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Cholinergic drugs
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- 4. M 1 Ganglia :depolarization Gastric Glands :secretion CNS- learning memory, motor function M 2 HEART - inhibitory action ↓HR ↓ AV conduction ↓ atrial contractility M 3 Visceral smooth Muscle - Contraction Iris : pupil constriction Cilliary muscle: contraction Glands – secretion Vascular endothelium: Vasodilatation due to NO GPCR
- 5. NN NM Autonomic ganglia: depolarization Neuromuscular junction:depolarizationof muscle end plate—contraction of skeletal muscle Adrenal medulla: catecholamine release CNS: site specific excitation or inhibition
- 6. Acetytcholinesterase (True) Butyrylcho/inesterase (Pseudo) Distribution All cholinergicsites, ABC, gray matter Plasma, liver, intestine, white matter Hydrolysis Very fast Low Function Termination of ACh action Hydrolysis of ingested esters
- 7. Heart ↓HR ↓ AVconduction ↓ atrial contractility Cholinergic effects M2receptor Blood Vessels – M3 – Vasodilatation BUT Very few vessels supplied – skin of face & neck
- 8. Muscarinic action EYE M3- • contraction ofcircular fibers : Miosis • Contraction of cilliary muscles -- spasm of accommodation (cyclospasm ) Vision fixed for near subjects • Improving patency of trabeculae - outflow of aqueous humor increases IOP - decrease Use in GLAUCOMA - Pilocarpine
- 9. • The irisis composed of two types of muscle fibres, the circular and the radial. The stimulation of parasympathetic cholinergic nerve supplying circular fibbers results into contraction of pupil called miosis. The stimulation of sympathetic adrenergic nerve supplying the radial fibres results into dilatation of pupil called mydriasis. Thus the iris regulates the size of pupil. • The ciliary muscle is innervated by parasympathetic cholinergic nerves. Its contraction reduce the focal length of lens causing accommodation for near vision.
- 10. Muscarinic action GIT –peristalsis ↑ - defecation Use – Post operative paralytic ileus Urinary tract sphincter relax detrusor contract voiding of bladder urination Bronchoconstriction – c/i in Asthma , COPD Use – Post Op urinary retention
- 11. Glands Gastric – acidsecretion - M1 M3 Salivation Lacrimation Sweating Tracheobronchial secretion ↑
- 12. Cholinergic Agonists ACh --rapid degradation by ChEs – not used Methacholine - - Muscarinic action > Nicotinic action Carbachol - - resistant to ChEs M + N action Bethanachol - resistant to ChE - Muscarinic action - git + bladder - used in Rx of POp urinary retention Pilocarpine - alkaloid - marked secretary effect IOP ↓ ---- Used in Glaucoma
- 13. Anticholinesterases - Anti-ChEs CholinesteraseInhibitors ACh Choline + acetic acid ChE Anti-ChEs ↑ACh level – cholinergic effects Reversible Irreversible
- 14. Anionic site Esteraticsite Normal ACh hydrolysis by ChE very fast reaction within milliseconds ACh + ChE ↓ complex ↓ Choline + Acetylated E ↓ H2O Choline + Acetic acid + E
- 16. Anionic site Esteraticsite REVERSIBLE Inhibitors Combines with BOTH sites carbamylated enzyme Hydrolysis --- SLOW ACh action prolonged Structure similar to ACh Effect 3- 4 hrs
- 17. Reversible – antiChEs Carbamates Physostigmine– natural alkaloid Neostigmine Pyridostigmine Rivastigmine Donepazil Galantamine Alzheimer's disease E drophonium – E xception binds ONLY to anionic site – rapid renal elimination action for 10 mins
- 18. Anionic site Esteraticsite IRREVERSIBLE Inhibitors Combines with esteratic site Phosphorylated enzyme But Hydrolysis --- very very SLOW ACh action prolonged Effects depend upon regeneration of new enzymes
- 19. Anionic site Esteraticsite IRREVERSIBLE Inhibitors Combines with esteratic site Phosphorylated enzyme But Hydrolysis --- very very SLOW ACh action prolonged Effects depend upon regeneration of new enzymes
- 20. Dyflos , Parathion, Malathion - insecticide Tabun , Soman – gas IRREVERSIBLE Anti ChEs Carbamate - Propoxur
- 21. Anionic site Esteraticsite IRREVERSIBLE Inhibitors Phosphorylated enzyme Hydrolysis --- total resistance Loss of alkyl group AGING process
- 22. Uses Myasthenia Gravis Autoimmune disorder Antibodyagainst Nm receptor - ↓ no of receptors Weakness , Easy fatigability Neostigmine / Pyridostigmine ACh level ↑ + direct action on muscle end plate But One Problem Overtreatment with Anti ChEs Causes persistent depolarization – WEAKNESS – = cholinergic crisis
- 24. Myasthenia Gravis Crisis =acute worsening of symptoms Myasthenic Crisis = Worsening of disease Cholinergic crisis = overdose of Anti ChE Edrophonium – IV 2 mg Shortest acting Anti ChE Improvement Worsening
- 25. Diagnosis Ameliorative test: • Edrophonium2 mg is injected i.v. as a test dose • Nothing untoward happens, the remaining 8 mg is injected after 30–60 sec. • Reversal of weakness and shortlasting improvement in the strength
- 26. • Provocative test: •Demonstration of anti-NR antibodies in plasma or muscle biopsy specimen
- 27. Other drugs • Corticosteroids •Immunosuppressant action • Inhibit production of NR-antibodies and may increase synthesis of NRs • Dose:30-60mg/day • Other immunosuppressant: cyclosporin, azathiopyrine • Thymetomy • Plasmapheresis
- 28. Use Alzheimer’s disease DEMENTIA Neurodegenerative condition lossof CNS cholinergic neurons ↓ ACh level Anti ChE ---- ↑ ACh level
- 29. Use Alzheimer’s disease RIVAstigmine DONepezil GALAntemine Anti ChE– able to cross BBB
- 30. increase the toneof Cilliary muscle + iris sphincter Pores of the canal of Schlemm open ↓ Facilitate Aqueous Humor drainage – through Trabecular pathway ↓ IOP decrease in OPEN ANGLE GLAUCOMA PILOCARPINE – is preferred 2nd / 3rd choice drugs Use Glaucoma
- 31. Other uses • Postoperative paralytic ileus:Neostigmine • Post operative urinary retention Neostigmine to be used • Post operative decurarization Neostigmine • Cobra bite - curare like effect -- – Neostigmine +Atropine prevent respiratory paralysis • Atropine overdose -- Physostigmine
- 32. Other uses Other drugoverdosages • Tricyclic antidepressants, phenothiazines • Additional anticholinergic property
- 33. Organophosphrus poisoning • Easilyavailable • Extensively used as agricultural and household insecticides • Accidental as well as suicidal and homicidal poisoning is common. • Local muscarinic manifestations at the site of exposure (skin, eye, g.i.t.) occur immediately
- 34. S alivation L acrimation Urination D efecation G I upset E mesis Miosis blurred vision Bradycardia fall in BP muscle weakness paralysis Tremor Convulsion Coma .. death ORGANOPHOSPHATE poisoning SLUDGE
- 35. General measures Termination offurther exposure to the poison— • fresh air, • Wash the skin and mucous membranes with soap and water, • Gastric lavage according to need Maintain patent airway, positive pressure respiration
- 36. Contd. Supportive measures— • maintainBP • hydration • control of convulsions with diazepam
- 37. Specific antidote Atropine • Highlyeffective in counteracting the muscarinic symptom • Higher doses are required to antagonize the central effects • Does not reverse peripheral muscular paralysis Atropine 2 mg i.v. repeated every 10 min till dryness of mouth or other signs of atropinization appear
- 38. Contd. Cholinesterase reactivators • Oximesare used • Pralidoxime • Restore neuromuscular transmission only in case of organophosphate anti-ChE poisoning • Dose: 1-2 gm i.v
- 39. Anionic site Esteraticsite ChE OXIMES PRALIDOXIME = cholinesterase REACTIVATOR NOT effective for Carbamate poisonings IMP for skeletal mucle symptoms
- 40. Physostigmine Neostigmine Source Naturalalkaloid Synthetic Chemistry Tertiary amine derivative Quaternary ammonium compound Oral absorption Good Poor CNS actions Present Absent Applied to eye Penetrates cornea Poor penetration Direct action on NM cholinoceptors Absent Present Important use Miotic Myasthenia gravis
- 41. MCQ • Cholinomimetics arenot used in • (a) Glaucoma • (b) Myasthenia gravis • (c) Post operative atony • (d) Partial heart block
- 42. • A patientpresents to emergency with pinpoint pupil, salivation, lacrimation, tremors and red tears. Plasmacholinesterase level was 30% of normal. Most probable Diagnosis is: • (a) Organophospahte poisoning • (b) Dhatura poisoning • (c) Opioid poisoning • (d) Pontine hemorrhage
- 43. • Which ofthe following cranical nerve does not contain parasympathetic motor (GVE) fibers? • (a) III • (b) VI • (c) IX • (d) X
- 44. • Major neurotransmitterreleased at end organ effectors of the sympathic division of the autonomic nervous system is: • (a) Adrenaline • (b) Noradrenaline • (c) Dopamine • (d) Acetylcholine
- 45. • Mechanism ofaction of pralidoxime is: • (a) Stimulation of ACh receptors • (b) Inhibition of breakdown of ACh • (c) Blockade of ACh receptors • (d) Reactivation of AChE enzyme
- 46. • Dr Sunilused edrophonium for differentiating myasthenic crisis from cholinergic crisis. He preferred it over other anticholinesterase agents because of its: • (a) Shorter duration of action • (b) Longer duration of action • (c) Direct action on muscle end plate • (d) Selective inhibition of true cholinesterase
- 47. • All ofthe following effects are seen with cholinergic muscarinic receptor stimulation except: • (a) Sweating • (b) Rise in blood pressure • (c) Bradycardia • (d) Urination
- 48. • A patientRaj Kishore was given pilocarpine. All of the following can be the features seen in him except: • (a) Sweating • (b) Salivation • (c) Miosis • (d) Cycloplegia
- 49. • Which ofthe following provides the best explanation for neostigmine being preferred over physostigmine for treating myasthenia gravis? • (a) It is better absorbed orally • (b) It has longer duration of action • (c) It has additional direct agonistic action on nicotinic receptors at the muscle end plate • (d) It penetrates blood brain barrier
- 50. • Which ofthe following properties make pyridostigmine different from neostigmine? • (a) It is more potent • (b) It is longer acting • (c) It produces less muscarinic side effects • (d) It does not have any direct action on NM receptors
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Editor's Notes
- #23 Edrophonium – shortest Test Help in differentiating Cholinergic Crisis or Myasthenic Crisis Inject → if improvement - - Myasthenic Crisis ↓ if worsening - - Cholinergic crisis
- #25 Edrophonium action – 10 -20 mins Edrophonium test for differentiating CRISIS in Myasthenia Gravis Crisis in Myasthenia are of 2 types Myasthenic Crisis= Worsening of disease 2 . Cholinergic crisis = overdose of Anti ChE To differentiate that Edrophonium is given IV = Shortest acting Anti ChE If improvement occurs --- Myasthenic Crisis If worsening occurs -- Cholinergic Crisis ( dose of Neostigmine / Pyridostigmine has to be reduced )
- #35 S alivation L acrimation U rination D efecation G I upset E mesis SLUDGE + Miosis At toxic dose Bradycardia fall in BP muscle weakness paralysis Tremor Convulsion Coma .. death Specific antidote - Atropine In case of OP poisoning Pralidoxime -- ChE reactivator to restore transmission at Neuromuscular junction Not used in Carbamate overdose
- #40 Atropine is virtually without effect against the peripheral neuromuscular compromise