial infarction has become the injection
of a clot- dissolving drug as quickly as possible, which prevent the myocardial
ischaemia that lead to tissue death.

Such drugs that can be used include: - IV alteplase, adult: 6-10mg bolus over 1-
2min followed by infusion of 60mg for 1 hr and 20mg next two hours.

Anistreplase – IV adult 30u inject over 2-5min; Reteplase – IV adult 10u over not
more than 2 min, followed in 30 minutes by another 10u.

Homeostatic drugs
Introduction

Are systemic or local agents used to control excessive bleeding eg in hemophilia

eg Aminoceproic acid.

Pharmacodynamics

It inhibits the activation of plasminogen to active enzyme plasmin.Lack of plasmin

inhibit dissolution of blood clots.
Indications

Used to protect blood clots in conditions like surgery of the prostate, after
ruptured cerebral aneurysm, patient with haemophilia after a tooth extraction.

Unwanted effects
Nausea, cramps, dizziness, headache, if given IV can cause irritation of vein

Vitamin K
Introduction

Is fat soluble vitamin required for synthesis of clotting factor II, VII, IX and X in
liver.

Humans cannot synthesize vitamin K but bacteria GI tract can synthesize vitamin
K.

Vitamin K. deficiency may occur because of: Prolong antibody, biliary diseases,
long term IV feeding, acute diarrhea in infant.Oral anticoagulant may drug
produce relative vitamin K deficiency by inhibiting its reactivation .Vitamin K is
available as vit. K1 (phytondione) & vit. K4 (menadil) for replacement therapy; but
only vit. K1 is effective as antidote for severe bleeding episodes caused by
overdose of oral anticoagulant.

Pharmacokinetivcs

The drug can be administered orally. IVadministration must be slowly with dilute
solution. Reaction to IVadministration may be manifested through flushing, heavy
feeling on chest, sweating, vascular collapse and anaphylactic reaction.IM or SC
admistration cause pain at injection site.
Local absorbable homeostatic drug
Local absorbable homeostatic provide a surface that promotes platelets adhesion
and thereby promote blood clotting where the agent is applied.

Absorbable gelatin sponge (gelfoam)

Is a sterile absorbable gelatin sponge that is moistened with sterile saline solution
and applied to bleeding capillary beds that cannot be readily sutured.Absorbed
within four to six weeks.

Absorbable gelatin film (Gelfilm)

Is a thin, sterile absorbable gelatin film used in neurologic, thoracic and ocular
surgery to repair membrane surface.Absorption takes 1wk – 6 months depend on
size and site of the film.

Microfibrillar collagin hemostat

Microfibrillar collagen hemostat (Aviten) is a wate insoluble powder that is
applied to bleeding surface to activate natural clotting.The collagin is absorbed in
7 weeks.

It’s used during surgery to control bleeding in capillary bed, liver, and skin graft
sites. It doesn’t interfere with healing of skin or bone.

Homeostatic Drug Replacement therapy for Hemophilia

Introduction

Hemophilia is an inherited disorder in which there is a deficiency of one of the

factor necessary factors for coagulation of the blood.
Dermopressin
It temporarily increases the concentration of factor VIII and vonwillebrand’s
factor.

These controls mild to moderate bleeding in patient with mild haemophilia A or

vonwillebrand’s disease.Its a synthetic analogue of pituitary hormone
vasopresion.

Contra indications
Not used for patient type IIB of von-willebrand’s disease.Caution for patient
hypertension or atherosclerosis

Drug to lower blood lipid level

Introduction

The lipid in blood are triglycerides and cholesterol.Triglyceride act as enery

source for muscles and stored in fat.Cholesterol is a fat like substance present in
cell membranes and is a percusor of bile acids and steroids.Triglycerides and
cholesterol are bound to special hormones to form soluble lipoproteins eg
chylomicron,VLDL,LDLand HDL.

Chylomicron & VLDL are largely composed of Triglyceride and transport them to
tissue for metabolic use or storage.LDL and HDL transport
cholesterol.Concentration of LDL is directly propotional to the concentration of
cholesterol. In atheresclorosis, there is increased total plasma cholestrol
concentration.Atheresclorosis plaque are formed which are initiated by platelet
aggregation and reduced blood flow.High blood cholesterol is major risk factor of
coronary heart diseases.
Drug to lower blood cholesterol
Major drugs used: - 3-hydroxy-3-methylglutaryl co-enzyme A (HMG - COA)
reductase s inhibitor e.g Atorvastatin (Lipitor),Erivastatin (Baycol),Fluvastatin
(Lescol), Lovastatin (Mevacor) ; bile acid sequestrants and nicotinic acid.There are
other drugs to include fibric acid derivative and estrogen .Pleasde note that
treatment based on LDL level rather than cholestrol.

Pharmacodynamics
It blocks early step in the synthesis of cholestrol by liver.This inhibition in
cholesterol production leads to cellullar increase the number of LDL receptors.
Increased number of receptors cause LDL to be removed from serum – lowering
LDL cholesterol by 20-60% where as HDL cholesterol increases by 5-15%,
triglycerides are lowered by 10-40%.

Pharmacokinetics
The above Statins are taken single dose in evening .Lovastatin taken with meal to
maximize absorption but other drug can be taken with meal or
without .Atorvastatin, lovastatin and simvastatin are metabolized to active
metabolite whereas cerivastatin, fluvastatin and pravastatin are active at
admnistration.LDL reduction stabilizes at 4-6wk of therapy.Metabolism is in liver
and excretion is primarily in the faeces.

Indication
Hypercholesterolemia which is caused by elevated LDL
Unwanted effects
Well tolerated.Unlike fibric acid, they do not increase risk of gallstones.The can
cause dyspepsia, flatulence, constipation and abdominal.Myopathy with
musceaches, soreness, is uncommon effects.

Contra indication
Allergy or in active liver disease .In pregnancy or nursing mothers because they
block synthesize of a key compound for growth and maintenance of future of
fetus.

Interaction
Concurrent administration with cyclosporin, gemfibrolil or niacin with some
statins will incease the risk to muscle damage and acute renal failure.

Bile acid sequestrants

Cholestyramin & colestipol are bile acid sequestrants used to treat high LDL
cholesterol level.

Pharmacodynamics

In intestine, they bind bile acids which are then excreted thereby interrupting
enteroheptic circulation of bile acid.This action cause liver to convert more
cholesterol to bile acids

Cholesterol is converted to bile acids which are subsequently converted to bile

salts.

With hepatic cholesterol lowered more LDL receptor formed on cells and LDL
removal is enhanced.
Pharmacokinetic
These are powders mixed with water or fruit juice.Taken one or 2 dose daily with
meal

Alternatively, one large dose after evening meal can be taken.The effect of
lowered LDL effect is seen within 2 weeks.

Indication
Cholestyramine of colestipol is effective in lowering LDL cholestrol.

Prescribed when diet therapy alone is not sufficient and patient is younger &
moderate hypercholesterolemia.

Unwanted effects & contra indication

GI tract symptoms – constipation, blooting, epigastric fullness, nausea, flatulence

Triglyceride level increase in some patients because of increased hepatic VLDL

production.

Contraindication

Increased triglyceride level.

Drug interaction
May bind other drugs during absorption eg
Digitoxin,Warfarin ,Thyroxine ,Thiazide diuretics and B-
blocker.Therefore,administer them at least 1 hr before or 4 hrs after each other .

Drug to treat anaemia

The requirements for red blood cells formation includes iron, folic acid and
vitamin B12

Drugs in this class include:

 Fe Deficiency anaemia (Fe salts)

o ferrous fumarate, ferrous gluconate, Ferrous sulfate (commonest)
 Vitamin B12 (cyanocobalamin)
o Usually used for pernicious anaemia
 Folic acid: Folic acid, Leucouorin calcium.Used for megaloblastic anaemia
 Hormone for anaemia eg Epoetin alfa.This is Human hormone
erythropoietin which is made by recombinant DNA technology
Prototype
Ferrous sulfate

Introduction

Iron is essential component protein that carry O 2 & CO2.Red colour of blood cause
by iron – O2 complex in heme portion.Iron is also part of electron transport
enzyme of mitochondria responsible for oxidation – reduction reactions

Pharmacokinetics

Almost 10-35% of iron is stored in body.Iron is lost by sheding of cells in GIT, skin,
fingernails, hair & fluids like bile, urine, sweat.

Iron for replacement therapy

Given orally as ferrous salt 50-100mg daily.Fe in ferrous form absorbed readily in
presence of gastric acid.Given before meal through many patients cannot tolerate
because of irritating effect. Enteric forms are not satisfactorily because pass
duodenum.

Over time time patient show better appetite, increase Erythrocyte cell &
decrease microcytic hypocromic anaemia.At least 6 months therapy is necessary
to restore Fe storage sites.It can be given parenterally as dextran ie by slow IV,
IM

Unwanted effects
Oral iron can cause GI tract discomfort, liquid form for infant can stain teeth

Allergic reaction is possible after parenteral administration.

Contra indication
Hemochromatosis/ hemosiderosis, hemolytic anaemia or thalassemia

Toxicity
Children are particularly vulnerable because the tablets are brightly colored and
look like candy.Toxicity manifested by metabolic acidosis,cardiovascular
collapse,extensive damage to liver & kidney.Treatement modalities include:
gastric lavage to remove un-dissolved Fe .An antidote used is deferoxamine
mesylate which combines with iron to form complex thatis excreted in urine(67%)
and feaces(33%).Chronic toxicity can lead to hemosiderosis

Interaction
Vitamin C increases its absorption while antacid prevent its uptake by mucosal
cells.
CRITICAL☺ ? THINKING ACTIVITY

1. Mary, age 58, is admitted in in a hospital for treatment of acute

thrombophlebitis in her right calf.The physician orders strict bed rest and heparin
5000U by IV bolus, followed by 1000U/hr.Why would heparin be the
anticoagulant of choice? How would you best monitor the effectiveness of the
heparin?

2.Mr mathenge has been on cholestyramine for 6 months .On follow up, he
indicates that he has been increasingly experiencing nosebleeds.What might be
happenimg to him?

DRUGS FOR RESPIRATORY SYSTEM

Introduction

Mechanisms that control functioning of the brochioles

Adrenergic mechanism controlling Bronchioles

No direct sympathetic innervation to bronchioles.

Symphathetic nerve terminals in pulmonary blood vessels release norepinephrine

which bind to beta 2 receptors but this stimulation is not strong.Beta 2 receptors
well stimulated by epirephine from adrenal medulla.Beta 2 adrenergic system
activation result to the following:Adenylate cyclase activation which result ot
increased cyclic-AMP(2rd messenger) which subsequently result to:

 Relax bronchiole smooth muscles

  Inhibit most cell degranulation
 Stimulate ciliary apparatus to remove secretions
Hence, the following drugs can be used as the act through manipulation of the
above system:

 B2 adrenergic agonists – acts through C-AMP

 Phosphodiesterase inhibitors -inhibit breakdown of C-AMP
 Xanthine compounds – bronchodilator effect by inhibiting
phosphodiesterase.
Cholinergic mechanism controlling bronchioles
Acetylcholine act on muscarinic receptors (M1, M2, M3) to cause
bronchoconstriction through 2nd messenger cyclic guanosine monophosphate (C-
GMP).Increased formation of C-GMP stimulate most cell degranulation.Intrinsic
asthma thought to arise from stimulation of guanylate-cyclase which synthesis C-
GMP .Noxions gases can stimulate this enzyme.

Drugs for Asthma treatment

A. Asthma control

1. Corticosterids

Prevent and inhibit inflammatory phase of the disease.Example of drug here

include: Beclomethasone dipropionate, triamcinolone, fluticasone propionate

Mechanism of action: Inhibitor phospholipase A2 hence reduce capillary

permeability and mucosal oedema.

2. Inhaled Non-steroidal antiallergy Agents.

 Cromolyn sodium, Nedocromil

Mechanism of action: Inhibit mast cell degranulation; hence bronchoconstriction.

3. Leukotriene modifiers eg Montelukast, Zafir lukast, Zileuton

Mechanism of action: Blocks leukotriene receptors in the smooth muscles hence

smooth muscles relax

4. Anticholinergics (antimuscarinic)

The most important agent hee is Ipratropium

Mechanism of action: Block the muscarinic receptor hence block vagal nerve
impulse to bronchioles.

B.Bronchodilators
These drugs are usually used for actual teatment of asthma

1. B2 Andrenergic receptors Agonists

Example of drugs in this cla include: Albuterol ,Bitolterol ,ephedrine

sulfate,terbutaline sulfate ,Salmeterol,salbutamol,fenoterol,Isoproterenol
sulfate.These can be metered aerosol,Nebulized, oral and Parenteral

2. Xanthines

Example of xanthine include theobromine, caffeine and theophylline.Theophylline

is the is usually used clinically in form of aminophylline.Theophylline (1, 3
dimethyl xanthine) plus ethylenediamine=Aminophylline which is 85%
theophylline. Oxtriphylline is 64% theophylline.
Mechanism of action

Increase cellular c-AMP which relaxes Smooth muscles (bronchodilator effect) &
inhibits most cell degranulation.Also inhibits phosphodiesterase which usually
degrades c-AMP.

Theophylline
Pharmacokinetics

Given IV as aminophylline to treatment bronchospasms in status Asthmaticus

It can also be given orally to control bronchospasms in mild, moderate, severe

asthma

Its poorly water soluble, hence it’s made in many forms to make it water soluble.

Aminophylline is the most common soluble form of theophylline and is the only
one administered iv.Half life is 3-12 hrs; it might be prolonged in extremes of age
and liver disease.In smokers half life is shorter while in non-smokers its 6hrs.This
is because it cigarette smoke induces live enzymes that metabolises
theophylline.It has a very narrow therapeutic index.hence should be admnistred
cautiously.

Indications

 Treatment & prophylaxis of asthma

 Cheyne – strokes respiration in which medullary sensitivity to hypoxia is
reduced
 Stimulates respiration in newborns who do not breathe well
Dosage: Therapeutic concentration 10-20 micrograms/ml
NB – Stimulates medulary centers of respiration hence the benefit for hypoxic
patients.

Unwanted effects

 GIT disturbances eg epigastric pain/ nausea

 Headache, dizziness, nervousness
 Mild diuresis
 Dilation of blood vessels
 Inceased hydrochloric acid secretion
Theophylline toxicity

Toxicity may manifest with the following sign and symptoms if the concentration
inceases to 20-30 ug/ml: agitation, exaggerated reflexes, fasciculation (mild
muscle tremors), seizures, and cardiac arrhythmias

Drug interactions

 Cigarette and marijuana induces metabolism of theophylline, hence dosage

increased in smokers by 50-100%
 Cimetidine, erythromycin, fluconazole, oral contraceptives,c++blockers
inhibit enzyme cytochrome p-450 hence metabplism of theophylline
reduced which increases its concentration in plasma
 Rifampicin, phenytoin, carbamazepine induce cytochrome P-450 which
reduces theophylline plasma concentrations.
Drugs used to control bronchial secretions

These drugs include:

 vi. Expectorants
vii. Musolytics
viii. Antihistamines
ix. Antitussives
x. Mucosal /nasal decongestants
2. Expectorants
Examples of drugs in this class include
 Glycerylguaiacolate(guaifenesin)
 Ammonium chloride
 Terpin hydrate
Pharmacodynamics

Expectorants render the cough more productive by stimulating the flow and
reducing the viscosity of respiratory tract secretions.Stimulate brochial glands to
produce respiratory tract fluid through vagal reflex.Less viscous fiuids are easily
removed by coughing.

Prototype

Glycerylguaiacolate

Pharmacokinetics
 Well absorbed from GIT; Metabolized in the liver;Excreted in the urine.
Indications

Used for the symptomatic relief of respiratory conditions characterized by dry

cough, non-productive cough.
Dosage: Adults and children above 12 years 100-400mg QID
Children 100-200mg QID.The drugs should not be used for more than 7 days.

Contra indication
In persistent cough like those occurring with smoking, asthma, or emphysema, or
if cough is accompanied by excessive secretions.

Pharmacodynamics
Reduce the adhesiveness and surface tension allowing the removal of viscous
mucus.

Unwanted effects
 Nausea and vomiting may occur in overdose.
 Dizziness ,headache ,rashes may occur
Drug Interactions
 May increase renal clearance for urate lowering the serum uric acid levels.
 It may increase urinary 5-hydroxyindoleacetic acid and interfere with the
interpretation of its testing for the diagnosis of carcinoid syndrome.
Mucolytics
Pharmacodynamics

They act on disulfide bonds hence liquefying tenacious secretions/mucus by

making secretions easy to be secreted..Water given by inhalation or orally is
perhaps the most useful agent in eliminating secretions.
Prototype

Acetylcysteine

Pharmacokinetics

 Absorbed from pulmonary epithelium following inhataion.

 Readily absorbed from the GUT
 Metabolized in the liver.
Indications

 Treatment for abnormally viscid mucous secretions present in clients with

acute and chronic bronchopulmonary disease or pulmonary complications
of cystic fibrosis.
 Used as part of tracheostomy care.
 Treatment of acetaminophan overdose
Pharmacodynamics
It reduces the viscosity of pulmonary secretions through the above mechanism
and facilitates their removal by coughing, postural drainage and mechanical
means

Unwanted effects

 Bronchospasm occurring rarely – If it occurs, it is delivered by use of

bronchodilators.
 Stomatitis (Redness of mucous membrane, dry mouth, burning of oral
mucosa).
 Rhinorrhea
 Nausea and vomiting
Contra indications and precautions
 Clients with bronchial asthma.
 Elderly and clients with severe respiratory insufficiency.
Drug interactions
 After exposure to air, solution should be refrigerated and used within 96
hours.
 Avoid contact with iron, copper or rubber.
Antitussives
Pharmacodynamics

Are drugs used to suppress cough.Act either on the central or peripheral nervous
system or on mucosa locally?

Centrally acting antitusives

 Suppress the cough center in medulla of the brain.
 Divided into two:Narcotics (opiates),Non-narcotics (Non-opiates)
Narcotics
 Codeine ,Morphine ,hydromorphine
Prototype codeine

For cough suppression. Taken orally, though parental administration is possible.

Dosage

Adult’s 15-60mg 4-6hrly: Children 0.5mg/kg 4-6hrly

NB

 Dosage for cough suppressants is lower than for pain.

  Dose of 15-30mg causes drowsiness, thickening of sputum and
constipation.
Non-Narcotic antitusives
Effective like narcotics .Given orally, and may cause amophine- like side effects.

Examples: Dextromethorphan hydrobromide, Levopropoxyphen, Carbetapentane

Prototype
Dextromethorphan hydrobromide

Pharmacokinetics
Absorbed readily from GIT, distribution unknown.Metabolized extensively by
liver.

Excretion 7-10% excreted in feces. Most excreted through the urine.Half life 11
hours

Pharmacodynamic

It is chemical analog of codeine but does not have analgesic or addictive

properties.

Indications

Non-productive cough

Dosage: Adults and children above 12 years – maximum of 120mg daily in divided
doses.Children maximum of 60mg daily in divided doses.Children age 2 to 5 years
maximum of 30mg daily in divided doses.Below two years must be individualized
Contra indications and precautions
In patients taking MAO inhibitors or within 2 weeks of stopping an MAO
inhibitors.Cautiously used in sedated patients.Patients with aspirin sensitivity

Unwanted effects
Drowsiness, dizziness, nausea and vomiting, stomach pains

Peripherally acting antitussives

Used for the symptomatic relief of cough

Prototype

Benzonatate

Pharmacokinetics

The onset of action is 20 minutes. Effects last 3-8 hours.Have no inhibitory effects
in the respiratory center.

Pharmacodynamics
Anesthetizes the stretch receptors in the respiratory passages, reducing cough
production.

Dosage: Adults and children above 10 years 100mg tid

Unwanted effects

Drowsiness, chilliness, headache, GIT upsets, constipation and sensation of

burning in the eyes.

Drug interaction
CNS effects occur when used with CNS depressants, including alcohol.
4. Antihistamines

These drugs have been discussed later and can be used to control the bronchial
secretions.

5. Mucosal decongestants

Pharmacodynamic

Causes r nasal and bronchial decongestion in allergic rhinitis, hay fever, common
cold, sinusitis by the process of vasoconstriction to prevent obstruction of
Eustachian tubes.

Available as oral preparations and nasal drops-Ephedrine 0.5%, Phenylehrine 1-

2%, xylometazoline 0.05%-0.1%, Oxymetazoline 0.025%.

Prototype

Ephedrine 0.5%

Pharmacokinetics

Absorption is unknown .Distribution widely distributed..Metabolized in the liver

Excretion rate is accelerated with acidic urine.

Indications and dosage

 Bronchodilation, nasal decongestion

 Adults and adolescents 25-50mg P.O. to maximum of 150mg in 24 hours
used as bronchodilator.
  Nasal decongestant, 0.5% solution applied as nasal drops to nasal mucosa.
Instill no more often than 4 hourly.
Contra indications and precautions
Patients taking MAO inhibitors, severe hypertension, Cardiac disease, Diabetes,
Nursing mothers

Unwanted effects: Anxiety, Tremor, dizziness, headache, Anorexia, nausea,

vomiting and dry mouth, difficulty in urinating
Dosage: Adults and adolescents age 12 and older. Maximum dose of 240mg daily
in divided doses.Children ages 6-11 years maximum dose of 120mg daily.Children
ages 2-5yesr maximum dose 60mg daily in divided doses.
ANTIHISTAMINES

Classes

They are divided into:

 The first generation drugs have strong sedatives effects than 2 nd generation
drugs.
 The second generation drugs have less sedation due to their less
distribution into CNS.
Pharmacokinetics

Agents are rapidly absorbed following oral administration.Peak concentrations

occur 1-2 hours after administration.Are widely distributed with 1st generation
entering CNS.

Metabolism – occurs in the liver – its by microsomal systems.Most 2 nd generation

drugs are metabolized by the CYP3A4 system thus are subject to interactions with
drugs like ketoconazole (it inhibits the subtype of P450 enzymes).They have an
effective duration of action of 4-6 hours following single dose.Medicine and most
2nd generation agents are longer acting (12-24 hrs).The newer drugs (2 nd
generation) are less lipid soluble and enter CNS with difficulty.Astemizole
ebastine, hydroxyzine, loratadine and terfenadine have active metabolites.The
active metabolics of hydroxyzine and terfenadine are available as drugs (cetirizine
and texofenadine)

Pharmacodynamics
H1 receptor antagonist blocks the actions of histamine by reversible competitive
antagonist of the H1 receptor.

Indications
Type 1 hypersensitivity receptors, Alleraic rhinitis, Urticaria, Angiooedema,
Motion sickness (promethazine & piperazines), Rhinorrhoea.

Unwanted effects

Sedation (1st generation), excitation & convulsions in children, postural

hypotension, allergic rxn after topical use, Cardiac arrhythmics

Drug interactions

 Cardiac toxicity & QT prolonation & lethal arrythmics in patients taking

terfenadine or astemizole combined with ketoconazole, Itiraconazole or
macrolide antibiotics e.g. erethromycin.
 Antimicrobiol drugs cause increase in blood concentration of
antihistamines.
  Grape fruit juice inhibits CYP3A4 thereby increasing tentenadines blood
levels.
FIRST GENERATION H1 ANTAGONIST

Sub-classes
a. Ethanolamines e.g.

- Carbinoxamine, Dimenhydrinace (Benadryl),Diphenhydramine,Doxylamine

b. Ethylenediamines

- Pyrilamine (New aweragen),Tripelennamine (PB2)

c. Piperazine derivatives
- Hydroxyzin (atarax),Cyclizine (Marezine),Medizine (Benine)
d. Alkylamines
- Brompheniramine (Dimetane),Chlorpheniramine (Chlor-Trimeton),
e. Phenothiazine
- Promethazine (Phenergan)
Second generation antihistamic
- Piperidines ,Astemizole (Hismanal),Fexotenadine (Allegra),Terfenadine
(Seldane)
Miscellaneous
- Lorated (clarifin),Cetirizine (zyrtec)
CHLORPHENIRAMINE MALEATE

Pharmacokinetics

Well absorbed after oral administration .Peek plasma levels occur within 2-6
hours.
Has rapid and extensive distribution.Half life 12-43 hrs.Metabolism is in the GIT
and has first pass metabolism through the liver after oral administration.Excretion
is in urine.

Pharmacodynamics
It binds competitively with histamine at H1 receptor. The binding is reversible. It
antagonizes the effects of histamine at the receptor sites.It crosses the blood
brain barrier causing CNS effects.

Indications

Seasonal & perennial allergic rhinitis .Common cold

Pharmaceutics
May be administered orally, S.C, im injection or IV infusion. Dose 4-8mg

Unwanted effects
Sedation, Drowsiness, Dry mouth, Hypertension, Blurred vision

Contra indications/ Precautions

Narrow angle glaucoma, Prostatic hypertrophy, Stenosing peptic ulcer,
Pylorodinodenal obstruction.Bladder neck obstruction

DRUG INTERACTIONS
Interacts with hyoscine, anticholinesterases CNS depressants, Corticosteroids,
Phomethezine.Caffeine counteracts its sedative effects .Photosensitivity reactions
occurs with sunlight exposure.

PROMETHAZINE
Pharmacokinetics
Absorbed from GIT.Duration of action ≥12 hours .Well distributed in tissues.

76-93% is protein bound.it crosses placental barriel but distribution in breast milk
is not established.Metabolized in the liver.Excreted in urine and faeces.Half life –
unknown.

Indications: Used to treat motion sickness, nausea and allergic rhimitis.

Also used as sedative.Dosage: Can be given orally, retail, im or IV Dose 10-25mg

Pharmacodynamics
As with chlorpheniramine above.

Unwanted effects

Sedation, Confusion, Disorientation

Contra indication
Similar to chlopheniramine

Caution
Cardio-vascular disease, Impaired liver function, Sleep apnea and seizure
disorders, pregnacy

Drug interactions
Promethazine interacts with: - anticholinesterases, hyoscine, CNS depressants,
corticosteroids, antacids, anticonvulsants, antihypertensives, oral antidiabetic
drugs, thiazide diuretics and ototoxic drugs.
TERFENADINE
Pharmacokinetics
It’s 70% absorbed in GIT after oral administration.Reach peak concentrations in 3-
6 hours & lasts 12 hours or more.Distribution properties not known.Its 97%
plasma protein bound

Undergoes first – pass metabolism in the liver and GIT

Its excecrated in faeces through biliary elimination

Pharmacodynamics
It binds slowly the H1 receptors and also dissociates from receptors slowly. It is
lipophobic and does not cross blood brain barrier.Instead; it binds selectively to
peripheral nervous system receptors.

Indications

Allergic rhinitis.Oronasopharyngeal irritation, Itching, Rhinorrhoea

Dosage: Adults and children above 12 years 60mg BD.

Efficacy in children < years not established.

Pharmacodynamics
It binds slowly the H1 receptors and also dissociates from receptors slowly. It is
lipophobic .Instead it binds selectively to peripheral nervous system receptors.

Should be administered with food or milk to minimize GI irritation

Unwanted effects

Drowsiness, sedation. Headache, nausea, vomiting, abdominal pain, dry mouth.

Arryhythmias & tachycardia

Contra indications/ precautions

Patient with significant liver dysfunctions.Conditions that prolong at intervals

Patients taking erethromycin, ketoconazole or itraconazole.

Drug interactions
Interacts with erythromycin, ketoconazole and itraconazole. The combination
prolongs QT interval producing tachycardua.Exposure to sunlight causes
photosensitivity.

CRITICAL☺? THINKING ACTIVITY

1. Mr Jacob, age 70 was admitted to the hospital with symptoms of fatigue,

weakness, dyspnea, malaise, and a persistent nonproductive cough.He was
diagnosed as having a viral upper respiratory tract infection.Would a mucolytic
drug be appropriate for this client? Why or why not?

2. What nursing intervention wuld be considered appropriate for the nursing

management of a client receiving a bronchodilating agent?

3. There are many clinically useful antiasthmatic drugs. Discuss factors that
influence their use in different clients
NERVOUS SYSTEM

DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM (ANS)

Introduction

There are two basic neurotransmitters acting in ANS.

Acetylcholine: From choline & acetate made by help of choline

acetylase .Degradation is by acetycholinesterase or non- specific cholinesterase in
blood or tissues.

Norepinephrine: Made in nerve end terminal from amino acid tyrosine.Once

released, its re-uptaken back into nerve ending. Its also made in adrenal medulla
and released on sympathetic stimulation.Monoamine oxidase and catechol-o-
methyltransferase (COMT) degrade Norepinephrine in blood.COMT is commonly
found in liver and kidney while
MAO is found in liver, kidney and other tissues.

Learning activity

Read on receptors on which the above two neurotransmitters bind to achieve

their physiological functions.Particularly read on the functions that they mediate
in relation to their locations.

Drugs acting on the sympathetic system

Sympathomimetics
These are drugs acting on the sympathetic system as agonist to the alpha and
beta receptors.They act like norepineprine or activate the release of the same.
Direct acting sympathomimetics
These ones act specifically on the adrenoceptors

E.g. Isoproterenol, Dobutamine, Albuterol

Indirect acting sympathomimetics

Drugs activate release of norepinephrine & other endogenous catecholamines

e.g. amphetamines.

Sympatholytic drugs/ adrenergic blocking drugs

Interfere with adrenergic activity at different points of the stimulation process.

Adrenergic Neuronal blockers: e.g. Methyldopa, reserpine, guanethidine prevent

synthesis & release of norepinephrine in sympathetic nerve endings. Adrenergic
receptor blockers e.g. Phentolamine, Phenoxybenzamine, propranolol, nadolol &
labetalol

NB 1: Drugs acting on sympatheic system have been covered under

cardiovascular system and therefore, the student needs to refere to it.

NB 2: That there is no parasympathetic supply to the sweat glands, skin and the
bloodvessels of skeletal muscles, hence some sympathetic fibers produce
acetylcholine.

Drugs acting on the parasympathetic system

Introduction
Muscarinic receptor is found on the smooth muscle, cardiac muscle and certain
glands e.g. salivary, mucous, and lacrimal and sweat glands while nicotinic
receptors are found in skeletal muscle and ganglia

Parasympathomimetics
Muscarinic cholinergic drugs e.g. Bethanechol, Carbachol, and Pilocarpine.They
directily act on muscarinic receptors. Nicotinic cholinergic drugs stimulate
nicotinic receptors in synapse between preganglionic and postganglioc neurons in
the autonomic ganglia.

Anticholinesterase/ indirectly acting cholinergic drugs/ cholinesterase inhibitors:

Potentiate effects of acetycholine at parasympathetic nerve endings e.g.
edrophominum, physostigmine, neostigmine and pyridostigmine.

Anticholinergic drugs/ parasympatholytic

Interfere with and block acetylcholine transmission at ganglia, postganglionic
parasympathetic receptors sites and neuromuscular junction.Acetylcholine
receptors include M1-gastric parietal cells,M3-smooth muscles and glands,M2-
heart muscles

Over view of drugs acting on the parasympathetic system

Parasympathomimetics/ cholinergics/ cholinomimetics

The act like the the acetylcholine where it is the neurotransmitter .They effect it
has depends on the location of different receptors eg Eye – pupils constriction/
miosis

Trachea – constriction, increased secretions; Bladder – Contraction of detrusor

muscle and relaxation of the trigone & sphincetr muscle; GIT – increased muscle
motility and tone i.e. peristalsis decrease,increased secretions ,sphincter tone
decrease ; CVS – decrease heart rate – negative chronotropic and inotropic effect.

Classification of parasympathomimetics
Direct-acting/ muscarinic agonist

Mimic effect of endogenous acetylcholine ie muscarinic agonists only enhance the

effects of acetylcholine at muscarinic receptor sites.Examples of such drugs
include carbachol, bethanechol chloride, pilocarpine, Muscarine, arecoline.Its
important to note that muscarine, arecoline are naturally occurring
cholinomimetic alkaloids.

Indications
Glaucoma (intraocular pressure increase), Pilocarpine/ carbachol eye drops x4
day, Reflux esophangitis, Paralytic ileus ,Urinary retenstion (especially post
operatively),GIT atomy ,diagnosis and tretment of myasthenia gravis.

NB Acetylcholine is metabolized by acetycholinestarase enzyme in blood stream.

But these drugs are metabolized slowly by non-specific pseudocholinesterase.
This permits increase of acetylcholine to therapeutic levels.

Indirect – acting/ cholinesterase inhibitors/ Anticholinesterase

Examples: Physostigmine, Pyridostigmine, Neostigmne, Distigmine,
Edrophonium .Metriphonate (used for treatment of schistosomiasis)
Pharmacodynamic

Inactivate cholinesterase that destroys acetylcholine allowing it to accumulate

hence produce intensified effects.Further classified as reversible or irreversible.

Reversible – reversible drugs are slowly hydrolyzed, allowing slow regeneration of

cholinestease.Irreversible drugs –It take long to reverse the whole process,
because new cholinesterase molecules must be synthesized before cholinesterase
enzyme can be produced.

Indication
Just as in direct acting but good for treatment of mysthemia gravis which is a
chronic, autoimmune neuromuscular disease in which the body produces
antibodies to the somatic nicotinic receptor sites. Hence, skeletal muscle
response is diminished.Hence, cholinestarase inhibitors can be used for diagnosis
(short acting) and treatment (long acting) .These drugs are also used to
differentiate myasthenia crisis and cholinergic crisis.

Tension/ edrophonium is used for this purpose.

NB: Very high doses at cholinesterase inhibitors produce muscle weakness due to
continuous muscle contraction leading to fatigue and fasciculations and eventual
paralysis.
Contra indications
 Asthma – because they enhance bronchoconstriction.
 CNS condition likes bradycardia, coronary insuffieciency, hypotension or
myocardial infarction – because they decrease rate and force heart beat.
  Clients with obstructive intestinal or urinary tract disease
Neostigmine (Prostigmin)

Pharmacokinetics

Half life is 2 hrs

Indications
 Principally myasthenia gravis
 Stimulate bowels and bladder after surgery
 Reverse effect muscle relaxant drugs e.g. pancurorium hence used in
anaesthesia.
Caution
Asthma, bradycardia, recent myocardial infarction, hypotension, parkinsonism,
vagotonia, peptic ulcerations, renal impairement.

Unwanted effects
Nausea, vomiting, incrased salivation, diarrhea, abdominal cramps

Signs of overdose
Increased GIT discomfort, bronchial secretions, sweating, involuntrary
defaecation & micturition, miosis, Nystagnus, bradycardia, hypotension.

Dose: By mouth Neostigmine bronude 15-30mg 3-4hrly per day.

Total daily dose 75-300mg but most patients can only tolerate max. Dose of
180mg/day.

Neonate: 1-5mg every 4 hrs; child upto 6 yrs -7.5mg 4 hrly; 6-12yrs -15mg 4 hrly.
By subcutaneous or intramuscular injection: 1-2.5 mg 4 hrly or
5-20mg/day.Neonate: 50-250 micrograms every 4 hours.
NB: Cholinergic poisoning e.g. by organophosphus compounds (irreversely) &
carbamate pesticides (reversibly) has the same mechanism has the above drugs i e
they inhibit cholinesterase. Manifestation for this poisoning includes Miosis,
Blurred vision, Muscular fascination, Increase bronchial secretions, Nausea &
vomiting, abdominal cramps, extreme salivation, involuntary defeacation/
urination, sweating hearing
Brady cardia.hypotension

Treatment: Atropine 2mg IV/IM soonest possible repeat every 15-60 minutes
mouth dryness – 70 beats/minutes.Large doses of atropine for muscarinic
symptoms (i.e. GIT, CVS, Resp. effects) 2mg IV/IM soonest possible reapeat 15-
60min.

Pralidoxime – a cholinesterase reactivator is used to treat the nicotinic symptoms

– skeletal muscle paralysis.

Anticholinergic/ parasympatholytic drugs

Introduction

Anticholinergic/ parasympatholytic drugs interfere with and block acetylcholine

transmission at ganglia, post ganglionic parasympathetic receptor sites and
neuromuscular junction.

There are many classes of anticholinergics:

Ganglianic blockers

Examples: Mecamylamine & trimethaphan

Pharmacodynamics
Inhibit the effect of Ach at nicotinic receptors by acting competitively (non-
depolarizing blockage) at both sympathetic and parasym autonomic ganglia.
These drugs decrease blood pressure by decreasing sympathetic tone to the
vasculature .

Prototype

Trimethaphan
Pharmacokinetics

Poorly absorbed orally. Usually IV infusion; short acting (< 10min); Active
secretion by kidney.Stimulates histamine release and may cause flushing,
dizziness, headache. Tolerance develops within 48hrs of continuous infusion.

Indications

It’s infrequently used for a autonomic hyperreflexia, acute dissecting aneurgysm

of the aorta.They are also used to produce controlled hypotension and minimize
bleeding during caecum types of skin surgery.

Unwanted effects
Mydriasis, cycloplegia; constipation due to decreased GIT tone & motility due to
blockage of enteric ganglia; dry mouth; urinary retention

Antimuscarinics
Examples: Atropine, oxybutynin, Benzhexol (artane), orphenadrine,
isopropamide, Hyoscine (scopolamine), Promethazine (also antihistamine);
Ipratropium; Hyoscine butybromide (Buscopan); Homatropine, propantheline
Pharmacodynamics
These are drugs that oppose acetylcholine. These drugs block competitively the
action of acetylcholine on their receptors ie acts on parasympathetic muscarinic
receptor sites.
Common Indications
 Benzhexol, orphanedrine – used against the rigidity and tremor of
parkinson’s disease
 Hyoscine and promethazine are used as antiemetics and in anaesthesia
due to the sedative effect.
 Homatropine & atropine used dilate pupils.
 Glycopyrronium, atropine & hyoscine used in anaesthesia to block vagus
nerve and reduce secretions.
 Ipatropium is an effective brochodilator so may be used in asthmatic
conditions.
 Favoxate, propantheline and oxybutynin are used to relieve muscle spam
accompanying injection in cystitis for dextrusaor instability.
 Atropine used in bradycardia folliwng myocardial infarction.
Contra indications

Hypersensitivity, obstructed airway, Obstructive disease of the of GIT

Myasthenia gravis, Angle – closure glaucoma

Precaution in: - Ulcerative colitis, Hyperthyroidism, Hepatic and renal disease,

Prostatic hypertrophy, esophangeal reflux, Severe heart disease.
Contraindications
 Pre-existiing tachycardia or heart block
  Acute myocardial ischaemia or infarction. They may increase heart rate
hence worsen ischaemia and increase zone of infarction.
Unwanted effects
Xerostomia, Susceptibility to heat stroke, Depression, drowsiness, Impotence,
Tachy cardia, Visual disturbance, Constipation, Urinary retenstion, Flushing,
Thickened mucus, Fever

Prototype: Atropine:

Pharmacodynamic
Competitive blockage at muscarimic receptors parents receptor activation by
endogenous acety/choline. Not all muscarinic receptors are equally sensitive to
blockage by atropine and most other muscarinic antagonists.

Pharmacokinetics:

Administered orally, topically {eyes} and infection via IM/IV /SC.Readily absorbed
if taken orally .Well distributed in body tissues to include CNS. Elimination-
unchanged in urine.Metabolism –under goes heptic metabolism .Half life-about 2-
3 hrs.

Indications

Pre-anaesthetic, eyes surgery, symptomatic brandycandia, Billiary colic, Intestinal

hypertonicity& hypermotility, muscarinic agonist poisonig. (Oganophosphates)
Dosage: Adult: 0.5-1Mg; Children: 0.01mgs /kgs body weight.May repeat within
4-6mimutes; maximum dose 0.4mgs or 0.3mgs/m3.
Precautions:
Patients with tarchycardian, Cardiac arrhythrnias, hypertension. Prostatic
hypertrophy],-Liver disorders,-Kidney disorders. Obstructive diseases of gut.
Antidote for anticholinesterase Insecticide Poisoning

Adults: 2-3mgs IV repeated 5-10minutes till muscarinic or symptoms disappears

or signs of atropine toxicity appears.Children: 0.05mgs/ kgs body weight IM OR IV
repeated 10-30 minutes until muscarinic signs & symptoms disappear.

Contra indications
Patients with drug hypersensitivity, Patient with acute angle closure glaucoma,
Obstructive uropathy, Obstructive disease of G.I.T., Paralytic ileus, Toxic
megacolon

Intestinal atony, Tachycardia, Myocardial ischaemia, Asthma, Myasthenia gravis

Adverse reactions

GIT

Dry mouth – xerostonia, Thirst, Constipation, Nausea, Vomiting,

ENT-Photophobia, blurred vision, myadriasis, cycloplegia, increased intraocular

pressure

Genital urinary- urine retention, impotence,

CNS-headache, ataxia, restlessness, disorientation, hallucinations, delirium, I

nsomnia, agitation, confusion,e xcitement
CVS-tachycardia,

Drug interactions

Antiacids decrease the absorption of anticholinergics. Drugs with anticholinergics

effects like TCAS, phenothiazines have synergistic effects with atropine.

Levodopa: Anticholinergics decrease gastric motility resulting increase gastric

deactivation of levodopa and decreased intestinal absorption, possibly leading to
a decrease in levodopa efficacy .Digoxin: serum levels may be increased by
anticholinergics when digoxin is administered as slow dissolution oral tablets.

CENTRALLY ACTING SKELETAL MUSCLE RELAXATIONS

These are drugs for the treatment of spascticity and spasms.

Spasticity: results from loss of inhibitory tone in the polysynaptic pathways of the
spinal cord, causing loss of fine control of motor activity.

Usually in patients whom inhibitory pathways have been disrupted through spinal
cord injury, strokes, multiple sclerosis or cerebral palsy

Patiientss show exaggerated reflexes (spinal plasticity inappropriate posture

(cerebral spasticity).Muscle spasms are local muscle contractions indicated by
muscle or tendon injury and inflammation.Usually occur in strains, bursitis,
arthritis, lower back pain

NB: Anxiety worsens a muscle spasm hence antianxiety drugs may be useful in the
Rx of spasms.

Drugs for treatment of spascticity

Pharmcodynamic: Not very clear

Postulate: Depression of polysynaptic pathways in spinal cord modulating muscle

tone. This can be achieved in different ways.

Benzodiazepines

Pharmacodynamic: refer to previous learning

Baclofen: Analog of inhibitory neurotransmitter GABA.Hence, it enhancse the

GABA effect on nerve transmission
Dantrolene: Is a not centrally acting skeletal relaxant but effects intracellular
release of ca++ necessary to initiate a contraction

Botulinum toxin: treats local muscle spasms by injecting it to a specific site.

Mephenesin: muscle relaxant –curare like effects

Other drugs that can be used for managing associated sign and symptoms
include: Anxiolytics, analgesics, Anti-inflammatory drugs

Drugs for treating muscle spasms

Examples: Carisoprodol, Chlorphenesin, Chlorzoxazone, Cyclobenzaprine,
Metaxalone

Methacarbamol, Orphenadrine

Pharmacodynamics
These drugs act in different ways eg cyclobenzaprine act as anxiolytics .Others act
as Analgesics ,Anti-inflammatory .Generally most of them cause depression of
post synaptic pathway in the spinal cord modulating muscle tone.
ANTICONVULSANTS
Introduction

Anti convulsants are drugs used in treatment of epileptic seizures which are
divided into partial and generalized seizures.The type of seizure determines the
drugs used, hence the need to classify seizures during assessment.

Classsification and examples:

 Barbiturates: - Phenobarbitol, mephobarbital, metharbital, amobarbital and

primidone.
 Hydantoins: - Phenytoin, mephenytoin, ethotoin.
 Succinimides: - ethosuximide, methuximide, phensuximide.
 oxazolidine diones:- paramethadione, trimethadione
 Benzodiazepine:- clonaxepam, diazepam, clorazepate
 Miscellaneous: - Valproic aid, carbamazepine, phenacemide acetazolamide
bromides.
Pharmacodynamics
The mode of action of the drugs is variable and not very clear for some drugs

Some inhibit the seizure by depressing neural excitability by stabilization of cell

membrane through suppression of sodium & calcium influx and also transfer of
potassium ions eg phenytion, carbamazepine, and valproic acid. They also act by
modifying synaptic transmission eg benzodiazepines, Phenobarbital facilitate
GABA mediated inhibition of neuronal activity.
Characteristic considered when selecting antconvulsants
 Should be highly effective and exhibit a low incidence of toxicity
 It should be effective against more than one type of seizures and for
mixed seizures.
 It should be long acting and non-sedative
 It should be well tolerated by the patient and inexpensive
 Tolerance to the therapeutic effects of the drug should not develop.
 It should control seizures and allow a patient to function effectively in
any environment.
Pharmacokinetics
They have same pharmacokinetic properties. The absorption is good; 80%-100%
of the dose is in blood circulation. Most drugs are not highly bound to plasma
proteins.Chiefly Undergo hepatic metabolism Many are converted to metabolites
that are cleaned by the liver.Half life is greater than 12 hours .Most antiepileptics
are potent micromosomal enzyme inducers/inhibitors eg
pheonbarbiral ,phenytoin, carbamazepine. Interactions can occur between
different anticonvulsants .Hence,they have a lot of potential for adverse dru
interactions.Monotherapy should be practiced to avoid the chance of these
interactionsWithdrawal should be gradual so that rebound seizures are not
precipitated .If on combination therapy,then one drug should be withdrawn at a
time.

UNWANTED EFFECTS
CNS: drowsiness, ataxia, behaviour problems, slurred speech Tremors,
mental confusion, vertigo, hyperirritability, emotional disturbance, excessive
sedation, hypokinchic behaviour, headache and fatigue.
VISION: Blurred vision, double vision and mystagmus.

GIT: Increased secretions, anorexia nausea, GI, upset vomiting.

BLOOD: Elevated SGOT and serum alkaline phosphate levels, thrombocytopenia

hirsutism.

Prototype

Phenytoin (diphenyl hydantoin)

It is a non-selective antiseizure drug. It is effective in suppressing tonic-clonic and

partial seizures. A drug of choice for initial therapy, for particularly treating adults.
Pharmacodynamics
It stabilizes neuronal membranes to depolarization by decreasing the flux of
sodium ions in neurons in the resting state or during depolarization. It also reduces
influx of calcium ions during depolarization and suppresses repetitive firing of
neurons. It produces some degree of drowsiness and lethalgy without progression
to hypnosis. It reduces propagation of abnormal impulse in the brain.
Indications
It’s effective for all partial seizures, tonic-clonic seizures and status epilepticus
caused by recurrent tonic-clonic seizures. Dosage: adult 100mg/day and children:
5mg/kg/day.

Pharmacokinetics
Oral absorption is slow, but distribution is rapid and high brain concentrationare
reasched. Oral administration is the commonest. It is largely bound to plasma
proteins. Five % of a given close is excreted unchanged in urine. It is metabolized
by hepatic hydroxylation system. Small increases in each dose can produce large
increase in plasma concentrations and hence result in drug induced toxicity. Has
large genetic variation in drug metabolism of the drug.

Unwanted effects
Depression of the central nervous system particularly in the cerebellum and
vestibular system causing nystagmus and ataxia.Gastro intestinal disturbances like
vomiting and nausea.Gingival hyperplasia may cause gums to grow over teeth,
especially in children. Hyperplasia regression after termination of
treatment.Coarsening of facial features occurs in children .Megaloblastic anaemia
occur because the drug interferes with vitamin B 12 metabolism .Behavioural such
as drowsiness, confusion,hallucinations.It inhibits antidiuretic hormone insulin
secretion which cause hyperglycaemia and glycosuria.

Teratogenic effects: It can cause fetal hydantoin syndrome which include cleft lip,
cleft palate, congenital heart disease, slowed growth and mental deficiency.
Drug interactions
Inhibition of microsomal metabolism of phenytoin in the liver caused by chloram
phenical, dicumarol, sulfonamides and isoniazid. These drugs increase
concentration of phenytoin in plasma.Carbamazepine enhance phenytoin
metabolism. It induces cytochrome P-450 which leads to increase in metabolism
of other antiepileptics, anticoagulants, oral contraceptions, quinidine,
doxycycline, cyclosporine, mexiletine, methadone and levodopa.

Phenobarbitol

Mechanism of action
Has inhibitory effect of y. aminobutyric acid (GABA) mediated neurons.
Therapeutic uses
- Simple partial seizure but not very effective for treatment of complex
partial seizures.
- Infantile seizures, that includes febrile seizures
- Recurrent tonic-clonic seizures especially to patients who do not respond to
ciazepam plus phenyoin
- Used as a mild sedative to relief nervous tension and insomnia.

Absorption and metabolism

- Well absorbed orally
- It freely penetrates the brain
- 75% of the drug in activated by hepatic microsomol system
- It includes P-450 system
- Chronical administration enhance metabolism of other drugs

Adverse effects
Sedation, ataxia, Nystagmus vertigo and acute psycholic reactions may occur.
Nausea and vomiting morbilliform rash seen in sensitive individuals. Agitation and
confusion in high doses.

Rebound seizure may occur in discontinuation of drug.

Dosage
Oral 15mg – 30mg
Benzodiazepine (are also sedative and hypnonic drugs) used to treat clonazepem
and clorazepate used for chronic treatment.

Diazepam used in circuit treatment of status eppileplicus.

Clonazepan effective in suppressing seizures spread from epileptogenic focus.

Also used in absence and myoclonic seizures.

They are safest and have less severe side effects. Benzodiazepine have sedative
effects; hence drowsiness somnolence and fatigue can occur with high doses.
Ataxia, dizziness and behaviour changes can also occur

Intravenous administration can cause respiratory depression and cardiac

depression.

Valium (Diazipam)

Dosage: adults 4-40mg/day oral

5-30mg prs or per day

children orally 3-10mg/day

iv/im 1-10mg
Pharmacokinetics
They are well absorbed widely distributed and extensively metabolized with many
metabolites. Onset of action is very rapid. Half-life 20-40hrs. has a low total body
clearance.

Excretion is through the kidney. Trace of unchanged benzodazepines appear in

urine.

CRITICAL☺? THINKING ACTIVITY

1.Mrs Arimi,a 24 yr old ,and her husband,have decided to start a family.She has
been on phenytoin since childhood for a seizure disorder and would prefer to
discontinue the medication before getting pregnant .What criteria will be involved
in the decision to wean Mrs Arimi from her medication?

2.Mr Thuku is receiving atropine 0.4mg PO 4hrly as part of his treatment for
irritable bowel syndrome.He complains of intolerance to heat,dry mouth and
constipation.How will you explain these symptoms to him? What instructions will
you provide to assist him to effectively manage his therapeutic regimen?

3.Mr Kathuri,a 59 yr old professor has been admitted to the hospital with atrial
tachycardia.He has been started on propranolol 30mg qid.What nursing
interventions will you take because Mr Kathuri also has diabetes mellitus?

4. To evaluate the effectiveness of skeletal muscle relaxant therapy for a client

with spasticity, what would constitute an appropriate assessment of the clent’s
status?
DRUGS USED TO TREAT CANCER
INTRODUCTION

Cancer occurs when normal cells become transformed by chemicals, viruses, or

unknown agents and hereby become resistant to normal regulation of cell division
and other cellular processes. Cancer refers to a group of interrelated
diseases.They occur when mormal cells become cancerous and show the
following characteristics:

 Uncontrolled proliferation
 Metastasis ie tending to spread
 De-differentiation and loss of function ie loss of distinct
characreristics,hence inability to perform their function
 Invasiveness ie they they tend to invade the surrounding cells
NB: Normal cells undergo mutation or chromosomal translocations and become
cancerous.This is ussaully brought about by carcinogens.

The greatest difficult in treating cancer is that the cancer cells and the normal
cells ar basically the same,hence inadequate exploitative advantage which
treatment would target.Its important to also note that caner cells are not
recognized as foreign by the immne system.Resistance may also occur as tumors
grow.Treatment modalities for cancer include surgery,irradiation and
chemotherapy.The treatment modality adopted depends on the type of tumor
and the stage of development of the cancer.Chemotherapy(drugs) can be used
alone or incombination with other treatment modalities.Drug used for the
treatment includes cytotoxics which are intended to cause death of cancer cells
but also tend to affect he normal cells,hence they have many unwanted
effects.These drug portay dose limiting toxicity ie unwanted effects that limit the
dose that can be used.There therapeutic index is very narrow.Chemoterapy
targets dividing cells ,hence normal cells of ovary,testes,hair
follicles,endometrium and other sites of fast cell division are usually
affected .Subsequently such adverse effect like bone marrow toxicity,hair
loss.depressed spermatogenesis and gastrointestinal problems tend to occur.

Drugs may be targeted to specific cancer cells by means of receptors eg

antiestrogens cantarget estrogen receptors and cause death of cancer cells that
depend on estrogen; Drugs that deprive prostate gland of androgens can be used
to treat cancer of the prostate.These drugs are usually used for treting cancers of
the reproductive system because these cancers are dependent on these
hormones ie androgens, estrogens and progestins

CHEMOTHERAPY (CYTOTOXIC DRUGS)

The classification could be based on:-

1. Chemical properties and origin of the drug: eg alkalyting agents and

antimetabolites.This is a old method based on properties ofa drug
that may not reflect the clinical experience or current understanding
in relation to mechanism of action of these drugs.
2. Based on the site in the cell cycle where the drug act ie this
clasasification is based on mechanism of action.The is a better
classification of the two.
CLASSIFICATION OF CYTOTOXIC DRUGS ACCORDING TO THE MECHANISM OF
ACTION

1. Agents that directly attack DNA

2. Agents that block DNA sythesis
3. Agents that block RNA or protein synthesis
4. Agents that prevent or arrest mitosis
Other drugs used in cancer therapy

Drugs used in supportive therapy.

I) Agents that directly attack DNA

Examples of drugs here include: Bleomycin,Altretamine,Busulfan,Carboplatin and

asplatin,Carmustine and lomustine,Chlorambuli,Cyclosphosphamide,Dacarbazine,
Ifosfamide, Mechlorethamine, Melphalan,Mitomycin, Mitoxantrone,Thiotepa

Pharmcodynamics

They attack DNA in its double-strauded form, attaching of various compounds to

one strand or the other agents may form cross- links or chemical bonds (covalent
bonds), between the strands. Because these strands must unwind and separate
during replication, cross- linking effectively blocks replication. A large group of
anticancer drugs called alkalating agents belong to this class.
Pharmacokinetics
Many drugs of this type are rapidly destroyed in the body. A few like asplatin,
mechlorethamine and melphalan are hydrolysed or destroyed by non-enzymatic
mechanism in many fluids and tissues.Other drugs like altretamine, bleomycin are
degraded be enzymes in many tissues.Generally, metabolism lowers the activity of
these drugs, but altretamine, chlorambucil, ifostamide and lomustine are activated
by metabolism or the metabolites retain significant activity.The duration of action
of this class of agents is quite variable. Drugs like mechlorethamine are destroyed
within seconds of administration, but biological effect may persist for weeks. Other
drugs like mitoxantrone bind tightly to DNA and other structures and persist in the
body for days to weeks.Excretion: Renal excretion is the most common route of
elimination with these drugs.Some like chlorambucil or lomustine are eliminated
as metabolites.Others like ifostamide or bleomycin are excreted largely
unchanged.Half life vary from seconds for mechlorethamine to days for
mitoxantrone.
Indications
Ovarian carcinomas,Palliative therapy for lymphomas, sequamous cell carcicomas
and testicular or ovarian carcinomas,Effective against lymphocytic leukemias &
lymphomas, Malignant melanoma and lymphomas, Germ cell testicular tumors,
Hodgkin’s disease, Multiple myeloma
Unwanted effects
Can destroy nucleic acids, Attack normal cells and is lethal when the cell attempts
cell division,Bone marrow suppression leading to leukopenia, thrombocytopenia;
Causes mucocutaneous reactions e.g. stomatitis ;Organ toxicity ;Acute or delayed
nausea & vomiting; Alkylating agents can be are mutagenic ; immunosuppresive
activity
Toxicity
As doses increase, the degree of bone marrow suppression increases with these
drugs. In addition to these expected effects on bone marrow, which is reflected in
lower numbers of various cells in the blood, some of them have also dose related
effects on other organs. For example bleomycin and carmustine cause pulmonary
toxicity whereas cyclosphosphamide and mitoxantrone cause cardiotoxicity.

Drug interactions
All drugs of this class except bleomycin may have significant interactions with
bone marrow suppressants or radiation because the combinations can be
profoundly depresses production of blood cells.Live virus vaccines are avoided in
patients who receive any of these drugs because generalized viral infections may
occur as a result of immunosuppresion these drugs produce.Oral polio vaccine
may also be contra-indicated .

Prototype

Mitomycin

It’s an antibiotic from cultures of streptomyces.Its activated by enzymes in the

body
Pharmacodynamic
It’s an alkalating agent that act by attaching DNA in its double stranded form and
attaches various compounds to one strand or the other. These compounds make
the strands not to unwind and separate during replication, i.e. blocks replication.

Pharmacokinetics
Not absorbed orally. Does not distribute in the brain.Should be given
intravenously

Dose: Adults – upto 20mg/m2 as single dose.Repeated no more often than every 6
weeks
Indications: Treatment of GIT tumors

Unwanted effects
Produces severe and progressive myelosupression; Leukopenia;
Thrombocytopenia occurs within 3 to 8 weeks; Nausea/Vomiting; Skin rashes,
Alopecia

Few patients may also suffer renal failure with haemolysis, liver toxicity and lung
damages. Can cause local necrosis if allowed to escape into cutaneous tissues
during iv injection.

Drug Interaction
Causes the expected interactions with bone marrow depressants and live virus
vaccines.

II Clients that Block DNA synthesis (S-phase inhibitors)

Examples of drugs in this class:

Cladribine, Cytarabine, Floxuridine and fluorouracil, Fludarabine, Hydroxyurea,
Mecarptopurine and thioguanine, Methotrexate, Procarbazine

Pharmacodynamics

Its only cells in the S-phase of cell cycle that synthesize DNA.Hence, these drugs
block or prevent action of an enzyme that is required for DNA in S-phase of cell
cycle synthesis

They are called cycle specific or phase specific agents because they primarily
affect cells in S- phase. Has no effect on non proliferating cells or cells in resting
phase.

Indications
Used for hairy cell leukemia; Palliative for solid tumors not repeated by other
means; Chronic lymphocytic leukemia; Melanoma, Carcinomas; HodgKin’s
lymphoma

Unwanted effects
These drugs are sensitive to normal cells (non-selective).Bone marrow depression
and suppression of lymphocyte formation reduces the ability of the patient to
fight infection.

There is also nausea, Vomiting and stomatitis. Toxicity: Bone marrow suppression
is dose related side- effect High doses have profound effects on the bone marrow.
Contra indications
In tissues with high growth fraction e.g. GI mucosa.
Drug interactions
Have serious interactions with bone marrow suppressants or radiation because
the combinations significantly depress production of blood cells.Immuno
suppression drugs used together with these drugs leads to generalised viral
infections

Prototype

1) Methotrexate

Pharmacodynamic
Prevents the regeneration of the metabolically active form of folic acid, ie
tetrahydro folate. This makes the cells not to transfer carbon reactions, and
normal metabolism is blocked at several points. One of these blockades prevents
the formation of thymidylic acid and others arrests adenine and guanine
nucleotide synthesis in an early state. Without these precursors, DNA synthesis is
inhibited.

Pharmacokinetics

Can be given orally, intramuscularly, IV, intraartenal or intrathecal.

Oral route is satisfactory because effective serum concentration are reached

within I hour.

Well absorbed in GIT.Parentral route leads to faster absorption rate.Intrathecal

route is recommended for leukemias that have penetrated to CNS.Does not pass
from the blood into the cerebrospinal fluid in adequate amounts.But generally its
well distributed in the body and may accumulate in some tissues.Metabolism
occurs in the liver.Excretion in the kidney where its excreted unchanged .

Indications: choriocarcinoma, Leukemia, Palliative treatment for carcinomas and

lymphomas

Dosage: Oral for adult and children 2.5mg /m2 once weekly depending on disease

Intramuscularly for adults and children: 15-30mg daily for 5 days or 3.3mg/m 2 in
combinations.Intravenously: Adults: 0.4-2.5mg/kg every 14 days.Intrathecal

Adults & children: 0.2 – 0.5mg/kg upto 15mg total.

Toxicity: Damages tissues of cell mucosal lining; Stomatitis and diarrhea are
common signs of toxicity that can call for discontinuation of drug.
Unwanted effects
Bone marrow suppression, Stomatitis ECT

Drug interactions
Bone marrow suppressants and live virus vaccine may produce unwanted effects
as discussed before. Aspirin increase toxicity by displacing of methotrexate from
binding sites which frequently produces toxicity.Acyclovir increases risk of CNS
effects when its administered intrathecally.Alcohol increase risk of liver
damage .Asparagluase block action of methotrexate action .Anti-inflammatory
drugs increases bone marrow effects of the drug.

III Agents that Block DNA or Protein synthesis

Examples include: Plicamycin, Dactinomycin, and Asparagluase, Epirubicin ,

doxorubucin, Daunorubicin, Idarubicin
Pharmacodynamics

They interfere or prevent RNA formation which is used as a template for protein
synthesis. It does this by binding highly to DNA and prevents reading of genes.

They are non specific.

Pharmacokinetics
The pharmacokinetics of these drugs is varied.Many persist for some time inside
cells

The effects of these drugs persist for days to weeks.

Read more on the pharmacokinetics

Indications

Lymphocytic leukemia in children; Choriocarcinoma, Will’ns tumor, Sarcomas

Carcinomas

Unwanted effects
Non -selective and attacks the dividing tissues.Causes bone marrow suppressions

Damage to epithelial cells, Nausea, Stomatitis, Damage to hair follicle loading to

alopaecia

Toxicity
Bone marrow suppression is dose related side effects

Drug interactions
Bone marrow suppressants and radiation accelerates the effects on bone marrow
suppression.Immunosuppression drugs increases risk of generalize viral
infections.

Live virus vaccine – puts patients at risk of role of getting the disease.

Prototype

Dactinomycin
Is an antibiotic derived from streptomyces.

Pharmacodynamics
Binds strongly to double stranded DNA and prevents the DNA from serving as a
template for RNA systhesis.

Pharmacokinetics
Not well absorbed orally.Can be admnistred through IV.Its corrosive to some
tissues

Clearance is rapid.Metabolism is in the liver.Excretion is through the bile.But small

amounts of unchanged drug is excreted in urine.

Indication: Choriocarcinomas willm’s tumor scarcoma, carcinoma.

Dosage: adult: 0.5mg/m2 once weekly for 3 Weeks: Children: 0.015mg/kg or

0.45mg/m2 for 5 days

Unwanted effects
Causes anaplastic anaemia, GI toxicity, Nausea, Vomiting, GI corrosion – mouth to
anal corrosion; Abdominal pains, Alopecia, Erythema – reddening of the skin.
Drug interactions
Bone marrow suppressants and live virus vaccines as seen above

IV.Agents that prevent or arrest mitosis

Examples include: Etoposide and teniposide, Paclitaxel, Vinblastine, Vincristine,

Vindesine, Vinorelbine
Pharmacodynamics

They cause the breakdown of microtubular structures by binding to tubulins

making them to be held in non-functional aggregates. The microtubes are
required for mitotic spindle formation that is necessary for mitosis/cell division.
Arrests of these spindles lead to arrest of cell division. No reproduction
proceeds.Also composes of a class that inhibit enzyme called topoisomarase II
which prevents normal DNA replication. This prevents the cell entering into
mitosis.

Pharmacokinetics
Most have long half life of few hours to more than 2 days .Metabolism occurs in
the liver and excretion in the bile

Indications

Small cell lining carcinoma, ovarian carcinoma, Testicular tumors, Lymphomas,

Leukemia, Neuroblastoma, willm’s tumour

Unwanted effects
Bone marrow suppression, Alopecia, Immunosuppression, Nausea/Vomiting
Toxicity is dose -related.
Drug interactions
All drugs of this class increases risk of severe generalized viral disease if the
patient recieves a live virus vaccine. Bone marrow suppressants also cause
excessive depression of the bone marrow

Prototype

Vincristine

Pharmacodynamic

Interfere with microtubules assembly, preventing the formation of a functional

mitotic spindle ultimately arresting the cell in mitosis.

Pharmacokinetics

Do not cross blood-brain barrier effectively enough to combat CNS spread of

leukemia.

Well distributed to other tissues.Metabolism in the liver. Half life is

short .Excretion usually in bile and little through the urine.

Contra indications: Liver impairement

Unwanted effects
Nerve dysfunction i.e. loss of Achilles tendon reflex is a sign of neuropathy,
Headaches

Mental depression, Alopecia, Constipation, Abdominal pains, Bone marrow

suppression
Stomatitis, leucopaenia

Drug interactions
Accelerate the effects of bone marrow when used with bone marrow
suppressants and immunosupresants

COMBINATION OF ANTI CANCER DRUGS

Combination therapy is usually more effective than single for many reasons:

1. Combination of drugs acting by different mechanisms reduces the chances of

development of drug resistance. Cancer cells develop resistance just like
microbials .Some may develop multiresistant drug pump which makes them resist
many drugs.

2. Allow the physician to select agents that produces different patterns of toxicity
and thereby reduce the damage directed at any one organ system.

3. Combining of anticancer agents that act at different stages of the cell cycle
allows for more tumor cells to be killed.

4. Adding a tissue specific increases the anticancer effect of the drug.

Common combination regimes used

REGIME DRUGS INCLUDED DISEASE

ABVD Dorobucin (Adriamycin) Hodgkin’s disease

Bleomyan (Blenoxane)

Vinblastine (Velban)
CHOP cyclophosphamide

Dororubicin Non-Hodgkin’s Lymphomas

Viucrushine

Prednisone

CHF Cyclophospanide

Methotrexate Breast caranoma

Fluoroucu

POMP Prednison

Viuashre (oucorin) acute lymphocytic leukemia

Methotrexate

Mercaptoporine

Why drugs don’t cure all Cancer

Cancer cells offer fewer targets for selective toxicity than do bacterial cells.

This is because cancer cells & normal cells are primarily the same. All drugs have
dose- limiting toxicity i.e. side effects that limits the dose of drug that can be
given. If high concentration of cytotoxic were given to kill all cancer cells, normal
cells would also be killed & patient would die i.e. most anticancer drugs have low
therapy index and a narrow safety margin.Furthermore,diagnosis made when
disease is advanced i.e. cells have multiplied so much that drug may not kill all of
them – the left ones tend to regrow hence earlier detection is advantageous for
chemotherapy e.g.In prostate cancer release prostate – specific antigen (PSA)
which can be detected in blood and early treatment started .

DRUGS USED IN SUPPORTIVE THERAPY OF CANCER PATIENTS

Other drugs are used in cancer patients either to relive symptoms of the disease
or to ease the adverse eeefects of drugs. Such drugs include:

Allopuriunol
Chemotherapy destroys cells that release breakdown products eg uric acid which
can damage the kidneys if allowed to accumulate .Allopurinal inhibits formation
of uric acid.

Analgesics
Narcotic analgesics for severe pain which usually accompanies the disease

Anti – emetics

Nausea and vomiting are very common side effects of cytotoxics drugs .It might
be severe to lead to electrolyte imbalance.Ussually Phenothiazide used as it has a
strong antiemetic effect

Drugs to control of direct drug toxicity

Eg ifosfamide and cyclophosphamide produce toxic substances that can cause
bladder damage.Mesna binds to metabolites of these drugs.Dextrazoxane
prevent heart damage by doxorubicin.

Drugs to control of hypercalcemia

Etidronate, pamidronate and gallium nitrate block overproduction of calcium.

CRITICAL☺? THINKING ACTIVITY

Mr Karanja has been receiving a course of anticancer therapy .His lab results are
returned with her platelet count at 46,000 cells.mm3 and her absolute
granulocyte count at 86 cells/mm3.What assessments should be obtained? How
should she be monitored on a daily basis? What safety precautions will you take
with her care?

ENDOCRINE SYSTEM DRUGS

PITUITARY AGENTS

Introduction

The pituitary gland is made up of two distinct glands – the anterior

(adenohypophylis) and posterior (neurolypophysis).It linked and communicate
with the hypothalamus.

Generally, gland secretes its hormones which are either water or lipid
soluble.Water based soluble hormones are protein based substances e.g. the
catecholamine (narepinephrine and epinephrine).The hormones bind to their
receptors on the cell surface & either directly activate the cell to perform a
function or cause a signal through a 2 nd message to generate response.Lipid
soluble hormones are the steroids and thyroid hormones.They cross plasma
membrane through diffusion and bind to receptors within the cell
nucleus.Hormone secretion is regulated by negative feedback mechanism.

Hormones of the Pituitary Gland

Anterior Pituitary :Adrenocarticotropic hormone (ACTH), Follicle stimulating
hormone (FSH),Growth hormone (GH), Prolactin (PH), Thyroid stimulating
Hormone (TSH)

Posterior Pituitary: Antidiuretic hormone (ADH), Oxytocin

Antipituitary Drugs

Examples include:

Somatropin, somatrem, octreotide, vasopressin, desmopressin and lypressin

Pharmacodynamics
Differ depending on the agent but overall they either augment or antagonize the
natural effects of pituitary hormones.Drugs that mimic Growth hormone are
somatropin and somatrem by promoting growth stimulating the anabolic
processes. Octreotide antagonizes the effects of natural Growth hormone
release.Drugs that affect the posterior pituitary include vasopressin, lypressin and
desmopressin. They mimic the actions of naturally occurring ADH.

Indications

 Replacement therapy for hormone deficiency.

 Drug therapy to product particular hormone response
 Patient with specific disorders
 Diagnostic aid – incase of hypofunction of hormones
Prototype

SOMATREM
Are growth hormone, somatropin also is a growth hormone.
Indication – Growth failure due to inadequate levels of GH

Contra indication: Drug allergy, intracerebral lesions, closed epighysealplates

Dosages: Paediatric IV/SC upto 0.1mg/kg 3 times wkly .Half life 25 minutes

General drug interaction

Additive potassium lowering effect when ACTH given with diuretic or
amphoterian B

Desmopressin when given with carbamazepine, chlorpropamide & clotibrate

results in additive therapeutic effect of desmopressin.Lithium, alcohol,
demeclocycline & heparin when administered together with desmopressin result
to decreased therapeutic effects of desmopressin.

Unwanted effect

Central Nervous System

Convulsions, Dizziness, Euphoria, Insomnia, Headache, Depression, Psychosis

Endocrine: Hyperglycemia, Ketosis, Hypothyroldism

GastroIntestinal: Nausea & vomiting, peptic ulcer perforation, Pancreatitis

Cardiovascular: Increased blood pressure.

Genitourinary: Water & Na2+ retention, Hypokalemia, Hypercalciuria

Others: Urticaria, rash, nasal irritation & congestion, Sweating,

Hyperpigmentation

Thyroid gland
Introduction

It is composed of two types of cells: Fullicular cells which manufacture thyroxin (T 4

and triodothyronine (T3). The two hormones are reffered to as thyroid hormones.
Their function is to control the metabolic activity of cells in the body.The second
group of cells is parafollicular cells which produce calcitonin which influences
calcium homeostasis.

Drug therapy for thyroid hormone deficiency and excess

A deficiency of thyroid hormone requires replacement therapy with drugs
containing T4, T3. These preparations are either: - Naturally occurring hormones or
synthetic derivatives.Thyroid hormone excess is treated with two groups of drugs:
- Antithyroid drugs, Radio active iodines

Drugs used to treat thyroid hormone deficiency naturally occurring hormones

include

Thyroid USP and thyroglobulin

Synthetic replacement include lerothyroxine sodium, liothyronine, Liotrix

Pharmacodynamics /Pharmacokinetics

Acts by increasing metabolic rates, resulting in increased cardiac output, oxygen

consumption, body temperature, and blood volume, and growth, development at
cellular level, respiratory rate and enzyme activity system.T 4 48-79% is absorbed
while

T3 95% absorbed.Metabolism is liver and excretion in the kidney.Excretion in

urine.
Indications
For thyroid replacement

Unwanted effects
Insomnia, Tremors, Tackycardia, Palpitations, Angina, Dysrhythmia, Weight loss
and changes in appetite, serious adverse reactions include thyroid storm.

Contra indications
Adrenal insufficiency, Myocardial infarction, Thyrotoxicosis

Precautions
Elderly, angina pectoris, Hypertension, ischemia, cardiac disease, diabetes
mellitus or inspidus, pregnancy and lactation

Drug interactions
i. Impaired absorption of thyroid products may occur when
administered with cholestyramine.
ii. Increased effects of anticoagulants, sympathominetics, tricyclic
antidepressants, catecholamines.
iii. Decreased effects of digitalis, glycosides, insulin, hypoglycermics.
iv. Decreased effects of thyroid products may occur with estrogens.

Prototype Levothyxine sodium

Action

Stabilization of client’s metabolic rate without complications of hyperthyroidism

Pharmacotherapeutics
Replacement of deficient hormone in clients with hypothyroidism

Simple non toxic goiter

Chronic lymphocytic (Hashimoto’s) thyroiditis myxedema comes or stupor.

Pharmacokinetics
Absorption 50-80% from GIT (oral administration)

Im absorption is poor.

Metabolism: liver

Elimination: bile, with 20% - 40% excreted unchanged in feces.

Pharmacodynamics
Binds to receptors throughout its body increasing metabolic rate of body tissues.

Promotes gluconeogeneosis

Stimulates protein systhesis and promote all growth and differentiation.

Pharmaceutics
Iv or im preparations.Dosage ;Hypothyroidism

Adult, elderly Oral: Initial dose, 0.05mg/d: Increased by 0.025mg q 2-3 weeks.

Maintenance 0.075 – 0.125mg/d.

Myvedema coma or stupor

Adults

Iv: Initial dose 0.4mg: follow with 0.1-0.2mg daily supplement.

Thyroid suppression therapy

Adult

Oral: 2.6mg/kg/d for 7-10 days

Parenteral: ½ oral dose

Congenital hypothyroidism

Oral

Children > 12g: 0.15mg/d

Children > 6-12years: 0.1 – 0.15mg/d

Children > 1-5years: 0.075 – 0.1mg/d

Children > 6-12 months: 0.025-0.05mg/d

Infants 0-6months: 0.025-0.05mg/d

Adverse effects
CNS: Anxiety, insomnia, tremors, headache.

CS: tachycardia, palpirtatiens, angina, dysrhythmia, hypertension.

GI: Nausea, diarrhoea, increased or decreased appetiete

Others: Menstrual irregularities, weight loss, sweating, heat intolerance and

fever.
Contra indications
Adrenal insufficiency, myocardial infaction, thyrotoxicosis, hypersensitivity to
beef, alcohol intolerance.

Precautions
Elderly, angina pectoris, hypertension, ischemia, cardiac diseases, pregnancy and
lactating.

Drugs for treating thryroid hormone excess

Antithyroid drugs
- Antithyroid drugs
- Radio active iodines
Antithyroid drugs
- Prpylthiourcil
- Methmazole

Radioactive iodines
- Radioactive iodine 13l
Antithyroid drugs
Prototype: propythionracil

Action

Blocks synthesis peripherally of T3, T4 inhibits organification of iodine.

Uses
Preparations for thyroidectomy

Thyroid crisis
Hyperthyroidism

Thyroid storm

Dosage
Preparation for thyroidectomy

Adult: 600-1200mg/day

Child: 10mg/kg/day divided doses.

Hyperthyroidism

Adult
Orally 100mg tid increasing to 300mg 98h if condition severe. Continue to
enthroid state then 100mg qd – tid

Child > 10 yrs

Oral 100mg tid: continue to enthyroid state

Then 25mg tid to 100mg bid.

6-10yrs: 50-150mg divided doses 98h

Neonate: 10mg/kg/day divided doses.

Adverse reactions/ side effects

Intergumentary: Rash, urticania, prunitus, hyperpigmentation

Urinary : Nephritis

CNS : Nausea, vomiting, diarrhea, jaundice, hepatitis.

MS : Myalgia, arthralgia, nocturnal muscle cramps, osteoporosis.

Agranulocytosis, leukopenia, thrombocytopenia, lymphodenopathy.

Pharmacokinetics
Half life 1-2 hours

Excreted in urine, bile, breast milk.

Cross placenta barrier.

Interactions
Increased anticoagulant effect: Heparin, oral antocoagulants, bone marrow
depressants.

Agranulocytosis: Phenothiazines

Contra indications

Hypersensitivity, pregnancy, lactation.

Precautions
Injection, bone marrow depression, hepatic disease.

Radio active iodenes

Prototype: Radio active iodine 13l

Action

Converted to protein bound iodine by thyroid gland for use when needed.
Uses
Thyroid cancer, hyperthyroisdism

Low dose: visualization to determine thyroid cancer.

Diagnostic in thyroid function studies.

Dosage
Adult: PO 4-10 mci

Side effects/ adverse effects

Hypothyroidism, hyperthyroid odenoma

Alopecia

Esinophilia, lympedema, leukemia, leukopenia, nausea, diarrhea, vomiting, sore

throat, cough.

Pharmacokinetics
Half life 3-6 days

Excreted in urine, sweat, feces, breast milk, cross placenta barrier.

Contra indication
Mycordial interaction, lactation, large nodular goiter, pregnancy and lactation.
Drugs affecting calcium metabolism

PARATHYROID GLANDS

It secretes porathorhone which regulates body’s calcium and phosphate levels.

Serum calcium levels raised by parathyroid hormone on three sites: bone, kidneys
and Gi tract.

In bones hormone stimulates oesteolast activity causing breakdown of hu bone

and increased re-absorption of calcium from bones.

In kidneys, acts directly on renal tubules to increase re-absorption of calcium and

promote execution of phosphate.

In intestines, it activates vitamin D, which acts on intestinal mucosa to increase

absorption of dietary calcium.

Drugs used to treat parathyroid disorders

Calcium regulators

Calcitonin

Etidronate sodium

Action
Decrease the serum calcium concentration and with D, which increases serum
calcium levels.

Prototype: Calcitonin

Action
Decreases bone re-absorption, blood calcium levels, increase deposits of calcium
in bones; opposes parathyroid hormone.

Uses
Paget’s disease post menopausal osteoporosis, hyperclcemia.

Dose
Calcitonin, human 0.5mg daily, sc

Calcitonin, salmon

Paget’s disease: 100iv (0.5ml)/day im or sc

Hypercalcemia: 4 iv/kg body weight 912h im or sc

Postmenopausal osteoporosis: 10010/day im or sc

Supplement calcium carbonate 1.5g daily and vitamin D 400mg daily.

Side effects/ adverse reactions

Intergumentory system: rash, flushing, prunitus of earlobes, edema of feet.

CNS: Headache, tetany, chills, weakness, dizziness, fever.

Urinary system: Dizziness, nocturia, urine sediment

GIT: Nausea, diarrhea, vomiting, anorexia, abdominal pain, salty taste, epigastric
pian

MS: swelling, tingling of hands

CV: Chest pressure

EENT: Nasal congestion, eye pain

Respiratory: dyspnea

Pharmacokinetics
Absorption – it is destroyed in GI tract

Distribution – unknown

Metabolism – kidneys, blood, peripheral tissues.

Onset of action after iv – immediate

Onset of action after im/sc – 15 minutes, peak action

4 hrs, duration of action 24 hrs

Contra indications

Hypersensitivity

Renal disease, children lactotian, osteogenic sarcoma, penicius anemia.

GLUCOCORTICOIDS AND MINERALOCORTICOIDS (STEROIDS)

Introduction

The term steroids refer to naturally occurring group of chemicals allied or related
to cholesterol. These includes Sex hormones e.g. estrogens, progesterone,
androgens;

Adrenal cortical hormones e.g. aldosterone, hydrocortisane (cortisol),

corticosterone and
bile acids e.g. chenodeoxycholic acid, cholic acid. However, the common usage of
the term implies implies: Adrenal glucocorticoids i.e. hydrocortisone (cortisol &
cortisone and synthetic analogues e.g. prednisolone and predinsone (pro-drug),
fluorocortisone,

desoxycorticosterone. Adrenal cortex also secrets aldosterone which has

mineralscorticoid effect.Most steroids have both glucocorticoid and
mineralocorticoid effects. But each steroid has varying magnitude of each e.g.
hydrocortisone has great glucocorticoid activity and weak mineralocorticoid
activity. Separating the two effects is difficult but dexamethasone has very little
mineralocorticoid effects.

Glucocorticoid effect
Applies to any steroid effect which promotes gluconeogenesis (formation of
glucose and glycogen from proteins), glyconeogenesis and which antagonises the
action of insulin.

Mineralocorticoid

It is sodium retaining effect.Remember that angiotensin II increases production of

aldosterone which increases retension of sodium.

Examples of steroids
Hydrocortisone (cortisol), Predinsolone (predinsone prodng), dexamethasone,
betamethasone, Aldosterone, Fludrocortisone, Methylprednisone, Triamcinolone

Desoxycorticosterone, Fluorocortisone
General indications of Steroids
Replacement therapy in Addison’s diseaese, adrenolectomy, acute adrenal
insufficiency (eg in abrupt withdraw of steroids); Suppression therapy eg in
adrenogenital syndrome and immunosuppression in organ/tissue transplant;
Inflammatory rxns eg rheumatoid arthritis, skin diseases eg exffolitative
dermatitis, topical use (eg in psoriasis, Eczema, interstitial keratitis)

Hydrocortisones

This steroid has both glucocorticoid and mineralocorticoid effects.However the

glucocorticoid effect is more than the other effects

On inorganic metabolism (mineralocorticoid effects)

Increased Na+, H2O retention by renal tubule; Increase K + excretion in urine;

Increase Ca++& phosphorous excretion in urine. Urinary calcium excretion is
increased & renal stones may form

On organic metabolism (glucocorticoid effects)

Carbohydrates metabolism:

Gluconeogenesis and glycogenesis increase and peripheral glucose utilization

(transport across cell membranes) may be decreased.This insulin antagonism may
result to hyperglycaemia & sometimes glycosuria result.

Protein metabolism: Anabolism

Conversion of amino acids to proteins decrease but catabolism continues
unabated or even faster hence their negative nitrogen balance with muscle
wasting.Osteoporosis (reduction of bone protein matrix) occurs, growth slow in
children, skin atrophies and this, with increased capillary fragility causes bruising
& striae.Healing of peptic ulcers/ wounds, fibrosis is delayed.

Fat deposition (obesity)

Due to guconeogenesis, there is increased fat deposition in shoulders, faces &

abdomen i.e. there is redistribution of fat.

Inflammatory response
Depressed regardless of cause: hence steroids are not good because they limit
useful protective inflammation which occur in
infections .Neutrophils,eosinophils,lymphocytes & macrophages function is
depressed .All this leads to increased susceptibility to infections.Allergic responses
suppressed. Antibody production reduced by heavy doses.

Lyphoid tissue is reduced (including leukaemic lymphocytes)

Effect on uric acid

Renal excretion of uric acid increased gout

Effect on mental health

Euphoria or psychotic states may occur which may be due to CNS electrolyte
changes.

Effects on steroid secretion

Suppression of hypothalamic/ pituitary adrenocortical system (with delayed
recovery) occurs with chronic use.Hence attempt withderawal leaves patient in a
state of adrenocortical insufficiency.Normal daily secretion of hydrocortisone is
10-30mg

Exogenous daily dose of 40-80mg hydrocortisone completely suppresses adrenal

cortex.

General pharmacokinetics of Corticosteroids, including hydrocortisone

Pharmacokinetics

Rapid absorption when given orally. Half life is 1-3hrs but maximum biological
actions occur after 2-8hrs.Usually given BD or TDS/ day – but to decrease change
of S/effects – alternate days – basically determined by seventy of
condition.Metabolism and excerion in liver and kidneys respectively.Topical
application: (skin, lung, joints) are also available allows absorption which may
have systemic effects.

Unwanted effects
 Iatrogenic Cushing’s syndrome – increased cortisol (hydrocort)
characterized by: moon face, deposition of fat on the body (obesity),
hypertension (mineralocorticoid effect), striae, bruising, acne, hirsutism,
muscle wasting & osteoporosis of spine (fractures of vertebrae, ribs,
femoral & feet)
 A vascular necrosis of bone (femoral heads) especially at higher doses. Due
to restriction of blood flow through bone capillaries and pain and
restriction of movement may occur.
  Psychiatric manifestations eg depression & psychosis, suicidal tendency,
paranoia, insomnia especially in those with history of mental disorder.
 Peptic ulceration. Peptic ulceration & haemorrhage occur in about 1-2%.
Other GIT S/E dyspepsia, acute pancreatic abdominal diastema. Not clear if
peptic ulcer can be attributable to glucococoid effect.
 Suppression of inflammatory response can lead to increased severity of
infection and delayed would healing
 Other unwanted effects include diabetes mellitus, Glaucoma & cataracts
(steroid catarcts 75%), menstrual disorders & fever, increased incidences of
infection.
NB; Rate of occurrence of unwanted effects depends on dosage, duration of use
and steroid used
Contra indications in systemic administration
Osteoporosis, increase blood pressure, Peptic ulcers, Cushing’s syndrome,
Psychoses

Severe neurosis, acute bacteria infection e g herpes simplex & herpes zoster eye
infection.

Caution: Congestive cardiac failure, diabetes mellitus, infectious disease,

Uraemia, Elderly patients

DRUGS USED FOR DIABETES MELLITUS

Introduction

Normally as food is consumed, it is converted into glucose and other energy

precursor by the digestive system. As the glucose is absorbed into the blood, the
serum glucose level rises. Elevated blood glusose levels stimulate insulin secretion.
Increased level of insulin facilitates the transport of glucose as glycogen in liver &
muscles. Increased level of insulin enhances fat deposition in adipose tissue,
inhibits protein degradation and accelerates the process of amino acid transport
into cells and protein synthesis.
Without insulin or sufficient insulin normal carbohydrates metabolism is impaired.
Although blood glucose rises to excessive levels, lack of insulin prevents cells
from receiving the needed glucose for intra cellular metabolic functions and
prevents storage of excess glucose and glycogen. Without treatment cells starve
from lack of glucose inspite of the hyperglycemia in the blood.Classification of
diabetes mellitus can be insulin dependent diabetes mellitus (type –1) or non-
insulin – dependent (type II) diabetes mellitus
Drug therapy for Insulin dependent diabete mellitus

Treatment is usually with insulin.

Pharmacokinetics and pharmaceutics

Absorption rate of insulin administered subcutaneously varies according to the

type of insulin. Absorption is most rapid from the abdominal areas, less rapid
from the arm and least rapid from the leg. If the client exercises the arm and legs
after injecting insulin into them, absorption is faster. Factors such as circulation
problems (edema or lymphotension), smoking and injection of regrigerated
insulin, delay or decrease insulin absorption.Even though insulin is distributed
widely in the body, some insulin is bound and inactivated by peripheral
tissues.Majority of insulin is metabolized in the liver and kidneys.

Short acting insulins

Examples
Regular insulin

Iletin II R - Velosulin

Iletin I R - Velosulin human

Humulin R - Regular

Humulin BR - Novalin R

Semilente (prompt insulin zinc suspension) eg Iletin 1/s, Iletin S/H, Semicentre

Solutions of regular and modified short acting insulin are available.

Regular insulin

It’s got from purified beef, purified pork, unpurified pork, and unpurified beef-
pork combinations .Given subcutaneously. Onset of action is within 30 to 60
minutes of injection.Its the only type of insulin administeredthat is administered
IV.Intravenous administration is helpful in unstable diabetic clients or in clients
whose requirement for insulin change rapidly. Regular insulin may be mixed with
other insulin preparation when given SC or IM – this prolongs the effect short
acting insulin.

A special formula of buffered regular insulin (Humilin BR) is developed for use in
the SC infusion pump. It has less potential for crystal formation in the tubing.
Humilin BR – should not be directly injected by syringe. Mixing Humilin BR with
other insulin products should be avoided since the interaction between buffer
creates a significant change in insulin action.Semilente (insulin zinc suspension) –
is a modified short acting insulin. It is used infrequently; in a solution containing
30% short acting insulin (semilente) and 70% long acting insulin (ultra lente). This
mixture forms intermediate acting insulin (lente), hence semilente has a longer
duration of action than regular insulin.Therefore, it’s not recommended for for
emergency or IV usage.

Nursing considerations for client receiving short acting insulin include:

 Administer regular insulin 30-45 minutes before meal – this allows the drug
to reach therapeutic level before client eats.
 Don’t administer short acting insulin if blood glucose level is below 70mg/dl
or if signs of hypoglycemia are present.
 Monitor the client carefully for signs of hypoglycaemia, especially near peak
action time of the insulin.Regular insulin is frequently administered as part
of a sliding scale i.e. dosage of insulin is based on the serum glucose level at
the time of administration for example – order may read: if the client’s
serum glucose level is 250 to 275mg/dl administer 8u of regular insulin or
276-300m/dl.
Intermediate acting insulin

Examples

 NPH e.g Iletin II N, Iletin I N, Insulated NPHm, NPH, Novolin N

 Lente (Insulin zinc suspension) e.g Iletin II L, Iletin I L, Iletin II L/H, Leute,
Novolin L
 NPH and regular mixed insulin mixture eg Mixtard 30% R/70%N; Novolin
mix 30%R/ 70%N
These are produced by combining insulin with protamine, a protein from fish or
with zinc. These additives prolong the action time of the insulin. Intermediate
insulin is administered SC. Their onste of action is 1 to 2 hours after injection.

Forms

Iso phase Insulin Suspension (NPH): Is the most common used. Human NPH
insulin preparation has a slightly shorter duration of action and faster onset of
action than NPH pork insulin. Human NPH produce dilute precipitate (flocculation)
or frosting that adheres to vial. In this case, insulin should not be used. Causes are
increased environment heat, prolonged use of vial and vigorous mixing of the
solution. NPH has a longer onset of action, so not used in ketoacidosis or
emergencies.NPH insulin may be mixed with regular insulin which slows the
absorption and the onset of action of the regular insulin.

NPH /regular premixed insulin

Contains 30% regular insulin and 70% NPH insulin. Onset an action is half an hour,
peak effect 4-8 hours, duration of action is 24 hours. (Mixtard, Novolin 70/30)

Lente (insulin /zinc suspension) insulin

A mixture a 30% short acting insulin/ zinc suspension (semilente) and 70% long
acting insulin/ zinc suspension (ultra lente).Should not be used in emergencies.
Lente insulin should be mixed only with other lente products. Mixture of lente
insulin and regular insulin are subject to binding of two insulins (regular and lente)
which yield an uncertain concentration of regular insulin .Onset of action 1-3
hours, peak effect 8-12 hours and duration of action 18-28 hours.
Nursing considerations

 Monitor for hypoglycemia during mid or tale afternoon.

 Observe client receiving lente insulin for adequate nutrition intake.The long
action time (12-18 hours) of insulin produces additional risk to
hypoglycemia.
 Incoporate evening snacks into the meal plan if the client receives
intermediate acting insulin before supper blood glucose level may drop to
dangerously low levels during sleep around mid night.
Long acting insulins

Examples:

 Ultraleute (extended insulin zinc suspension) eg Iletin I U, Iletin II U/H,

Humilin ltraleute
 Protamine zinc insulin (PZI) suspension eg Protamine zinc and iletin ,
Protamine zinc and iletin I
They have very slow onset of action of 4-8 hours and a prolonged duration of
action 18-72 hrs. They are mostly combined with short acting insulin to provide
blood glucose control throughout the entire day and night. Because of their
prolonged action time it can be difficult to determine the optimal dosage.

Forms

Protamine zinc insulin (PZ1) suspension

Not suitable to use in emergencies or IV administration. Hyperglycemic reactions
from PZ1 are unpredictable.

Ultralente (extended zinc suspension) insulin

It does not contain modifying proteins, hence reduced incidence of

hypersensitivity, May be combined with human regular, lente or semilente
insulins.

Unwanted effects

Blurred vision, dry mouth, flushing, rashes, urticaria, warmth, swellings, redness,
hypoglycemia, rebound hyperglycemia, anaphylatis

Contra indications /Caution

Hypersensitivity to protamine and caution taken in pregnancy

Pharmacokinetics

Route Onset/hrs Peak /hrs Duration/hrs

SCuspro rapid ½ -1 hr 3-4 hrs

SC NPH 1-2 hr 4 – 12 18 – 24

SC Regular susp. ½ hr 4–8 12 – 24

SC regular ½ - 1 hr 2–4 5–7

IV regular 10-30min 10-30min ½ - 1 hr

SC Regular conc. ½ - 1hr 2 – 5 hr 5 – 7hr

SC zinc susp. Conc 4 – 8hrs 10-30hrs 7 – 36 hrs

Metabolism takes place in the liver, muscles, and kidneys while excretion is in
urine.

Drug Interactions

Increased hypoglycemia might be caused by the following drugs salicylates

alcohol, B-blockers, anabolic steroids, fenfluramine, phenylbutazone,
sulfinpyrazone, MAOLs, TCAs.Other drugs may decreased hypoglycemia eg ,
thyroid hormone, oral contra captives ,corticosteroids, estrogen, dobutamine
epinephrine.

Pharmacodynamics of insulin

Decrease blood sugar by transporting insulin into cells and the conversion of
glucose to glycogen, indirectly increasing blood pyruvate and lactate, decreases
phosphate and potassium. Insulin may be pork, human (processed by
recombinant DNA technoligies)

Indications

Adult onset diabetes, juvenile diabetes, ketoacidosis types I and II, type I DM, type
II DM .Insulin uspro may be used in combination with salfonylureas in children
>3yrs.

Dosage and date

Insulin isophane suspension: Adult: SC dosage, individualized by blood, urine

glucose, and usual dose 7-26 u – may be increased by 2-10u/day.
Regular insulin (ketoacidosis)

Adult – IV 5-10u, then 5-10u/hour until desired response is is achieved, then

switch to SC dose. IV/Intermediate 2-12u (50u/500ml of normal saline).Child – IV
0.1 u/kg

Replacement

Adult and child SC 0.5-1u/kg/day QID given 30min ac

Adolescent SC 0.8 –1.2 mg/kg/day – dose used during rapid growth.

DRUG THERAPY FOR NON-INSULIN DEPENDENT DIABETES MELLITUS

Oral antidiabetic drugs

Clients with DM type 2 produce limited amount of insulin from the pancreas,
which is not sufficient to maintain blood glucose levels within normal
values.These drugs enhance the release of insulin from the beta cells in the
pancreas, decrease liver glycogenolysis and gluconeogenesis and increase the
sensitivity to insulin in body tissues. So they reduce blood concentration in
persons with a functioning pancreas.Insulin (isophane insulin) might be added to
the oral therapy or substitute it if there is no adequate control of blood sugars.

Sulfonylureas/sulphonylureas

Introduction
These generally augment the action of insulin; hence they are used when some
residual pancreatic beta cell activity is present.

1. First generation sulfonylureas

o Acetohexamide( intermediate acting drug)

o Chlorpropamide (Diabinese) – long acting oral hypoglycemic agent
o Tolazamide (Tolenace) - intermediate acting drug.
o Tolbutamide) – short acting drug
Prototype

Chlorpropamide – Diabenese

Pharmacodynamic

Stimulates insulin release from the pancreas beta cells, reduce glucose output
from the liver, insulin sensitivity is increased at peripheral target cells.

Pharmacokinetics

Protein bining is 60% to 90%.Half life is 30-42 hours which can be prolonged in
elderly or patients with renal disease. End stage renal disease half life is 50-
200hrs.

Time peak concentrations are reached within 3-4 hours.Metabolism occurs in the
liver while excretion in the urine.Onset of action for oral dose is within 6-8 hours

Contra indications

Cross- sensitivity may exist with other hypoglycemics or sulfonamides. Do not use
with type I diabetes,in renal, hepatic, thyroid or other endocrine decrease;
diabetes complicated by ketoacidosis, alcohol abuse, dietary warnings.Patients
should be properly instructed in the early detection and treatment of
hypoglycemia.

Drug interactions

Decreased effect – Thiazides and hydantoins of phenytoin decrease

chlorpropamide effectiveness and may increase blood glucose.Increased effect/
toxicity – chlorpropamide may cause alcohol- associated disulfiram reactions.
Chlorpropamide may increase oral- anticoagulant effects. Salicylates may cause
increased chlorpropamide effects and lower blood glucose more than
expected.Sulphonamides may decrease dulorpropamide clearance and enhance
blood glucose lowering effects.Chloramphenicol may increase the half life of
chlorpropamide. Chlorpropamide serum levels may be increased if taken with
food.

Unwanted effects

Headache, dizziness, hypoglycemia (mild), constipation, diarrhea, heart burn,

weight gain anorexia. Polyuria, rash, articaria, photosensitivity

Toxicity

Symptoms of overdose include low blood glucose levels,tingling of lips and

tongue, tachycardia, stupor, convulsions and coma. Antidote is glucose.

Dosage: Adult oral – should be individualized based on the patient response.

Initial dose is 250mg/day in mild to moderate diabetes in middle aged stable
diabetic.

Elderly: Initial 100mg once daily, increase by 50-125mg/day at 3 to 5 days interval

– severe diabetes may require 500mg/day maximum daily dose 750mg.Given
orally mainly before breakfast.

2. Second generation sulfonylureas

Examples include glipizide (Glucotrol), Glyburide (Diabeta, micropase)

Prototype

GLIPIZIDE

Pharmacvodynamics

Stimulates insulin release from the pancreatic beta cells, reduces glucose output
from the liver, insulin sensitivity is increased at peripheral target sites.

Contra indications – hypersensitivity to glipizide, any component, and other

sulphonamides type I DM.Warning – use with caution with severe hepatic disease

Drug interactions

Decreased effect of glipizide occurs with beta blockers, cholestyramine,

hydantoin, and rifampin, thiazide diuretics and charcoal. Increased effects ie
hypoglycemic effect occurs with H2 antagonists, anticoagulants, androgens,
cimetidine, fluconazole, salicylates, probenecid, Sulfonamides, MAO inhibitors,
methyldopa and digitalis.Delayed release of insulin may occur if glipizide is taken
with food. Should be administered 30 minutes before food to avoid erratic
absorption.

Unwanted effects

Headache, dizziness, Hypoglycemic (mild) to severe, constipation, diarrhoea,

heart burn, weight gains and anorexia,polyuria, rashes, articaria, photosensitivity

Overdose/ toxicity

Symptoms include – low blood sugar, tingling of lips and tongue, nausea, yawning,
convulsion, agitation, sweating, convulsions, coma and stupor. Antidote – glucose.

Pharmacokinetics

Absorption – delayed when given with food.Protein binding is 92% to 99% while
half life is 2-4 hrs. Metabolism takes place in the liver and excretion in urine and
feaces.

Peak blood glucose reduction occurs within 1.5 – 2hr while donation of action is
12-24 hrs.Dosage: Adults – oral 2.5-40mg/day. Doses >15-29mg/day .Should be
divided and given BD max-dose 40mg.Elderly – oral initial 2.5mg/day increase by
2.5-5mg at 1 to 2 week intervals. Max daily dose 40mg

2. BIGUANIDES

The most important agent here is Metformin (glycophage) which is capable of

lowering blood glucose level.
Pharmacodynamics: Decreased hepatic glucose production, decrease intestinal
absorption of glucose and improves insulin sensitivity (increases peripheral
glucose reuptake and utilization)

Indications

Management of non-insulin dependent DM (type II) of a monotherapy when

hyperglycemia cannot be managed by diet alone.

Contra indication – hypersensitivity to metformin, renal disease, acute or chronic

metabolic acidosis with or without coma.

Drug interactions

Decreased effect – Drugs which tend to produce hyperglycemia e.g. diuretics,

corticosteroids, phenothazides, thyroid production, estrogen, oral contraceptives,
phenytoin, nicotinic acid, sympathomimetics, calcium channel blocker isoniazid –
all may lead to loss of glucose control.Increased effect/ toxicity – furosemide
increases the metformim plasma and blood without altering metformin renal
clearance in a single dose. Cationic drugs e.g. digoxin, amiloride, morphine,
quinine, procaunamide, guanidine, ranitidine, trimethoprim and
vancomycin.These drugs have the potential for interaction with metformim by
competing for common renal tubular secretion systems. Cimetidine increases (by
60%) peak metformim plasma and whole blood concentrations.
Unwanted effects

Headache, anorexia, nausea, vomiting, diarrhea, flatulence, constipation, heart

burn, weight loss, lactic acidosis, a plastic anemia, blood dyscrasias, hemolytic
anemia, bone marrow suppression, agranulocytocin.Overdose can cause
hypoglycemia with ingestion of upto to 85g. Hemolysis may be useful for
removal of accumulated drug from patients. Treatment is supportive.

Pharmacokinetics

Bioavailability is absolute 50% to 60% under fasting condition and food decrease
the extent and delay the absorption .Protein binding is 92% to 99%.Half life is 6.2
hours (prolonged in renal impairement). Excretion is through renal tubular
secretion.

Onset of action is within days and maximum effect lasts up to 2 weeks .Dosage for
– adult by oral 1-2 weeks between dose initiations is 500mg BD. Dosage increases
should be made in increments of 1 tablet every week given in divided doses upto
a maximum of 2500mg/day. Doses upto 2000mg/day may be given TDS with
meals.For the 850mg tablets – initial dose is 850mg OD. Dose may be increased
upto 2550mg/day. Maintenance dose is 850mg BD or TDS.

CRITICAL☺? THINKING ACTIVITY

1. A client arrives in emergency department unconscious.His medical alert-bacelet

indicates that he is diabetic.The client may be in diabetic coma or insulin
shock.How would yo tell which and what treatment would you recommend for
esch condition?

2. John is receiving somatren to enhance growth process.In the last 6 months he

has grown 3.0cm,would you consider the drug effective ?His current x-ray
indcatse that epiphyseal closure.What impact will this have on his therapy?

3.A 28 year old man is admitted after road traffic accident.A neurological exam
reveals an absence of light touch and pinprick sensation in both
extremities,lower-extremity paralysis,and no reflexes below the groin.He is
started on high-dose methylpredisolone.Why is a corticosteroid indicated?What
observations and interventions by the nurse will be necessary?

4. Why is clinical response more important than blood hormone level in thyroid
preparation therapy? What signs and symptoms should the nurse be monitoring
to determine the effectiveness of the therapy?

DRUGS ACTING ON THE FEMALE REPRODUCTIVE SYSTEM

Drugs affecting labour and delivery

UTERINE STIMULANTS
Inroduction
Normally spontaneous labour begins as a result of hormonal changes in the body.
One of these hormones is oxytocin, which is synthesized in the hypothalamus and
transported via neural tracts to the posterior pituitary. Oxytocin is secreted by the
posterior pituitary throughout pregnancy, but uterine sensitivity to it increases at
the end of pregnancy as myometrial receptors Increase. Situations arise in which
the labour process must be initiated even though spontaneous labour has not begun.
These situations include pregnancy-induced hypertension, premature rupture of
membranes, chorioamnionitis, intrauterine fetal demise, postterm gestation, and
maternal medical conditions such as diabetes mellitus or renal disease. In these
situations exxogenous oxytocin is administered to stimulate uterine contractions.
This procedure is referred to as induction of labour. Small amounts of oxytocin are
also administered during abnormally prolonged or arrested spontaneous labour.
This is called augmentation of labour.

UTERINE STIMULANT PROTOTYPE

OXYTOCIN
Exogenous oxytocin (Pitocin, Syntocinon) is currently the only drug approved for
use in induction and augmentation of labour. Pharmacotherapeutics Exogenous
oxytocin is indicated for induction of labour when delivery would clearly be the
best for mother and baby. It is also indicated when augmentation of existing labour
is necessary because of weak and ineffective contractions. The decision of when to
start oxytocin is based, in part, on a Bishop score. This score is determined after an
evaluation of cervical dilation, effacement, station of the fetal head, consistency of
the cervix, and cervical position. A score of 5 or more indicates that the cervix is
favourable for oxytocin induction. Oxytocin can also be given to facilitate the
emptying of the uterus in spontaneous abortion, but the uterus is less responsive to
oxytocin in early pregnancy. Another indiication is administration in the
postpartum period to aid the uterus in contracting, thus preventing or controlling
postpartum hemorrhage.
Pharmacodynamics: Acts directly on myofibrils, producing uterine contractions;
stimulates milk ejection by the breast.
Indications: Stimulation, induction of labour, missed or incomplete abortion;
postpartum bleeding
Dosage and routes:
Postpartum hemorrhage
Adult: IV IO u infused at 20 - 40 mU/min Adult:
1M IO u after delivery of placenta fetal stress test
Adult: IV 0.5 mU/min, increase q20min unitl3 contractions within 10 min
Stimulation of labour: Adult: IV 1-2 mU/min, increase by 1-2 mU q15-60
min unitl contractions occur; then decrease dose.
Incomplete abortion: Adult: IV INF 10 U/500 ml DsW or 0.9% NaCl at 20-40
mU/min Avalable forms: Inj 10 U/ml

Unwanted effects:
Conclusions, titanic contractions, Hypotension, hypertension, dysrhythmias,
increased pulse, brandycardia, tachycardia, Dysrhythmias, jaundice, hypoxia,
intracranial hemorrhage. Anorexia, nausea, vomiting, constipation. Abraptio
placentae decreased uterine blood flow. Increased hyperbilirubinemia, Rash,
Aspphxia
Contraindications: Hypersensitivity, serum toxaemia,
cephalopelvic
Disproportion, fetal distress, hypertonic uterus
Precautions: Cervical/uterine surgery, uterine sepsis, primipara> 35 yr, 1 st, 2 nd
stage of labour.
MISCELLANEOUS DRUGS IN CATEGORY
Methylergonovine maleate (Methergine) is a synthetic ergot alkaloid that acts
directly on myometrial cells to cause sustained uterine tetany. It is indicated for the
prevention or treatment of postpartum hemorrhage.
UTERINE INHIBITORS

Preterm labour refers to the onset of labour before 37 weeks' gestation. Preterm
deliveries account for more than 75% of all perinatal morbidity and mortality.
Many different therapies are used to prevent or treat preterm labour, including bed
rest, Hydration and tocolysis (administration of drugs that inhibit uterine
contractions). Several drugs are used to inhibit uterine contractions, including
magnesium sulfate and indomethacin. Magnesium sulfate relaxes the myometrium
by antagonizing calcium, and indomethacin (Indocin), a nonsteroidal anti-
inflammatory agent, inhibits prostaglandin synthase. The most common tocolytic
agents used are (l3-adrenergic agonists. Beta-Adrenergic agonists cause smooth-
muscle relaxation. Their use in the prevention and treatment of preterm labour.
Both ritodrine hydrochloride and terbutaline sulfate are used by clinicians for
achieving labour tocolysis Ritodrine hydrochloride has been approved by the FDA
for tocolysis, but terbutaline sulfate (Brethine) has not·

Ritodrine
Action: Reduces frequency, intensity of uterine contractions by stimulation of the
132reeptors in uterine smooth muscle. Indications include management of preterm
labour
Dosage and routes
Adults: IV INF 150 mg/500 ml (O.3mg/ml) given 0.1 mg/min, increased gradually
by 0.05 mg/min q 1 Omin until desired response.
A vialble forms: Inj 10 mg/ml, 15 mg/ml.
Side effects/adverse reactions:
Ertythema, rash, dyspenea, hyperventilation, gycosuria, lactic acidosis.
Hyperglycemia, hypokalemia, headache =, restlessness, anxiety, nervousness,
seating, chills, drowsness, tremor. Nausea, vomiting, anorexia, malaise, bloating,
constipation, diarrhea. Altered materenal, fetal heart rate, B/P, dysrhthmias,
palpitations, chest pain, and maternal pulmonary edema.
Contraindications: Hypersensivity, eclampsia, hypertension, dysrhthmias,
thyrotoxicosis, before 20TH week of pregnancy, antepartum hemorrhage,
intrauterine fetal death, maternal cardiac disease, pulmonary, pheochromocytoma,
brachial asthma. Precautions: Migaine, sulfite sensitivity, pregnancy-induced
hypertension, diabetes, pregnancy (B).

Pharmacokinetics:
Absorption is immediate, distribution is good, half life is 10 hr; metabolized in
liver, and 90% excreted in urine; crosses placenta.
Drug interactions:
Pulmonary edema: corticosteroids
Increased CV effects of ritodrine: magnesium sulfate, diazoxise, meperidine,
potent general anesthetics .Increased effects of sympathomimetic amines. Systemic
hypertension: atropine .Decreased action of ritodrine: Beta-blockers
Drugs active on male reproductive system
ANDROGENS
Introduction
Androgens produce both their androgenic and anabolic effects by binding to
androgen receptors in the target organs of skeletal muscles, the prostate gland, and
bone marrow. This binding stimulates development in those organs and also
increases protein synthesis. Effects of the androgens are evident in masculinization
of male sex accessory tissues. These masculinization effects include gonadotropin
regulation, spermatogenesis, and sexual restoration and development. Androgens
also cause retention of nitrogen, sodium, potassium, and phosphorus. They
decrease the urinary excretion of calcium, thus elevating serum calcium levels.
Androgens increase protein anabolism and decrease protein catabolism. Protein
anabolic effects produced by androgens include increased bone density, increased
muscle mass and increased red blood cell mass.

Pharmacotherapeutics
The primary use of androgens In males is as a hormone replacement for
hypogonadism. If for some reason (e.g., pituitary failure, primary testicular failure,
or hypothalamic failure) the testes fail to produce adequate amounts of
testosterone, replacement therapy is required. Androgens also can be used for male
contraception. These drugs inhibit spermatogenesis by suppression of the
hypothalamus and pituitary, which in turn suppresses the luteinizing hormone (LH)
and folliclestimulating hormone (FSH). Micropenis in children and delay of
puberty in adolescence are also treated with androgens. Androgens may be
prescribed for the older adult male with evidence of androgen deficiency to restore
libido, increase ejaculate volume, and enhance expression of secondary sex
characteristics.

Hereditary angioedema is another condition for which androgens may be

prescribed. In a client with hereditary angioedema an inhibitor of the (complement
system is deficient. Without this inhibitor, there is uncontrolled activation of the
complement cascade, resulting in increased vascular permeability and angioedema.
Androgens are administered to increase plasma levels of the deficient inhibitor.
General Characteristics
If unmodified testosterone is administered orally, it is rapidly absorbed in the
portal blood. After first-pass metabolism by the liver, only small amounts of the
drug reach the systemic circulation. When testosterone is administered
parenterally, it is also rapidly absorbed from the injection site and degraded. For
this reason, testosterone is chemically modified to retard the rate of absorption and
catabolism. Common modifications of the chemical structure of testosterone
include (i) esterification of the 17-r3-hydroxyl group; (i) alkylation at the 17-a-
position; and (3) changes in the ring structure of testosterone.
MISCELLANEOUS DRUGS IN CATEGORY
As indicated previously, androgens contain a 17-a-droxyl group. Esterification of
this group increases the duration of action of the drug preparation. (Esterification is
the conversion of an acid into an ester by combining the acid with an alcohol and
removing a molecule of water.
i) Testosterone cypionate is an oil-soluble ester of testosterone "that is
available for 1M injection. The sterile solution of testosterone cypionate contains
cottonseed oil, which increases the drug's solubility and delays its absorption.
ii) Testosterone enanthate is also a testosterone ester. This drug preparation
is
also administered intramuscularfy; the vehicle for testo-t-rone enanthate is sesame
oil. Another testosterone ester
iii) Testosterone propionate is insoluble in water but is freely soluble in
Alcohol, ether, or vegetable oils. This drug preparation contains sesame oil and
must be administered intramuscularly.

A-Alkylated androgen androgen protype

Methyltestosterone
Methyltestosterone is a synthetic derivative of testosterone. It is used clinically for
its androgenic and anabolic action. Because of its similarity to testosterone, only
the major differences between the drug groups are discussed.
Pharmacotherapeutics - Methyltestosterone is prescribed for replacement therapy
in clients with deficient or absent endogenous testosterone, in females 1 to 5 years
postmenopausal with metastatic breast cancer, and in females with postpartum
breast engorgement. It is also used to treat delayed puberty.
Pharmacokinetics - Methyltestosterone is well absorbed. The rate of absorption
depends on the route of administration. The peak serum concentration level is
reached 2 hours after oral administration of the drug. Methyltestosterone is
extensively metabolized in the liver. It has a half-life of 1 hour initially. This
changes to 3% hours within 3 to 4 hours of receiving the dose. Approximately 10%
ofthe dose is recovered in feces. Buccal administration allows direct absorption
and has almost twice the potency of oral administration. Peak serum
concentrations, when given buccally, are reached 1 hour after administration.
Pharmacodynamics - The action of methyltestossterone depends on its reduction
to dihydrotestosterone, which binds to cytosol-receptor proteins. The androgen
receptor complex is transported to the nucleus where it initiates cellular changes
related to androgen action.
Pharmaceutics - Oral preparations are available as uncoated tablets, capsules, and
sublingual and buccal dosage forms eg Testosterone cyppionate, Testosterone
enanthate Testosterone gel, Testosterone long acting, Testosterone pellets,
Testosterone transdermal TESTOSTERONE CYPPIONATE
Pharmacodynamic: increase weight by building body tissue, increases potassium,
phosphorus, chroride, nitrogen levels, and bone development.
Uses: Female breast cancer, eunuchoidism, male c1imactereric, oligospermia,
impotence, osteoporosis, weight loss in AIDS patients, vulvar dystrophies, low
tesotesrone levels. Dosage and routes:
Replacement Interactions:
Adult: 1M 25-50 mg (base or propionate) or 50.-400 mg (enanthate or
cypionate) Adult: Trans Testoderm 4-6 mg; Androderm, AndroGel 5 mg
Breast cancer
Adult: 1M 50- I 00 mg (propionate) or 200 - 400mg (cypionate or
enanthate) Delayed male puberty .Child> 12 yr: 1M up to 100mg

CRITICAL☺? THINKING ACTIVITY

1.Cecilia ,55 year old and 3 yaers postmenopausal has an estrogen

dependent tumor .The physician has prescribed testosterone for her
condition.What do tou need to teach Cecilia about the effects of
testosterone on women?
2. Mary,age 51 has been experiencing distressing menopausal symptoms
for which her physician has prescribed estrogen replacement therapy.She
seems hesitant to take her prescription and says “these pills cause cancer”
What action should the nurse take?

ANAESTHETICS
Introduction
Anesthetic agents were introduced in mid 19 th CENTURY i.e. diethyl ether, chloroform
was introduced. These are currently obsolete. Mostly anesthetic agents were
introduced in the last 40yrs.Initially; surgery was done at high speed under
alcohol, opium, cannabis etc.

Stages of GA
Surgical anaesthesia using a single slow acting agent e.g. ether is classically
divided into 4 stages:

Stages of General Anaesthesia

Surgical anaesthesia using a simple agent e.g. ether is classically divided into 4
stages with stage 3 made of 4 planes. Slow acting anaesthetic – these occur as
concentration increases in blood.

Surgical anaethesia (sleep, analgesia & muscular relaxation) using a single drug
achieved at high doses may have S/E e.g. Slow & unpleasant recovery, Decreased
CUS function

NB: Different drugs have been used to attain each objective so that the classic
stages no longer occur in visible succession.
Stage I: Analgesia: Analgesia is partial till stage 2 is about to be reached.

Consciousness and sense of touch are retained & sense of hearing is increased.

Subject is conscious, drowsy; response to painful stimuli is decreased.

Stage 2: Delirium/ Excitement : Pt unconscious, May move automatically .May

shout coherently/ incoherently; become violent, leap up & run around. Skilful
induction of anaesthesia prevents these features. Death may result from vagal
inhibition of the heart or sensitization of heart to adrenaline – may occur in a
violent second stage .No response to non painful stimuli but respond in a reflex
fashion to painful stimuli. Other reflexes e.g. cough/ gagging in response to
pharyngeal stimulation are exaggerated.

NB:- Dangerous state & modern anaesthetic procedures eliminate it.

Stage 3: surgical anaesthesia

Divided into 4 planes:

Plane I
Marked by:-Loss of eyelash reflex,Pattern of respiration that is regular in rate &
depth.

Unresponsive to surgical stimulation, moist and mobile eyes and constricted

pupils & intercostals ventilation.

Plane II
Dry & immobile eyes & mid-dilated pupils. Onset of lower intercostal paralysis
with increased diaphragmatic ventilation.

Plane III
Absence of corneal reflex & further pupil dilation ,skeletal muscle relaxation,
intercostals paralysis & total diaphragmatic breathing.

Plane III
Maximal pupils’ dilatation, apnea & circulatory depression.

Stage 4 – Medullary Paralysis

Marked by medullary paralysis. Arrival at this stage constitutes an overdose.

NB:- Single anaesthetic agents rarely used on their own & progression through
this stages in seldom experienced in practice. For clinical purposes the
anaesthetic state consists of three components:-

- Loss of consciousness
- Analgesia &
- Muscle relaxation
In practice these effects are produced with a combination of drugs, not a single
agent. Would require extremely high dosage – increased S/E e.g. unconsciousness
–caused by propofol. Hence to achieve the above the following drugs can be
used:

- Maintain unconscious & analgesia – nitrous oxide & halothane

- Muscle paralysis – neuromuscular blocking drugs e.g. atracurium,
pancuronium
These procedures result in faster induction & recovery & surgery is carried in
short time without impairment of homeostatic reflexes.

NB: Balanced anesthesia: Ideal anesthesia would produce: Analgesia,

Unconsciousness, Muscle relaxation and Reduction of reflex
activity .Characteristics of such anesthetic agents: Act promptly, rapidly
eliminated, Remaining unmetabolized, Producing no unwanted effects is body
tissues. Because no anesthesia has all these properties, several drugs are used in
combination to achieve these goals as seen above.

For surgical anesthesia, combination includes: Opioid, Nitrous oxide, skeletal

muscle relaxant .Anasthesia is induced with barbiturate or diazepam or other
agents, then nitrous, oxide, then skeletal muscle relaxant .Choice of opiods
depends on length of surgery.

Advantages of balanced anesthesia:

- Cardiovascular system is neither depressed nor sensitized to

catecholamine.
- Respiratory depression occurs but controlled ventilation is available &
opioid antagonist can be used to reverse depressed respiration
postoperatively.Incidence of Nausea & Vomiting & pain is low.
But: Awareness during anaesthesia & unpleasant post operative recall are
occasional side effects of balanced anesthesia. Beware what you say about that
patient during operation.

GENERAL ANAETHETICS (GA)

Act on CNS to abolish perception of pain & reaction to painful stimuli.

Requires specifically trained personnel.

Types of GA

Inhalation Anaesthesia: e.g.

Methoxyflurane ,Desflurance ,Halothane ,,Nitrous oxide ,Isoflurane

Sevoflurane ,Enflurane ,desflurane

MOA
Gases, volatile liquids administered as gases.

- Alter lipid structure of cell membranes, so physiologic functions are

impaired.
- Thought to also enhance inhibitory function of GABA. Cl - enter neurons &
hyperpolarisation occurs-no impulse transmission .Hence, ascending RAS don’t
transmit information to higher centers for processing.
Pharmacokinetics

Inhaled via the lungs.Distribution of anesthesia determined by blood flow – brain,

liver, kid reach equilibrium faster.Excretion – lungs .Anaesthetic that is in solution
– metabolized by liver.Halogenated hydrocarbons e.g. methoxyflurare, halothane,
engflurane, metabolized to products that may damage the liver.
Emergence: Time during which pt regain consciousness after anaethesia is
discontinued.

Observe vital signs in Recovery room & watch/ Rx for symptoms of nausea, pain,
vomiting.

Adverse Reactions: Reduced BP, Myocardial depression, Respiratory depression

(all except Nitrios oxide) hence in surgery and recovery, ventilatory assistance &
O2 required. Decreased Blood flow to liver, Decreased Glomerular
filtration .Uterine muscle relaxants (all except No) hence fetal manipulation
possible during this period.
NB: Shivering is a common reaction during recovery & represents a response to
heat loss & to the recovery of the neurologic function.
Toxicity
- Hepatotoxicity e.g. enflurane, halothane & methoxyflurane
- Nephrotoxicity – methoxyflurane hence not widely used.
- Malignant hyperthermia-Rare toxic reactions to inhaled anaesthesia &
occur in genetically susceptible individuals.Symptoms include:
Trachycardia,increased BP, acidosis, hyperthermia, hyperkalemia, muscle rigidity.
Treatment
Administer IV dantrolene, decrease body temperature, and restore electrolyte &
acid base balance. Assignment- check MOA of dantrolene.Chronic toxicity to
operating room personnel has been reported due to long exposure e.g.
miscarriage.Operating room should have vents to remove anaesthetics.

Intravenous Anesthetics

Examples : Barbiturates ,Methohexital sodium ,Thiopental sodium

Benzodiazepines: Diazepam,Midazolam
Opioids: Alfentanil Hcl,fentanyl citrate,Remifentanil Hcl,Sufentanil citrate
Miscellaneous agents: Droperidol,Etomidate,Ketamine,Propofol
MOA
Many agents are used for IV anaesthetics as seen above.Have various MOA e.g.
Barbiturates depress reticular activating system, probably by promoting the
inhibitory synaptic action of neurotranomiter GABA.Benzodiazepines (See
previous notes)

Ketamine: Block effect of glutamic acid at N-methyl-O-aspartate (NMOA)

receptors.

Pharmacokinetics
Iv anaesthetics are lipid soluble.Initially, they are distributed to the brain, liver &
kidney (organs with largest blood flow) but later the drug is redistributed to body
fat, skeletal muscle, which are less well perfused.Redistribution lowers circulating
concentration to that which no longer maintains anaesthesia. This redistribution
is responsible for their short duration of action.Metabolism proceeds as drug
passes through the kidney.

Effective seconds after administration. Only ketamine is a true anaesthetic i.e.

abolishes perception of pain & reaction to pain.Barbiturates & benzodiazepines
do not abolish reflex reaction to pain even when administered in doses larger
enough to render pt unconscious.Benzodiazepines cause conscious sedation
through amnestic, sedative & analgesic effect without complete loss of
consciousness. This is useful for many diagnostic therapeutic & minor surgical
operation.

Barbiturates

Cause deep sedation

Achieved by thiopental, ketamine, propofol & IV spiods.

Pt in a controlled state of anaesthesia with decreased conciousness & not easily

aroused. Loss of protective reflexes, inability to maintain an open airway & lack of
response to surgical stimuli.

Neuroleptanalgesia
Refers to combination of fentanyl and droperidol to produce a quite state with
reduced motor activity reduced anxiety and indifference to the
surroundings.Good for such procedures such as endoscopy, radiologic studies, &
changing dressings.

Concurrent administration of 65% nitrous oxide in O2 produces

neuroleptanesthesia.

Local anaesthetics
Medical or dental procedures may require anaesthetics of a small portion of the
body.

L.A. – achieved by drugs that inhibit nerve conduction to produce loss of

sensation and loss of muscle activity .Inhibition of nerve conduction persists till
drug diffuses & enters the circulation for subsequent degradation & excretion.All
neurons i.e. pain, motor, autonomic in area of administration are affected, hence
other than loss of pain, there is Loss of sensory ,Loss of motor &Loss of autonomic
functions . The smaller nerves (sensory) are more sensitive than bigger (motor)
nerves, hence sensation lost before regained faster than sensation.

MOA
Act by blocking sodium channels and the conduction of action potentials along
sensory nerves. Produce a transient and reversible loss of sensation (analgesia) in
a circumscribed region of the body without loss of conciousness. Nonmyelinated
type c fibres & slightly myelinated type A fibers that carry pain & temperature are
blocked before heavily myelinated type A fibers which transmit sensory
proprioception and motor functions.

Most are not lipid soluble. Local anaesthetics administered by:-

- Infiltration into tissues to bathe local nerves (topically)

- Injection directly around the nerves and their branches
- Injection into epidural or subarachnoid spaces.
Factor influencing rate & extent of absorption.

Lipid solubility ,Dose ,Drug’s physiological properties, Tissue blood flow –

vascularisation ,Drug binding ,LA – enter circulation & can affect other organs.

All local anaethetics except cocaine are vasodilators at therapeutic doses.

Co-administration of vasoconstrictor epinephrine (1:200,000 or less) with local

anaesthetics of short or intermediate duration of action reduces local blood flow.

This reduces systemic absorption of the local anaesthetic from the site of
application and prolongs its action(by 50-100%) and reduces potential for toxicity.
However, this co-adminitration shouldn’t be used on toes, fingers because this
cause necrosis/ ischemia because these are supplied with end arteries. Also
contra indicated in epidural anaesthesia (constrict uterine vessel),cardio vascular
disease and thyrotoxicosis.

Types
Amides e.g. Lidocaine (xylocaine),Mepivacaine (carbocaine),Prilocaine (citanest),
Bupivacaine (Mecaine, sensorycaine),Etidocaine (duranest)
Esters e.g. Procaine (Novocain),Chloroprocaine (Nesacaine),
Cocaine – short acting alkaloid. For topical anaesthesia of mucons membranes.

Controlled substance prone to abuse.Systemically block re-uptake of

catecholamines into nerve terminals & may induce intense vasoconstriction.
Tetracaine (Pontocaine), Dibucaine (Nupercainal), Benzocaine
(americaine),Proparacaine (Alcaine)

Other local anaesthetics

- Dyclonine (Dyclone)
- Pramoxine (Tronothane)
NB:Adverse effects of LA is usually Due to overdose or inadvertent injection into
vascular system.eg
CNS: Visual disturbances,Tremors,Dizziness,Sedation – lidocaine/ procaine
Nystagmus, tonic-donic seizures, coma, death at high concentrations

CVS – at increased dose than CNS effects : Bradycardia,Hypotension

Allergic rxns :Rare rash,Edema,Analphylaxis

L.A. Uses
Ussualy used as surface anaesthesia or infection

Only Lidocaine,Dibucaine,Tetracaine,a re used for both surface & injection.

Surface local anaesthetics e.g.Benzocaine,Butamben,Cocaine Hcl,Dibucaine

Hcl,Lidocaine ,Pramoxine,Tetracaine Hcl. Forms – drops, sprays, ointments,
creams lotions.Applied to eyes, skin & mucous membranes.Poor absorbed – little
systemic absorption but mucus membrane increase systemic absorption.S/E –
allergy i.e. dermatitis

NB

Application on mucus membrane e.g. nose, mouth, throat, rectum, urethra,

vagina can cause systemic effect hence apply lower concentration possible.

L.A. Injection e.g.

Lidocaine,Mepivacaine,Prilocaine,Tetracaine,Procaine,Etidocaine ,Bupicavaine
etc.Potency increase with lipid solubility.Onset determined by:-Size of nerve and
concentration of drug

NB
Before infiltrating an area with local Anaesthesia the syringe should 1 st be used to
ensure blood vessels has not been entered.This is important because
concentration of a drug is high and could prove fatal if injected systemically.
Anaesthesia produced is described by the technique of injection.

Infiltration Anaesthesia

Superficial application of L.A. e.g. in dental procedure, suture a cut.

Small incisions require small vol. & low concentration of drug. Have little systemic
activity.

Nerve block Anaesthesia

Injection of a LA along a nerve before it reaches the surgical site. Volume of
Anaesthesia larger than above e.g. IV regional anaesthesia (Biers block) used for
surgery of forearm, hand or foot & distal leg.

LA around nerve roots near spinal cord to produce epidural or spinal Anaesthesia.

Epidural Anaesthesia – LA administration outside the durameter. Nerve roots

blocked at the point after they emerge from the durameter .Caudal anaesthesia
(form of epidural anasthesia) where anaesthesia is administered epidurally at
base of the spine.

Affects pelvic region & legs. Used in obstetrics, surgery on rectum, anus &
prostate gland.

Spinal Anaesthesia
LA injected into subarachnoid space between arachnoid & paimater membranes
in lumbar area between 2nd lumbar & 1st sacral vertebrae & well below the spinal
cord proper. Same density (isobaric) remain there – difuse slow

In spinal Anaesthesia pt is awake, breathing & CVS function is not affected & there
is good muscle relaxation present but sympathetic outflow blocked hence
vasodilatation with decreased BP common problem with spinal Anaesthesia. Used
widely in obstetrics e.g. cesarean section.

General Adverse Reactions of LA

1. If absorbed systematically produce CNS stimulation:Anxiety,Tingling
(parenthesis),Tremors,Tinnitus,Convulsions .Increased dose of LA cause CNS
depression leading to decreased BP,Resp. depression ,Coma

2. CVS

Lidocaine & procainamide – used as antiarryhythmines – affect Na +

channels.Increased

Levels of LA e.g. Bupivacaine, Etidocaine are cardiotoxic i.e. decreased electrical

activity.

3. Allergy, especially with esters like chloroprocaine, procaine, Tetracaine.

4.Hypotension by spinal Anaesthesia.Neurons controlling vasomotor tone are in

spinal cord.Severe headache after spinal anaesthesia.This headache may last for
hrs or days. Post spinal headache – reflect a drop in the pressure of CSF caused by
a leak where the durameter was penetrated. Incidence of spinal head is reduced
when pts are kept flat on their back & instructed not to raise their heads for 12
hrs after spinal Anaesthesia.

This minimizes hydrostatic pressure of the CSF on the head.

Neuromuscular – Blocking Drug

Acts peripherally.

Produce muscle relaxation by preventing muscular contraction.

Assisted ventilation is mandatory when using short/long acting NMJ blockers.NMJ

blockers don’t inhibit pain/amnesia. Produce mascule relaxation during surgery
esp. abdominal muscles without deep.GA. GA depress abdominal muscles by
depressing spinal cord.Also used for:-Endotracheal intubation,Relieve spasms of
larynx,Prevent convulsive muscle spasms during ECT. Most NMJ blockers are non-
depolarising i.e. bind to the receptor without depolarizing the muscle
membrane.Only succinylcholine is a depolarizing agent.

Non-depolarising NMJ blockers e.g.

Tubocurarine, pancuronium, vecuronium, doxacurium, mivacurium,

pipecuronium. Atracurium,metocurine

MOA
Bind to Ach receptors (Nicotinic) without initiating depolarization of the muscle
i.e. No activation of the receptor.Are competitive antagonist at nicotinic
receptors.

Prototype

Tubocurarine
Curare administered slowly (60-90sec) IV injection.

Maximal paralysis within 5-miutes & persist for 60min (range 25-90min)
progression of paralysis :Eyelids,Face,Extremities ,Diaphragm – results in
censation of spontaneous breathing.40% excreted unchanged in urine.Renal
failure/ acidotic pts require less dosage.

NB

Poisoning with NMJ blockers

Use acetylcholinesterase inhibitors e.g.

Adrophonium,Pyridostigmine,Neostigmine ,Physostigmine
Indications: Surgery ,ECT,Decreased in spasms in tetanus, endotracheal
intubation ,Allow controlled ventilation., Diagnosis of myasthenia gravis –
occasionally – use very small dose. Used if tests with edrophorium, neostigmine
are inconclusive.
A/R
- Increased release of histamine – bronchospasm - decreased BP
- Ganglionic blockage – decreased BP
Interactions
- Halothane, ether, methoxyflurane & enflurane potentiate action of
tubocurarine
- Aminoglycosides & polymyxins (antibiotics), bacitracin,lincomycin,and
clindamycin potentiate effects of tubocurarine
Depolarizing NMJ blockers :Succinylcholine chloride (Suxamethorium .Agonist
at ach nicotinic receptors .The only dep. Agent in use .
MOA:Bind to nicotinic receptors for Ach & cause depolarisation of muscles. I.e.
prevent stimulation of contraction by Ach. Excessive depolarization causes loss of
electrical activating.NB: - Prevents repolarisation & maintains an open state of
membrane ion channels. Prolonged depolarization. Fascination occurs, then
paralysis
Pharmacokinetics :Has briefest duration of Action (5-10min) of all NMJ blockers.
Reason: Plasma cholinesterase readily degrades it hydrolysis.
Duration increased by cholinesterase inhibitors. Make NMJ blockers ineffective
(antagonize).Hence used for short surgical procedures e.g. tracheal intubation,
endoscopy, orthopedic procedures, ECT, terminating laryngospasms.
A/R: Children require increased dose since they are not sensitive as adults.
Cause fasciculation before muscle is paralyzed – believed to be the cause of
stiffness & soreness 12-24 hrs after receiving succinylcholine- Post operative pain.

Transiently raises intraocular pressure & should be given before eye surgery.

Malignant hyperthermia – rare but fatal due to increased muscle metabolism.

Interactions
Hyperkalaemia

Burns, tetanus, massive trauma, brain & spinal injury increase K levels – hence
prolong acting of succinylcholine.

CRITICAL☺? THINKING ACTIVITY

1. Diferentiate between different regional block anesthesia- caudal, saddle, and

spinal.Under what circumstances would each be the regional block of choice?

2. Wha would be the additional nursing observations required if the client

received a local anesthesic with epinephrine rather than one without
epinephrine?