Cholinergic agent

Cholinergic agent
classification, structure, synthesis, use etc.

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

2. Cholinergic Agent T hese 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 M uscarinic N icotinic

7. Classification C holinergic agonists Choline esters Acetyl choline Methacholine Carbachol Bethanechol Alkaloids Muscarine Pilocarpine Arecoline

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

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

10. 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.

11. Synthesis of Acetylcholine p repared by the interaction of trimethylamine and 2-chloroethyl acetate .

12. SAR for acetylcholine

13. SAR for acetylcholine Quaternary nitrogen is essential Decreased activity

14. 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 SAR for acetylcholine α β

15. 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 SAR for acetylcholine

16. Minimum of two methyl groups on quaternary nitrogen Lower activity Active SAR for acetylcholine

17. Methyl group of acetyl group cannot be extended SAR for acetylcholine Much lower activity

18. Trp-307 Asp311 Trp-613 Trp-616 Asn-617 Binding site (muscarinic) hydrophobic pocket hydrophobic pocket hydrophobic pockets H- bond Ionic bond

19. 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

20. Acetylcholine analogues METHACHOLINE O vercome 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.

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

22. Acetylcholine analogues Carbamic acid ester of choline Carbamate more stable ester toward hydrolysis NH 2 and CH 3 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

23. Synthesis of Carbachol P repared by reacting choline chloride with phosgene in chloroform solution followed by treatment of the product with ammonium hydroxide.

24. 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

25. 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.

26. 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

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

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

29. Anticholinesterases CARBAMATES : 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 S ide effects It contain tert . Nitogen and can cross BBB (CNS toxicity)

30. 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

31. 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

32. Synthesis of Pyridostigmine P repared 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

33. 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

34. Synthesis of Edrophonium P repared 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 .

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

36. Irreversible Acetylcholinesterase inhibitors Organophosphates Nerve gases Irreversible binding to AchE

37. Mechanism of Action

38. 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

39. Clinical Uses of acetylcholinesterase inhibitors

40. THANK YOU