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Cholinergic agent
This document discusses cholinergic agents, which are drugs that produce effects similar to acetylcholine by directly interacting with cholinergic receptors or increasing acetylcholine availability. It classifies cholinergic agonists and anticholinesterases. Cholinergic agonists include acetylcholine and analogs like methacholine and carbachol. Anticholinesterases reversibly or irreversibly inhibit the enzyme acetylcholinesterase, leading to acetylcholine accumulation. Common anticholinesterases discussed are physostigmine, neostigmine, pyridostigmine, and organophosphates. The document provides examples of clinical uses and synthesis for several cholinergic agents.
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Cholinergic agent
- 1. Cholinergic Agent Presented by- - AshokGautam Skb college of pharmacy
- 2. •Cholinergic Agent These aredrugs 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)
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- 5. What makes acetylcholineexceptionally 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
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- 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 - Aceticacid ester of choline
- 11. Cholinergic agonists Acetylcholine asan 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 preparedby the interaction of trimethylamine and 2-chloroethyl acetate.
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- 14. SAR for acetylcholine Quaternarynitrogen is essential Decreased activity O CMe3 H3C O O NMe2 H3C O
- 15. • Distance fromquaternary 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 ofAcetyl 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 twomethyl 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 ofacetyl 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 fitbetween 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 Overcomethe 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 Preparedby the addition of propylene chlorohydrin to trimethylammonium, which on acetylation with acetic anhydride yields the official compound.
- 23. Acetylcholine analogues Carbamicacid 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 Preparedby reacting choline chloride with phosgene in chloroform solution followed by treatment of the product with ammonium hydroxide.
- 25. β Methylcarbacholine 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 Bethanecholchloride 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: Analkaloids 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 andOxotremorine : Act on the muscarinic receptors in brain. Used in Alzheimer’s disease. Muscarinic agonists
- 29. Anticholinesterases Inhibit cholinesteraseenzyme and Lead to Ach accumulation… have cholinergic effect.
- 30. Anticholinesterases CARBAMATES: 1. Physostigmine Indolealkaolid 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 Usedin 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 profileas 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 Preparedby 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 isused 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 Preparedby 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 OrganophosphatesNerve gases Irreversible binding to AchE
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- 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 acetylcholinesteraseinhibitors
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