This document summarizes the pharmacology of the cholinergic system. It describes the synthesis and release of acetylcholine, the types of cholinergic receptors, and the metabolism of acetylcholine by acetylcholinesterase. It also discusses the pharmacological actions of acetylcholine and different classes of cholinergic drugs, including cholinergic agonists and anticholinesterases.

1. Pharmacology ofCHOLINERGIC SYSTEM Dr.U.P.Rathnakar MD.DIH.PGDHM www.scribd.com/Urval R

2. ANS Clinically Relevant Hypertension Angina Benign Prostatic Hypertrophy Heart Failure Alzheimer’s Disease Anaphylactic Shock Asthma

3. Peripheral Nervous system

4. Flight, Fight and Fright Sit & Digest Sympathetic P.Sympathetic

5. Parasympathetic outflow:Cranio-sacral

6. Cholinergic system NN NN NN NM M12345

7. Cholinergic Transmission

9. Inhibitory[IPSP]Termination of neurotransmitter action [Diffusion, destruction, reuptake]

11. Pharmacology of cholinergic system Ach and Cholinomimitics Anticholinesterases OP poisoning Glaucoma/Ganglion blockers Antimuscarinics Skeletal muscle relaxants

12. Acetylcholine (ACh): Ach is synthesized in the cholinergic nerve endings. ATP + Acetate + CoEn-A Acetylcholine + CoEn-A = Acetyl CoEn-A + Choline acetyl transferase Choline

13. Synthesis and Release of Acetylcholine [Cholinergic transmission]

14. Modification of synthesis & release of ACh Hemicholinium blocks choline uptake Vesamicol blocks vesicular uptake of ACh. Botulinum toxin prevents the release of ACh Black widow spider toxin induces massive release and depletion of ACh. Anticholinesterases

15. Black widow spider

16. The male of the species deliberately seeks out a 'fat' female who is full-up before mating

17. Cholinoceptors Muscarinic(M) – M1,M2,M3,M4&M5 Nicotinic ( N ) – NM & NN. M – G-protein coupled receptor. N - Ion channel receptor.

18. Subtypes and Characteristics of Cholinoceptors Location Rec types G P C R Gastric glands, Autonomic ganglia & CNS M1 SA node, AV node, Atrium, Ventricle, Auto rec., M2 Visceral smooth muscle, Iris, Ciliary muscle, Exocrine glands, Vascular endothelium. M3 CNS M4 M5 Ion Channel NM junction NM Autonomic ganglia, Adrenal gland. NN

19. Location of cholinergic receptors: M1: Gastric glands, Autonomic ganglia & CNS. M2: SA node, AV node, Atrium, Ventricle, Cholinergic nerve endings. M3 : Visceral smooth muscle, Iris, Ciliary muscle, Exocrine glands, Vascular endothelium. M4 & M5 : Brain NM : Neuromuscular junction. NN : Autonomic ganglia, Adrenal gland.

20. Metabolism of ACh: ACh is metabolized by acetylcholinesterase. 1.Acetylcholinesterase (True) : Cholinergic sites, RBC, Gray matter. 2.Pseudocholinesterase: Plasma, Liver, Intestine, White matter. + Acetylcholinesterase

21. Metabolism of ACh: By Acetylcholinesterase[AChE] Acetyation [Ach] [AChE] Choline <1msec

22. Cholinesterases True Pseudo Butyrylcholinesterase Liver, plasma Slow Sensitive -OrganoPhospahtes Hydrolysis of ingested esters Pseudocholinesterase deficiency and succinylcholine Acetylcholinesterase Cholinergic sites, RBC Fast Sensitive –Physostigmine Termination of Ach action

23. Pharmacological actions of AcH [Effects of Parasympathetic system] SIT REST DIGEST

25. Ach on CNS Does not cross BBB Ach on Eye Ach on Heart

26. Ach on BV Ach on GIT Ach on RS

27. Ach on UB Ach on Exocrine glands

29. Actions of ACh: ORGAN RESPONSE EYE Iris Miosis Ciliary muscle Contraction for near vision HEART SA Node -ve chronotropy Atria -ve inotropy AV Node -ve dromotropy[conduction] Ventricle Small decrease in contractile strength BLOOD VESSELS Arteries Dilation[EDRF], constriction-direct, high dose Veins --------”””””””---------- LUNG Bronchial muscle Constriction Bronchial glands Secretion GIT Motility Increase Spincters Relax Secretion Stimulation SIT REST DIGEST URINARY BLADDER Detrusor Contraction Trigone & Spincter Relaxation GLANDS Sweat, salivary,lacrimal, nasopharyngeal Secretion

30. Actions of ACh: (Muscarinic) Heart[Cardiac glycosides, antiarrhythmic agents,] Decrease in heart rate. Decrease in contractile strength. Decrease in conduction velocity. Increase in refractory period. Blood Vessels Vasodilatation due to release of EDRF (Endothelium dependent relaxing factor) which is ‘NO’. Also coronary Symp/P.Symp interaction-not simple

31. Actions of ACh: (Muscarinic)…….. Smooth muscle Contraction Glands Secretions are increased. Eye Miosis. Spasm of accommodation. Decrease in intraocular tension.

32. Cholinergic Drugs [Cholinomimitics] [Cholinergic Agonists] [Anticholinesterases]

33. Cholinergic Agonists[Agonists] Cholineesters Acetylcholine Methacholine Carbachol Bethanechol Alkaloids Pilocarpine Muscarine Arecoline

34. Properties of Choline Esters Uses Ach-too short acting & non selective Methacholine-PSVT-Obsolete

35. Bethanochol Therapeutic Uses: To reverse Non obstructive urinary retention as in post-operative atony of bladder and neurogenic bladder. To treat GIT atony without obstruction as in paralytic ileus. Cevimeline-(EVOXAC) is a newer muscarinic agonist available orally for use in treatment of xerostomia

36. Pilocarpine:[Pilocarpine is too toxic for systemic use] Actions: Mainly muscarinic [Initial]---- Fall of BP [Peripheral] [Persistent]--- Rise in BP[Ganglionic] Therapeutic uses: Opthalmicuse: ( Eye drops) Open angle glaucoma. To counteract mydriasis. In iridocyclitis to break adhesions between iris and lens. This action exception to pilocarpine

37. Muscarine:Muscarine occurs in poisonous mushrooms: Symptoms of muscarine actions Reversed by Atropine Early mushroom poisoning Inocybe

38. Late mushroom poisoning Symptoms of mucosal damage[GIT, Liver, Kidney-inhibition of RNA synthesis] Supportive tt[No sp tt] Amanita phalloides Majority of fatal mushroom poisonings worldwide

39. Hallucinogenic type Blockmuscarinic receptors in brain-Hallucination Atropine is contra indicated! Pilocybe Mexicana

40. Folk traditions concerning the defining features of poisonous mushrooms Fly agaric Non-poisonous Destroying angel Poisonous! Poisonous mushrooms are brightly colored

41. Folk traditions concerning the defining features of poisonous mushrooms Poisonous! Insects/animals will avoid toxic mushroom Poisonous mushrooms taste bad

42. Anticholinesterases[Indirectly acting cholinergics] Reversible anticholinesterases CarbamatesAcridine Tacrine. Physostigmine Neostigmine Pyridostigmine Edrophonium Ambenonium Demecarium Rivastigmine, Donepezil, Galantamine. Irreversible anticholinesterases

43. Irreversible anticholinesterases Organophosphates: Carbamates: Carbaryl* Propoxur* Echothiophate Parathion* Malathion* Diazinon* Tabun# Sarin# Soman# *Insecticides # Nerve gases-chemical warfare a