FINAL TOUCH

FOR Medicinal
CHEMISTRY- i

SANJEEV KHANAL [B. PHARMA 16TH BATCH]

► Success is not the key to happiness. Happiness is the key to success. If you love what you
are doing, you will be successful.
- Herman Cain
 Special Thanks For:
Prof. Baikuntha Rajbhandari
Prof. Mohan Amatya
Prof. Ashutosh Kar
Prof. Rama Rao Nadendla

THIS BOOKLET IS DADICATED FOR MY JUNIOR

PLEASE USE TEXTBOOK FOR DETAIL STUDY

THIS BOOKLET IS WRITTEN SURFACELY AND ORIENTED

ONLY TOWARDS EXAM BASED PATTERN

BEST OF LUCK FOR YOUR STUDY JOURNEY

 [Introduction to Medicinal Chemistry]

In medical chemistry, medicinal chemist always attempts to design and synthesis the
medicine or drug or pharmaceutical agents that will benefit always to humanity. Drugs are
the pharmaceutical compounds which interact with biological system to produce a beneficial
biological response. The therapeutic index helps to measure drug beneficial state at low dose
to its harmful effect at higher dose. Those drugs are truly good which have no toxic effect or
unwanted side effect and can easy to take. Therefore, the discipline of medical chemistry is
devoted to the discovery and development of new pharmaceutical agent for treatment of
diseases.

The main molecular target for drugs is Protein [Enzyme, Receptors and Transport protein]
and Nucleic acid [RNA and DNA]. These target molecules are called as Macromolecules.
The interaction of drug with macromolecular target occurs through binding process. Binding
is occured on specific area of macromolecules which is known as binding site. Many drugs
interact through weakest forms of bonds which are known as intermolecular bonds such as
Ionic bond, Dipole-dipole interaction, Vender Waal force or Electrostatic bond. If the
interaction is taken place within a molecule than they are called as intermolecular bond. A
specific region where intermolecular interaction takes place is known as bonding site. The
subject of medicinal chemistry explains the design and production of compounds that can be
used for the prevention, treatment or cure of human and animal diseases. Medicinal
chemistry includes the study of already existing drugs with their biological properties and
their structure- activity relationships. Medical chemistry was defined by IUPAC as “It
concerns about discovery, development, identification and interpretation of mode of action of
biologically active compounds at molecular level”.

1 | Sanjeev Khanal, B. Pharma 16th Batch, MMC, Final Touch for Medicinal Chemistry-I
Medicinal chemistry covers the following stages:
i. In the first stage, drugs are identified and prepared from natural sources, organic chemical
reactions or biotechnological processes. They are known as lead molecules.
ii. In second stage, optimization of lead structure is done to improve potency and to reduce
toxicity.
iii. Third stage is development stage which involves optimization of synthetic route for bulk
production and modification of pharmacokinetic and pharmaceutical properties.

Drug molecule and Drug like molecule: A drug molecules are the smallest particles of
substance that retain the chemical identity of given drug. They are composed of two or more
atoms which are held together by chemical bonds such as Hydrogen bond, Electromagnetic
bond. They are organized on different families on the basis of functional groups.
A functional group is an assembly of atoms that generally reacts in the same way of the
molecule in which it is located. Drug molecules possess one or more functional groups
placed on three dimensional spaces on a structural framework that holds functional groups in
a defined geometrical array and helps the molecule to bind specifically to a targeted
biological macromolecule and receptor to produce biological response. A drug like molecule
[DLM] possesses the physical and chemical properties of drug if drug identify an appropriate
receptor.
Drug molecules should be hydrophobic enough to dissolve in blood steam and
lipophilic enough to cross fat barrier within the body. It should contain enough polar groups
to enable it to bind with receptor but not so much that it would be eliminated too quickly
from the body through urine to exert therapeutic effect. Lipinski [Rules of five dose]
enumerate the properties of Drug Like Molecules such as:
► Molecular weight should be less than 500.
►A log partition value should be less than 5.
► Present of less than five hydrogen bonding donors is needed.
► Present of less than ten hydrogen bonding acceptors.

Drug as composite of Molecular fragments: Drug molecules are conceptualized as being

assembled from biologically active building blocks [Biophores] that combine together to
form an overall molecule. Biophores are a fragment of molecule composed of:

1. Pharmacophore: The three-dimensional arrangement of atoms within a drug molecule that

permits specific binding interaction with desired receptor is called as Pharmacophore. The
atoms that constitute pharmacophore are a face of molecule that establishes intermolecular
interaction with the receptor site. A pharmacophore is the assembly of geometric and
electrical features required by drug molecules to ensure both an optimal interaction with its
target receptor and generation of biological response.
The term pharmacophore does not represent the single real molecule but also a portion of a
molecule. The portion of drug molecule which is not a part of pharmacophore is called as
molecular baggage. The role of this molecular baggage is to hold the functional group atoms
of pharmacophore in fixed geometrical arrangement with minimal conformational flexibility
to permit a specific interaction with toxicity mediating receptors and metabolic through liver
and rapid excretion as on kidney problems associated with pharmacokinetics phase.

2. Toxicophore: The toxicophore is the three-dimensional arrangement of atom in a drug

molecule which is responsible for toxicity eliciting interaction. When drug molecule has
multiple toxicities arising from several undesirable interactions then it may possess more
than one toxicophores. From the perspective of drug design when toxicophore does not
overlap with pharmacophore in a given drug molecule then it may be possible to redesign the
molecule which may support to eliminate the toxicity. However, when pharmacophore and
toxicophore are congruent with each other than toxicophore cannot give desired
pharmological action.

3. Metabophore: It is three dimensional arrangements of atoms in a drug molecule that are

response for metabolic properties. Since functional groups are possible not only for drug
receptors but also for metabolic properties. From view point of drug design, it is possible to
manipulate structure of either pharmacophore or molecular baggage portion of the drug
molecule to achieve metabophore that overcomes problems with liver mediated first pass
effect or hastens renal excretion.

A bioactive face is the portion of drug molecule that interacts with the receptor and
molecular baggage. The pharmacophore permits bioactive face to interact with receptor. The
toxicophore is fragment that is responsible for toxicity and metaphore is the fragment that is
responsible for metabolism. When these various fragments are separated as on Fig. B than
toxicity can be designed out of the drug molecule. Similarly, when they overlap as on Fig. C
than there may be impossible to separate toxicophore from pharmacophore.
Some Terms:
1. Affinity: The ability of the drug to get bound to receptor is known as affinity.

2. Intrinsic activity: The ability of drug to produce a pharmacological action after

combining with receptor is known as intrinsic activity of drug.

3. Agonist: A drug that is capable of producing pharmacological action after binding to the
receptor is called agonist. Ex: Morphine, Adrenaline

4. Antagonist: Drugs that bind with receptor but are not capable of producing
pharmacological action are called agonist. Antagonist has only affinity but not intrinsic
activity. They produce receptor blockade. Ex: Naloxone, Atropine

5. Partial agonist: Drugs that has affinity to the receptors but less intrinsic activity is called
Partial agonist. Ex: Pindolol, Buprenorphine

Physiochemical Factors in relation to Biological Activity of Drugs: The biological

activity of targeted drug molecule is solely depend on its physiochemical characters.
Modulating the structure of the drug for biological activity implies introduction, elimination
of substitution of certain groups in the drug which lead to develop new drug with similar
characters to the lead compound. Thus, physiochemical properties of drug play an important
role on modifying the biological activity of many dugs.

Certain physiochemical factors for drug activity are as:

1. Solubility 2. Partition coefficient
3. Dissociation constant [PKa] 4. Hydrogen bonding
5. Molar refractivity [MR] 6. Ionization
7. Drug shape 8. Complexation
9. Surface activity 10. Protein binding
11. Bioisosterism

Hydrogen bonding: A hydrogen bond is the electrostatic attraction between two polar
groups that occurs when a hydrogen atom covalently bound to a highly electronegative atom
such as nitrogen (N), oxygen (O) or fluorine (F).The two bonds attached to hydrogen can’t
be both covalent because hydrogen has only one stable orbital and can form only covalent
bond so another bond must be ionic. Atoms capable of forming H-bonds should have at least
one unsaturated electron pair with complete octet electrons.
Classification of Hydrogen bonding:
1. Intermolecular Hydrogen bonding: Hydrogen bonding occurs between two or more
molecules is called as intermolecular Hydrogen bonding. Ex: Water, P-nitrophenol

2. Intramolecular Hydrogen bonding: Hydrogen bonding occurs within the molecule is

called as intramolecular Hydrogen bonding. Ex: Salicylic acid, O-nitrophenol

Multiple hydrogen bonding groups in any drug molecule would greatly increases its potential
for aqueous solubility then minimal aqueous solubility is essential for the entire drug
molecule to transport to the site of action on a receptor. For example, 1 phenyl 3 methyl 5
pyrazolone shows no analgesic properties while 1 phenyl 2,3 dimethyl 5 pyrazolone
(Antipyrine) is well known analgesic agent because of presence of intermolecular hydrogen
bonding on 1 phenyl 3 methyl 5 pyrazolone while absence on 1 phenyl 2,3 dimethyl 5
pyrazolone (Antipyrine).
Similarly, salicylic acid (O-hydroxy benzoic acid) has appreciable antibacterial activity but
Para isomer (P-hydroxybenzoic acid) is inactive because salicylic acid is the ortho isomer
that can form intramolecular hydrogen bonds. Salicylic acid has higher partition coefficient
but Para hydroxyl benzoic acid has low partition coefficient and low antibacterial action.

Effects of hydrogen bonding:

 Intermolecular hydrogen bonding increases the boiling point of the compound due to
association of several molecules of the same compound while intramolecular hydrogen
bonding decreases the boiling point of the compound because the chelation between the
groups of same molecule restricts the possibility of intermolecular hydrogen bonding.

 Solubility of a substance increases tremendously when hydrogen bonding is possible

between the solvent and the solute. Ex: Methanol and ethanol are highly soluble in water due
to hydrogen bonding between molecules.

 The compounds which possess hydrogen bonding are found to have higher surface tension
and viscosity. Glycerol, glycol, sulphuric acid, sugar syrup and phosphoric acid are viscous
liquids due to extensive hydrogen bonding between their molecule.

Partition coefficient: Partition coefficient is defined as solute distribution when it dissolved

between two immiscible solvents in contact with each other and its molecular conduction
should be same on both solvents. The ratio of concentration between solute of phase 1 and
phase 2 should also be on constant temperature. If C1 and C2 are the concentrations of
solute in two liquids 1 and 2 respectively then:
C1
K [Constant] =
C2
Where k is called distribution or partition coefficient

The partition coefficient is one of the physicochemical parameters which influences drug
transport and distribution. The contribution of each functional groups and their structural
arrangement help to determine the lipophilic or hydrophilic character of the molecule.
Partition coefficient mainly influences drug transport characteristics i.e. the way in which the
drugs reach the site of action from the site of application. Since the blood distributes drugs
and traverse to many cells to reach the site of action.
Phenobarbitone has a lipid/water partition coefficient of 5.9 while Thiopentone sodium has a
partition coefficient of about 100 so it is highly soluble in lipid and can easily pass through
blood brain barrier than Phenobarbitone. The partition coefficient i.e. P is dimensionless and
its logarithm [Log P] is widely used as the measure of lipophilicity. The partition coefficient
is also a very useful parameter that may be used in combination with the pKa to predict the
distribution of a drug compound in a biological system. Factors such as absorption, excretion
and penetration into the CNS may be related to the Log P value of a drug. Drugs should be
designed with the lowest possible Log P to reduce toxicity, nonspecific binding, increase
ease of formulation and bioavailability.
Narcotics and General anesthetics show greater affinity as shown by partition
coefficient value in water and oil mixture. They fix primarily to CNS cells which are rich in
lipid and exhibit higher biological action on CNS. Hansch suggested that many biological
responses depend on the capability of drug molecules to move through various anatomical
and physiological compartments composed of aqueous and liquid vesicles. The drug
molecules with structural features that enable them to move between compartments with
minimum change in free energy are the drugs with perfect hydrophilic balance [HLB] and
have best chance to reach to the site of action. Partition coefficients are difficult to measure
in living systems. They are generally determined in vitro by using n-octanol as a lipid phase
and aqueous phosphate buffer at PH of 7.4 as a water phase.

Hansch recommended π as Substituted Hydrophobicity Constant to measure the contribution

of the constituent group to the HLB of the drug molecules. The Hydrophobicity Constant i.e.
π can be measured as:
π = log PX -logPH Where PX = Partition coefficient for compound with subsituent group
PH = Partition coefficient for standard compound

Ionization and PKa value: If the biological activity of the drug results from ions, the
activity intensifies with the increase in the degree of ionization. However, if the activity
result from un-dissociated molecules then increase in the degree of ionization of active
compound causes a decrease in activity. Increase in ionization intensifies a drug’s solubility
and decrease its lipo-solubility. Most of the drugs are weak acids and base. For example,
Hydrochloric acid is a strong acid because it completely dissociated into hydrogen [H + ] and
chloride ion [Cl− ].
H + + Cl− HCl

Thus an acidic drug can be present in un-dissociated form [HA] and in ionized form such as
[H + +A− ].
HA H + +A−
The acidic drugs are Ampicillin, Aspirin, Furosemide, Phenobarbitone and Sulfonamide
while basic drug are Allopurinol, Amphetamine, Chlorpromazine, Imipramine, Morphine
and Propranolol. Ethanol is an example of a neutral drug. The extent to which a drug
molecule in solution behaves as an acid or a base depends not only on its nature but also in
the H + ions concentration. The negative logarithm of the H + ion is called as PH. The PH of
intestinal fluids is alkaline while the PH of urine is ranges from 4.6 to 8 therefore it can be
predicted that degree of ionization of compound is considerably variable at different
condition of PH. The PKa of a molecule is a measure of its strength of an acid. It is the
negative logarithm of Ka [Dissociation constant]. It is also defined as PH at which the
concentration of ionized and unionized forms of drug is equal.

For Acidic buffer solution: For Basic buffer solution:

[Ionized drug] [Unionized drug]
PH= PKa + log PH= PKa + log
[Unionized drug] [Ionized drug]
10(PH−Pka) 10(Pka−PH)
% Drug ionized = (PH−PKa) ×100 % Drug ionized = ×100
1+10 1+10(PKa−PH)

Ionization constant affects the extent of absorption, excretion and nature of distribution. For
example, ephedrine has a PKa value of 9.6. In gastric PH most of ephedrine is in ionized
form. There is negligible absorption of ephedrine from the stomach region. However non-
ionized form of aspirin [Pka is 3.5] is readily absorbed from the stomach. The percentage of
non-ionized form of aspirin is decreased with the increasing in the PH of surrounding fluid.
Similarly, Streptomycin is fully ionized and is not absorbed from gastrointestinal tract.

While considering the binding of drug to plasma proteins, it is found that the acidic drug
principally binds to albumin and basic drug binds to α1 acid glycoprotein. The biological
activity of certain acidic and basic drugs directly depends on their degree of ionization. In
those cases, PH play important role for biological activity of drugs i.e. acids are more active
at lower PH and bases are more active at higher PH.

Chelation: The term chelates applied to those compounds that result from a combination of
an electron donor with a metal ion to form a ring structure. The compounds capable of
forming a ring structure with metal are design as ligands. Usually all he metals can from
chelates and complex. However, the electron donor atoms in the chelating agents are N, O
and S while electron acceptors are various bivalent and trivalent metals those of transition
group. The bonds which are formed between the ligands and metals are co-ordinate covalent
bond and covalent bond.
Examples:
i. 8- Hydroxyquinoline forms complex with Fe++

ii. Glycine forms complex with Cu++

A ligand such as ammonia that has a single basic

group capable of binding to the metal is a unidentate
ligand. A ligand having more than one accessible
basic binding site is called multidentate. For
example, Ethylene diamine i.e. NH2 CH2 CH2 NH2 is
a bidentate ligand form and chelates with Cu++ .

Importance of chelating agents on Medicine:

i. Antidote for metal poisoning:
Dimercaprol: It is used on treatment of poisoning of arsenic and mercury metal.
Penicillamine: It is mainly used on treatment of copper toxicity.

ii. Sequestration of metals to control the concentration of metal ions on buffer solution.
iii. Elimination of toxic metals from organism body. For example, of EDTA is use as an
antidote for treatment of lead poisoning.
iv. 8- Hydroxyquinoline acts as antibacterial and antifungal agent by chelating with iron or
copper.
V. In the pharmaceutical field, EDTA has been used to prevent discoloration in antibiotics
and in anti-histamine and anesthetic preparations.
Vi. Chelates of P-amino salicylic acid has been shown to have anti-tubercular activity.
Vi. Chelating agents are also used to improve metal absorption.
Plasma protein binding: Protein binding generally refers to the binding of a drug to protein
in blood plasma. The interaction can also be between the drug molecule and tissue
membrane, red blood cells and other components of the blood. Most of the drugs have
physiological affinity for plasma proteins (mostly albumin and α1 glycoprotein). Acidic
drugs like penicillin and barbiturates bind to albumin while basic drugs like quinidine and
methadone binds to α1 glycoprotein. The bond fraction of drug is pharmacologically inactive
and acts as temporary storage of the drug while free fraction is responsible for
pharmacological activities.

Factor affecting drug protein binding:

1. Factor relating to the drug
⇒ Physicochemical characteristic of drug
⇒ Concentration of drug in the body
⇒ Affinity of drug for a particular component

2. Factor relating to the protein and other binding component

⇒ Physicochemical characteristic of the protein or binding component
⇒ Concentration of protein or binding component
⇒ Number of binding site on the binding site

3. Drug interaction
⇒ Competition between drug for binding site [Displacement interaction]
⇒ Competition between drug and normal body constituent

4. Patient related factor [Age, Disease state]

Clinical importance of Plasma Protein binding [PPB]:

1. Drug that are highly bound to plasma proteins have low volume of distribution.
2. PPB favors drug absorption.
3. PPB delays metabolism of drugs.
4. Bound form of drug is not available for filtration at the glomeruli therefore excretion of
highly plasma protein bound drugs is delay.
5. More than one drug may bind to same sites of plasma protein i.e. Albumin. The drug with
higher affinity can displace the drug with lower affinity and increases free drug concentration
of the drug with low affinity which may cause toxicity. For example, salicylates can dis place
methotrexate causing increased free drug concentration of methotrexate leading to toxicity.
6. In disease states like anemia, hypo-albuminemia, chronic liver diseases and renal failures
there is low albumin level due to which concentration of free form of drug will increase
which may cause toxicity.
7. High protein bound drugs have longer duration of action. Ex: Sulphadiazine is less plasma
protein bound and has duration of action of six hours while sulphadoxine is highly plasma
protein bound and has duration of action of one week.
Four major drug binding sites on
Human Serum Albumin [HAS]:
Site 1= It is known as Warfarin binding
site. In this region large numbers of drugs
are bound. Ex: NSAIDS [Phenylbutazone,
Naproxen, Indomethacin], Sulphonamides
[Sulfadimethoxine], Phenytoin, sodium
valproate.

Site 2 = It is known as Diazepam binding

site. Drugs which bind to this region
include benzodiazepine, ibuprofen,
ketoprofen, Cloxacillin.

Site 3: It is known as Digitoxin binding site.

Site 4: It is known as Tamoxifen binding site.
 [Cholinergic Drugs]

The para-sympathomimetic or cholinergic drugs are the agents which produce actions similar
to those shown by stimulation of parasympathetic nerve system. Those agents mimic the
effects of cholinergic stimulation. Therefore, they are called as cholinomimetics.

Classification of Cholinergic drugs

A. Directly Acting:
1. Ester of choline
i. Natural: Acetylcholine
ii. Synthetic: Methacoline, Carbacol
2. Alkaloids Derivatives: Muscarinic, Pilocarpine
3. Miscellaneous: Tremorine, Oxotremorine

B. Indirectly Acting [Anti-cholinesterase]

1. Reversible:
i. Natural Alkaloids: Physostigmine
ii. Quaternary compound: Endrophonium, Neostigmine, Pyridostigmine
2. Irreversible:
i. Organophosphate: Ecothiophate, Parathion, Malathion
ii. Carbamates: Propoxur, Carbaryl

Synthesis of Acetylcholine: Acetylcholine is synthesized from Acetyl COA and Choline

with the help of Choline acetyl transferase [ChAT]. The Ach is then stored on storage
vesicles. It is released into synaptic cleft when action potential reaches nerve terminals. The
released Ach interacts with cholinergic receptors of an effectors cell and activates them in the
synaptic cleft then the Ach is rapidly hydrolyzed by acetylcholinesterase enzyme.

Cholinesterase: Acetylcholine is hydrolyzed to Choline and Acetic acid by the

cholinesterase enzyme.
1. True cholinesterase: It is found on cholinergic neurons, Ganglia, RBC and Neuromuscular
junction. It is rapidly hydrolyze Ach and Methacholine.
2. Pseudo cholinesterase: It is found on plasma, liver and ganglia. It can act of various ester
derivatives drug including Ach but not hydrolyze Methacholine.

Cholinergic Receptors and their actions:

1. Muscarinic receptors: These receptors have been found on ganglia of the peripheral
nervous system and on the autonomic effector organs such as the heart, smooth muscle, brain
and exocrine glands. Muscarinic receptors belong to the class of G protein coupled receptors.
Receptors Locations Functions
M1 GIT Stimulates HCl secretion in stomach and support for
peristalsis movement of digestive particles
M2 Heart Stimulation of negative chronotropic [decrease on heart
rate], ionotropic [decrease on contractility of heart] and
dromotropic [decrease on conduction of heart] effects
M3 Blood vessels Stimulate the release of NO from endothelium of blood
vessels and result for vasodilation
Glands Increase on salivation, lacrimation and sweeting
Urinary bladder Stimulate contraction of detrusor muscle which cause relax
of the trigone of bladder and result on increase in micturition
Eye Stimulate miosis [Constriction of pupillae sphincter] and
also contraction of ciliary muscle for accommodation for
near vision

2. Nicotinic receptors: Nicotinic receptors are located in the CNS, adrenal medulla,
autonomic ganglia and the neuromuscular junction [NMJ]. These receptors in addition to
binding ACh also recognize nicotine.

Receptors Locations Functions

NN Adrenal medulla Responsible for secretion of epinephrine or nor-
& autonomic epinephrine and also support for increase GI motility.
ganglia
NM Neuromuscular Responsible for skeletal muscle contraction.
junction

SAR of Acetylcholine:
1. Present of nitrogen in quaternary ionic form
along with three methyl group is needed for
agonist activity.
2. Introduction of methyl group on Beta carbon
support to give stronger Muscarinic action.
3. Introduction of methyl group on Alpha carbon
support to give stronger Nicotinic action.
4. Replacing the ester with carbamate, ether or
ketone group resists hydrolysis and maintains
activity.
5. The positive charge on nitrogen atom is essential for drug activity. Replacing it with
neutral carbon atom decreases structural activity.
6. The distance from nitrogen to ester group is important.
Acetylcholine Chloride: It is direct acting cholinergic drug which exerts its effect by
stimulating muscarinic as well as nicotinic receptors.

Physiochemical Properties: It is used as chloride salt

which occurs as white crystalline powder or colorless
crystals. It is very hygroscopic in nature and soluble on
methylated chloride, water and alcohol. Its aqueous
solution is unstable. Systematically administered Ach is
rapidly hydrolyzed by acetyl choline esterase therefore it
has no clinical use for long duration. Although it is use as cardiac depressant and effective
vasodilator.

Synthesis:

Uses: In the peripheral nervous system, acetylcholine activates muscles and is a major
neurotransmitter in the autonomic nervous system. Topically it is uses to induce mitosis
during certain intraocular surgical procedures such as Cataract surgery [Ridectomy] and
Keratoplasty.

Carbachol: It is cholinomemetic alkaloids and act as a

direct acting cholinergic drug. Physiochemical
Properties: It is white and hygroscopic on nature. It is
soluble on water and alcohol while insoluble on
acetone. It is the ester of carbomic acid on which
methyl group of Ach is replace by amino group.
Carbachol is poor substrate for acetyl cholinesterase
and is not readily hydrolyzed. It has also both
muscarinic and nicotinic action.

Uses:
1. Used in ophthalmic practice in 0.7% to 3% to lower intraocular pressure on glaucoma
2. Sometime it is also used for treatment of urinary retention.
Pilocarpine: It is parasympathomimetic drug agent mainly used as hydrochloride or nitrate
as mitosis in the treatment of glaucoma during ophthalmological procedure.

Physiochemical Properties: Pilocarpine is alkaloid

obtained from the leaves of Pilocarpus microphyllus
and other species of Pilocarpus. It mainly occurs on
hydrochloride or nitrite form. Both Pilocarpine
hydrochloride and Pilocarpine nitrite occurs as viscous,
odorless, hygroscopic, colorless or white crystalline
powder. Pilocarpine hydrochloride is soluble on water,
chloroform and alcohol while insoluble on ether.
Similarly, Pilocarpine nitrite is soluble on water and alcohol while insoluble on chloroform
and ether. A 0.5% solution of pilocarpine hydrochloride and 5% solution of pilocarpine salts
can be degraded by Hydrolysis and Epimerization in the present of hydrogen atom or
hydroxide ions. Its solutions are stable at PH of 4 to 5.

Uses:
1. A 0.5% to 4% solution is used topically in the treatment of open-angle and acute
congestive glaucoma. It also causes miosis by contracting sphincter pupillae by opening the
trabecular meshwork around the Schlemmm’s canal and facilities drainage of aqueous humor
and reduces intraocular pressure.
2. Used to counter dryness of mouth during the radiotherapy for cancer of head and neck.
3. Used to reverse the pupillary dilation after refraction testing.
4. Used alternatively with mydriatics to break adhesions between iris and lens.

Cholinesterase inhibitors:
Cholinesterase inhibitors are
the drugs that prevent the
degradation of acetylcholine
by acetylcholinesterase. By
preventing inactivation of Ach,
the cholinesterase inhibitors
enhance the actions of Ach
released from cholinergic
nerves. Therefore, they are
also called as Indirect acting
cholinergic agonists. They can
intensify transmission at all cholinergic junctions such as Muscarinic, Ganglionic and
Neuromuscular junctions and can elicit wide range of responses. Therefore, they have limited
therapeutical applications.
Physostigmine: It is an alkaloid obtained from plant Physostigmine venenosum. It is tertiary
ammonium compound and does not carry charge due to which it can cross Blood Brain
Barrier.

Physiochemical Properties: It exerts as almost

white crystalline powder and is hygroscopic on
nature. It is soluble on water and alcohol. It
gradually becomes red when exposed to light. It
melts at 1450c with decomposition. Its aqueous
solution is unstable. In aqueous solution,
physostigmine is hydrolyzed to Eseioline which is
oxidized by hydrogen atom and hydroxide ions.
Its solutions are more stable at PH of 3.7.

Uses:
1. Physostigmine is the drug of choice for treatment of poisoning caused by atropine and
other drugs such as Antihistamine and Tricyclic antidepressant that causes muscarinic
blockade. Physostigmine counteracts anti-muscarinic poisoning by causing accumulation of
Ach on muscarinic junctions. The accumulated Ach then competed with muscarinic blocker
for receptor binding by reverse the blockade. Physostigmine is preferred than Neostigmine
for anti-muscarinic poisoning because of lacking of charge and it also able to cross brain
blood barrier to reverse muscarinic blockade in the CNS. The usual dosage to reverse anti
muscarinic poisoning is 2mg given by IM or slow IV injection.
2. It also used to lower intraocular pressure in patient with glaucoma.

Neostigmine: It is quaternary ammonium anticholinesterase. It works by blocking the action

of acetylcholine-esterase due to which levels of acetylcholine will increases.

Physiochemical Properties: It occurs as

colorless or white crystalline powder. It is
odorless and has bitter taste. It is hygroscopic
in nature. It is soluble on chloroform, water
and alcohol while insoluble on ether. It reacts
at esteric site of acetylcholine esterase and
converts it to inactive dimethyl carbomyl
derivatives of enzyme. Its dose is about 15-30mg.
Uses:
1. Use to treat Myasthenia gravis.
2. Used to diagnose Paralytic ileus and Urinary retention problem.
3. To promote expulsion of intestinal flatus [Gas in stomach or intestine] before radiography
of kidney and uterus.
4. To antagonize muscular relaxation due to curare like drugs used on anesthesia.

Synthesis:

Melathion: It is an irreversible cholinesterase inhibitor. It is an insecticide used to treat

insect and mite infection such as pediculosis or scabies or to control insect vector of diseases
such as black flies, lice and mosquitoes.

Physiochemical properties: It is yellow to

deep brown liquid with a characteristics
odor. It is slightly soluble on water while
miscible with alcohol, ether aromatic and
alkylated aromatic hydrocarbon and
vegetable oils. It is sensitive to heat and is
degraded at temperature above 300c. The
phosphorus-sulphur double bond prevents
on melathion helps to prevent it from
antagonizing the active site on the acetyl
cholinesterase enzyme.
Uses: Melathion is an organophosphorus pesticide and is more patent cholinesterase
inhibitor. It shows both muscarinic and nicotinic effects. So, it is use as Acaricide [Agent that
destroy mites] in the treatment of pediculosis and scabies. Methion is also used on veterinary,
agriculture and horticulture. It is also used on manufacture of shampoos and lotions.

Anti-cholinergic Agent: Anti-cholinergic agents are classified as Anti-mucarinic drugs,

Ganglionic blocker and neuromuscular blockers. Those drugs that blocks muscarinic
receptors are called Anti-mucarinic agents. Similarly, the drugs that blocks NN cholinergic
receptors are called as Ganglionic blocker while those drugs that blocks NM cholinergic
receptor are called neuromuscular blockers agents.
I. Anti-mucarinic drugs
1. Natural alkaloids: Atropine, Hyoscine [Scopalamine
2. Semi- Synthetic derivatives: Homatropine, Ipratropium bromide
3. Synthetic substituents:
a. Mydriatics: Cyclopentolate, Tropicamide
b. Antisecretory - Antispasmodic: Dicyclomine, Oxyphenonium, Glycopyrrolate
c. Antiparkinsonian agents: Benzhoxal, Proclidin
II. Ganglionic blocker: Trimethaphan
III. Neuromuscular blockers agents: Tubocurarine chloride, Succinylcholine

Clinical Uses of Anti-Muscarinic Agents:

1. Due to the Antispasmodic effect they are used to treat Renal colic, Biliary colic, Bronchial
asthma due to bronchial spasm, Irritable bowel syndrome such as Spastic colitis and Motion
sickness.
2. Due to Anti-secretory effect they are used to treat Anesthesia premedication to inhibit
excessive bronchial and salivary secretion, Rhinitis and hay fever.

3. Due to their mydriatic [Dilution of pupil] and cyclophegic [Paralysis of accommodation

for near vision] effect they are used in ophthalmoscopy in examination of retina deflect.
4. They help to reduce secretion of gastric juice including HCl. Therefore, they are used on
smooth muscle spasm, hyper-motility and to reduce pain in ulcerative colitis.

5. Atropine and other anticholinergic drugs are used to treat Parkinsonism as they penetrate
blood brain barrier and blocks CNS effects of acetyl choline.
6. They are also used on treatment of poisoning by organophosphate compound such as
insecticide which combines with cholinesterase and causes accumulation of acetylcholine.
7. It is also useful in myocardial infraction and abolish AV block due to excessive vagal
activity.
Atropine: Atropine is an alkaloid which is excreted from solanaceous plants such as Atropa
and Hyosymus species.

Physiochemical Properties: Atropine occurs as white

crystalline solid. It melts at 1160C - 1170C. It is optically
inactive, basic on nature and has bitter taste. It is slightly
soluble on water but freely soluble in alcohol. It is official
use as sulfate salt which contains one molecule of water
of crystallization. When it is treated with fuming nitric
acid and mixture is evaporated to dryness on water bath
then it leaves yellow residue. In acidic and alkaline
medium it is highly hydrolyzed to give tropine and tropic acid. Atropine sulfate efflorescence
in dry air due to the present of water of crystallization.

Uses:
1. Used to treat parkinsonism to reduce muscular rigidity and salivation.
2. Used as mydriatic in ophthalmoscopy practice.
3. Used as anti-spasmodic to treat renal and biliary colic and brachial asthma.
4. Use for anesthetic premedication to inhibit excessive salivary and bronchial secretion & to
prevent bronchospasm.
5. To treat Sialorrhoea [Secretion of saliva], acute coryza, rhinitis and hay fever.
6. To treat poisoning by organophosphate compound such as insecticide.
7. To treat gastric and duodenal ulcer.
8. Use with morphine to treat respiratory depression.
9. To prevent excessive peristalsis and acute pain produced by irritant purgative.

Steps involve on Synthesis of Atropine:

a. Synthesis of Tropic acid
b. Synthesis of Tropine:

c. Condensation of Tropic acid and Tropine:

Tropicamide: It occurs on white

crystalline powder and is odorless. It is
slightly soluble on water while freely
soluble on chloroform and solutions of
strong acids. When it is dissolved on
mixture of acetic acid and acetic
anhydrite and heated on water bath
with citric acid then it gives reddish
yellow color.
Uses: It induces mydriatic and cyclophegia for ophthalmoscopy. It has quicker onset of
action and shorter duration of action and helps to maintain intraocular pressure on normal
patient.

Homatropine: It is anti-muscarinic drug.

Officially it is odorless and white crystalline
powder. It is freely soluble on water,
sparingly soluble on alcohol and slightly
soluble on chloroform and ether. In aqueous
solution, drug is hydrolyzed into tropine and
mandelic acid. Hydrolysis is catalyzed by
hydrogen ions and hydroxide ions.

Uses:
1. Use on ophthalmology as mydriatic.
2. Use to treat corneal and cycloplegia ulceration and iritis.
3. Occasionally used as antiplasmic in the dose of 20mg by oral dose.

Hyoscine [Scopolamine]: It has Anti-muscarinic effect which has a depressant effect on the
CNS.

Properties: Hyoscine is alkaloid obtain from species

of Datura. It is officially used as the hydro bromine
salt which occurs as odorless and white crystalline
powder. It is freely soluble on water, chloroform and
alcohol. It is Laevorotatory on nature.

Uses:
1. Use to prevent motion sickness during journey.
2. Use for esophageal and gastro intestinal spastic conditions, peptic ulcer, spasm of ureter
and bile duct. 3. Use as cyclophagic and mydriatic in ophthalmology.
4. Sometime hyoscine is given with pethidine to provide sedation and amnesia during labour.
5. Depresses the cerebral cortex so use on mania and cerebral excitement.

Dicyclomine hydrochloride: It is tertiary amine with anti-muscarinic agent. It occurs as

colorless and odorless white crystalline powder with bitter taste. It is soluble on water,
alcohol & chloroform and insoluble on ether. PH of 1% of its solution is 5 to 5.5.
Uses:
i. Use on gastro-intestinal spasm, irritable bowel
syndrome and is also given with antacids in
treatment of peptic ulcer.

ii. Use on prophylaxis of motion sickness.

iii. Use on dysmenorrhea, pylorospasm and

biliary dysfunction.

Synthesis:
► Skeletal Muscle Relaxants: Skeletal Muscle Relaxants are drugs which are used to
reduce unwanted spasm and spasticity or to cause paralysis of skeletal muscle without
interfering with consciousness. The drugs causing relaxation of skeletal muscles may be
discussed under three categories. The first category drugs cause muscle relaxation by
interruption of transmission of the nerve impulse at the neuromuscular blocking agent. These
agents are use as adjuvants to anesthesia to get relaxation of skeletal muscle especially of
abdominal wall during surgery. Muscle relaxation is importance on various orthopedic
manipulations such as correction of dislocation and alignment of fracture.
The drug of second category is centrally acting and brings about depression on
appropriate nerves in the CNS. They are mainly responsible for relieving muscle spasm or
spasticity because of musculoskeletal and neuromuscular disorder. Similarly drugs of third
category are directly acting muscle relaxants. These drugs directly interfere with the
contractile mechanism of voluntary muscle.

Classification:
1. Peripherally acting muscle relaxants: They act peripherally on neuromuscular junction.

They are derived into two categories:

a. Non- depolarizing blockers [Competitive blockers]: These drugs prevent the access of
Ach to NM receptors of motor end plate and prevent its depolarization. Competitive blockers
act by competing with Ach for nerve binding to nicotinic M receptors on the motor end plate.
Muscle relaxation persist more amounts of agents at neuromuscular junction which should be
sufficient to prevent receptor occupied by Ach. Muscle function is restored by eliminating
blocking agent from the body site or increases the amount of Ach at NMJ. Ex: Tubocurarine,
Doxacurium, Gallamine

b. Depolarizing blockers [Persistent blockers]: They produce excessive depolarization

which persists for longer duration at NMR [Neuromuscular Receptors]. The mode of action
of persistent blockers follows the mechanism as caused by drugs which are structurally or
functionally similar to Ach and cause depolarization. This depolarization cause transit
muscle contractions then instead of dissociation rapidly the drug get remain in bind form.
Then drug maintains the end plate in the state of constant depolarization by the help of
remaining bind form drug. Then drug ability to keep end plate depolarized causes paralysis
on drug action. Finally, paralysis on drug action until the decline on plasma level cause drug
to dissociate from receptors. Ex: Succinyl choline
2. Centrally acting muscle relaxants: These drugs reduce skeletal muscle tone by a
selective action on cerebrospinal axis without altering consciousness.
a. Mephensine group: Carisoprodol, Chlorzoxazone, Chloromezanone
b. GABA derivatives: Baclofen
c. Benzodiazepine group: Diazepam, Clonazepam
d. Central ∝2 agonist: Tizanidine

3. Directly acting muscle relaxants: These drugs directly interfere with contractile
mechanism of voluntary muscle. Ex: Dantrolene

Tubocurarine chloride: Tubocurarine chloride is competitive neuromuscular blocker used

intravenously to produce skeletal muscle relaxation during surgical procedure.

Properties: It is alkaloid which is obtained

from extracts of stem of Chondrodendron
tomentosum. Tubocurarine chloride officially
has been use as salt of dextrorotatory
tubocurarine. This alkaloid possesses two
benzyl tetra hydro isoquinoline moieties. One
of nitrogen of the base has been quaternary in
nature while other has been in tertiary amine
form. Tubocrarine is yellowish green or greyish
white crystalline powder. It is soluble on water,
alcohol and solution of alkyl hydroxide and
insoluble on acetone, chloroform and ether. Its
1% solution on water has PH of 4 to 6.

Uses:
1. It support for muscle relaxation during surgery.
2. It also used to relax vocal cord to enable the free passage of endotracheal tube for
examination of GI tract or aspiration.
3. Skeletal muscle relaxants are also used while giving ECT to avoid convulsion and trauma.
4. It is also usually use to treat status epilepticus, tetanus and poisoning by convulsant
substances by preventing forceful contraction of muscles.
Gallamine triethiodide: It is non-
polarizing muscle relaxant. It is white,
hygroscopic, odorless and amorphous
powder. It is soluble on alcohol,
chloroform and water while insoluble
on ether. Its 2% solution in water has
PH of 5.3 to 7. Gallamine is used for
muscle relaxant during general
anesthesia and mechanical relaxation.

Synthesis:

Succinylcholine: This is bis-quaternary compound which is structurally very similar to

acetylcholine. It is ester of succinic acid with choline.

Chemical Properties: It is odorless white crystalline

substances with slightly bitter taste. Its aqueous solution
has PH of 4. It is soluble on water, ethanol and
chloroform while insoluble on ether. It is hygroscopic in
nature. It is unstable in alkaline solutions while relatively
stable in acid solutions. It is not hydrolyzed by acetyl
choline esterase. It is officially used as bromide or
chloride salts.
Uses:
1. To provide skeletal muscle relaxation during abdominal or thoracic surgery and for
endotracheal and endoscopic intubation.
2. To counter laryngospasm during barbiturate anesthesia.
3. To prevent reflex muscle contraction during surgery.
4. Succinylchloine with diazepam used to prevent injuries of fractures due to exclusive
convulsion from Electro-convulsion Therapy [ECT].
5. Used on spastic conditions like tetanus or status epilepticus which are not controlled by
diazepam.
 [Adrenergic Drugs]

Adrenergic drugs are those agents which mimic the actions of sympathetic stimulation. The
adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. These
drugs are also called as sympathomimetic.

Classification:
1. Based on the presence or absence of catechol nucleus:
a. Catecholamine: Adrenaline, Nor-adrenaline, Dopamine, Isoprenaline
b. Non-catecholamine: Ephedrine, Amphetamine

2. Based on mode of action:

a. Directly acting sympathomimetic by interacting with adrenergic receptors: Adrenaline,
Nor-adrenaline, Dopamine, Isoprenaline
b. Indirectly acting sympathomimetic by releasing NA from nerve terminals: Amphetamine
c. Mix action amines: Ephedrine, Methoxamine

3. Based on therapeutic or clinical uses:

i. Vasopressors: Nor adrenaline, Methoxamine, Metaraminol
ii. Cardiac stimulants: Adrenaline, Dopamine, Isoprenaline, Ephedrine
iii. CNS stimulants: Amphetamine, Ephedrine
iv. Bronchodilators: Adrenaline, Isoprenaline, salbutamol, Terbutaline, Formoterol
v. Nasal decongestants: Ephedrine, Pseudoephedrine, Oxymetazoline, Xylometazolinevi.
Appetite suppressants: Fenfluramine, Dexfenfluramine
vii. Uterine relaxants: Salbutamol, Terbutaline, Isoxsuprine, Ritodrine
Adrenoceptors:
A. Alpha receptors:
1. Major actions of α1 receptors:
► Vasoconstriction on blood vessel
►Increase on blood pressure
► Increase on contraction of trigone on urinary bladder
► Mydriasis on eye

2. Major actions of α2 receptors:

►Decrease in Nor-epinephrine release
►Reduction of aqueous humor secretion on eye
►Decrease in insulin secretion by beta cells of islets of Langerhans on pancreas
►Inhabitation of acetylcholine release

B. Beta receptors:
1.Major actions of β1 receptors:
►Positive chronotropic, ionotropic and dromotropic effect
►Increase release of renin by kidney

2. Major actions of β2 receptors:

►Vasodilation of blood vessel and Bronchodilation of bronchus
►Increase muscle and liver glycogenolysis
►Increased release of glucagon
►Relaxed uterine smooth muscle

3. Major action of β3 receptor:

► Lipolysis

Adrenaline [Epinephrine]: Adrenaline is an

adrenergic agonist. Adrenaline is a
catecholamine belongs to biogenic amines. It
is officially as the free base and is bitartrate
salt. It occurs as creamy white crystalline
odorless powder. It is freely dissolved in
solutions of mineral acids, potassium
hydroxide and sodium hydroxide while
sparingly soluble on water. Similarly, it is
insoluble in ethanol and ether. It is levorotatory in nature. Adrenaline tartrate salt is freely
soluble in water.
Storage: Adrenaline is light sensitive and easily oxidized on exposure to air because of the
catechol ring system. The development of pink to brown color indicates oxidative
breakdown. To minimize oxidations, solutions of the drug are stabilized by the addition of
reducing agent such as sodium bisulphite. Adrenaline should be stored in well closed light
container and protected from light.

Therapeutic uses:
1. Adrenaline has an ability to cause α1 mediated vasoconstriction due to which it has been
used for:
i. Delay adsorption of local anesthetics
ii. Control superficial bleeding
iii. Reduce nasal congestion
iv. Elevate blood pressure

2. Activation of α1 receptors on the iris is employed to produce mydriasis during

opthalmologic procedure.
3. Activation of β1 receptors by adrenaline is used to overcome AV heart block and restore
cardiac function in patients with cardiac arrest.
4. Activation of β2 receptors in lung promotes bronchodilation in patients with asthma.
5. Adrenaline has ability to activate combine effect of α and β so it is used as drug of choice
for treatment of anaphylactic shock.

Phenylephrine: It is a α1 selective adrenergic

agonist. It is almost white crystalline powder. It is
freely soluble in ethanol, water and glycerol. It is
relatively stable in alkaline solution. Phenylephrine
differs from adrenaline by lacking the 4th OH group
on the benzene ring and subsequently resistant to
COMT [Catechol O methyl transferase]. It does not
cross BBB. In aqueous solution, it is gradually
oxidized with the formation of colored products. Discoloration is retarded by sodium
metabisulphite and disodium edetate.

Therapeutic uses:
1. It acts as nasal decongestant and use to treat nasal allergy, hay fever, acute rhinitis and
headache due to sinusitis.
2. It is use for mydriatics procedure but it is not associated with any loss of light and raise on
intraocular tension.
3. It is also associated to prolong action of local anesthetic and to prevent a blood pressure
during spinal anesthesia.
Salbutamol: It is almost white crystalline powder
with a slightly bitter taste. It is sparingly soluble
on water but freely soluble in ethanol. It is
officially found in the form of sulfate salt which is
freely soluble in water, alcohol and ether.

Therapeutic uses: It is β2 agonist with relaxant

effects on smooth muscle of bronchi and uterus.
So, it is a drug of choice in the treatment of
bronchial asthma. It is also used to arrest
premature labour.

●Isoprenaline: It is synthetic catecholamine

with predominately stimulates β1 and β2
adrenergic receptors. Its action of β3 is to
increased lipolysis but it has negligible α
receptor action.

Physiochemical properties: It is almost

white crystalline powder which is freely
soluble in water and sparingly soluble on
alcohol. Similarly, it is insoluble on
chloroform and ether. It is gradually darken on exposure to air and light. Solution becomes
pink to brownish pink on exposed to air.

Therapeutic uses:
i. It is used in the Stokes Adams syndrome for temporary prevention or control of attacks but
for long term management the use of pacemaker is more preferable.
ii. It is also useful in severe bradycardia such as heart block.
iii. Isoprenaline has been used for its powerful bronchodilator effects in the symptomatic
relief of bronchial asthma but β2 selective sympathomimetic agent such as salbutamol is
more preferred.
iv. It is used as an Anti-arrhythmic agent and in treatment of shock to increase heart rate.

● Ritodrine: It is officially found as Ritodrine hydrochloride which occurs as white

colorless and odorless crystalline powder. It is freely soluble on water, propyl alcohol and
practically insoluble on ether. Its 2% solution has PH between 4.5 and 6.
Therapeutic uses: Ritodrine can be used as short acting β2 stimulant and also used
parentally for delaying premature delivary of foetus.

Amphitamine: It is an indirect acting

sympathomimetic amine. Its action depends on release
of nor-adrenaline from adrenergic nerves. It is the
synthetic compound found officially as sulphate salt
and occurs as white odourless crystalline powder with
bitter taste. It is soluble on water and alcohol while
insoluble on ether. D form of amphetamine is 3-4
times more potent than L isomer. It is well absorbed
orally and parentally. The duration of action is 30 minutes for oral and 5 minutes for
subcutaneous administration and action lasts after 4-6 hours

Therapeutic uses:
1. Narcolepsy: Amphetamine helps to improve narcolepsy and prevent attacks of day time
sleep. The drug should not be given after 4pm as it will disturb the nocturnal sleep resulting
into compulsions to have day time sleep.

2. Attention deficit hyperactivity disorder [ADHD]: This syndrome is characterized by

impulsiveness, impaired interpersonal relationship, excitability and difficulty in sustaining
attention which result on loss in academic achievements.

3. Weight reduction: Amphetamine has anorexic actions and can be used to the treatment of
obesity.

4. Epilepsy: Amphetamine can be used as adjuvant and to counter the secretion due to
antiepileptic.

● Ephedrine: Ephedrine is an alkaloid obtained from the steams of various species of

Ephedra.

Physiochemical Properties: Ephedrine alkaloid occurs as

waxy solid or as crystals or granules with characteristics
odour. It is soluble on water, ethanol, ether and
chloroform. It is unstable in light and gradually become
darken on decomposition. Therefore, it should be stored
in airtight container and should protect from light.

Therapeutic uses:
1. To relief from acute and chronic attack of asthma
2. To relief from nasal decongestant which is mainly occur by activation of α1 receptor.
3. For treatment and prevention of hypotension.
4. For treatment of Stocks Adams syndrome but isoprenaline is more prefer than ephedrine.
Stocks Adam syndrome is characterized by unconsciousness with convulsion and is mainly
cause by interference in blood flow on the brain.
5. Ephedrine eye drops are employed to produce mydriasis without cycloplegia.
6. It is also used on narcolepsy because of its central effect but amphetamine is more prefer
than ephedrine.
7. It is also support for prevention of nocturnal enuresis [Passing of urine at night] and relief
from whooping cough.

Synthesis:

Terbutaline: It is officially use as sulfate

salt form which is grayish white crystalline
powder. It is odourless and has bitter taste.
It is freely soluble in water but sparingly
soluble on methanol. Similarly, it is
practically insoluble on chloroform and
ether. It is gradually darkens on exposure
to air and light. Presence of metal also
causes discoloration. It is stored on in
airtight container at 150C to 300C and
should protect from light.

Therapeutic use: It is mainly used to treat bronchospasm in bronchial asthma and in chronic
bronchitis.

Dopamine: It is the natural precursor of nor-adrenaline and adrenaline and itself is a

neurotransmitter of the central and peripheral nervous system.
Physiochemical properties: It is almost white crystalline
powder. It is freely soluble on alcohol and water while
sparingly soluble in acetone and methylene chloride. It is
ineffective orally because it is a substrate for both MAO and
COMP. It does not readily cross BBB.

Therapeutic uses: Dopamine exerts both CVS effect by interacting with D1 dopaminergic
receptors especially in the renal, mesenteric and coronary part. At high concentration
dopamine acts on β1 Adrenergic receptor and causes positive ionotropic effects and also
cause release of nor-adrenaline.

Generally, dopamine has following uses:

i. To treat cardiogenic and hypovolemic shock which is cause due to low cardiac output
ii. It is used to treat congestive cardiac failure. Dopamine has the advantage over nor-
adrenaline in a sense that dopamine can increase the cardiac output within renal vasodilation.
iii. It is also given in the patients of pheochromocytoma after surgical removal of the tumor.

Dobutamine: It is used clinically as a racemic mixture of two enantiomer forms. The L form
is potent agonist at α1 receptor while D form is potent antagonist at α1 receptor and also acts
as powerful agonist at β1 receptor. Thus net cardiovascular effects of dobutamine is to
counter balance the activity of α1 receptor stimulates by L and D form and also the action of
β1 receptor stimulated by D form enantiomer.

Physiochemical properties: It is officially as Dobutamine hydrochloride which occurs as

white crystalline powder. It is sparingly soluble in water and methanol.

Therapeutic uses: It is used in patients of heart failure associated with myocardial infraction
and short-term management of acute congestive heart failure. Dobutamine increases cardiac
output and stoke volume without affecting heart rate, peripheral resistance or blood pressure.
Clonidine: Clonidine is a central α2 adrenergic agonist which
reduces blood pressure and slow heart rate by reducing
sympathetic stimulation.

Physiochemical properties: It is officially used as

hydrochloride salt which occurs as white crystalline powder.
It is soluble on water and dehydrated alcohol, slightly soluble
on chloroform. Its 5% solution in water has a PH of 4 to 5.

Therapeutic uses:
i. To treat moderate primary hypertension.
ii. To control diarrhea in diabetic patients with autonomic neuropathy.
iii. For prophylaxis of migraine.
iv. To treat dysmenorrhea
v. For management of withdrawal symptoms of alcohol, nicotine and opoids

SAR of adrenergic drugs:

1. SAR of adrenaline and Nor-adrenaline:

i. These drugs are catechol derivatives drugs.

ii. Substitution on the meta and para positions of aromatic ring and on the alpha and beta
positions of ethylamine side chain support for structure activity relationship of these drugs.

iii. Methyl or ethyl substitution on the alpha carbon of the ethylamine side chain reduce
direct receptor agonist at both alpha and beta receptors.
iv. An alpha alkyl group increases the duration of action of phenyl ethyl amine agonist by
making the compound resist to deamination by MAO.

v. Substitution on the beta carbon generally decreases central stimulant activity due to low
lipid solubility of these agents. Thus ephedrine is less potent than methamphetamine.

vi. Laevorotatory nor adrenaline and adrenaline are ten times more potent as their isomers.
vii. Substitution of primary and secondary amines performs good adrenergic activity whereas
substitution of tertiary amines and quaternary ammonium salt does not support for their
proper activity.
viii. The amino group should be separated from aromatic ring by two carbon atoms for
proper adrenergic action.

ix. The naturally occurring nor-adrenaline has 3,4 dihydroxy benzene catechol ring which
active at alpha and beta receptors. However, adrenaline has poor oral activity because it is
rapidly metabolized by COMT. Similarly, while on 3,5 dihydroxy benzene catechol ring as
in metaproterenol, oral activity is good because its resistance to metabolism by COMT.

x. As bulk of nitrogen substituent increases alpha receptor agonistic activity decreases and
beta receptor activity increases. Thus, NA that is effective against β1 receptors is also potent
against α1 agonist while adrenaline is potent agonist against α, β1 and β2 . Similarly, as size
increases from hydrogen in nor-adrenaline to methyl in adrenaline then activity of alpha
receptor decreases while activity of beta receptor increases.

2. Replacement of catechol functional group of isoproterenol with the resorcinol structure

gives the metapoterenol which is selective β2 receptor agonist.

3. Maximal activity is seen on beta phenyl ethylamine derivatives containing hydroxyl

groups on the meta and para positions of catechol ring and beta hydroxyl group of correct
sterochemical configuration on the amine position of the molecule.
 [Adrenergic Blockers]

The adrenergic antagonists [Adrenergic blockers or sympatholytic agents] bind to

adrenoceptors but do not trigger the usual receptor mediated intracellular effects. These
drugs act by either reversibly or irreversibly attaching to the receptor by preventing its
activation by endogenous catecholamines. These drugs will interfere with the functions of
the sympathetic nervous system. Numerous adrenergic antagonists have important roles in
clinical medicine primarily to treat diseases associated with the cardiovascular system.

Alpha blockers: Alpha-blockers are pharmacological agents that act as neutral antagonists
or inverse agonists of α-adrenergic receptors. Alpha blockers cause blood vessels to dilate
and lower the blood pressure. These medications are also used to treat prostate enlargement
in men.

Classification of alpha blockers:

A. On the basis of receptor selectivity and MOA:
a. Non-selective alpha blockers [Block both α1 and α2 receptors]
i. Reversible: Phentolamine, Tolazoline
ii. Irreversible: Phenoxy benzamine
b. Selective alpha blockers:
i. α1 blockers: Alfuzosin, Doxazosin, Prazosin, Tamsulosin, Terazosin
ii. α2 blockers: Yohimbine
c. Miscellaneous Alpha blockers: Ergotamine, Dihydro-ergotamine, Chlorpromazine

B. On the basis of chemical structure:

a. β haloalkylamine derivatives: Dibenamine, Phenoxy benzamine
b. Natural and dehydrogenated ergot alkaloids: Ergotamine, Ergocristine, Ergocornine
c. Imidazoline derivatives: Tolazoline, Phentolamine
d. Quinazoline: Prazosin, Doxazosin, Terazosin

Uses of alpha blockers:

1. Pheochromocytoma: It is a tumor of adrenal medulla which release large amount of
adrenaline and Na. The sign and symptoms include a sudden or paroxysmal rise in BP with
headache, palpitation and excessive sweating. The definite treatment for pheochromocytoma
is surgery. In the preoperative period, pheochromocytoma is used to control hypertension and
restore blood volume during surgery.

2. Hypertensive emergencies: Intravenous phentolamine can be used for control

hypertensive crisis due to clonidine withdrawal and cheese reaction.
3. Essential hypertension: Selective α1 antagonists are preferred in the treatment of mild to
moderate hypertension. They cause less tachycardia and have favorable effects on lipid
profile.

4. Benign prostatic hyperplasia: Transurethral resection of the prostate is commonly used

method to relieve urinary symptoms of BPH. Selective α1 blockers are used in BPH as they
reduce the resistance to urinary flow. Prazosin, Doxazosin, Terazosin and Alfuzosin are
particularly useful in patients who have hypertension. Tamsulosin is preferred for BPH in
normotensive patients.

5. Tissue necrosis: Phentolamine is used locally to prevent tissue necrosis due to

extravasation of alpha agonist.

6. Male sexual dysfunction: Local injection of phentolamine with papaverine may be used
to treatment of male sexual dysfunction.

● Phentolamine: It is an imidazole
derivative. It blocks alpha receptors and also
has a direct action on vascular smooth
muscle. It is an odorless white crystalline
powder with slightly hygroscopic nature. It is
almost soluble in water and alcohol while
sparingly soluble in chloroform. Its freshly
prepared 1% solution in water has a PH of
4.5 to 6.5. Phentolamine solution slowly deteriorates on storage and its absorption is also
very poor.

Uses:
1. Phentolamine is used to prevent paroxysmal hypertension in the patient with
pheochromocytoma and as prophylaxis against catecholamine induced hypertensive crisis
during surgery.

2. It has been used for treatment of acute left ventricular failure [Cardiogenic shock] which is
followed by myocardial infraction.

3. Phentolamine has also been used for management of hypertensive crisis due to overdoses
with sympathomimetic agents in patients taking monoamine oxidase inhibitors and in the
patients with rebound hypertension due to clonidine withdrawal.
Prazosin: It is anti-hypertensive agent that
blocks postsynaptic α1 adrenergic
receptors in the periphery and is capable of
crossing blood brain barrier by decreasing
sympathetic outflow in the brain. It is
synthetic quinolone derivative and used as
hydrochloride salt.

Physiochemical Properties: Prazosin HCl is white and hygroscopic in nature. It is slightly

soluble on water, methanol while insoluble in chloroform. It melts at about 277-2800C.

Metabolism: Prazosin is extensively metabolized primarily by demethylation and

conjugation and excreted mainly through bile and faeces.

Uses:
1. Prazosin is used for treatment of hypertension of various etiology. Renal blood flow and
glomerular filtration are not impaired by long term oral administration. Prazosin can be used
safely in hypertension along with impaired renal function.
2. Prazosin is indicated in the treatment of severe refractory congestive heart failure. It can
be added to the therapeutic regimen in those patients who have congestive heart failure
disorder along with cardiac glycosides derivatives.
3. It is also indicated for treatment of Raynand’s syndrome.
4. Prazosin is also indicated as an adjunct in the symptomatic treatment of Urinary
obstruction caused by benign prostatic hyperplasia.

Beta blockers: Beta adrenergic receptors act on β1 or β2 receptors or on both of them and
antagonize the effect of catecholamines which are mediated through these receptors. Some of
these drugs also possess membrane stabilizing action [Local anesthetic action] and intrinsic
sympathomimetic activity.

Classification of Beta-adrenergic blockers:

A. On the basis of receptor selectivity:
a. Non-selective Beta Blockers [Blocks both β1 and β2 receptors]: Propranolol, Sotalol,
Timolol, Pindolol
b. Selective Beta Blockers:
i. Selective β1 Blockers: Metoprolol, Atenolol, Acebutolol, Bisoprolol, Esmolol, Betaxolol,
Celiprolol
ii. Selective β2 Blockers: Butaxamine
c. Mixed alpha and beta blockers: Labetalol, Carvedilol
B. On the basis of chemical structures:
a. Beta blockers with intrinsic sympathomimetic activity [ISA]: Oxaprenolol, Pindolol
b. Beta blockers with membrane stabilizing activity: Propranolol
c. Specific beta blockers: Timolol, Nadolol
d. Beta blockers with cardio selective activity: Metoprolol, Atenolol, Acebutolol, Esmolol
e. Beta blocker with additional alpha blocking property: Labetalol, Carvedilol

Uses of beta blockers:

1. Hypertension: Beta blockers are useful for all grades of hypertension. These drugs
reduced stroke volume and heart rate due to which cardiac output automatically decrease and
fall on both on systolic and diastolic pressure. Hypertension can also be maintained by
decreasing aldosterone production i.e. sodium-water retention mechanism.

2. Cardiac arrhythmias: Beta blockers reduce cardiac automaticity and increase refractory
period. They are used in arterial flutter and fibrillation. These agents are particularly useful in
arrhythmia precipitated by sympathetic over activity.

3. Myocardial infraction: Immediate treatment with beta blockers in MI reduces infarct size
while late use prevents additional infraction. In addition to blocking sympathetic activity,
beta blockers helps for reduction of platelet aggregation and enrichment of fibrinolysis which
are the major advantages offer by these agents in MI.

4. Congestive cardiac failure [CCF]: Chronic use of beta blockers such as Carvedilol,
Metoprolol and Bisoprolol has shown to reduce mortality rate in chronic heart failure.

5. Anxiety: Propanol prevents the acute panic symptoms seen in public speaking,
examination and other anxiety provoking situations. Performance in musicians can be
improved. Tremors, tachycardia and other sympathetic over activity are alleviated.

6. Prophylaxis of migraine: Propanol reduces the frequency and severity of migraine

headache.

7. Glaucoma: Timolol and Betaxolol are generally used for decrease IOP by reducing
production of aqueous humor in eye and help to treat glaucoma.

8. Pheochromocytoma: Propanol is given with beta blockers before surgery to control

surgery to control hypertension.
9. Thyrotoxicosis: Propanol controls palpitation, tremors and affords symptomatic relief in
thyrotoxicosis.
10. Alcohol withdrawal: Propranolol also helps for treatment of patients undergoing alcohol
withdrawal by reducing central sympathetic over activity during the phase of withdrawal.
Propranolol: Its Levo isomer is 100
times more active than dextro isomer.
Propranolol is secondary amine. It is
used as hydrochloride salt which
occurs as odorless white powder with
bitter taste. It is soluble on water and
alcohol. It is affected by light.
Oxidation occurs in its aqueous
solution and causes discoloration. Its solution is most stable at PH of 3.

Uses: It is non-selective beta agonist and has equal affinity for both β1 and β2 receptors. It is
generally used on:
i. Hypertension ii. Cardiac arrhythmia
iii. Angina pectoris due to coronary atherosclerosis iv. Migraine headache
v. Myocardial infraction

Synthesis:

Timolol: It is beta blocker agent. It is officially

used as malate form which occurs as a white
odorless crystalline powder. It is highly soluble
on water and alcohol while sparingly soluble
on propylene glycol and insoluble in ether and
cyclohexane solutions. Its 2% solution in water
has PH of 3.8 to 4.3.
Uses:
i. It is use on treatment of glaucoma as eye drops.
ii. It also use for treatment of hypertension, angina pectoris and myocardial infarction as well
as on prophylaxis of migraine.

Atenolol: It is selective β1 adrenergic

blocker. It is white odorless powder. It is
sparingly soluble in water while freely soluble
in alcohol.

Uses: It is one of most commonly used beta

blocker for:
i. Hypertension
ii. Angina pectoris

Labetalol: It is phenyl ethanol amine derivative that is competitive inhibitor at both β1 and
β2 adrenergic receptors and at α1
receptor. It is officially used as
hydrochloride salt which occurs as white
powder or granules. It is sparingly
soluble in chloroform, ether and
methylene chloride. Its 1% solution in
water has PH of 4 to 5. It is use on
hypertensive emergencies and
pheochromocytoma.
 [Central Nervous System Depressants]

General anesthetics: They are groups of CNS depressant drug which produce partial or total
loss of sense of pain with controlled and reversible depression of the functional activity of
CNS. Therefore, absolute loss of sensation is term as Anesthesia and this word is derived
from Greek word which meaning as Insensitivity or Lack of feeling. In general, anesthetic
brings descending depression of CNS i.e. starting from the cerebral cortex to the basal
ganglia and then cerebellum and finally to spinal cord. These drugs are use on surgical
operation to induce unconsciousness or to abolish the sense of pain.

General anesthetic is divided into three groups according to the method of administration:
I. Inhalation anesthetics: These are given through inhalation on vapor form. Ex: Ether,
Cyclopropane, Nitrous oxide, Halothane, CHCl3.
II. Intravenous anesthetics: Thiopental sodium, Ketamine HCl, Methohexital sodium,
Thiamylal Na
lll. Basal anesthetics: These are agents which induce state of unconsciousness in not enough
for surgical procedure. These are given on many ways such as through oral, IM or Rectal.
Ex: Fentanyl citrate, Tribromoethanol and Paraldehyde.

Stages of anesthetics:
i. Analgesia: In this stage, consciousness is maintained and analgesia is produce within the
depression of high cortical central area. This stage is also called as cortical stage.

ii. Delirium or stage of excitement: In this stage consciousness is loss and further removal
of cortical inhabitation leads to excitement and patient may be shouting or struggle violently,
salivate, vomit or develop cough. Analgesia and Delirium stage are collectively called as
Induction period.

iii. Surgical anesthetics: In this stage skeletal muscle are relax and consciousness is loss and
most of surgical procedure are performed on this stage. If depth of anesthetics is increase in
this stage, there will be decrease on respiration and may be fatal.

iv. Respiratory paralysis or Medullary paralysis: This stage is toxic and terms as overdose stage
in which respiratory and cardiovascular function are collapsed and tissue rapidly become anoxic.

Halothane: It is volatile halogenated hydrocarbon with boiling point of 50oc. It is clear

colorless, odorless and non-flammable dense liquid. It is miscible with CHCl3, ether and
absolute alcohol while slightly soluble on water. It is light sensitive therefore it should be
store on well closed brown bottles at temperature of 8oc to 15oc and is stabilized by addition
of 0.01% Thymol.
Uses: It is relatively safe and potent volatile anesthetics
administered by inhalation. It was first used on 1956 and gain
rapid acceptance because its non-inflammability. In
fluorinated hydrocarbon and ether like halothane and
Fluroxene [CH3-CH2-O-CH=CH2] there is decrease in
toxicity and boiling point within the increase of anesthetic
potency. Therefore, halothane is two time potent than
chloroform and four time potent than ether. It may produce
any depth of anesthetics without causing hypoxia. Being non-
irritant, its inherent hypotensive effects retard capillary bleeding and renders comparatively
blood loss field during surgery.

Metabolism: Halothane is non-inflammable, non-explosive fluorinated volatile anesthetics

which invariably mix with air or oxygen. 20% of administrated drug undergoes to
metabolism. The triflorinated methyl group is quite stable because of electro negativity of
fluorine which stabilize C-F bond while C-Cl, C-Br and C-H bond are destabilize. Therefore
breaking of C-Cl, C-Br and C-H are the probable sites for metabolic entry and metabolite are
Chlorine, Bromine ions and trifluoroacetic acid.

Mechanism of action: The metabolite 1,1 difluoro 2 chloro 2 bromo ethylene reacts with SH
group of Glutathione to form Glutathione adduct. Glutathione is tripeptide [𝛾 Glutamyl,
Cysteinyl and Glycine] which is found on most tissue. The present of GSH is required in the
body to maintain the normal function of immune system and main role for the multiplication
of Lymphocyte. Then Glutathione adduct undergoes further biotransformation to give
mercapturic acid derivatives. It involved two enzymatic cleavage i.e. Glycine and Glutamic
acid. In this process these cleavages decrease rate of firing of neuron then neural activity of
brain will decrease which results on reduce of blood pressure and frequently decrease on the
pulse rate and produce anesthetics.
Synthesis: It can be synthesis by bromination of 2 chloro 1,1,1 trifluoro ethane. Then
halothane is separated by fractional distillation.

Side effects: Hypertension, Respiratory depression, Low incidence of hepatic necrosis.

Nitrous oxide:
Physiochemical properties: It is odorless and test less gas. It is soluble on water, alcohol
and ether. This gas at room temperature become liquid and supplied as a liquid gas on metal
cylinder.

Uses: It is good analgesic but required high concentration in the inspired mixture up to 80%
to achieve anesthetics. It is weakest and safest inhalation anesthetic agent. It is usually
administered in conjugation with other potent inhalation anesthetics such as Methoxy furnace
or halothane but its anesthetics regimen can be enhanced by the in-corporation with Neuro-
muscular blocking agent such as Tubocurarine [Atropine antagonist]. N2O with 50% oxygen
is widely used for analgesia.

Metabolism: N2O once bound at receptor side, it agonist the receptor activity site then
muscle relaxant activities are increased to the considerable extent so that some patient often
get an attack of hysteria. Therefore, N2O is considered as Laughing gas.

Mechanism of action: No specific mechanism has been known yet for mechanism of action
but it is state that N2O exerts anesthetics activity through irreversible oxidation of cobalt
atom in a Vitamin B12. It may ultimately render the inactivation of specific enzymes such as
Thymidylate synthase, Methionine synthase. Methionine synthase helps for formation of
Myelin while Thymidylate synthase helps for formation of Thymidine.

Synthesis: It is prepared by heating ammonium nitrate at 200oC to produce Nitrous oxide and
water.

Side effect: Hypoxia

Barbiturates: They are cyclic ureides and formed when dicarboxylic reacts or condense with
urea in the present of sodium ethoxide.

Parabanic acid is cyclic ureide which on hydrolysis by alkali helps to regenerate the
corresponding acid and urea. Many cyclic ureide are derived from malonic acid or malonic
esters.

Uses of Barbiturates:
1. May be used before surgery to relieve anxiety and tension.
2. Some of barbiturates are used as Anti-convulsant to control seizures in certain disease
such as Epilepsy.
3. They are also been used to treat insomnia.
4. They are also used to relieve nervousness or restlessness during daytime.

Classification of Barbiturates:
1. Long acting barbiturates: Their duration of action is about six hours or more. Ex: Barbital,
Phenobarbital, Mephobarbital
2. Intermediate acting barbiturates: Their duration of action is about three to six hours.
Ex: Allobarbital, Butobarbitone, Amobarbital
3. Short acting barbiturates: Their duration of action is about less than three hours.
Pentobarbital, Cyclobarbital
4. Ultra-short acting barbiturates: Their duration of action is within the second.
Ex: Thiopental sodium, Thiamylal sodium
SAR of Barbiturates:
1. Sum of carbon atom of both substituents at C5
should be between 6 to 10 in order to obtain optimal
hypnotic activity.
2. Greater the branching more potent will be drug.
3. Introduction to halogen atom into C5 alkyl
substituents increases potency of drug.
4. Introduction of more sulfur atom on C4 and C6
position decrease hypnotic activity.

5. Introduction of polar substituents such as NH2-, SO3H, COOH and OH- into aromatic
substituents at C5 position decrease lipid solubility and potency.

6. Replacement of oxygen by sulfur at C2 carbon position shortens onset of action and

duration of action and increase lipid solubility.

7. Within same series branch, isomers have greater lipid solubility and hypnotic activity with
a short duration of action.
►When substituents carbon is 7 to 9 = Rapid onset with short duration of action
► When substituents carbon is 5 to 7 = Intermediate duration of action
► When substituents carbon is 4 = Longest duration of action

8. Methylation at position C1 enhances excitatory side effects.

Thiopental Sodium: It is yellowish white

hygroscopic powder with characteristics
alliaceous odour and bitter taste. It is soluble on
water, alcohol but not stable on aqueous form
because it is hydrolysable and loss their
property. Therefore, solution for injection is
prepared by dissolving immediately before use.
The sterile contains of sealed container in the
require amount of water for injection.

Uses: It is mostly employed intravenously to cause rapid un-consciousness for both surgical
and basal anesthesia. It also used on treatment of seizures or epilepsy or sedative or short-
term hypnotics. It is also use for the control convulsions. Since it is called as ultra-
barbiturate.
Metabolism: Liver is primary site for metabolism. As it is generally introduced
intravenously and it is lipid soluble anesthetics drug and has slow duration of action. It can
rapidly cross Blood Brain Barrier and redistributed away from central circulation towards
muscle and fat tissues. Once it is redistributed the free fraction on blood then metabolize to
liver. The non-polar barbiturates or thiopental sodium undergoes desulfuration and goes on
first pass metabolism [Metabolism where concentration of drug is greatly reduced before it
reaches to systematic circulation] and then converted to pentobarbital. And this phenobarbital
is pharmacologically inactive and ultimately excreted on urine. In metabolism 80% of drug is
bound to plasma protein and elimination half-life is about 3 to 8 hours.

MOA: When thiopental sodium is given then it binds with GABA receptor and enhances
GABA receptor inhibitory activity. When GABA receptor is enhanced, chloride channel
opening is more and more chloride ions enter from extracellular fluid to intracellular fluid
and more chloride on ICF cause hyperpolarization of neurons which results on decrease on
action potential generation and decrease excitation and produce anesthetics.

Note: GABA is nervous primary inhibitory neurotransmitter found on brain and spinal cord.
The main function of GABA is to stimulate relaxation and sleep. It mainly supports to
control anxiety.

Synthesis:
1. Preparation of Diethyl ester of ethyl (1-methyl butyl) malonate:
2. Condensation with thio-urea:

3. Preparation of sodium salt:

Side Effects:
- It increases barbiturates level on blood.
- It may cause respiratory depression.
- It may also cause Nausea, vomiting, Headache, Delirium, Hallucinogens.

Thiamylal sodium: It is a highly hydrophobic thiobibuturate and has closely related to

thiopental sodium.
Uses: It is ultra-short acting barbiturates.
Mainly used for intravenous anesthesia in a
condition of comparatively for short
duration. After intravenous administration,
unconsciousness is produced within a
second and consciousness will regain
within 30 minutes. It is also effective for
different types of convulsions treatment.

Note: MOA and Metabolism of Thiamylal

sodium is similar to Thiopental sodium.

Ketamine HCl: Dissociative Anesthesia is the physiological defense mechanism in which

one’s identity, memory, feelings of perception or
events are dissociated i.e. separated from
consciousness. Among the dissociative anesthesia
commonly used are Ketamine HCl.

Physiological Properties: It is white crystalline

powder having slight characteristic odor. It is freely
soluble on water, methanol and alcohol while
sparingly soluble on chloroform. On sterile solution of
water for injection ketamine hydrochloride is not less than 95%. It is stable under normal
condition.

►Uses:
⇒ It is used to treat neuropathic pain, depression, and alcoholism addiction.
⇒ It is rapid acting anesthetic agent used for induction of anesthesia.
⇒ It reduces pain, perception and cause sedation.
⇒ Its duration of anesthetic activity is relatively short i.e. 10-25 minutes.
⇒ It is capable of producing dissociative anesthesia so it is used as recreational drug.

Metabolism: It is rapidly absorbed and distributed in body tissues and brain. When
administered intravenously a sensation of dissociation occurs within 30 seconds. In
metabolism it goes N dealkylation of cyclohexane ring and then conjugated with glucorunoic
acid and dehydration of the hydroxylated metabolite to form cyclohexane derivatives.
Cyclohexane derivatives are 3/4rd active as ketamine hydrochloride and approximately 91%
is excreted in the urine and 3% is excreted in faeces form.
Mechanism of Action: Ketamine HCl acts as antagonist with cationic channel of NMDA
receptors [N-Methyl, D-Asparatase Complex] by preventing the flow of cations through the
channel. Ketamine HCl prevents neuronal activation which normally required for conscious
state. It also acts as Nor-adrenergic uptake inhibition and it also interacts with other receptor
to produce effect of analgesia. It blocks voltage sensitive calcium channel and depress the
sodium channel. The activity of Ketamine HCl is also the interaction with opoid receptor or
sigma receptor to shows analgesic activity.

Side effect: Several confusions, Hallucination, Extreme fear, Diplepia, Jerky muscle
movement, Insomia, Nausea, Vomiting, Dizziness.

Anxiety: It is an unpleasant emotional state that has less clear source.

Anti-anxiety drugs: Drugs that are used for the primary treatment of anxiety disorder are
known as Anti-anxiety drugs or Anxiolytic drugs. Ex: Benzodiazepines

Sedative and Hypnotics: These types of drugs depress CNS and produce sleep and quieting
effects. These hypnotics and sedatives drugs are classified as barbiturates and Non
barbiturates. Non-barbiturates: These are compound which do not have barbiturates structure
but have anxiolytic, sedative and hypnotic effects. Ex: Benzodiazepines, Chlordiazepoxide
HCl, Alprazolam, Lorazepam, Halazepam, Nitrazepam

SAR of Benzodiazepines:
1. Ring A substitution:
i. Electron withdrawing substituents [Cl, NO2 and CF3]
at position 7 increases the activity while substituent at
position 8 and 9 decrease the activity.

ii. Electron releasing group at position 7 decrease the

activity.

2. Ring B substitution:
i. If methyl group substitution on position 1 increase the
activity.
ii. Introduction of carbonyl function at position 2 and
phenyl substitution on position 5 increases the
anxiolytic activity.
iii. Reduction of carbonyl function and introduction of
hydroxyl group on position 2 decreases activity.
iv. Hetero-aromatic or cyclo alkyl substituents at position 5 decrease the activity.

3. Ring C substitution:
i. Substitution of Cl and Fl on Ortho position increase the activity.
ii. Any substituents on Meta or Para position decrease the activity.
► Diazepam: Diazepam is almost white to pale yellow
crystalline powder with bitter taste. It is sparingly
soluble on water while fully soluble on organic solvent.
It can be purified by autoclaving and filtration. It should
be stored on light resistance container.

Metabolism: Diazepam undergoes N-methylation to

form Desmethyl diazepam. This desmethyl diazepam
then hydroxylase to form oxazepam. Then oxazepam
conjugated with glucuronide and it is excreted into
breast milk crossing placenta and finally to urine. When
diazepam is administer orally, it rapidly observed and have fast onset of action. The duration
of peak pharmacological effect is 15 minute to one hour. Diazepam is highly lipid soluble
and is widely distributed through our body. It easily can cross BBB and placenta and is
excreted to breast to breast milk. After absorption it is redistributed into muscle and adipose
tissue then it is primarily metabolized by hepatic enzymes with very little unchanged drug
eliminated in urine.

MOA:
1st Pathway: Diazepam actions are mediated through GABAA receptor activation. When
diazepam is given, it bends to benzodiazepine receptors which are different from GABAA
receptors. As a result, the frequency of chloride channel opening is increase so that chloride
ions enter from ECF to ICF. The more chloride ion on ICF causes hyperpolarization of the
neurons which decrease the action potential of the neurons and decrease the excitation and
produce anesthesia.

𝟐𝐧𝐝 Pathway: Diazepam acts on the areas of Limbic system [Paleomammalian brain i.e.
thalamus and hypothalamus] that induce anxiolytic effect due to the enhancement of GABA
activity.

Uses:
i. It is given orally or parentally and used as anxiolytic agent in anxiety due to fear or other
emotional activity.
ii. It is use as anti-convulsant agent in muscle spasm and various spastic disorders.
iii. It is use as primary drug for treatment of seizure in epilepsy.
iv. It is use for management of alcoholic withdrawn syndrome.
v. It uses as sedative and high dose hypnotics.

Adverse Effects: Dizziness, Headache, Somnolece [Sleep disorder], Ataxia [Movement

disorder of body], Euphoria, Nervousness.
Synthesis of Diazepam:
►Alprazolam: Alprazolam is white crystalline powder. It is
insoluble in water while soluble on ethanol and methanol.

Metabolism: When alprazolam is administered orally, it is

rapidly absorbed and protein binding is 70% lower than
other benzodiazepines. In first pass metabolism, oxidative
metabolism of methyl group is taken to form methyl alcohol
i.e. alpha hydroxyl alprazolam is formed and this metabolite
is approximately has one half biological activity then
alprazolam. The peak plasma concentration depends on
doses and activity of alprazolam that occurs 1-2 hour after
administration. The other metabolites are extremely low and
excreted in the urine as glucuronides and some of drug is excreted in unchanged form also.

MOA: MOA of Alprazolam is similar to Diazepam.

Synthesis of Alprazolam:
Uses:
i. It is given orally in the treatment of anxiety disorder and panic disorder [Panic disorder is
caused by panic attack i.e. intensive fear].
ii. It possesses anxiolytic and hypnotic skeletal muscle relaxant anticonvulsant and amnestic
properties to regain memory.
iii. It may uses in combination with other medications for chemotherapy to induce nausea
and vomiting.

Side effects: Its main side effect is hypotension. Its over doses also causes Somndence,
Dizziness, Muscle weakness and its high dose also may cause coma.

Lorazepam: It is almost white crystalline powder. It is

practically insoluble in water but soluble in organic solvent.
This drug is required to keep in well closed light resistant
container at room temperature of 150 C-300 C. Generally
oral and injectable solution should be kept on refrigerator at
20 C-80 C.

Uses:
i. It is used for the management of anxiety disorders and
anxiety associated with depression.
ii. It is used effectively for insomnia and panic disorder.
iii. It is used in combination with other medication to prevent nausea and vomiting during
chemotherapy.
iv. It is used for prevention and treatment of alcohol withdrawal.

Metabolism: It is highly protein bound i.e. protein binding is 85 to 90% and is extensively
metabolized into pharmacologically inactive metabolites that are in glucuronide form. Due to
its poor lipid solubility it is relatively absorbed slowly by mouth and unsuitable for rectal
administration. Due to its poor lipid solubility and high protein binding its volume of
distribution is mainly to the vascular tissues on vascular compartments having prolonged
peak effects. Therefore, it has high relative potency than diazepam. The half-life of
Lorazepam is 10-20 hours.

Note: MOA and side effect of Lorazepam is similar to Diazepam.

Chlordiazepoxide: It is almost white or light-yellow

crystalline powder. It is practically insoluble in water and
soluble on organic solvent and should be stored on well
closed light resistant container. Chlordiazepoxide is less
potent than diazepam and possesses less anticonvulsant,
muscle relaxant and sedative property.
Metabolism: It is long acting benzodiazepine drug. The half-life of chlordiazepoxide is 5-30
hour but its metabolites desmethyl diazepam which has half-life about 36-200 hours and it is
excreted in the urine.

MOA and Side Effects: Same as diazepam

Uses:
i. It is indicated for short term treatment of anxiety i.e. 2-4 weeks which is severe.
ii. It is used for the treatment and management of acute alcohol withdrawal syndrome.

Chlorpromazine: Chlorpromazine base is

white or creamy white powder or waxy
solid. It is practically insoluble in water
and soluble in organic solvent. It darkens
on exposure to light so it should be kept in
well closed light resistant container. Its
hydrochloride salt decomposes on
exposure to air and light becoming yellow,
pink and finally violet and it is very soluble in water then solution can be sterilized by
autoclaving.

Uses:
i. It is widely used in management of psychotic condition and used to control hyperkinetic
state.
ii. It is used as anti-emetic and used to control nausea and vomiting during chemotherapy.
iii. It is effective for alleviation of intractable hiccup.
iv. It is used for treatment of tetanus and to control intermittent porphyria.

Metabolism, MOA and Side Effects: Same as diazepam

Phenobarbital
SAR of Phenobarbital:
i. Optimum activity is observed when one of the
substituents at C5 is phenyl.

ii. The 5-5 diphenyl derivatives have less activity then

phenobarbitone.

iii. 5-5 dibenzyl barbituric acid causes convulsions.

Physiochemical Properties of Phenobarbital:
It is white crystalline solid with slight bitter
taste. It is very slightly soluble in water while its
salt phenobarbitone sodium is hygroscopic white
powder or crystalline granules and very soluble
in water and it should be kept in well closed tight
resistant container.

Uses of Phenobarbital:
i. Phenobarbital and phenobarbitone sodium have hypnotic, sedative and anticonvulsant
action. They are used on treatment of Grand mal seizures or psychomotor seizures and Petit
mal seizures.
ii. Phenobarbital is commonly used for convulsive disorder and it is the drug of choice for
seizures in infants up to 2 month ago.
iii. Phenobarbital is also used for treatment of Partial and generalized tonic clonic seizures in
all age group. Tonic clonic usually begins with an abnormal electric discharge in small area
of brain then entire area.

Metabolism of Phenobarbital: Phenobarbital is a weak acid whose Pka value is 7.4 i.e.
approximately 50% is ionized at physiological PH of the body. The metabolism of
phenobarbital is primary takes in the liver in the endoplasmic reticulum and is well
distributed into CNS. Oral absorption is slow but nearly complete i.e. bioavailability is 80% -
100%. It has long plasma half-life of 2-6 days and yields extremely stable plasma
concentration. About 25%-50% of phenobarbital dose is excreted unchanged in the urine and
remainder is metabolized primarily by hydro-oxidation.
Phenobarbital is potent liver enzyme inducing drug of Cyp3 A4 enzyme and increases
the ability of liver to metabolize many drugs. It also induce UGT [UDP Glucuronosyl
Transferase] enzyme and increase the formation glucuronidation therefore phenobarbital
induces its own metabolism and acts as an auto-inducers.

MOA of Phenobarbital: It binds to GABA receptor and enhance the inhibiting activity of
GABA receptor so that Cl− channel opening is more and more Cl− ions enters from ECF to
ICF and causes hyperpolarization of the neurons which results in the decrease of action
potential generation and decrease excitation and produce anesthesia.

Side Effects of Phenobarbital: Most common side effects are sedation, drowsiness and
irritation in children and confusion may develop on old age patient. In newborn baby
coagulation defects may be seen.
Synthesis of Phenobarbital:
Miscellaneous Hypnotics and sedatives barbiturate drugs: There are number of
compounds which do not essentially possess the barbiturate structure but exhibit well
hypnotic and sedative activities and very similar to barbiturates.

Miscellaneous Hypnotics and sedatives barbiturate drugs are classified as:

i. Amides and Imides: These classes of drugs are also called as tranquilizers and muscle
relaxant having good sedative properties. Ex: Oxanamide, Glutethimide, Diethyl acetamide

ii. Alcohols and their carbamate derivatives: Carbomyl amine alcohol generally increased
depressant potency so they are used as sedative and hypnotic agent. Ex: Meprobamate,
Ethinamate

iii. Aldehyde and their derivatives: Ex: Choral hydrate, Paraldehyde

Glutethimide: It is colorless crystal or white powder. It is

insoluble on water but soluble on organic solvent and is should
be stored on well closed light resistant container. It is safely
used for inducing sleep in all types of insomnia without causing
depression of respiration. It has effective sedative and hypnotic
properties. Its hypnotic action is similar to intermediate acting
barbiturates.

Metabolism: Metabolism is extensive and drug itself is enzyme inducer. It is very

hydrophobic and absorption from GIT is somewhat erratic. Its onset of action is within 30
minutes after administration.

MOA: It acts as GABA agonist which help to induce sedation and also induce Cyp2 D6
enzyme. When it is taken with codine it enables the body to convert higher amount of codine
to morphine so general sedative effect will be increases.

Side effects: Blurred vision, Drowsiness, Confusion and Hypersensitive effects.

►Meprobamate: It is white crystalline

powder slightly soluble on water. It is mild
tranquilizing drug with some anti-convulsion
and muscle relaxant properties. It is used for
treatment of anxiety and tension but is less
effective than benzodiazepines.

Metabolism and MOA: Same as of Glutethimide

Side Effects: Dizziness, Headache, Nausea, Itching, Hypersensitive disorders.

Choral hydrate: It is colorless crystalline solid with
pungent odor and bitter taste. It volatilizes slowly on
exposure to air and it is very soluble on water. It should be
stored in well closed light resistant container. It is mainly
used for nocturnal and preoperative sedation. It frequently
administrated in combination with barbiturates to treat
anxiety in first stage of labour. It is also used in patients
having gastritis and given through rectum with olive to treat
enema. It must be avoided in patients having kidney and
liver disorders

Metabolism: It is metabolized within 4 minutes into trichloro ethanol by erythrocytes and

plasma esterase and later on it is converted into trichloro acetic acid and this trichloro acetic
acid metabolized depressed respiration and blood pressure. Therefore, it is used for short
term treatment of insomnia.

MOA: Its MOA is unknown but it is suggested that it has effects at multiple sites in CNS
including in thalamus and limbic system binds to GABA receptor and interrupt neuronal
communication in the reticular formation and spinal cord causing sedation and alter
perception of pain.

Paraldehyde: It is clear colorless or slightly yellow liquid

with strong characteristics odor and freely soluble in water.
Its sterilization by filtration and its contact with rubber
should be avoided because it dissolves rubber. It should be
stored in well filled tightly closed container at dark room at
the temperature of 8-150C. If it is solidifies, the whole
contents of containers should be liquefied by warming
before use.

Uses: It is one of oldest hypnotic drug usually employed in delirium tremens, status
epilepticus and patient with alcohol withdrawal. It is also used by IM injection for the
treatment of convulsions.

Metabolism: It is rapidly absorbed in GI tract and IM injection sites. About 70-90% of dose
is metabolized hepatically. Onset of its hypnotic action is within 15 minutes. Peak serum
concentration occurs orally in 30-60 minutes. Rectal administration is about 2 hours and
most of the metabolites are excreted through urine.

MOA: Its mechanism of action is unknown but it suggested that it may depress many parts
of CNS including ascending reticular activating system to produce imbalance between
facilitating and inhibiting mechanism.
Synthesis: It is prepared by treating three molecules of acetaldehyde with small quantity of
SO2 , HCl and COCl2 or ZnCl2 to produce Paralaldehyde. Then the resulting mass is frozen
and subsequent distillation is carried out for liquefaction.

Drugs used on spasticity: Spasticity is a disease which make difficult to move the body
movement. Spasticity is caused by cerebral palsy which is characterized by poor muscle
control, paralysis and other neurological disorder resulting from brain injury that can occur
during pregnancy, during birth or before age of five year. The drugs that are used for
spasticity are Baclofen, Dantrolene sodium, Buspirone.

Baclofen: It is almost white powder which is slightly soluble on water while fully soluble in
organic solvent. It should be stored in well closed light resistant container.

Uses: It is used in spasticity involving disease of spinal

cord. Its Levo form is active agonist at GABAB receptors
while its Dextro form is inactive at GABAB receptors. Its
racemic mixture and salt form are known as lioresal
which is approved to be used as spasmolytic agent.
Baclofen is also used for treatment of spasticity in
Paraplegia [Paralysis of both legs], Quadriplegia, multi
sclerosis and traumatic lesion [Spine injury].

Metabolism: Baclofen is completely absorbed from GIT tract after oral administration and
undergoes minimal hepatic metabolism and excreted mainly in urine and small amount of
faeces. Its oral absorption period is nearly two hours and its elimination half-life ranges
between 3-4 hours.

MOA: The muscle relaxant action of this drug invariably resolves from the action take place
in the spinal cord. Baclofen is structurally variant of GABA which is inhibitory transmitter
within CNS and it is agonist characteristic site of GABAB receptor and subsequently coupled
with G-protein activated K + and opening of neuronal K + channel leads to hyperpolarization
of primary afferent fibre terminals and reduce the release of neurotransmitters and produce
excitement.

Side Effects: Vertigo, Sedation, Dizziness, Excessive weakness

Dantrolene Sodium: It is hydantoin derivatives but does not exhibit epileptic activity. Since
it has poor water solubility so water soluble analog of dentrolene is used i.e. Azumolene.
Dantrolene decreases the release of Ca++ ion by the sarcoplasmic reticulum and blocks the
contraction of skeletal muscle. It is useful in cerebral palsy, muntiple sclerosis and malignant
hyperthermia. Its common side effect is severe muscle weakness.

Busiprone: It is first chemical introduced on anxiolytic group that affects seretoninergic

system. It is found to be useful in treatment
of anxiety and its effectiveness is farly
comparable with diazepam. It elevates
anxiety without producing sedation or
functional impairment. Busiprone attains
peak plasma concentration within 40-90
minutes of administration. It bounds to plasma protein to nearly 90%. The excretion through
urine varies between 29-63% and 18-38% through faeces. The elimination half-life of
unchanged drug is approximately between 2 to 3 hours and it is generally administration by
oral route.

Anticonvulsant drugs or Antiepileptic drugs: Anticonvulsants are the drugs used in the
treatment of various type of epilepsy. Epilepsy is a disease due to CNS disorder. It is
characterized by more or less frequent reoccurrence of seizures. Seizure is the response to an
abnormal electrical discharge in the brain. Anything that irritates the brain can produce
seizures in which there are convulsions with disturbance in consciousness. Disorder on brain
can be measures by ECG [Electro Encephalograph]. The electrical abnormal activity in the
brain may lead to higher firing excitable neurons in the brain.

Classification of seizures:
A. Partial: Partial seizures involve only a portion of the brain. The symptoms of each
seizure type depend on the site of neuronal discharge and on the extent to which the electrical
activity spreads to other neuron in the brain. Consciousness is usually preserved.

1. Simple partial: These seizures are caused by a group of hyperactive neurons exhibiting
abnormal electrical activity which are confined to a single locus in the brain. The electrical
discharge does not spread and the patient does not lose consciousness. The patient often
exhibits abnormal activity of a single limb or muscle group that is controlled by the region of
the brain experiencing the disturbance.
2. Complex partial: These seizures exhibit complex sensory hallucinations and mental
distortion. Motor dysfunction may involve chewing movements, diarrhea or urination.
Consciousness is altered. Simple partial seizure activity may spread to become complex and
then spread to a secondary generalized convulsion.

B. Generalized: Generalized seizures may begin locally and then progress to include
abnormal electrical discharges throughout both hemispheres of the brain. Primary
generalized seizures may be convulsive or non-convulsive and the patient usually has an
immediate loss of consciousness.

1. Tonic-clonic: These seizures result in loss of consciousness followed by tonic

[Continuous contraction] and clonic [Rapid contraction and relaxation] phases. The seizure
may be followed by a period of confusion and exhaustion due to the depletion of glucose and
energy stores. It is also called as Grand mal seizure.

2. Absence: These seizures involve abrupt and self-limiting loss of consciousness. The onset
generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond. An
absence seizure has a very distinct three-per-second spike and wave discharge seen on
electroencephalogram. It is also called as Petit mal seizure.

3. Myoclonic: These seizures consist of short episodes of muscle contractions. They

generally occur after wakening and exhibit as brief jerks of the limbs. Myoclonic seizures
occur at any age but usually begin around puberty or early adulthood.

4. Febrile seizures: Young children may develop seizures with illness accompanied by high
fever. Febrile seizures consist of generalized tonic-clonic convulsions with short duration.

5. Status epilepticus: In status epilepticus, two or more seizures occur without recovery of
full consciousness between them. These may be partial or primary generalized and
convulsive or non-convulsive. Status epilepticus is life-threatening and requires emergency
treatment.

Classification of Anticonvulsant drugs:

According to chemical structure and therapeutic aspect anticonvulsant drug are classified as:
1. Barbiturates: Phenobarbital, Methylphenobarbitone
2. Hydantoins: Phenytoin sodium, Mephenytoin
3. Oxazolidine diones: Trimethadione, Paramethadione
4. Succinimides: Phensuximide, Ethosuximide
5. Urea and monoacyl ureas: Phenacemide, carbamazepine
6. Benzodiazepines: Diazepam, Lorazepam, Alprazolam
7. Miscellaneous antiepileptics: Primidone, Sodium valproate
General mechanism of action of anticonvulsant drugs:
1. Many carbonic anhydrase inhibitors such as Acetazolamide and Methazolamide are found
to possess anticonvulsant or antiepileptic activity because carbonic anhydrase plays
important role in promoting the elimination of excess CO2 from the brain and blood
circulation. These drugs exert anticonvulsant action by decreasing the cerebral respiration.
2. The generation of seizures are due to discharge of neurotransmitters. Various
anticonvulsant drugs such as Phenobarbital and Diphenyl 2 pyridylphosphine increases level
of serotonin in the brain which causes non-specific depression of CNS function and control
the release of neurotransmitters.
3. The anticonvulsant activity of barbiturates is believed to exert conformational
rearrangement of oxidative enzymes which are essential for brain respiration.
4. GABA level in brain is also important to prevent the spread of seizures and many
anticonvulsant drugs are reported to increase GABA level in brain.

Phenytoin Sodium: It is the white

odorless crystalline powder. It is very
slightly soluble in water while its
sodium salt i.e. phenytoin sodium is
usually is very soluble on water and
hygroscopic powder which on exposure
to air absorbs CO2 with the liberation of
phenytoin.

Uses: Phenytoin is commonly used as anti-epileptic agents without sedative properties. It

acts to suppress the abnormal brain activity seen in the seizures so sodium salts are generally
used to control Grand mal and psychomotor epilepsy and it generally less used on Patit mal
seizures. It is also used in the treatment of cardiac arrhythmias. It is generally administered
orally and intravenously. Now days instead of Phenytoin, Fosphentoin is generally used.

Metabolism: Phenytoin is a weak acid and has erratic GI absorption. When taken orally it
precipitates in the stomach acid and metabolism occurs in the liver and is catalyzed by
hepatic microsomal enzyme. Peak blood level occurs within 3-12 hours in single dose
ingestion and absorption can be extended up to two weeks. Then metabolites are excreted
through the urine.

MOA: Phenytoin exerts its action on motor cortex and it blocks voltage sensitive sodium
channel in the neurons which leads to delay in neuronal recovery from inactivation. This
inhibitory effect is depended on the voltage and frequency of neuronal cell firing present in
the neuronal membrane. Selectively it blocks the neurons that are firing at high frequency.
Besides this it enhances calcium binding to the phospholipids which prevents the electrical
spread of irritable tissue from entering to the normal tissue.
Adverse Effects: Ataxia [Muscle weakness], Dysarthria [Condition in which the muscles for
speech are weak], Thrombocytopenia

Synthesis:
SAR of Hydantoins:

R 𝐑𝟏 𝐑𝟐 Drug name
-H -H -NH Hydantoin
-C2 H5 -C6 H5 -H Phenyl ethyl hydantoin
-C6 H5 -C6 H5 -H Phenytoin

1. A 5-phenyl or other aromatic substituents are essential for anticonvulsant drugs.

2. Alkyl substituents at position at 5 may contribute to sedation and this property is absent in
phenytoin.
3. Phenyl ethyl hydantoin has both anticonvulsant and sedation properties.

Note: When hydantoin react with dilute HCl glycine is form. Hydantoin are more effective
against Grandmal and ineffective in patitmal seizures.

Ethosuximide: It is white, odorless powder or

waxy solid with slightly bitter taste. It is freely
soluble in water while insoluble in organic solvent.
It is used in the treatment of Petit mal epilepsy and
is administered with Antiepileptic drugs. Its major
metabolite is N-hydroxy ethosuximide [inactive]
and is excreted in conjugation with urine. About
20% of oral dose is excreted in unchanged forms.
Its side effects are Dizziness, Sleeping disorder,
Drowsiness, Gastrointestinal disorders.

Carbamazepine [CBZ]: It is almost white powder.

It is practically insoluble in water while soluble in
alcohol and acetone. Chemically it is also known as
tricyclic depressant drug.

Uses: It is anticonvulsant and mood stabilizing drug

primarily used on treatment of Grand mal and
Psychomotor epilepsy and Bipolar disorder [Manic
depressive disorder]. It also used as analgesic in the
treatment of trigeminal neuralgia [Suicide disease]
and anxiety.
Metabolism: Since the carbamazepine is lipophilic in nature therefore it has large volume of
distribution and enters on brain rapidly. Peak plasma level occurs at 4-8 hours. The primary
site of its metabolism is liver. Its metabolite is also active which may increase the duration of
symptoms in toxicity. In its metabolism primarily oxidative enzymes help to oxidase
carbamazepine to form carbamazepine 10,11-epoxide metabolite which is active then it
conjugates with glucuronic acid and finally gets excreted in urine.

MOA: Carbamazepine is a sodium channel blocker. Voltage gated sodium channels are the
molecular pores that allow brain cell to generate action potential and these electrical events
allow neurons to communicate over long distance after sodium channel opens and they
become inactivated in closing the channel. Therefore, carbamazepine stabilizes the
inactivated state of sodium channels by making brain cells less excitable. Carbamazepine is
also being shown to be potentiate towards GABA receptor and increases GABA level in the
brain and slow for the seizures.
Carbamazepine may also reduce propagation of abnormal impulses in the brain by
blocking sodium channel or by inhibiting the generation of repetitive action potential in the
epileptic forms.

Synthesis:

Valproic acid [VPA]: Valproic acid is slightly soluble on water while freely soluble on
organic solvent. Sodium valproate is deliquescent white crystalline powder which is freely
soluble in water. Valproic acid is liquid at low temperature and can react with NaOH to form
sodium valproate.
Uses: It is used as mood stabilizer and anticonvulsant drug. It is used to control Petit mal,
Grand mal and Epileptic seizures as well as Juvenile myclonic epilepsy. It is also used as
second line treatment of Status epilepticus and as an alternative to the phenytoin.

Metabolism: Tablets and syrup form are rapidly absorbed by GI tract. Blood concentration
is 50 to 100mg/ml when reach at therapeutic level. Peak plasma level occurs after 15- 60
minutes after administration in syrup form and 1-4 hours in tablets forms. Half-life of
valproic acid is 8-9 hours. It is principally metabolized in the liver within several metabolites
but only 2 propyl 2 pentanoic acid has been shown to accumulate in the brain and acts as
anticonvulsant.

MOA:
i. Sodium valproate affects the function of neurotransmitter GABA. It enhances
Neurotransmission of GABA by inhibiting GABA transaminase enzyme and GABA will
increase its concentration.
ii. Valproic acid also blocks voltage gated sodium channel and Ca++ channel and acts as a
broad spectrum.
iii. Valproic acid is an inhibitor of the Histone Deacetylase 1 [HDAC1] enzyme. HDAC 1
plays a major role in the regulation of eukaryotic gene expression.

Side Effects:
i. Severe allergic reactions like swelling of lips and tongue
ii. Constipation, Diarrhoea, Dizziness, Mild hair loss

Primidone: It is white and odorless crystalline powder.

It is slightly soluble in water but freely soluble on
organic solvent.

Uses: It is potent anticonvulsant drugs used either in

conjugation with other antiepileptic drugs or used alone
in the treatment of Psychomotor or focal epileptic
seizures.

Metabolism: Approximately 60-80% of oral dose is absorbed in GI tract and slowly

metabolized in the liver to Phenobarbital and Phenylethylmalonamide [PEMA] and these
metabolites have anti-seizures effects but PEMA appears to be weaker and more toxic.

MOA: It works by interaction with voltage gated sodium channel which inhibits high
frequency of repeated firing of action potential.

Adverse Effects: Dizziness, Drowsiness, Depression, Suicidal thought.

Clonazepam: It is light yellow crystalline powder with faint
aromatic odor. It is practically insoluble in water while soluble
on organic solvent. It should be stored in well closed light
resistant container.

Uses: It is high potent benzodiazepine drug having anxiolytic,

anticonvulsant, Muscle relaxant and hypnotic properties. It
may be used alone or together with other medications for
treatment of seizures disorder.

Metabolism: Metabolism occurs with hydroxylation of 3 position followed by

Glucuronidation and Nitro group reduction and Acetylation. It is lipid soluble drug salt
which can crosses BBB rapidly and penetrates the placenta. It is extensively metabolized by
nitroreduction by the enzyme P450 . Its elimination half life ranges from 19-60 hours however
blood concentration reach at 4-5 hours. Its metabolites are 7 aminoclonazepam, 7
acetoaminoclonazepam and 3 hydroxyclonaxepam. These all metabolites are active.

MOA: Clonazepam exerts its action by binding to the benzodiazepines sites or GABA
receptor which caused enhancement of electric effect of GABA on neurons and increase the
influx of Cl− ions into the neurons that result the inhabitation of synaptic transmission across
the CNS but it has no effect on GABA level and no effect on GABA transaminase enzyme
level but it effect on Glutamate Decarboxylase activity.

Side effects: Sedation, Dizziness, Depression, Sleep disorder

Clorazepate: It is found in clorazepate dipotassium form. It

is present on white or light-yellow crystal form. It is soluble
on water while insoluble on acetone, chloroform and ether. It
should be kept on well closed light resistant container. This
drug possesses anxiolytic, hypnotic, sedative, skeletal muscle
relaxant and anticonvulsant properties. Its MOA is same as
diazepam

Uses: It is used for treatment of anxiety disorder, insomnia and seizures disorders. It is
generally prescribed in treatment of alcohol withdrawal epilepsy.

Metabolism: As benzodiazepine it is widely distributed in the tissue and highly bound to

plasma protein and can crosses BBB and placenta. Its active metabolite as desmethyl
diazepam is mainly responsible for therapeutic effect of clorazepate. The plasma level of
active metabolites is seen between 30 minutes to 2 hours after oral administration and it is
completely metabolized as desmethyl diazepam on GI tract.

Side effects: Confusion, Ataxia, Dizziness

 [Local anesthetics]

Local anesthetics are the drug which produces insensitivity in a limited area around the sites
of application or injection of the drug. They act mainly by preventing generation and
conduction of impulses along nerve fibres and nerve ending and their effects are reversible.
They are mainly used in dental and surgical procedures to prevent pain. Local anesthesia in
contact with nerve trunk can prevent the initiation and transmission in both sensory and
motor nerves.

Sites of action of local anesthetics:

1. Tropical anesthetics: It is used to relief pain or itching at mucous surface, damaged skin
surface, wounds and burns.

2. Infiltration anesthetics: It is the diffusion or accumulation on tissue or cells and it is

injected on minor operation at one or more sites around the operation area.

3. Nerve block: In this case higher concentration of local anesthetics is injected as dose as
possible to main nerve trunk.

4. Spinal block: Local anesthetics is injected into subarachnoid space to block the roots of
those nerve supplied to the site of operation.

5. Peridural block: Local anesthesia are injected through its catheters (tube) placed into the
epidural space or peridural space. These types of local anesthesia are use in obstetrics during
thoracic and lumber surgery.

Classification of local anesthesia:

i. Esters: Ar-COOH-R Ex: Benzocaine, Novocaine, Cocaine, Tetracaine
ii. Amides: Ar-CONH-R Ex: Bupivacaine, Lidocaine or Lingocaine
Procaine: It is the one of the oldest man-
made anesthetics drug and still in used.
Procaine is local anesthetics drug of
amino ester group. Its official compound
is as procaine hydrochloride which is
colorless or white crystalline powder. It
is odorless compound and very soluble
on water and PKa value is 8.9. It is freely
soluble on ethanol and slightly soluble in chloroform while almost insoluble in ether. It has
low lipid solubility. The stability of aqueous solution of the drug depends upon on PH of the
solution. For example, at 200 C the solution with PH of 3.6 has a 10% loss of potency and
this drop of potency increases with increase in temperature. Buffer solution may be sterilized
caarefully by controlled autoclaving. Generally, procaine solution for injection has PH values
varies from 3 to 3.5.

Uses: It is one of less toxic and most commonly used local anesthetics because due to its lack
of local irritation, minimal systemic toxicity, longer duration of action and low cost. It is
effectively used for anesthesia by infiltration, nerve block and epidural block or spinal
anesthesia. It is not use for tropical application because of its poor mucus membrane
absorption.

Synthesis:
1. From 2 chloro ethyl p amino benzoate
2. From P-amino benzoic acid

Metabolism: Procaine is mainly hydrolyzed in plasma by plasma cholinesterase enzyme to

produce P- amino benzoic acid [PABA] and Diethyl amino ethanol. Then PABA inhibits the
action of sulphonamides. A 70% of metabolites are metabolized in liver and both of these
metabolites are excreted in urine.

Mechanism of action: Procaine acts mainly by inhibiting Na+ influx through voltage gated
Na+ channel in the neuronal cell membrane of peripheral nerve. When sodium influx is
interrupted, action potential can’t arise and signal conduction is inhibited. The receptors sites
is thought to be located at the cytoplasmic inner portion of the sodium channel so procaine
can binds or antagonize the function of N-methyl D-aspartate receptors i.e. NMDA as well as
of Nicotinic acetylcholine receptors and serotonin receptors and forms ion channel complex.

Lidocaine or Lignocaine: It is first synthesis

amino amide type of local anesthesia. It is
white to slightly yellow crystalline powder. It
is almost insoluble in water but soluble in
alcohol, benzene, ether, chloroform and oils.
The aqueous solubility decreases in increase
on temperature. The aqueous solution of
lignocaine is restricted to hydrolysis under
acidic and basic condition. The official compound Lignocaine HCl is white odorless
crystalline compound with bitter taste and is very soluble on water and alcohol. PKa value is
7.5 at 250C.
Uses: It is widely used by injection for local application to mucous membrane. It has rapid
onset of action and effects are more prolonged than procaine. Its onset and duration of action
are increased by addition of adrenaline. For example, in dentistry 10% adrenaline or nor-
adrenaline is generally used. Lignocaine is suitable for infiltration, nerve block and surface
anesthesia. It is also used as anti-arrhythmic drug for treatment of ventricular arrhythmias.

Metabolism: It is mainly metabolized in a liver [95%] by CyP3 A4 enzyme. Its metabolite is

Monoethyl glycylxylidine which further metabolized to Glycylxylidine. Both of these
metabolites have longer half-life than lignocaine and are less potent sodium channel blockers
and exhibit local anesthetic action. The elimination half-life is approximately 90-120 minutes
and this may be prolonged in patient with hepatic impairment. The elimination half-life may
be 340 minutes for congestive heart failure.

Mechanism of action: Lignocaine alter signal conduction on neurons by blocking fast

voltage gated sodium channel in the neuronal cell membrane which is responsible for signal
propagation. It suppresses automaticity of conduction tissue by increasing electrical
threshold of ventricle and blocks both initiation and conduction of nerve impulses and by
decreasing the neuronal membrane permeability to Na ion and causes depolarization.

Synthesis:

Side effects: Hypotension, Hyperpigmentation, Urticaria

Cocaine HCl: Cocaine is an alkaloid
obtains from leaf of Erythroxylum
coca. It was the first chemical
substance found to possess local
anesthetics property. Cocaine has
tropane skeletal and it is levoratory
base.

Physiochemical properties: Cocaine is the ester of benzoic acid with nitrogenous alcohol. It
occurs as white crystalline powder and slightly volatile on nature and practically insoluble in
water while its hydrochloride salt occurs as hygroscopic and white crystalline powder and
very soluble in water. It is incompatible with hydroxides and carbonate. It should be
protected from light and moisture.

Use: Cocaine is used as surface anesthetics because of its systemic toxicity effects and
danger of causing addiction. Its use is now restricted entirely to eye, ear, nose and throat
surgery. It is a stimulant of CNS and appetite suppressant and topical anesthetics.
Specifically, it is serotonin-norepinephrine-dopamine reuptake inhibitor and also Known as
TRI [Triple Reuptake Inhibitors].

Metabolism: It is metabolized primarily on liver. Only 1% dose is excreted unchanged on

urine. The minor metabolites are P hydroxyl cocaine and m hydroxyl cocaine. These
metabolites are also active as cocaine.

MOA: The MOA of cocaine involves complex relationship with neurotransmitter. It inhibits
monoamine uptake and also effect in CNS by blockade of dopamine transmission.

Benzocaine: It is white crystalline powder with bitter taste. It is very slightly soluble in
water but freely soluble on organic phases.

Uses: Generally, it is used in ointments to get ride

from pain due to wounds and ulcer on mucous
surface. Its anesthetic property is usually seen for the
period as it remains in contact with skin or mucous
surface. It is used as importance ingredients in
various types of creams, ointment, powders,
lozenges, aerosol and sprays to relief the pain of skin
surface. It has low systemic toxicity and may be
used orally to relief the pain of gastric ulcer or
gastric carcinoma.

MOA: It binds to sodium ions channels and reversely stabilizes the neuronal membrane
which decreases its permeability to sodium ions then depolarization of the neuronal
membrane is inhibited and blocks the initiation and conduction of nerve impulses.
Bupivacaine HCl: An official compound as
Bupivacaine salt is crystalline powder which
gets soluble in water and the solution can be
sterilized by autoclaving of filtration.

Uses: It is indicated for local anesthesia as local

infiltration, nerve blocks, epidural and
intrathecal anesthesia. Intrathecal anesthesia generally occurs on arachnoid membrane. It is
also administered by epidural injection before total hip orthoplasty. It is commonly injected
to surgical wounds sites to reduce pain for 20 hours after surgery.

MOA: Bupivacaine binds to the intracellular portion of sodium channel and blocks sodium
influx in nerve cell membrane which prevents depolarization. Since pain transmitting nerve
fibres tends to be thinner and can be either unmyelinated or myelinated can be diffuse more
readily into thicker nerve fibres and produce anesthesia. It also blocks the specific potassium
ion channels and reduces potential depolarization for resting cell membranes.
 [Histamines and Antihistamines]

Histamines are widely distributed in animal tissues. Due to their wide spread occurance in
body tissue they are also term as tissue amines. Histamines are first isolated from liver in
1907. Histamines are found to be involved on diversified physiological process. They are
released in the body in response to the tissue injury, tissue inflammation and allergy. The
higher concentration of histamine is found on skin, intestinal mucosa, lungs, bone marrow or
the organs which are exposed to external environment. In the brain histamine is found on
significant amount. In living organism histamine is synthesis through enzymatic
decarboxylation of histidine [Alpha amino acid].

Histamines are stored on mast cells and blood basophils. An excess of antigens derived from
food products, pollens, dust mites, house dust, human hair or sheep wool may cause serious
allergic and anaphylactic manifestation in human being due to the release of histamines.
Releases of histamine give rise number of physiological actions which can be activated by
histamine H1 and H2 receptors. Some of histamines effects include dilation and enhance
permeability of capillaries with edema, vasodilation, cardiac acceleration and bronchial
constriction. The mild release of histamine in the body causes allergic reactions. Extreme
release may cause anaphylactic shock which may be fatal.

Anti-histamines or Histamine Antagonist: Anti-histamine are pharmaceutical drugs that

inhibit the action of histamine by blocking it from attaching to histamine receptor. H1 Anti-
histamines are used to treat symptoms of allergy such as runny nose and watery eyes. Allergy
is caused by Type I hypersensitive response to allergens such as pollens or dust particles. H1
anti-histamine is used to reduce local inflammation that results from various conditions such
as insect bites. Similarly, H2 antagonist such as cimetidine is widely used for treatment of
acid reflex and stomach ulcers as it decreases gastric acid production.
Classification of H1 antagonist:
1. Amino alkyl ethers: Diphenhydramine, Bromodiphen hydramine, Doxylamine succinate
2. Ethylene diamines: Mepyramine maleate, Tripelennamine, Zolamine
3. Thiophene derivatives: Methapyrilene, Thenyldiamine, Chlorothen citrate

4. Cyclic basic chain analogues:

a. Imidazoline derivatives: Antazoline
b. Piperazine derivatives: Cyclizine, Meclizine
c. Piperidine derivatives: Thenalidine tartrate
d. Non sedative anti-histamines: Terfenadine, Chlorpheniramine, Acrivastine, Pheniramine,
Loratadine, Cetirizine
e. Miscellaneous anti-histamines: Cyproheptadine

Diphenhydramine HCl: It is white crystalline

powder with bitter taste. It is soluble on water
[1:1], alcohol [1:2] and chloroform [1:2]. Its salt
form has PKa value of 9 and its 1% aqueous
solution has a PH value of 5. It slowly darkens on
exposure to light so it should be stored on well
closed light resistant container.

Metabolism: Diphenhydramine HCl is found to be well absorbed in the GI. After oral
administration, first pass metabolism is so predominant that only 40-60% reaches in systemic
circulation in almost unchanged form then remain metabolites undergoes N-demethylation
for twice a time for formation of 20 amine and 10 amine subsequently and finally undergoes
deamination to form carboxylic acid metabolites than conjugate with H1 receptors and
blocks the synthesis of histamine.
Mechanism of action: Antihistamines are drug which abolish the main action of endogenous
release of histamine in the body. They do not prevent the formation of histamines but act
probably by occupying the receptor in the infected cell for exclusion of histamine. Therefore,
diphenhydramine HCl acts as anti-allergic agent by more than one mechanism.
1. By pharmacological actions which are opposite to that of histamines.
2. By pharmacological reagents which prevent access of histamine to its receptors by
complete antagonism.

Therapeutical uses: It is frequently used in mild local allergic reactions due to insect bites.
It possesses sedative, emetic and anti-trussive properties so it can be used in seasonal allergic
rhinitis and allergic manifestation due to urticaria and allergic conjunctivitis of inhalant
allergens.

Synthesis:

Dose:
i. Oral: 25mg for 3 to 4 times daily
ii. IV or IM: 10mg for 3 to 4 times daily

Side effect: Most common side effect is drowsiness

Promethazine HCl: It is also known as tricyclic
antihistamine. It is white crystalline powder with
bitter taste. It is very soluble in water, hot
absolute alcohol and chloroform. Its aqueous
solutions are slightly acidic to litmus. On
prolonged exposure to light, it slowly gets
oxidized becoming blue in colour. Its solutions
are sterilized by autoclaving. It should be placed
in the containers on which air has been replaced
by nitrogen gas. It is incompatible with alkalis
and should be protected from light.

Uses:
⇒ Promethazine has prolonged antihistamine action but its effects are slow on onset.
⇒ It has pronounced sedative effects and has local anesthetic properties so it is use as
antiemetic and also use on formulation of various anti-trussive agents.
⇒ It also possesses some anticholinergic and anti-serotonergic properties. The salt of
promethazine base with 8 chloro theophylline is called promethazine theoclate [Avomine].
Avomine is mainly used as antiemetic in the treatment of motion sickness. It may also use in
postoperative vomiting, nausea and vomiting of pregnancy.

Metabolism: Promethazine is found to be well absorbed in GI. The peak optimum effects
invariably take place within 20 minutes after adequate oral, rectal, IV or IM administration.
Promethazine is metabolized primarily to promethazine sulphoxide and small quantity to
desmethyl promethazine. Peak plasma concentration of the sulphoxide metabolite occurred
earlier after oral administration than after intravenous administration.
Promethazine initially undergoes N demethylation for twice a time for formation of
2 amine and 10 amine subsequently then it undergoes deamination for formation of
0

carboxylic metabolites. Then inactive N quaternary glucuronide and sulphoxides metabolites

are form and excreted gradually in urine and faeces form. Similarly, remaining carboxylate
group conjugate with H1 receptors and inhibit the synthesis of histamines.

MOA:
⇒ The pharmacology of promethazine is complex. It is suggested that toxicity of
promethazine is mainly due to anticholinergic action in muscarinic receptors.
⇒ Promethazine acts by blocking H1 receptor site by preventing the action of histamine on
the cell.
⇒ Promethazine rapidly crosses the BBB and it is thought that the sedative effect of
promethazine is due to blockade of H1 receptor on brain.
⇒ The antiemetic effects of promethazine may be due to the blockade of dopaminergic
properties in the CTZ [Chemoreceptor Trigger Zone] of medulla.
⇒ Anti-motion sickness properties may be due to the central anti-muscarinic action.

Synthesis:

Dose: Oral: 20-50mg per day IV: 12.5-25mg within the interval of 4-6 hours
Side effects: Epigastric distress, drowsiness, sedation

Chlorpheniramine: It is second
generation non sedative anti-histamine
drug. Its salt form is white crystalline
powder. It is soluble in water [1:3],
alcohol [1:] and chloroform [1:10]. Its
Pka value is 9.2 and PH of its aqueous
solution lies between 4-5. It has faint
amine like odour and it should be
protected from heat and light. Its
solution is sterilized by autoclaving.
While store in containers the air should
be replaced by nitrogen gas.

Uses: This drug is widely used for formulation of anti-trussive agents. It is also used for
treatment motion sickness and Parkinson's diseases. It also acts as antiemetic agent in case of
vomiting due to liberation of histamines. Its dextro form is more active than Levo form.
Metabolism and MOA: The presence of alkyl amino group in the chloropheniramine create
shorter duration of action and causes less sedation action. Chlorpheniramine initially
undergoes N-demethylation for twice a time for formation of 20 amine and 10 amine
subsequently and finally undergoes deamination to form carboxylic acid metabolites than
conjugate with H1 receptors and blocks the synthesis of histamine.

Synthesis:
Dose:
⇒ Usual: 2-4mg, 3 or 4 times a day
⇒ IV or IM: 5-40mg according to requirement

Side effects:
⇒Common side effects: Drowsiness, Restlessness, Muscular twitching
⇒ Aderse effect: Respiratory failure

Pheniramine maleate: Pheniramine

maleate is white crystalline solid with faint
amine like odour. It is soluble in water [1:3]
and alcohol. It should be protected from
light. It is anti-histamine drug which has
less potent activity than promethazine. It
has short duration of action and causes less
sedation. It is marketed as recemic mixture.
Dextro form is more stable than Levo form.

Uses: It is use as anti-trussive and anti-emetic agent and also use for treatment of motion
sickness.

Metabolism and MOA: Pheniramine initially undergoes N-demethylation for twice a time
for formation of 20 amine and 10 amine subsequently and finally undergoes deamination to
form carboxylic acid metabolites than conjugate with H1 receptors and blocks the synthesis
of histamine.

Cyclizine HCl: It is white crystalline powder having

bitter taste. It is slightly soluble in water [1:15],
alcohol [1:15] and chloroform [1:75]. Its injection
form should be store on cold place because a yellow
tint may be developed if stored at room temperature.
It is used primarily in prophylaxis and treatment of
motion sickness. Its lactate form i.e. cyclizine lactate
is used for intramuscular injection.

Metabolism and MOA: Cyclizine initially undergoes N-demethylation for twice a time for
formation of 20 amine and 10 amine subsequently and finally undergoes deamination to form
carboxylic acid metabolites than conjugate with H1 receptors and blocks the synthesis of
histamine.

Dose: Oral or IM: 25-50mg in the interval of 4-6 hours

Inhibitor of Histamine Release:The anti-histamines act by occupying the receptor sites in
the effector cells for the exclusion of histamine. After discovery of broncho-dilating activity
of natural product such as bischromones it is found that bischromones are the compounds
that inhibit the release of histamines and other mediator of inflammation. For example,
Cromolyn sodium

Cromolyn sodium: Cromolyn

sodium belongs to complete noble
class of compound and bears no
structural relationship to other
commonly used anti-histamines. Its
salt form is hygroscopic and it is
found on hydrated white crystalline
powder. It is tasteless at first and later
on it become slightly bitter. It is soluble in water. Its Pka value is about 2.

Uses: It is used in prophylactic treatment of asthma. Cromolyn is not smooth muscle relaxant
or bronchodilator but it has antihistaminic or anti-inflammatory action. For bronchial asthma
and allergic rhinitis sodium cromolyn sodium is main drug for prophylaxis treatment in adult.
In order to cromolyn to act effectively it must be administered at least 30 minutes before
antigen challenge. This drug is administrated only by inhalation either alone or mixed with
small quantity of isoprenaline.

MOA: It works by preventing the release of substances in the body that cause inflammation.
It inhibits the release of histamines, leukotrienes and other potent substance from mast cells
during allergic response. Its action on mast cells is only after the sensitization stage and
before the antigen challenges. It does not seem to interfere with antigen-antibody reaction but
it seems to suppress the responses of this reaction.

Dose:
⇒Intra nasal: 5.2 mg on each nostril, 3 or 4 times daily at regular intervals
⇒ Ophthalmic: 1 drop of 2% to 4% solution, 4 to 6 times daily

Side effects: Dry throat, sneezing, stomach pain, vomiting, nausea, dizziness, watery eyes

Proton Pump Inhibitors: Proton pump inhibitors are groups of drug whose main action is
long lasting reduction of gastric acid production. They are inhibitors of acid secretion and are
also called as H2 antagonist. H2 antagonist drugs are used to block the action of histamine on
parietal cells in the stomach. These drugs decrease the production of acid and used in
treatment of dyspepsia. For example, cimetidine, Omeprazole, Ranitidine
MOA of Proton Pump Inhibitors: Proton Pump Inhibitors act irreversively by blocking
H + -K + Adenosine triphosphate [H + -K + ATPase] enzyme system found on gastric parietal
cells. Proton pump is terminal stage in gastric acid secretion which is directly responsible for
secreting hydrogen ion in the gastric lumen making it as ideal site for inhibiting acid
secretion. Proton pump inhibitors are given in inactive form. The inactive form is neutrally
changed or lipophilic in nature and they readily cross from cell membrane to intracellular
compartments that has acidic environment. Then inactive form of drug is protonated and
rearrange to active form and active form of drug will covalently and irreversively bind to
gastric proton pump and deactivate it.

Omeprazole: Omeprazole is white

crystalline powder. It is very slightly
soluble on water. It is amphoteric
compound and is acid labile so
omeprazole product is formulated as
delayed release capsule containing
enteric coated granules.

Uses: It is used to treat Gastro-esophageal reflux disease [GERD], Gastric ulcer, Duodenum
ulcer, Gastritis and Zollinger-Ellison syndrome [Formation of one or more tumors in
pancreas or on upper part of small intestine i.e. duodenum]. It is also used in combination
with antibiotics like amoxicillin or metronidazole for the treatment of H. Pylori.

Metabolism: The absorption of omeprazole takes places in small intestine and usually
completed in 3-6 hours. The systemic bioavailability of omeprazole after repeated dose is
60%. Its bioavailability can be significantly impaired by presence of food so patient should
be advice to take omeprazole with glass water on empty stomach. Plasma portion binding is
about 95%. It is completely metabolized by Cyt P450 mainly on liver and is converted to
sulfone, sulfide and hydroxy omeprazole metabolites. These metabolites exert no significant
effect on acid secretion. About 80% of orally given dose is excreted as metabolites in urine
and remaining metabolites are excreted from feces. The drug has plasma half- life of 1 hour.
A secretory action persists for 24-72 hours after the drug disappeared from plasma.

MOA: It is selective and irreversible proton pump inhibitors. It suppresses gastric acid
secretion by inhibition of H + -K + Adenosine triphosphate [H + -K + ATPase] enzyme system
found at secretory surface of parietal cells. It inhibits the final transport of H+ ions into
gastric lumen. Since its H + -K + ATPase enzyme system is regarded as the acid pump enzyme
system of gastric mucosa. Omeprazole is known as gastric acid pump inhibitor. The
inhibition effect is depended upon on its dose.
Dose:
⇒ Duodenal ulcers: 20mg once a day before meal
⇒ Gastric ulcers: 20 mg orally once a day
⇒Zollinger-Ellison syndrome: 60mg orally once a day and also can increased up to 120mg
for 3 time daily
⇒ GERD: 20 mg once a day for 4 to 8 weeks and also can increased up to 40mg per day if
necessary

Side effects: Diarrhoea, Dizziness, Confusion, Fast heartbeat, Muscle cramps, Stomach pain
and Various allergic reactions

Cimetidine: Cimetidine is white crystalline

powder. It is slightly soluble in water, alcohol
and chloroform while insoluble on ether. It is
clinically used first H2 blocker. It is used for
treatment of Duodenal ulcers, Gastric ulcers,
Gastro-esophageal reflux disease [GERD],
Gastric hyper-secretory disorder and dyspepsia.

Mechanism and MOA: Same as Omeprazole

Dose:
⇒ Duodenal ulcers: 800mg at bed time or 300mg for 4 times in a day
⇒ Gastric ulcers: 800mg at bed time or 300 for 4 times in a day
⇒ Regimen for GERD: 400mg for 4 times in a day
⇒ Heart burn: 200mg for single or twice a day

Side effects: Constipation, Diarrhoea, Insomnia, Muscle pain and Various allergic reactions
 [Analgesic Agents]

I. Anti-inflammatory Analgesics: Anti-inflammatory agents are the drugs used to reduce

inflammation and pain. There are two types of Anti-inflammatory agents:
1. Steroidal Anti-inflammatory drugs
2. Non-Steroidal Anti-inflammatory drugs

Steroidal Anti-inflammatory drugs Non-Steroidal Anti-inflammatory drugs

[SAID]
They have steroidal ring. Steroids have three
six-sided carbon ring and one five-sided
carbon ring.
They have more narcotic properties as
compared to NSAID.
They are less effective than NSAID.
SAIDS produce severe side effects such as
immunosuppression and hypertension.
[NSAID]
They lack steroidal ring.
They have fewer narcotic properties as
compared to SAID.
They are more effective than SAID.
NSAIDS produce minor side effects such as
nausea, vomiting or allergic reactions.

Non-Steroidal Anti-inflammatory drugs [NSAID]: They are the drugs with antipyretic,
anti-inflammatory and analgesic properties. NSAIDS are also used for treatment of arthritis,
headache, fever and gout.

Classification of NSAID:
A. Nonselective COX inhibitors:
1. Salicylic acid derivatives: Aspirin, Sodium salicylate
2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen
3. Anthranilic acid derivative: Mephenamic acid
4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac
5. Oxicam derivatives: Piroxicam, Tenoxicam
6. Indole derivative: Indomethacin.
7. Pyrazolone derivative: phenylbutazone, Oxyphenbutazone
B. Preferential COX-2 inhibitors: Nimesulide, Nabumeton
C. Selective COX-2 inhibitors: Celecoxib, Parecoxib.
D. Analgesic-antipyratics with poor anti-inflammatory action:
1. para aminophenol derivatives: Paracetamol
2. Pyrazolone derivative: Metamizol, Propiphenazone
3. Benzoxazocine derivative: Nefopam
MOA of NSAID: Prostaglandins which are produced by cells of body promotes
inflammation, pain and fever and also support for blood clotting function and protect the
lining of stomach from the damaging effects of the acids. COX I and COX II both enzymes
produced prostaglandins that promote pain, fever and inflammation. Therefore, NSAID are
given to blocks the COX enzymes to reduce prostaglandins throughout the body than pain,
fever and inflammation symptoms will be reduces. Similarly, prostaglandins that support
blood clotting and protect the lining of stomach from the damaging effects of the acids will
also be reduce which may cause bleeding and ulcer of stomach.

Aspirin: It is the derivatives of salicylic acid. It has been used in medicine for its analgesic,
antipyretic and anti-inflammatory action.

Physiochemical properties: It occurs as white odorless crystalline powder with slightly

bitter taste. It is slightly soluble in water, alcohol, chloroform and ether. It is also dissolved
easily on glycerin. It is stable in dry air but gradually hydrolysis in contact with moisture into
acetic acid and salicylic acid. It should be stored on air tight closed container.

Uses:
1. As analgesic and antipyretic agent: Aspirin is used in mild to moderate pain of
musculoskeletal system such as headache, toothache, myalgia, dysmenorrhea and backache.
It is also used in symptomatic treatment of fever.

2. As anti-inflammatory agent: Aspirin commonly used to treat inflammatory conditions

such as asthma. 3. As anti-rheumatic agent: Aspirin administer in sufficiently large dose
produce dramatic relief of sign and symptoms of inflammation in acute rheumatic fever.

4. As antiplatelet agent: Aspirin is used to prevent formation of platelet fibrin thrombus. In

lower dose it has been recommended as prophylactic for the prevention of heart attacks.

5. Aspirin has also been found useful in reducing erythema due to sunburn.
6. In local application it has shown mild antiseptic and antifungal properties.
Dose:
⇒ For relief from minor aches and mild to moderate pain: 325-650mg within every four
hours
⇒ Antiplatelet dose: 75-150mg per day

Synthesis:

Sodium salicylate: Sodium salicylate is non-steroidal analgesic

and anti-inflammatory agent. It is also salicylic acid derivative. It
is colourless crystalline powder and is odourless or has faint
characteristics odour with sweet saline test. It is soluble in water,
alcohol and chloroform but insoluble in ether. Its concentrated
aqueous solution is liable to deposit crystals of hexahydrate on
standing. It should be stored on air tight closed container and
protected from light.

Uses: Sodium salicylate has been used in musculoskeletal and joint disorders and rheumatic
fever. It has also been used in postoperative dental pain and symptomatic therapy of gout. It
is usually administered with sodium bicarbonate to reduce gastric distress.

Methyl salicylate: Methyl salicylate It occurs as a colourless or

pale-yellow liquid with characteristics aromatic odour. It is
soluble in water and miscible with alcohol and chloroform. It is
stored from light. As it gets readily absorbed through skin, it is
applied in liniment or ointment for relieving pain of rheumatic
conditions.
Ibuprofen: It is propionic acid
derivative compound.
Ibuprofen is a white
crystalline powder with
characteristics odour. It is
practically insoluble in water
solution but soluble on
alcohol, chloroform, ether,
acetone and aqueous alkali hydroxide solution. It is stored in well closed container.
Ibuprofen is an analgesic, antipyretic and anti-inflammatory drug. It is employed for
treatment of postoperative pain, rheumatic pain, migraine, dysmenorrhea and osteoarthritis.

Synthesis:

Dose:
⇒ Dysmenorrhea: 200 to 400mg for 4 to 6 times per day
⇒ Rheumatoid arthritis: 300 t0 400mg for 3 to 4 times per day

Mefenamic acid: It occurs as white crystalline

powder with characteristics odour. It is practically
insoluble in water solution but slightly soluble on
alcohol. It is stored in well closed container. It is
usually indicated for the treatment of dysmenorrhea,
menstrual pain and pain due to dental extraction.
Indomethacin: Indomethacin is white or yellow
crystalline powder which is odourless and has
bitter taste. It is insoluble in water solution but
slightly soluble on alcohol. When its alcoholic
solution is treated with sodium hydroxide
solution, it gives deep yellow colour which
changes to greenish yellow and finally becomes
pale yellow. It is stored in well closed container.

Uses: It is used for treatment of Rheumatic arthritis, osteoarthritis, acute gout, dysmenorrhea
and acute muscle skeletal disorders such as neck pain, myalgia and lumbago.
Paracetamol [Acetaminophen]: It occurs as white odourless
crystalline powder with bitter taste. It is soluble on alcohol, water
and chloroform while insoluble in petroleum ether. When it is
treated with ferric chloride, it gives violet blue color. It is stored
in well closed container. Its dose is about 325-650mg on every 4
hours. It is given orally 200mg twice a day.

Uses:
i. As antipyretic
ii. As analgesic for relief of pain such as headache, toothache, neuralgia, rheumatism,
osteoarthritis, acute gout, dysmenorrhea and acute muscle skeletal disorders such as neck
pain, myalgia and lumbago.

Nimesulide: It is selective COX-2 inhibitor and used as

analgesic and anti-inflammatory agent. It is sulfonamide
compound. It occurs as yellowish crystalline powder. It is
soluble on acetone and anhydrous ethanol while insoluble
in water. It is stored in well closed container and protected
from light. It has analgesic, antipyretic and anti-
inflammatory properties. It is employed for treatment of
postoperative dental pain, rheumatic pain, sprains,
dysmenorrhea and osteoarthritis.

Piroxicam: It is an oxicam derivative compound. It

occurs as white or light yellow odourless crystalline
powder. It forms monohydrate compound which is
yellow on colour. It is slightly soluble in water, dilute
acids, alcohol and aqueous alkaline solutions while
freely soluble on methylene chloride. It is stored in
well closed container and should be protected from
light.
Uses: It has analgesic, antipyretic and anti-inflammatory properties. It is employed for
treatment of postoperative dental pain, rheumatic pain, ankylosing spondylitis and
osteoarthritis.

Dose: Orally 20mg per day

Phenylbutazone: It occurs as white odourless

crystalline powder. It is tasteless at first time
which becomes bitter after taste. It is slightly
soluble in water while freely soluble in ether,
acetone and alcohol and in solution of alkaline
hydroxide. It is stored in well closed container
and should be protected from light.

II. Narcotic or Opioid Analgesics: Narcotic or Opioid Analgesics are those drugs which
provide relief from pain due to the depression of central nervous system. They are act on
opioid receptors. Since most of them induce sleep so they are referred as narcotic analgesics.

Classification of Narcotic or Opioid Analgesics:

1. Natural narcotic analgesics: Morphine, Codeine, Noscapine
2. Semi synthesis narcotic analgesics: Heroine, Dihydroxymorphinone, Pholcodine
3. Synthetic narcotic analgesics: Pethidine, Fentanyl, Methadone, Tramadol

Morphine: It is obtained from papaver somniferum plant.

It is phenanthrene derivative. It is a solid compound having
melting point of 2540 C. Natural morphine is Laevorotatory
with a specific rotation of -1310 . It is soluble in ethanol,
ethyl acetate and diethyl amine while insoluble in water
and benzene. It gives ferric chloride test for phenols due to
the presence of phenolic hydroxyl group. It dissolves in
aqueous sodium hydroxide to give mono-sodium salt.

Therapeutic uses:
i. It is used for symptomatic relief of moderate to severe pain associated with cancer and for
post-operative pain.
ii. It is also used as hypnotic when sleeplessness is due to pain.
iii. It helps to reduces intestinal motility and also used in treatment of myocardial infarction,
fracture of bones, burns and pleurisy.
iv. It is also indicated for suppression of cough and relief of anxiety.
v. It is also given as premedication before surgery.
Mechanism of action:
⇒ Morphine exerts its action by interacting with kappa receptor of opioids receptors.
⇒Opioids receptors are coupled with inhibitory G proteins which are responsible for closing
of voltage sensitive calcium channels.
⇒ Then there will be stimulation of potassium efflux which leads to hyperpolarization and
there will be reduced on cyclic adenosine monophosphate [cAMP] production.
⇒ Thus, there will be decrease on release of excitatory transmitters from nociceptive nerve
terminals and in the spinal cord and lead to reduce on pain.

Metabolism:
⇒ Morphine is generally metabolized by conjugation with glucuronide.
⇒ Morphine conjugate at 6 position yield Morphine 6-glucuronide which is more active as
an analgesic than morphine whereas the conjugate at the 3-position yield inactive compound.
⇒ Morphine glucuronides are excreted in the urine.
⇒ The duration of action of morphine is 4 to 6 hours.

SAR of Morphine:

1. Physiological activity of morphine is attributed in the presence of phenanthrene skeletal.

2. Conversion of 3-OH to 3-CH3 yield codeine which reduces drug activity to 15% of
morphine.

3. Conversion of 6-OH to 6-CH3 yield heterocodeine which increases drug activity by six
times of morphine.
4. If the alcoholic hydroxyl group is oxidized to ketone functional group than activity of
morphine increases and toxicity also get increases.

5. When phenolic hydroxyl of morphine is masked than activity of drug will decreases.
6. If the alcoholic hydroxyl group at C6 is shifted to C8 position than activity of morphine
decreases.
7 Cleavage of 4,5 oxygen bridge and substitution of the aromatic ring lower the activity of
morphine.
8. If the both phenolic and alcoholic hydroxyl groups are acetylated, it forms heroin
compound which is powerful analgesic and is more addicting than morphine.

9. Substitution of alcoholic hydroxyl group by chlorine tends to increase the potency of

morphine by three times.
10. When hydroxyl group at C6 is substituted by hydrogen (Dihydrodesoxymorphine) then
potency of morphine is increased by ten times.

11. Substitution of phenyl ethyl group in place of methyl group on nitrogen (N-CH3 ) tends to
increase the potency of morphine.
12. Substituting the aromatic hydroxyl group by an ethyl group gives ethyl morphine which
is potent as morphine and is used as eye drop.
13. Reduction of 7,8 double bond result in slight increase in the activity of drug as in
dihydromorphine and dihydrocodeine.

Codeine: It is naturally occurring opium alkaloid. Its activity

is similar to morphine but it is weaker as compare to
morphine. It is given orally. Codeine is used as sulphate and
phosphate form. Both salts occur as white crystalline powder.
They are soluble on water while insoluble in chloroform and
ether. They effloresce on dry air and are affected by light
therefore they should be stored on light resistant container.

Therapeutic uses:
i. To suppress cough iii. To treat diarrhea
ii. To suppress mild to moderate pain iv. As sedative and hypnotic

Synthesis of codeine from Morphine:

Synthesis of codeine from L-Tyrosine:
Pethidine [Meperidine]: It is piperidine derivative. It is a
synthetic opioid analgesic with properties similar to
morphine but it has more rapid onset of action and shorter
duration of action. Officially it is used as hydrochloride salt
which occurs as white crystalline powder. It is odourless
and has bitter taste. It is soluble on water, alcohol and
chloroform while slightly soluble in ether. When it is
treated with formaldehyde in presence of sulphuric acid
then it gives orange red colour. It is affected by light therefore it should be stored on light
resistant container.

Therapeutic uses:
i. To relieve from moderate to severe pain due to spastic conditions of intestine, uterus,
urinary bladder and bronchi.
ii. As preanasthetic medication
iii. As an obstetrical analgesic (analgesic during labour)
iv. To relieve from abstinence syndrome (treatment of morphine addiction)

Dose: Usual dose is 50 to 100mg given through IM but occasionally given also by oral route

Pentazocine: It is a synthetic opioid analgesic

with both agonist and antagonist activity and is
administered orally or by injection or rectally for
control of severe pain It occurs as white
odourless crystalline powder. It melts at about
1500 C to 1550 C. Its hydrochloride salt is soluble
in water, alcohol and chloroform while insoluble
in ether. It is affected by light therefore it should
be stored on light resistant container.

Therapeutic uses:
i. To relief of moderate to severe pain
ii. Has low dependence producing properties compared to morphine

Dose:
⇒ IM dose: 30-60mg
⇒ Oral dose: 50-100mg
Fentanyl citrate: It occurs as white odourless crystalline powder. It is freely soluble on
water and methanol and slightly soluble on chloroform. It is affected by light therefore it
should be stored on light resistant container. It has rapid onset of action i.e. 4 minutes and
short duration of time.

Therapeutic uses:
⇒This is noble anilide derivative with 80 times more analgesic activity than that of
morphine.
⇒ It is used primarily used as adjuvant with nitrous oxide for use on neuroleptanalgesia
[An intense analgesic and amnesic state produced by administration of narcotic analgesics
and neuroleptic drugs].
⇒ It is also available as transdermal release for management of chronic pain.

Dose: 0.05 to 0.1mg before surgery and 0.5 to 0.1mg for rapid analgesic action

Narcotic Antagonist: Narcotic drug are the addictive drugs such as opium that reduces pain,
alter mood and behavior and usually induces sleep. Narcotic Antagonist are those drugs used
to counteract the effects of narcotics agonist especially for depression of respiration.

Naloxone: Naloxone HCl occurs as white crystalline

powder. It is hygroscopic in nature. It is freely soluble
in water. It should be stored on light resistant container.

Therapeutic uses: It blocks or reverses the effects of

opioid medication including extreme drowsiness,
slowed breathing or loss of consciousness. It is useful
both in acute opioid overdose and in reducing
respiratory or mental depression due to opioids. It can
also be used as an antidote in overdose of clonidine.
Mechanism of action: Naloxone specifically antagonizes the opioid effect such as
respiratory depression, psychometric effects and pupillary constriction by means of
competitive action on the receptor sites and this drug usually disappear from the serum in
rapid fashion. After IV administration it is distributed in the liver primarily by glucuronide
conjugation and ultimately excreted in the urine. It is not orally active due to first pass
metabolism. Because of its short duration of action it is necessary to administer this drug on
multiple dosing systems.

Dose: 0.4mg by parental route

III. Antitussive agents: Antitussive agents are those drugs which are employed for control
the cough by depressing the cough center strategically situated on the medulla. Several
analgesics such as codeine, ethylmorphine, dimorphine are also used as antitussive agents.
Some of the antitussive agents are as Noscapine, Dextromethorphan, Terpin hydrate

Classification of Antitussives drugs:

1. Centrally acting antitussives: These drugs reduce cough as a result of their central
action. They depress the area of the CNS which controls the cough reflex. They are mainly
useful in the symptomatic relief of dry irritant type of cough. These include opoids like
codeine and Pholcodeine and non opoids like Dextromethorphan and Noscapine

2. Central as well as peripherally acting antitussive: Benzonatate is the antitussive agent

structurally related to local anesthetic tetracaine. It not only inhibits afferent cough impulse
to suppress the central cough center but also inhibits pulmonary stretch receptors therefore it
has both central as well as peripheral cough center.

3. Peripherally acting antitussives: These agents act peripherally in the respiratory tract to
reduce the impulses which stimulate the cough center. Ex: Prenoxidiazine

Noscapine: It is tasteless white crystalline powder. It is insoluble in water while freely

soluble on chloroform, acetone and benzene and slightly soluble on alcohol and ether. It is
also used as hydrochloride salt which is freely soluble in water and hygroscopic on nature. It
should be stored on light resistant container.

Therapeutic uses: It is employed in the control and management of cough due to bronchial
asthma and pulmonary emphysema. It remarkably reduces both frequency and intensity of
paroxysm. It also possesses weak bronchodilator and stimulates respiration. Noscapine
should not be given with warfarin because anticoagulant effect of warfarin is drastically
increased by noscapine which may leads to fatal thinning of blood.
MOA: Noscapine antitussive effects appear to be
mediated by its σ receptor agonist activity
Pretreatment with Rimcazole [σ specific antagonist]
causes a dose dependent reduction in antitussive
activity of noscapine. It is suggested that noscapine
is centrally acting antitussive agents which inhibits
bradykinin formation by antagonizing bradykinin
receptors. Its mode of action is supposed to be
induced by angiotensin converting enzymes.

Dose: 15 to 30mg foe 3 to 4 times a day

Dextromethorphan: It is morphine synthetic

derivatives used as antitussive agent exclusively. It
occurs as odorless white to slightly yellow crystalline
powder. It is freely soluble in chloroform while
insoluble on water. It is commonly used as hydro
bromide salt. It should be stored on light resistant
container

Therapeutic uses: It has report that dextromethorphan possess cough suppressant potency
nearly to one half of codeine.

MOA: It decreases the sensitivity of cough receptor and interrupts cough impulse
transmission by depressing the medullary cough center through the σ receptor stimulation.

Dose:
⇒Adult oral dose: 10mg to 30mg for 3 to 4 times a day
⇒ Children [6-12 year] dose: 2.5mg to 5mg for 6 times a day
⇒ Children [3-6 year] dose: 1.25mg to 2.5mg for 3 to 4 times a day

Side Effects: Nausea, Dizziness, Gastrointestinal disorder, Blurred vision

Terpin hydrate: It occurs as colorless or white crystalline powder. It

has slight odour and it efflorescent in dry air. It can dissolve on water,
alcohol, chloroform and ether. Anhydrous terpin hydrate has melting
point of 104.70 C but terpin hydrate melts between 115-1170 C. It is
frequently used as expectorant in bronchitis in combination with other
component such as dextromethorphan hydrochloride and codeine
phosphate to suppress cough.
 [Eicosanoids and Prostaglandins]

Eicosanoids: It is the collective term for oxygenated derivatives of three different 20 carbon
containing essential fatty acids. These three fatty acids are Linoleic acid, Linolenic acid and
Arachidonic acid. The major three examples of eicosanoids are:
1. Eicosapentaenoic acid [EPA] or ω3 fatty acid with 5 carbons double chain
2. Arachidonic acid [AA] or ω6 fatty acid with 4 carbons double chain
3. Dihomo gamma linolenic acid [DGLA] with 3 carbons double chain

Eicosanoids are known as super hormone because they affect the synthesis of every other
hormone on the human body. Eicosanoids are derived from ω3 fatty acid or ω6 fatty acid.
An ω6 Eicosanoids are more pro-inflammatory than ω3 eicosanoids. Eicosanoids are also
called as cellular check and balance system. The amount of balance of the fats in person diet
will responsible for the eicosanoids control function on body. An imbalance of eicosanoids
can be responsible for allergies, asthma, heart attack, high blood pressure, cancer, depression,
chronic infection and Alzheimer disease.

There are four families of eicosanoids:

1. Prostaglandins [PG]
2. Prostacyclins [PGI]
3. Thromboxanes [TX]
4. Leukotrines [LT]

⇒ Prostaglandins are medication of inflammatory and anaphylactic reaction.

⇒ Prostacyclines are active on resolution of inflammation.
⇒ Thromboxanes are mediators of vasoconstriction.
⇒ Leukotrines are fatty signaling molecules. They are found to be used on both autocrine
and paracrine signaling to regulate body response.

Prostaglandins: They are unsaturated carboxylic acid consisting of 20 carbon skeleton with
five member ring. They are biochemically synthesis from arachidonic acids.
Nomenclature of Prostaglandins: Structurally PG are derived from prostanoic acid having
cyclopentane ring with two side chains attached to adjacent carbon 8 and 12.

Classification of PG is based on:

1. Cyclopentane ring:

2. In the nature of side chain:

3. Nature of configuration: Sometimes PGE can be converted to PGF by reduction in C9

position.

Prostaglandin F2𝛂: It is naturally occurring prostaglandin

used in medicine to induce labour and use as abortifacient. It
is used in treatment of Hydatidiform mole (tumor of uterus).
Its half-life time is 3-6 hours in amniotic fluid while less
than one on plasma level. It is given by IV to induce labour
and by intra-amniotic to induce abortion.
It is group of hormone like substance that support for wide range of body function such as:
⇒ Relaxation and contraction of smooth muscle
⇒ Dilation and constriction of blood vessels
⇒ Control of blood pressure
⇒ Resolution of inflammation
⇒ Constriction of uterine and bronchial smooth muscle

Dosage form: 5mg/ml ampule

Side effects: Bronchial spasm, Hypoxia, Abdominal cramps, Diarrhoea, vomiting

Prostaglandin E1: It is naturally occurring

prostaglandin. It is particularly used in maintaining
potent ductus arteriosus in infants with congenital
defects that restricted the systemic or pulmonary blood
flow. It relaxes smooth muscle of ductus arteriosus
producing vasodilation. It inhibits platelets aggregation
and stimulation of intestinal and uterine smooth muscle.
It induces erection by relaxation of trabecular smooth muscle by dilation of cavernosum
arteries. It is administered intravenously continuously at a rate of approximately to
0.1μg/kg/min to temporarily maintain the potency of potent ductus arteriosus until corrective
surgery can be performed.

Dose: For congenital heart disease: 100μg/kg/min

Side Effects: Low blood pressure, Diarrhoea

Prostaglandin E2: It is naturally occurring

prostaglandin used in labour for softening the
cervix and causes uterine contraction. It is also
used to stimulate bone reabsorbing activities
through osteoblasts. It also induces fever like other
PG and also used as abortifacient. It also causes
vasodilation on smooth muscle and also inhibits
the release of nor-adrenaline from sympathetic
nerve terminal. It does not inhibit platelets aggregation. It works by binding and activating
PGE2 receptors. PGE2 is released by blood vessels wall in response to infection or
inflammation that acts in a brain to induce fever. It is administered by dose of 20mg by
vaginal suppository.
MOA of Prostaglandins: Many of the actions of prostaglandins are mediated by their
binding to a wide range of distinct cell membrane receptors that operates through G protein
which subsequently activate or inhibit adenylyl cyclase or stimulate phospholipase C. This
causes an enhanced formation of diacylglycerol and inositol 1,4,5 triphosphate.
Prostaglandin F2α, Leukotrines and thromboxanes A2 mediate certain action by activating
phosphatidylinositol metabolism and causes an increase of intracellular calcium level.

Uses of Prostaglandins:
⇒ To induce childbirth or abortion [PGE2 or PGF2]
⇒ To prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart
defects (PGE1)
⇒ To prevent and treat peptic ulcers [PGE]
⇒ As a vasodilator in severe Raynaud's phenomenon or ischemia of a limb
⇒ In pulmonary hypertension
⇒ In treatment of glaucoma with ocular hypotensive activity [PGF2α]
⇒ To treat erectile dysfunction [PGE1]
⇒ As an ingredient in eyelash and eyebrow growth beauty products due to side effects
associated with increased hair growth

Role of Prostaglandins in platelet homeostasis: TXA2 is produced by activated platelets. It

promotes adherence and aggregation of circulating platelets and contraction of vascular
smooth muscle and finally promotes formation of blood clots (thrombin). Prostaglandins
[PGI2] produced by vascular endothelial cells inhibits platelets aggregation and stimulates
vasodilation and create obstruction on thrombogenesis. The opposing effects of TXA2 and
PGI2 limit thrombin formation to the sites of vascular injury.
Oxytocin: These are drugs which stimulate the smooth muscle of uterus. It is mammalian
hormone and acts primarily as neuromodulator in the brain. Oxytocin is best known for its
role in female reproduction. It is released in large amount after distention of cervix and
uterus during labour. It is also released during breast feeding. Recently it is studies that
oxytocin has role in various behaviour such as orgasm, social recognition, anxiety and
maternal behaviour. Oxytocin is also referred as Love Hormone.

Biochemical structure: Oxytocin is a cyclic peptide of nine amino acids secreted by

posterior lobe of pituitary gland.

Cys = Cysteine Tyr = Tyrosine

Ile = Isoleucine Gln = Glutamine

Asn = Asparagine Pro = Proline

Len = Leucine Gly = Glycine

Uses:
⇒ Oxytocin is used as in injection form and it is sterilized by filtration and distributed
aseptically in sterile container which is than seal properly. The biologically active form of
oxytocin is commonly measured by RIA [Radio Immune Assay] or by HPLC.
⇒ Oxytocin injection should be stored in cool place but should not be allowed to freeze. The
label in oxytocin injection should be state the potency of drug, number of units per ml and
date after which the contents are not intended to be used.
⇒ Oxytocin stimulates both the frequency and force of contraction of uterine smooth muscle.
It also stimulates the modified smooth muscle (myoepithelium) or mammary glands and
causes milk ejection.
⇒ Oxytocin also used for induction and maintaining of labour and to control postpartum
hemorrhage.

MOA: Oxytocin has peripheral hormonal action and also has an action on brain. The actions
of oxytocin are mediated by specific high affinity oxytocin receptor known as OXTR.
OXTR is G-coupled protein receptor which functions as receptor for hormones and
neurotransmitter. The oxytocin receptor required magnesium and cholesterol for their proper
functions.
Peripheral action of oxytocin:
1. Lets down reflex i.e. release of milk in lactating mother
2. Uterine contraction i.e. cervical dilation before birth
3. Increased plasma oxytocin at orgasm
4. Recently intranasal administration of oxytocin was found to increase emotions recognition
in children 6. Increase trust and reduce fever

Action within the brain: Oxytocin secreted from pituitary gland cannot enter the brain
because of Blood Brain Barrier. However, the behavioral effects of oxytocin are thought to
be reflecting from centrally projecting neurons.

Metabolism: Oxytocin is destroyed in GI tract so it is administered by injection or by nasal

spray. It has half-life of 3 minutes in the blood in the significant quantities. It is excluded
from the brain by blood brain barrier. Oxytocin nasal spray has been used to stimulate breast
feeding.

Side Effects:
⇒ Increase on heart rate
⇒ Decreased on blood pressure
⇒ Hypersensitive conditions such as vomiting and nausea
⇒ Anaphylaxis

Dose:
For induction of labour
⇒ Initial dose should be 0.5-1milli units through IV on time interval of 30-60 minutes.
⇒ It can also be gradually increased from 1-2milli units until desired contraction is obtained.