This document summarizes parasympathomimetics (cholinergic agonists). It discusses how the parasympathetic nervous system uses acetylcholine as a neurotransmitter and how cholinergic agonists mimic acetylcholine's actions. It classifies cholinergic agonists into direct-acting and indirect-acting types. Direct agonists bind receptors, while indirect agonists inhibit acetylcholinesterase to increase acetylcholine levels. Examples of both types are provided along with their structures, mechanisms of action, and uses. The document also covers acetylcholine synthesis and catabolism as well as structure-activity relationships of parasympathomimetics.

1. PARASYMPATHOMIMETICS
(CHOLINERGIC AGONISTS)
BY
KENCHA SWATHI
ASSISTANT PROFESSOR
DEPT.OF MEDICINAL CHEMISTRY
ADITYA BIPER
BANGALORE

2. CLASSIFICATION OF NERVOUS SYSTEM
NERVOUS
SYSTEM
CNS PNS
SYMPATHETIC
NERVOUS
SYSTEM
PARASYMPATHETIC
NERVOUS SYSTEM
AUTONOMIC NS

3. PARASYMPATHETIC NEUROTRANSMITTER
 The cholinergic nervous system is composed of organized nerve cells that use the
neurotransmitter acetylcholine in the transduction of action potentials.
 The nerve cells are activated by acetylcholine or they contain acetylcholine and release
acetylcholine during the propagation of a nerve impulse.
 Parasympathetic nervous system is also considered as cholinergic nervous system
 Neurotransmitter in cholinergic system is ACETYLCHOLINE & BUTYRYLCHOLINE
 Cholinergic agents are the drugs which mimic the action of acetylcholine in the
parasympathetic nervous system.
 Acetylcholine is the neurotransmitter at the neuromuscular junction between the motor nerve
and the skeletal muscles.

5.  Acetylcholine is biosynthesized in the body using the amino acid –L-serine .Serine undergoes
decarboxylation by using enzyme serine decarboxylase to produce ethanolamine.
 Ethanolamine in the presence of choline-N-methyl transferase enzyme (transfers the methyl
groups) to produce choline .choline is the compound ,it contains quaternary nitrogen with 3
methyl groups.
 Choline reacts with acetyl group of acetyl coenzyme A (acetyl donor) in the presence of
choline acetyl transferase enzyme for the formation of neurotransmitter- acetylcholine.
 The released acetylcholine stores in the storage vesicles at the neuro-muscular junction.
 At the time of release it enters the NMJ and binds with the cholinergic receptors(either
nicotinic or muscarinic receptor)

6. Catabolism of acetylcholine
Acetyl cholinesterase H₂O
(synaptic cleft)
+
 Acetylcholine is metabolized into two compounds –acetate or acetic acid and choline groups
 Metabolism occurs in the presence of acetylcholinesterase enzyme at synaptic cleft. This reaction also
involves H₂O molecule to undergo hydrolysis.
ACETYLCHOLINE
ACETIC ACID CHOLINE

8. CHOLINERGIC RECEPTORS
NICOTINIC
MUSCARINIC

9. RECEPTORS AND THEIR DISTRIBUTION

10. PARASYMPATHOMIMETICS
 Parasympathomimetics are the drugs or chemical agents which mimic the actions of
acetylcholine.
 These drugs bind with the cholinergic receptors and shows the stimulative action
similar to acetylcholine .
 Parasympathomimetics are also called as cholinergic agonists or cholinomimetics.
 Cholinergic agonists have a direct action on the receptor for acetylcholine action.
 Cholinergic agonists are classified into two types:
A.Direct acting cholinergic agonists
B. Indirect acting cholinergic agonists.

11. SAR of Parasympathomimetics
 Basic structure is acetylcholine
 The acetylcholine structure can be divided as 3 parts
1.Acetyl group
2.Ethylene bridge
3.Onium group or quaternary ammonium group

12.  The acetyl group should contain an oxygen atom like ester to form a hydrogen
bond for agonistic activity.
 Replacement of acetate group with ether,ketone results in decreased activity.
 There should be a two carbon chain between acetyl group and quarternary
nitrogen group.
 The carbon attached to the N atom is α carbon and the adjacent carbon is β
carbon.
 Methyl group substitution at α carbon increases muscarinic receptor activity than
nicotinic receptor. Eg:Methacholine

13.  Methyl group substitution at β carbon increases nicotinic receptor activity than
muscarinic receptor.
 Presence of N atom in quaternary ionic form is important for agonistic activity.
 Presence of 3 methyl groups on N atom is required for agonistic activity.
 There should not be more than 5 atoms between quaternary N and the terminal
hydrogen(Rule of five) for agonistic activity.
 Replacement of methyl groups on N atom with other groups leads to antagonistic
activity.
 Replacement of quaternary N atom with As or P leads to toxicity or no activity.

14. DIRECT ACTING CHOLINERGIC AGONISTS
 The drugs which binds to the cholinergic receptors either muscarinic or nicotinic and
shows the action similar to acetylcholine are called as direct acting cholinergic
agonists.
Eg: Acetylcholine
Carbachol
Bethanechol
Methacholine
Pilocarpine

15. ACETYLCHOLINE
 Structure:
 Uses: 1. Used as miotic (constriction of the pupil of the eye)
2. To treat myasthenia gravis(Neuromuscular disease leads to skeletal muscles
weakness)
3. To treat post operative paralysis/urinary retention
4. To treat cobra bite
5. To treat Alzheimer’s disease

16. CARBACHOL
 Structure:
 Uses: 1.To treat wide angle glaucoma (High pressure in the eye becoz of damage of
optic nerve).
2. To produce miosis during eye surgery.
3.Carbachol is used during ophthalmic surgery and cataract surgery.

17. BETHANECHOL
 Structure:
 Uses: 1. Bethanechol is used to treat urinary retention, which occurs after surgery,
delivery of baby and other conditions.
2. Used to treat GIT atony and bladder atony after surgery
3. It binds to the muscarinic receptor to show the agonistic activity.
4.To treat paralytic ileus.

18. METHACHOLINE
 Structure:
 Uses: 1. Methacholine is used for the diagnosis of asthma .
2. It causes bradycardia and hypotension by binding with the
muscarinic receptor.

19. PILOCARPINE
 Structure:
 Uses: 1. Pilocarpine increases saliva secretion in the mouth.
2. It is used to treat dry mouth during the treatment of certain
cancers.
3. Pilocarpine is used to treat glaucoma.

20. MECHANISM OF ACTION
 Direct acting cholinergic agonists binds to the cholinergic receptors (either
muscarinic or nicotinic receptor) and activate the receptors then shows similar action
like acetylcholine.

21. SYNTHESIS OF CARBACHOL

22. INDIRECT ACTING CHOLINERGIC AGONISTS
 Drugs or chemical agents which inhibits acetylcholinesterase enzyme thereby
increasing the concentration of acetylcholine levels at the neuromuscular junction or
synaptic cleft.
 Then the drugs enhance the cholinergic functions via activation of muscarinic or
nicotinic receptors.
 Acetylcholinesterase is the enzyme responsible for breakdown of acetylcholine into
acetate ion and choline.
 Inhibition of this enzyme leads to excess amount of AcH at NMJ.
 Indirect acting cholinergic agonists are also called as cholinesterase inhibitors or
Anticholinesterases.

23. CLASSIFICATION
 Indirect acting cholinergic agonists are classified as :
1. Reversible cholinesterase inhibitors: The drugs binds to the cholinesterase enzyme
for a period of few minutes to few hours and later release the acetylcholinesterase
enzyme are called as reversible cholinesterase inhibitors.
Eg: Physostigmine,Neostigmine,pyridostigmine,Edrophonium,Tacrine
2.Irreversible cholinesterase inhibitors: Drugs bind to the cholinesterase enzyme
and forms a permanent covalent bond to form drug-enzyme complex Irreversibly for a
long time are called as irreversible cholinesterase inhibitors.
Eg: Parathion, Malathion, Ambenonium chloride, Isofluorphate,
Echothiophate
3. Cholinesterase reactivator: Drugs of this group reverse the inactivation of
acetylcholinesterase enzyme which is inhibited by irreversible anticholinesterases.
Eg: Pralidoxime

24. REVERSIBLE CHOLINERGIC AGONISTS
 Carbamates - Eg:Physostigmine
Neostigmine
Pyridostigmine
 Non-carbamate quaternary compounds - Eg:Edrophonium chloride
 Acridine derivatives -Eg: Tacrine chloride

25. PHYSOSTIGMINE
 Structure:
 Uses: 1.Used as a miotic drops to decrease Intraocular pressure in
glaucoma.
2.To treat Alzheimer’s disease
3.Used in atropine poisoning

26. NEOSTIGMINE
 Structure:
 Uses: 1.Reversible cholinergic agonist containing quaternary ammonium group.
2. In the treatment of Myaesthenia gravis.
3.Used in the treatment of paralytic ileus,urinary retention.
4.Antidote for curare intoxication

27. PYRIDOSTIGMINE
 Structure:
 Uses: 1. Pyridostimine is less potent than neostigmine.
2. In the treatment of myasthenia gravis.
3. It is having longer duration of action

28. EDROPHONIUM CHLORIDE
 Structure:
 Uses: 1.It is used in the diagnosis of Myaesthenia gravis.
2.Edrophonium makes a clear distinction between myasthenia gravis and cholinergic
crisis.
3.Edrophonium is a short and rapid acting cholinergic drug.

29. TACRINE CHLORIDE
 Structure:
 Uses: 1. Tacrine is used to treat mild to moderate alzheimers disease.
2.Tacrine improves the nerve cells in the brain.
3.Used to treat dementia – memory loss (People having less amount of AcH ,which is
essential for memory,thinking and reasoning)
HCl

30. Side effects
 Bradycardia
 Hypotension
 Increases Saliva secretion
 CNS effects
 Convulsions
 Hepatotoxicity(Eg:Tacrine)
 Carbamate poisoning
Saliva secretion

31. MECHANISM OF ACTION
 Reversible cholinesterase inhibitors binds at the active of cholinesterase enzyme.
 Acetylcholine reacts with water in the body very rapidly and makes the esteratic site become free with
in a milli fraction of second.
 Drugs binds in this site and forms drug-enzyme complex or carbamated enzyme.
 This carbamated enzyme reacts slowly and releases slowly in the NMJ.
 More amount of Acetylcholine is available in the synaptic cleft.

32. SYNTHESIS OF NEOSTIGMINE

33. IRREVERSIBLE CHOLINESTERASE INHIBITORS
 These drugs bind covalently to cholinesterase enzyme and can permanently
inactivate the enzyme.
 Irreversible inhibitors are only organophosphate inhibitors.
 The effect of organophosphates can last as long as one week.
Eg: : Parathion
Malathion
Ambenonium chloride
Isofluorphate
Echothiophate

34. PARATHION
 Structure:
 Uses: 1.Broad spectrum Organophosphorous insecticide
2.Agricultural pesticide

35. MALATHION
 Structure:
 Uses: 1. Used as agricultural pesticide
2.Nerve poision
3.To kill ova and adult mice in field(rodenticide)

36. AMBENONIUM CHLORIDE
 Structure:
 Uses: 1.Used for the treatment of myasthenia gravis in the patients who does not respond
to carbamate drugs.
2.It is having long duration of action

37. ISOFLUORPHATE
 Structure:
 Uses: 1.As a miotic during chronic glaucoma in veterinary field
2.Used in opthalmology

38. ECHOTHIOPHATE
 Structure:
 Uses: 1.Irreversible cholinergic agonist used in the treatment of wide angle
glaucoma

39. CHOLINESTERASE REACTIVATOR
 Cholinesterase reactivator reverses the functioning of Acetylcholine .This process
occurs before the aging of acetylcholine.
Eg: Pralidoxime
Structure:
Uses: Antidote for Organophasphate drugs

40. MECHANISM OF ACTION
 Organophosphate drugs phosphorylate the cholinesterase enzyme at the active site
of serine.
 They form acovalent bond with the enzyme permanently.
 This permanent covalent bond forms a organophosphate drug – enzyme complex
for days.
 Acetylcholine levels increases in the NMJ.
 This bond can be reversed before aging of the enzyme by cholinesterase
reactivator.

41. REFERENCES
 Wilson and Gisvold’s textbook of pharmaceutical and medicinal
chemistry.
 Textbook of medicinal chemistry by Graham Patrick.
 Textbook of Medicinal chemistry by Ashutosh Kar.
 A textbook of medicinal chemistry by Ilango.