classification sar propertis mechanism of action and uses

1. PARASYMPATHO MIMETICS DRUGS
OBJECTIVES
> INTRODUCTION
> BIOSYNTHESIS, STORAGE AND RELEASE OF ACETYLCHOLINE
> ACETYLCHOLINE RECEPTORS (MISCARININS, NICOTINIC)
> PARASYMPATHO MIMETIC DRUG CLASSIFICATION
> SAR OF PARASYMPATHO MIMETIC DRUGS
> PARASYMPATHOMIMETIC DRUGS AND THEIR PROPERTIES
> ACETYLCHOLINESTERASE INHIBITORS
> QUESTIONS
INTRODUCTION:
Autonomic nervous system is divided into two parts
1. SYMPATHETIC
2. PARASYMPATHETIC
Parasympathetic nervous system also known as cholinergic nervous system. Acetylcholine is a
neurotransmitter which propagates nerve impulse transmission in the parasympathetic nervous system.
Cholinergic neurotransmitter:
O
©
CH3—C—O—CH2—CH2— N-
Acetyl choline
CH3
-CH3
'CH3
It is an ester of acetic acid choline. In the rain it acts as a neuromodulator and as a neurotransmitter.
BIOSYNTHESIS, STORAGE AND RELEASE OF ACETYLCHOLINE
Synthesis of acetylcholine is done by cholinergic neurons. Acetylcholine is synthesized by choline and
acetyl coenzyme A. choline synthesized in the liver by the reaction between serine and ethanolamine.
The biosynthesis of acetylcholine (Ach) depends on the uptake of choline via sodium dependent carrier.

2. STORAGE AND RELEASE OF ACETYLCHOLINE:
❖ The highly polar choline is taken up in to the axoplasm by the specific choline transporters.
❖ The newly formed Ach is loaded in to the storage vesicles by the vesicular Ach transporters.
❖ Each storage vesicle contains about 1000 to 50000 molecules of Ach. Large amount of Ach is also
present in extravascular cytoplasm.
❖ Ach is transported in to the storage vesicle by a carrier which can be inhibited by a chemical agent
called vesamicol.
RELEASE OF ACETYLCHOLINE: Ach is stored in vesicle along with other potential co transmitters
such as ATP. Release of Ach and co-transmitters occurs following depolarization of the membrane, which
allows the entry of ca2+ through voltage dependent ca2+ channels. During activation of nerve membrane,
ca2+ is enters the axoplasm through voltage gated channels and to active. Protein kinase that
phosphorylates synapsis. As a result, vesicles close to the membrane are detached from their anchoring and
allow to fuse with presynaptic membrane. During fusion, vesicles discharge their contents in to the
synaptic gap and simultaneous insert specific choline-transporter CHT in to the plasma membrane. Ach
quickly diffuses and exocytosis through the synaptic gap. Ach is rapidly hydrolyzed and inactivated by
specific enzyme Acetyl cholinesterase localized and soluble enzyme present in serum and interstitial fluid.

3. Catabolism of acetylcholine: After the release of Ach rapidly hydrolyzed by cholinesterase and its forms
choline and acetic acid.
Acetylcholine ^ choline + acetic acid
ACETYL CHOLINE RECEPTORS (MUSCARINIC, NICOTINIC):
MUSCARINIC RECEPTORS: These receptors belong to the family of g protein coupled receptors which
activates other ion -channels. Ach when binds to muscarinic receptors it causes conformational changes in
the receptor, causes activation of an intracellular G-protein which intracellular events.
Muscarinic receptors are of five types:
1. M1: present in autonomic ganglia, gastric gland and in the CNS. It causes depolarization, histamine
release and acid secretion.
2. M2: present in the heart. It decreases velocity of conduction and also decreases the strength of
contractility.
3. M3: present in the smooth muscles of blood vessels and of the lungs. It causes contraction of
smooth muscles and release of (nitrous oxide) NO to produce vasodilation.
4. M4: present in the CNS and heart has no significantly clinical effects.
5. M5: present in the CNS and no clinical effects produced by this type of receptors.
Nicotinic receptors:
Nicotinic receptors inotropic receptors which is linked to ion channels. Nicotinic receptors are activated by
nicotine and blocked by d-tubacurarine. This receptors causes depolarization and generation of action
potential. Nicotinic receptors are two types:
1. Muscle type nicotinic receptor (Nm): located in the skeletal neuromuscular junction. Causes
muscle contraction
2. Neuronal type nicotinic receptors (Nn): located in the adrenal medullary cells. It produces
excitatory functions and secretion of catecholamines.
PARASYMPATHO MIMETIC DRUG CLASSIFICATION
Para sympatho mimetic drugs which mimic the action of acetylcholine. These drugs classified on the basis
of their direct and indirect action on the acetylcholine receptor.

4. Direct acting Para sympathomimetic drugs (reversible): This drug directly binds to nicotinic and
muscarinic receptors and causes excitation of cholinergic system.
Indirect acting Para sympathomimetic drugs (irreversible): This drug inhibits the hydrolysis of
acetylcholine by inhibiting cholinesterase and hence increases the life of acetylcholine and causes increased
concentration of Ach at the receptor site to produce excitation of cholinergic system.
CHOLINERGIC AGONISTS:
CHOLINE ESTERS: ACETYL CHOLINE, METHACHOLINE, CARBACOL,
BETHANICOL
ALKALOIDS: MUSCARINE, PILOCARPINE, ARECOLINE
,-ANTICHOLINE ESTERASES:-
^-REVERSIBLE-^
CARBAMATS ACRIDINE
PHYSOSTIGMINE TACRINE
PYRIDOSTIGMINE
NEOSTIGMINE
ENDROPHONIUM
RIVASIGMINE
GALANTAMINE
IRRIVERSIBL
T
ORGANOPHASPATES
DYFLOS, ECHOTHIOPHATE
PARATHION, MALATHION
DIAZINON, TABUN, SARIN, SONAM
CARBAMATES
CARBORYL
PROPAXU
CHOLINESTERASE REACTIVATOR: PRALIDOXIME CHLORIDE

5. SAR OF PARASYMPATHO MIMETIC DRUGS:
Acetylcholine is the prototype drug in the category of directly acting Para sympathomimetics.this drug gets
rapidly hydrolyzed by the enzyme acetyl cholinesterase.
A large number of modifications has been made to synthesize new derivatives which are more selective
and have longer duration of action.
1. The quaternary ammonium gourp is required as it helps in binding to the cholinergic receptors.
The replacement of ammonium group by other onium groups like sulphonium or phosphonium
cusses loss of activity.
2. The methyl group of quaternary ammonium group can be replaced by larger alkyl group. For
example dimethyl ethyl derivative of acetylcholine is more active than the parent drug.
3. Replacement of more than one methyl group of quaternary ammonium group leads to
complete loss of cholinergic activity.
4. The ester group of Ach helps in hydrogen bonding formation with the receptor. If
large aromatic groups are inserted in to the ester group it will produce ACH
antagonists may act as anticholinergic drug.

6. 5. Acetate group of Ach may be replaced by a carbamate group. For example carbachol is
more active and more stable than the parent drug.
6. The ethylene chain maintains the distance between the ester group and ammonium group.
Increases in the chain length decreases the activity while branching in the chain produces
change in activity. For example, Methacholine is more potent than acetycholine.
7. Ester group of acetylcholine can be replaced by other groups like ether and ketone to give
compounds which are chemically stable and potent compounds and have some
cholinergic activity. For example P-methyl choline ethyl ether.
Various directly acting drugs are as follows:
1. Acetylcholine:
o CH3
II ©I
H3C—c—o—CH2—CH2— N—CH3
*CI
CH3
Properties: a very hygroscopic, white crystalline powder, very slightly soluble in water, freely
soluble in alcohol, it should be protected from light and store in airtight container.

7. Mechanism of action: acetylcholine is direct acting quaterammonium cholinergic drug that has
the muscarinic effects of acetylcholine. It’s inactivated by cholinesterase.
Uses: it’s used as mitotic agent in cataract surgery to reduce ocular pressure. used as vasodilator
and cardiac depressant. Its increases lachrymal, salivary secretions.
2. Carbachol
Synthesis:
Properties: it is white powder, freely soluble in water, sparingly soluble in alcohol, stored in air
tight container.
Mechanism of action: it is a quaternary ammonium Para sympathomimetic possess both
muscarinic and nicotinic action of acetylcholine.
Uses: it is used as an alternative to pilocarpine in the management of glaucoma. It’s used as
mitotic agent in cataract surgery to reduce ocular pressure.
3. Bethanechol:
Properties: it is white crystalline or color less crystals or white crystalline powder.
Freely soluble in water and in alcohol insoluble in chloroform and in ether.it is stored in
air tight container.
Mechanism of action: it is choline ester mainly exhibit the muscarinic action of Ach.it is
not inactivated by cholinesterase.
Uses: it is usually employed in stimulation of G.I.T and urinary bladder to relieve
postoperative atony. It has prolong effect than acetylcholine.

8. 4. Methacholine:
Properties: it is colorless or white crystalline powder which is hygroscopic in nature. Solution is
neutral to litmus. Soluble in water, insoluble in chloroform. It is stored in air tight container.
Mechanism of action: it is a quaternary ammonium Para sympathomimetic with the muscarinic
action of acetylcholine. Its action is more prolonged.
Uses: it is used in the treatment of Renaud’s syndrome and glaucoma. It is used to diagnose
bronchial hyper reactivity.
5. Pilocarpine :
Properties: it is colorless crystal or white which is hygroscopic.it is very soluble in water
and in acohol.it is stored in air tight container and protected from light.
Mechanism of action: Pilocarpine is a direct acting tertiary amine cholinergic that has
muscarinic effects of acetylcholine.
Uses: used mainly in the treatment of glaucoma and in treatment of dry eye or dry mouth.
Used in the treatment of open angle glaucoma.
INDIRECT ACTING AGENTS /CHOLINESTERASE INHIBITORS
> These agents are also known as acetyl cholinesterase inhibitors. Acetyl cholinesterase is
an enzyme which terminates the action of acetylcholine at the junctions of the various
cholinergic nerve endings.
> This drug inhibits the AChE enzyme and causes accumulation of ACH in the cholinergic
nerve terminals.
> This agents produces effects similar to that of cholinergic agents. anticholinesterases are
of two types

9. REVERSIBLE INHIBITORS: This drug binds to reversibly to the choline subsite and
causes acylation of the hydroxyl group of the serine residue of acetylcholinesterase. this
agents form ester like carabonate or phosphate and covalently binds to the active site of the
enzyme. For example physostigmine, and neostigmine, pyridostigmine.
IRRIVERSIBLE INHIBITORS: This drug produces irreversible inactivation of the
acetylcholinesterase. Various organophasporus agents come under this category. drugs are
parathion and malathion.
1. Physostigmine salicylate:
Properties: it is white shining, odorless crystals or white powder. It acquires a red tint on when
exposure to heat.it is sparingly soluble in water and stored in air tight containers at a temperature
250, protected from light.
Mechanism of action: it is reversible tertiary amine inhibitor of cholinesterase activity with
actions similar to those of neostigmine.
Uses: used as mitotic agent in the treatment of glaucoma to reduce ocular pressure.
2. Neostigmine bromide:
Synthesis:

10. Properties: it is colorless, white crystalline powder. It is very soluble I water, freely soluble in
alcohol, protected from light. It is poorly absorbed by GIT.
Mechanism of Acton: neostigmine indirectly stimulates both muscarinic and nicotinic receptors.
It binds to the anionic and esteric site of cholinesterase and block the activity of
acetylcholinesterase.
Uses: it is used in the treatment of myasthenia gravis. It is also used in the treatment of
management of glaucoma.
3. Pyridostigmine :
Properties: it is white crystalline hygroscopic powder having an agreeable characteristic odour.it
is freely soluble in water, alcohol and in chloroform but practically insoluble in ether.it is stored
in air tight container.
Mechanism of action: it is blocks acetyl cholinesterase enzyme and inhibits the destruction of
released acetylcholine.
Uses: used in the treatment of myasthenia gravis.it has been used in post-operative urinary.
4. Endrophonium chloride :
CH3
Properties: a white odorless crystalline powder very soluble in water.it should be kept in a well
closed container and protected from light.
Mechanism of action: it is a quaternary ammonium compound that is reversible inhibitor of
cholinesterase activity. It has shorter duration of action than neostigmine and pyridostigmine.

11. Uses: Used in the treatment of myasthenia gravis but due to its short duration of action it is not
suitable for routine treatment of myasthenia gravis.
5. Echothiophate iodide :
Properties: it is white crystalline powder with molecular mass of 383.228 g/mol. it is soluble in
water.
Mechanism of action: it is irreversible acetylcholinesterase inhibitors. It covalently binds to
cholinesterase and permanently inactivates the enzyme.
Uses: it is used as an ocular antihypertensive in the treatment of chronic glaucoma.
6. Parathion :
Properties: it is brown to yellow liquid with odour of garlic.it is soluble in water and
insoluble in petroleum ether. On metabolism in liver it forms p-nitro phenol and 4-
nitrophenyl phosphate.
Mechanism of action: it is irreversible acetylcholinesterase inhibitors. It covalently
binds to cholinesterase and permanently inactivates the enzyme.
Uses: it is used in the treatment of chronic glaucoma.

12. 7. Malathion :
Properties: Malathion is a colorless to yello brown liquid with a characteristic unpleasant odour.it
is soluble in most organic solvents except paraffin.
Mechanism of action : it inhibits the acetylcholinesterase activity by binding serine residue on the
cholinesterase enzyme and irreversibly deactivates the enzyme.
Uses: Malathion low dose used in the treatment of head lice and body lice. Used in the treatment
of scabies.

13. I. MULTIPLE CHOICE QUESTIONS
■ Which of the following L a clinical u« for a muscarinic agonist ?
A, Treatment of myasthenia gravis
li. "Swifting off" the gastrointestinal tract prior to surgery
C, swifting on the urinary tract after surgery
D. Increasing heart muscle activity in certain heart defects
2. Acetylcholine can exist in how many number of conformation?
A- 2 B. 3
C' 5 D, 4(synplanar, synclinal, anticlinal and antiplanar)
3. Why the quaternary ammonium group is essential for inrinsic activity
of acetylcholine?
A. because it acts as electron donor
B. because it act as electron acceptor
C. because of its action as a detecting group
D. None of the above
4. On substitution of methyl group on quaternary ammonium with amine
group, which amine group shows more activity ?
A, Primary B. Secondary
C. Tertiary D. None of above
5. Which group of Ach contributes to the binding of compound to the
muscarinic receptor?
A. ammonium group metV g^P
C Ester group & All of above
6. Effects of cholinergic nerve stimulation are called-
A. Sympathetic Parasympathomimetic
C. Cholinergic B & C Both
1 J! 7. Replacement of methyl group by ethyl group or large alkyl groups
cause ?
A. Increacse in activity of compound B. Decrease in activity
of compound
C. Inactivation of compound D. No change
8. Ester of aromatic or higher molecular weight acids possess*
A. Cholinergic agonist activity B. Cholinergic antagonist activity
C. Anticholinergic agonist activity D. Anticholinergic antagonist
activity

14. V .
10.
11.
12.
13.
14.
15.
16.
17.
18.
In ethylene Hridge Incorporation of beta-substitution leads to reduction of
. . B Nicotinic activity
A. Muscarinic activity
, D. All of above
C. No change .
Placement of alpha-substitution in choline moiety results m¬
A. Decrease in nicotinic activty
B. Decrease in muscarinic activity
C. Increase in nicotinic activity
D. both a and b
Replacement of ester group with ether or ketone produce*
A. Chemically Unstable Compound
B. Chemically Stable Compound
C. No Change
D. None of The Above
The nicotinic action at autonomic ganglia are blocked by*
A. Hemicholinium B. Atropine
C. Hexamethonium D. Tubocurarine
Choline is synthesised -
A. by itself in liver B. not by itself
C. not in liver D. none of above
What short of receptor is the nicotinic receptor-
A. G-protein coupled receptor B. kinase linked receptor
C. an intracellular receptor D. an ion channel
Muscarinic sub receptors are.......................types-
A. 3 B. 4
c 5 D. 2
Which of the following statement is wrong about Ach>
A. Hygroscopic in nature B. Soluble in water and alcohol
C. Induce mitosis n in __a
u used in cataract surgery
Which of one is wrong statement about methacholine-
A. Treat Reynaud’s syndrome B.Treat glioma
. . . . Soluble in alcoholand
a ‘Tl * ,UPAC 2 K N-trimethyl
B. Bethanechol
B Pilocarpine
C. Insoluble in water
Ach agonist
drug I
A.
Methacholine
C Carbachol

15. 19. Tetrahydrofuran ring comes in the structure of.......... drug
A. Methacholine B. Bethanechol 8'
C. Carbachol
20.
21.
22.
23.
24.
25.
26.
27.
D. Pilocarpine
Physostigmine Salicylate is an example one of following class-
A. Reversible Cholinesterase Inhibitors
B. Irreversible Cholinesterase Inhibitors
C. Direct acting Ach agonist
D. None of above
Drug having IUFAC 3-[(Dimethylamino carbonyl)oxy]-l-methyl pyridinium brom
A. Pyridostigmine B. Edrophonium
C. Neostigmine D. Tacrine
Drug is used as insectiside in agriculture*
A. Parathion B. Edrophonium
C. Neostigmine D. Tacrine
IUPAC name of Pralidoxime chloride isA. 2-
I(Hydroxyamino)methyl]-l-methyl pyridine-l-ium chloride
B. Ethyl-(3-hydroxyphenyl)dimethyl-ammonium chloride
C. 3-[(Dimethylamino carbonyl)oxy]-l-methyl pyridinium chloride
D. 2 (AcetoxyhN, N, N-trimethyl propan-l-aminium chloride
Bethanechol chloride given by which route of administration-
A. Intramuscular Intravenous
C. Subcutaneous D. None of the above
Which is the selective agonist for nicotinic receptor-
B. Tubocurarine
D. Carbachol
A. Nicotine C. Hexamethonium
Location of M* receptor isA.
Autonomic ganglia C. Visceral
smooth muscle
Indirectly acting ChoIIinergic drugs areA.
Neostigmine C. Edrophonium
B. Heart
D, None of the above
B. Physostigmine D. All
of these