1. Pharmacology of Cholinergic Synapse Cholinergic synapses 1. Para symp. Post gang. Neuro.Effector junctions 2. All autonomic ganglia (pregang.symp and parasymp. Nerve endings), 3. Pregang.symp.N.endings to adrenal medulla 3. 4. Skeletal neuromuscular junctions 5. Sweat glands ( sympathetic-cholinergic) 6. CNS- brain & spinal cord

2. Renshaw Cell Inhibition Ach  motor neuron Renshaw cell Glycine Collateral Skeletal Muscle Spinal cord Nic-Rc

3. Cholinergic Synapse Acetyl CO-A + Choline Ach-receptors Ach-esterase Choline CH3-co+HO-CH-CH2-N(CH3)3 CH3-CO CH2.CH2.N.(CH) 3 Ach Acetate + Diet Acetyl transferase Ach O

4. Cholinergic Synapse Acetyl CO-A + Choline Ach-receptors Ach-esterase Choline CH3-C= O+HO-CH 2 -CH2-N +( ( CH3)3 =( CH 3 ) 3 N + -CH 2 -CH 2 -O-C-CH 3 Ach Acetate + Diet Acetyl transferase Ach Ca ++ O Hemicholinium Botulinum Latrotoxin Vesamicol

5. 2 AUTONOMIC GANGLION ACH NIC.RC ACH 3. SKELETAL NEUROMUSCULAR JUNCTION Ach ACh Nic-RC

6. Classification of cholinergic Recep. Muscarinic Nicotinic Ach e.g. Muscarine Smooth muscles Cardiac Muscles Exocrine/Endo Glands/CNS ANS Gang. NMJ CNS M 1 , M 2 M 3

7. Nature of Muscarinic Receptors 1. Glycoproteins (Mol.Wt. 80,000) 2. Mediated by G-proteins, PLC, IP 3 & DAG leading to increased cytosolic Ca ++ 3. 5 subtypes: M 1, M 2, & M 3 M 1 = Autonomic ganglia & secretory glds. M 2 = Heart M 3 = Smooth muscles

8. Organ responses to Muscarinic Receptors

9. Muscarinic Recptors Activation

10. Muscarinic Receptors Activation

11. Nature of Nicotinic Receptors 1. Ligand gated ion channels 2. Pentameric proteins=4 diff.polypeptides(  2  ) 3. Autonomic ganglia/ adrenal medulla 4. Motor endplate membrane, 5. CNS 5. Activation- increased permeability to Na + & K +

12. Activation of Nicotinic Receptors

13. Parasympathomimetics Classification of Cholinergic Drugs : Directly Acting Indirectly Acting Directly Acting I. Natural& Synthetic Choline esters II. Naturally Occuring alkaloids

15. N + --CH 2 --CH 2 --OH (CH 3 ) 3---- Choline N + --CH 2 --CH 2 -- (CH 3 ) 3---- (CH 3 ) 3---- O--CO- CH 3 N + --CH 2 --CH 2 -- O--CO- CH 3 (CH 3 ) 3---- CH 3 (CH 3 ) 3----c N + --CH 2 --CH 2 -- CH 3 O--CO--NH 2 (CH 3 ) 3---- N + --CH 2 --CH 2 -- O--CO- NH 2 Acetyl Choline Methacholine Carbachol Bethanechol

17. Acetylcholine Not therapeutically useful , Why? Short duration of action Orally inactive Nonspecific in action

18. Pharmacologic effects of Ach & its Esters

19. Methacholine(Acetyl  -methyl choline) Has methyl group at the second carbon of the Ach molecule Resistant to acetylcholine esterases Longer duration Potent muscarinic agonist Not therapeutically useful

26. Iris Ciliary muscle Pupil Canal of Schlem Cornea Lens Pharmacology of Eye-Glaucoma

28. Classification of Acetylcholine Esterases Specific-True Nonspecific- Pseudo Acetyl ChE Butyryl ChE Neurons Synaptic clefts NMJ RBCs Glial cells Plasma Liver Other organs

29. Indirectly Acting Cholinomimetics 1. Reversible Choline esterase inhibitors: Physostigmine Neostigmine Edrophonium Pyridostigmine

30. Irreversible Choline Esterase Inhibitors OrganoPhosphates Insecticides Nerve gases Anthelmintics Pesticides Insecticides Herbicides

32. Hydrolysis of Acetylcholine N H 3 C H 3 C CH 3 CH 2 CH2 C--CH 3 O O Esterophilic Anionic + Acetylchoine esterase Choline Acetic acid Regenerated Enzyme 3x10 5 Ach mol./mol.of enzyme--150 usec. + Acetyl Co-A + H 2 O

34. H 3 C-N-C-O- H O N N CH 3 Physostigmine CH 3 CH 3

36. H 3 C H 3 C N--C-- O O N + (CH 3 ) 3 Neostigmine

37. Mode of action of Neostigmine N N(CH 3 ) 2 CH 3 CH 3 CH 3 O C=O + N:O AchE Anionic Esteratic + H 2 O=HO-C-N(CH 3 ) 2 O N,NDMCA + Regenerated Enzyme T1/2= 3-4hrs

39. H 3 C H 3 C N--C-- O O N + (CH 3 ) 3 Pyridostigmine

41. O N + C 2 H 5 Edrophonium CH 3 CH 3 H

42. Mode of Action of Edrophonium N CH 3 CH 3 CH 3c CH 3 OH + N + CH 3 CH 3 OH N N Regenerated Enzyme T 1/2 = 15-30 min.

45. Chemical classification of Organophosphates R 1 R 2 P O X A. X= Halide, Cyanide, or thiocyanate DFP= Diisopropyl fluorophosphate Tabun has cyanidate Sarin has fluoridate Soman has fluoridate B. X= alkylthio, arylthio, alkoxy or aryloxy Paraoxon

46. Group C: X = thiol or thionophosphorous compounds Parathion Fenthion Diazinon Malathion Group D : X= Pyrophosphates, TEPP Group E : X= Quaternary ammonium compounds Echothiophate

50. Mode of Action of Organophosphates F O P OC 3 H 7 H 7 C 3 O N:---H---O Anionic Esteratic P OC 3 H 7 O H 7 C 3 O F N:---H---O N:---H---O Phosphorilated enzyme

58. Mode of Action of 2-PAM H 7 C 3 O-P-OC 3 H 7    Esteratuc Anionic CH 3  + C=N-OH  Pyridine 2-Aldoxime      

59. Mode of Action of 2-PAM N + CH 3 C=N----O---P O OC 3 H 7 H 7 C 3 O N:H--O Regenerated Enzyme Oxime-phosphonate Kidneys ___ Electrophilic Nucleophilic

73. Autonomic Ganglion Stimulants& Blocking Agents ACh N-Rc Ganglionic stimulants : Nicotine, Lobeline Ganglion Blockers : Nicotine Hexamethonium,Tetraethylammonium ,Chlorisandemine, Mecamylamine

76. Dominance of ANS Ganglia