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Cholinergics

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cholinergics

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Cholinergics

  1. 1. Cholinergics Dr.Elza Emmannual
  2. 2. Nervous system  Central nervous system (CNS)  Peripheral nervous system 1. Autonomic nervous system 2. Somatic system, innervating skeletal muscle
  3. 3. Autonomic nervous system Most organs receive both sympathetic and parasympathetic innervation Functionally antagonistic Sympathetic /adrenergic system Parasympathetic/cholinergic system
  4. 4. Sites where the Ach acts as neurotransmitter  NMJ  All ganglia  Postganglionic parasympathetic nerves  Postganglionic sympathetic nerves of sweat glands  Adrenal medulla
  5. 5. Sympathetic Parasympatheti c origin thoracolumbar craniosacral distribution wide Head, neck, sacral region ganglia Away from organ Close to organ Pre:Postganglioni c Fibre ratio 1:20-1:100 1:1-1:2 neurotransmitter Nor adrenaline(NA) Acetyl Choline(Ach) function Fight & Flight response Rest & digest response
  6. 6. Autonomic nerve CNS Preganglionic Nerve fibre Postganglionic Nerve fibre Ganglia Effector organ
  7. 7. Steps in neurotransmission  Synthesis  Storage  Release  Receptor action  Termination
  8. 8. CHOLINERGIC TRANSMISSION
  9. 9. Choline +AcetylC oA ACh ACh V A T Choline acetyl transferase Ca 2+ ACh Choline Acetate SNAP VAMP Choline esterase Choline Transporter
  10. 10. Choline TransporterCholine +AcetylC oA ACh ACh V A T Choline acetyl transferase Ca 2+ ACh Choline Acetate SNAP VAMP Choline esterase Hemicholinium Vescamicol Botulinum toxin A Botulinum toxin B & Beta bangarotoxin Black widow spider toxin Tetradotoxin Saxitoxin
  11. 11. Toxins Action Local anaesthetics,tetradotoxins(Puffer fish),saxitoxins(Gaunyaulax)(shell fish consumed red algal blooms) Block voltage-gated sodium channels Hemicholiniums Block uptake of choline Vesamicol Inhibits VAT Ω conotoxin(marine snails) Blocks nerve terminal calcium channels Alpha Latrotoxin(Black widow spider venom) Explosive transmitter release Alpha Bengarotoxin(cobra venom) Nm receptor antagonist Beta bengarotoxin(Krait venom) Inhibits release of acetylcholine Batrocotoxin(South African frog) Selective increase in permeability of sodium channels Scorpion toxin Persistant depolarisation by inactivation of Sodium channels
  12. 12. Cholinergic Receptors Muscarinic receptorsM1, M2, M3,M4,M5 Nicotinic receptors NM, NN
  13. 13. Rec epto r Site Action Nature Agonist Antagonist M1 CNS Ganglia Gastric parital cells CNS Learning & Memory Gastric glands gastric secretion G protein coupled (Gq) Oxotremorin e Pirenzepine Heart Presynaptic SA node heart rate AV node velocity of conduction Atria & Ventricles contractility Gi coupled Methacholin e Methoctrami ne M2 Smooth muscle including iris & ciliary muscles Glands Endothelial cells Visceral smooth muscle Contraction except urinary& intestinal sphinctors Exocrine glands Secretion Vascular endothelium: release NO vasodilation Ciliary muscle contraction Iris constriction of pupil Gq coupled Bethenechol Darifenacin M3 Ganglia Autonomic ganglia & Adrenal medulla Catecholamine release Ion channel DMPP Trimethapha n NN NMJ Neuromuscular junction Contraction of skeletal muscle Ion channel PTMA dTC ,Alpha Bangarotoxi n NM
  14. 14. Actions of ACh CVS HEART ↓ HR AV node - ↓ conduction Atria - ↓contraction BLOOD VESSELS Vasodilation M2 M3
  15. 15.  Smooth muscle  ↑contraction  GIT - Tone & peristalisis in GIT ↑, Sphincters relax Abdominal cramps & evacuation of bowel  Ureter peristalsis↑, Detrusor contracts, Bladder trigone & sphincter relax: Voiding  Bronchospasm  Eye  Contraction of circular muscles of iris MIOSIS  Contraction of ciliary muscles  ↑outflow of aqueous humur↓ IOP M3 M3
  16. 16. GLANDS  Secretion from all glands ↑  Salivation , Sweating, lacrimation, Gastric & Tracheobronchial secretion M3
  17. 17. NICOTINIC AUTONOMIC GANGLIA Sympathetic + Para sympathetic stimulation SKELETAL MUSCLES Contraction of muscle NN NM
  18. 18. Cholinergic drugs classification DIRECTLY ACTING Choline Esters Cholinomimetic Alkaloids INDIRECTLY ACTING Anti choline esterases Acetyl Choline Methacholine Carbachol Bethanechol Pilocarpine Muscarine Arecoline
  19. 19. Anti choline esterases Reversible Irreversible Carbamates Physostigmine Neostigmine Pyridostigmine Edrophonium Rivastigmine Donepezil Galantamine Acridine Tacrine Organophosphates Malathion Parathion Dyflos Echothiophate Diazinon Nerve gases Carbamates Propoxyfur Carbaryl
  20. 20. Choline ester Susceptibility To choline esterase Muscarinic action Nicotinic action Acetylcholine ++++ +++ +++ Methacholine + ++++ None Carbachol Negligible ++ +++ Bethanechol Negligible ++ None
  21. 21. Uses  To reverse postoperative atony of bladder  To expel gases from intestines prior to radiological examination  To revert postoperative paralytic ileus of gut  To treat salivary gland malfunction
  22. 22. Pilocarpine  Source leaves of Pilocarpus Microphyllus  Crosses BBB  Too toxic for systemic use  USES 1)3rd line drug - open angle glaucoma 2)To counteract mydriatics 3)Prevent adhesions in iridocyclitis by altering with mydriatics
  23. 23. Muscarine Amanita phalloides Amanita muscaria Mycetism-Mushroom poisoning Treatment-Atropine 1-2mg IM every 30 minutes
  24. 24. Arecoline  Chief alkaloid of areca or betel nut
  25. 25. Anticholine esterases Drugs that inhibit choline esterase enzyme prevent the hydrolysis of Ach potentiates Ach action Classification
  26. 26. Anti choline esterases Reversible Irreversible Carbamates Physostigmine Neostigmine Pyridostigmine Edrophonium Rivastigmine Donepezil Galantamine Acridine Tacrine Organophosphates Malathion Parathion Dyflos Echothiophate Diazinon Nerve gases Carbamates Propoxyfur Carbaryl
  27. 27. Mechanism of action Choline esterase has 2 sites anionic site & esteratic site Carbamates bind to both A & E A E A E Carbamylated enzyme react slowly so hydrolysis of Ach is inhibited
  28. 28.  OP bind to esteratic site only  Phosphoylated enzyme react very slowly irreversibly inhibit Ach degradation  Phosphorylated enzyme undergoes “aging” become totally resistant to hydrolysis A E
  29. 29. Actions LIPID SOLUBLE – ( Physostigmine & OP)  Marked Muscarinic & CNS effects LIPID INSOLUBLE – ( Neostigmine)  Effect on Skeletal muscle & stimulate ganglia  Dont penetrate CNS & have no central effects Fasciculation & twitching
  30. 30. USES 1) Glaucoma  ↑ tone of ciliary muscle outflow facility is ↑  Pilocarpine  Physostigmine 2) To reverse the effects of mydriatics 3) MYASTHENIA GRAVIS Neostigmine Edrophonium (for diagnosis
  31. 31. 4)Post operative paralytic ileus/ urinary retention Neostigmine 5)Post operative decurarization Atropine (Block Muscarinic action) followed by Neostigmine 6)Cobra bite Neostigmine + Atropine 7) Belladona(Atropine) poisoning Physostigmine 8)Alzheimers disease Tacrine , Donepezil , Rivastigmine
  32. 32. OP poisoning  lacrimation, salivation, sweating , miosis, blurring of vision, breathlessness, colic, involuntary defecation & urination cardiac arrhythmias Muscle fasciculations convulsions, coma & death ( RESPIRATORY FAILURE) Agricultural & household insecticide
  33. 33. TREATMENT Termination of further exposure to poison – fresh air, wash the skin with soap & water, gastric lavage Maintain patent airway Supportive measures Maintain BP, Hydration ,  control of convculsions diazepam
  34. 34. SPECIFIC ANTIDOTES 1. ATROPINE Highly effective in counteracting muscarinic symptoms Doesn’t reverse peripheral muscle paralysis (Nicotinic)
  35. 35. 2) OXIMES (Pralidoxime) OP A E A E OP OXIME Its oxime end reacts with Phosphorous atom attached to anionic site: Oxime Phosphonate  diffuses away leaving reactivated Ach Esterase
  36. 36. Not effective in Carbamate poisoning because anionic site is not free CI Carbamate poisoning
  37. 37. Thank you… Thank you…

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