1. Cholinergic
Agent
Presented by-
- Ashok Gautam
Skb college of pharmacy

2. •Cholinergic Agent
These are drugs which produce actions
similar to that of Acetylcholine, either by
directly interacting with cholinergic
receptors (cholinergic agonist) or by
increasing availability of Acetylcholine at
these sites (anticholinesterases)

3. Biosynthesis

4. L-serine
choline Acetylcholine
ethanolamine

5. What makes acetylcholine exceptionally prone to hydrolysis
is the possibility of folding to form an intramolecular dipole
bond that will increase the positive charge of the ester carbonyl
Biological hydrolysis of Ach

6. Cholinergic Receptors
Muscarinic Nicotinic

8. Classification
Cholinergic agonists
Choline esters
• Acetyl choline
• Methacholine
• Carbachol
• Bethanechol
Alkaloids
• Muscarine
• Pilocarpine
• Arecoline

9. Anticholinesterases
Reversible
Carbamates Acridine
• Physostigmine
Tacrine
• Neostigmine
• Pyridostigmine
• Edrophonium
• Rivastigmine
Irreversible
Organophosphates
• Dyflos
• Echothiophate
• Malathion
Carbamates
• Carbaryl

10. Cholinergic Agonist
Acetylcholine
2-Acetoxy-N,N,N-trimethylethanaminium
- Acetic acid ester of choline

11. Cholinergic agonists
Acetylcholine as an agonist
Advantages
• Natural messenger
• Easily synthesised
Disadvantages
• Easily hydrolysed in stomach (acid catalysed hydrolysis)
• Easily hydrolysed in blood (esterases)
• No selectivity between receptor types
• No selectivity between different target organs
Use
Used in cataract surgery, iridectomy, trophic ulcers, paroxysmal tachycardia,
gangrene and Raynaud’s disease.

12. Synthesis of Acetylcholine
prepared by the interaction of trimethylamine and 2-chloroethyl acetate.

13. SAR for acetylcholine

14. SAR for acetylcholine
Quaternary nitrogen is essential
Decreased activity
O
CMe3
H3C
O
O
NMe2
H3C
O

15. • Distance from quaternary nitrogen to ester is important
• Ethylene bridge must be of 2 carbon length
• Substitution on α-c = decreases M effect and increases N effect
• Substitution on β-c = increases M effect and decreases N effect
e.g Methacholine, Bethanechol
Decreased activity
O NMe3
H3C
O
OH3C
O
NMe3
SAR for acetylcholine
α
β

16. • Replacement of Acetyl group with Carbamoyl group shows no change in action
eg- Carbacholine
• If the acetyl group is replaced by higher homologues the resulting esters are less
Potent and have antagonistic activity
Decreased activity
O
NMe3
H3C
NMe3
H3C
SAR for acetylcholine

17. Minimum of two methyl groups on quaternary nitrogen
Lower activity
O
N
H3C
O Et
Et
Et
Active
O
N
H3C
O Et
Me
Me
SAR for acetylcholine

18. Methyl group of acetyl group cannot be extended
SAR for acetylcholine
O
NMe3
O
H3C
Much lower activity

19. Trp-307
Asp311
Trp-613Trp-616
Asn-617
O N
H
H
CO2
Binding site (muscarinic)
hydrophobic
pocket
hydrophobic
pocket
hydrophobic
pockets
O O
CH3
N
CH3
CH3
CH3
H- bond
Ionic bond

20. Conclusions:
• Tight fit between Ach and binding site (Receptor)
• Methyl groups fit into small hydrophobic pockets
• Ester interacting by H-bonding
• Quaternary nitrogen interacting by ionic bonding
SAR for acetylcholine

21. Acetylcholine analogues
METHACHOLINE
 Overcome the instability of Ach:
 β- methyl Acetylcholine
 Steric shield: add large group to change the conformation of Ach:
 3X more stable than Ach.
 More selective on muscarinic (M2) over nicotinic receptors.
 S-enantiomer is more active than the R-enantiomer
USE:- Terminate attacks of supraventricular, paroxysmal tachycardia
Dose : Usual paroxysmal tachycardia, 10 to 25 mg ; subcutaneous for peripheral
vascular disease, 10 to 25 mg.

22. Synthesis of Methacholine
Prepared by the addition of propylene chlorohydrin to trimethylammonium, which on
acetylation with acetic anhydride yields the official compound.

23. Acetylcholine analogues
 Carbamic acid ester of choline
 Carbamate more stable ester toward hydrolysis
 NH2 and CH3 are equal sizes, Both fit the hydrophobic pocket
 Long acting cholinergic agonist.
 Can be administered orally.
USE:-
Used topically in primary glaucoma, urinary retention, peripheral
vascular disease
Dose : Topical, 0.1 ml of a 0.75 to 3% solution.
CARBACHOL

24. Synthesis of Carbachol
Prepared by reacting choline chloride with phosgene in chloroform solution
followed by treatment of the product with ammonium hydroxide.

25.  β Methyl carbacholine
 More stable.
 More selective on muscarinic receptor (M3).
 Used to stimulate GIT and urinary bladder after surgery.
 It is not inactivated by hydrolysis in the presence of enzyme
cholinesterase, thereby shows prolonged
parasympathomimetic action
Dose : Oral, 5 to 30 mg 3 or 4 times per day; subcutaneous, 2.5 to 10
mg 3 or 4 times daily.
Acetylcholine analogues
BETHANECHOL

26. Synthesis of Bethanechol
Bethanechol chloride is prepared by the interaction of β-methylcholine chloride with
phosgene in chloroform solution followed by treatment of the resulting product with
ammonium hydroxide.

27. Muscarinic agonists
Pilocarpine:
 An alkaloids from Pilocarpus shrubs.
 Used in glaucoma.
 Used Topically
Clinical uses:
 Treatment of open angle glaucoma.
 Stimulate GIT and UT after surgery.
 In some heart defects.
 Pilocarpine nitrate is less hygroscopic than its corresponding hydrochloride and
hence it is more easy to handle
Dose : Topical, 0.1 ml of 0.5 to 6% solution into the conjunctival sac 1 to 5 times in a day.
Pilocarpine

28.  Arecoline and Oxotremorine :
 Act on the muscarinic receptors in brain.
 Used in Alzheimer’s disease.
Muscarinic agonists

29. Anticholinesterases
 Inhibit cholinesterase enzyme and Lead to Ach
accumulation… have cholinergic effect.

30. Anticholinesterases
CARBAMATES:
1. Physostigmine
 Indole alkaolid
 Physostigma venenosum
 It is used chiefly as a miotic
 Use in Open angle Glaucoma, myasthenia gravis and
Alzheimer’s disease.
 Used as antidote for atropine poisoning
Side effects
It contain tert. Nitogen and can cross BBB (CNS toxicity)

31.  Neostigmine
 Used in Tubocuranin poisioning
 Neostigmine has less CNS side effects and more stable.
 Both used in myasthenia gravis, urinary retension.
 It has qurt. N and hence can not cross BBB, less side effect
Anticholinesterase agents

32. Pyridostigmine
 Same profile as Neostigmine.
 was used by troops to protect against nerve gases.
 Is it orally available?
 Used in myasthenia gravis, treat orthostatic hypertension
Anticholinesterase agents

33. Synthesis of Pyridostigmine
Prepared by the interaction of 3-pyridinol with dimethyl carbamoylchloride in the presence of
a basic catalyst like dimethyl amine with the loss of a mole of HCl. The resulting product is
quaternized and methyl bromide to yield the official compound

34. Edrophonium
• It is used in the diagnosis of myasthenia gravis.
• It may also be employed to make a clear distinction
between a myasthenic crisis and a cholinergic crisis
Edrophonium

35. Synthesis of Edrophonium
Prepared by quaternization of meta dimethylaminophenol with ethyl iodide in a
suitable organic solvent. Edrophonium chloride may now be obtained via
treatment with moist silver oxide followed by neutralization with HCl.

36. Irreversible Acetylcholinesterase
inhibitors
 Organophosphates
 Irreversible binding to Cholinesterase active site
 Longer acting
 Used in the treatment of glaucoma

37. Irreversible Acetylcholinesterase
inhibitors
 Organophosphates Nerve gases
 Irreversible binding to AchE

38. Mechanism
of
Action

39. Antidote for AchE “poisoning”
 Pralidoxime chloride
(Protopam;PAM)
 Antidote for pesticide or
nerve gas poisoning
 Most effective if given
within a few hours of
exposure
Cl-

40. Clinical Uses of
acetylcholinesterase inhibitors

41. THANK
YOU