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Cholinergic Receptors

Cholinergic Receptors. Cholinergic Receptors: Types. Muscarinic receptors Nicotinic receptors Based on selective activation and antagonism. Subtypes and characteristic of cholinoceptors. g. d. a. a. b. Receptors and signal transduction in the ANS: Nicotinic Receptors.

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Cholinergic Receptors

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  1. Cholinergic Receptors

  2. Cholinergic Receptors: Types • Muscarinic receptors • Nicotinic receptors Based on selective activation and antagonism.

  3. Subtypes and characteristic of cholinoceptors

  4. g d a a b Receptors and signal transduction in the ANS: Nicotinic Receptors

  5. Receptors and signal transduction in the ANS Cholinergic Receptors Nicotinic Muscarinic M1 M3 M5 M2 M4

  6. Receptors and signal transduction in the ANS: Muscarinic receptors are 7 transmembrane domain, G-protein coupled receptors

  7. Receptors and signal transduction in the ANS: Muscarinic receptors(M1, M3, M5) NH 3 Phospho - (+) G lipase C q PIP 2 IP Diacylglycerol COOH 3 2+ Increase Ca Activate Protein Kinase C Response

  8. Receptors and signal transduction in the ANS: Muscarinic Receptors (M2 and M4)

  9. The major groups of cholinoceptor-activating drugs

  10. Cholinergic agonists • Two (2) types • Direct – • occupy and activate receptors • Indirect • inhibit acetylcholinesterase • levels of Ach increase • Ach stimulates receptors

  11. Esters of Choline

  12. Esters of Choline • hydrophilic • differ in breakdown by Ach’esterase • acetylcholine - very susceptable • methacholine - 3X less susceptible • bethanechol - not susceptible • methacholine & bethanechol • longer duration of action than Ach • mostly activate muscarinic receptors

  13. Direct • Esters of choline – mostly activate muscarinic receptors • methacholine • bethanechol • Alkaloids – activate both muscarinic and nicotinic receptors • pilocarpine • nicotine

  14. Properties of choline esters

  15. Alkaloids(pilocarpine and nicotine) • Highly lipid soluble • well absorbed from GI tract • get into brain • Capable of both muscarinic and nicotinic receptor activation

  16. Effect of direct-acting cholinoceptor stimulants

  17. Eye • pupillary sphincter muscle contraction (miosis) • ciliary muscle contraction • opens drainage canals in anterior chamber • lowers intraocular pressure • lens thickens for near vision

  18. CV Effects • Direct effects on heart • decreased SA and AV conduction velocity • decreased force of atrial contraction • Reduced vascular resistance – • activation of receptors on endothelium • generation of nitric oxide (NO) • NO causes vascular muscle relaxation • Effects on BP modified by reflexes

  19. Cardiac Conduction - Ach • Increased K+ conduction – slows conduction • SA node • AV node • Decreased inward Ca++ current – reduces force of contraction • Slowed pacemaker rate opposed by reflexes • Ventricles are less directly affected (parasympathetic innervation of ventricles much less than atria)

  20. Respiratory Effects • bronchial smooth muscle contraction • respiratory gland secretion • asthmatics highly sensitive

  21. GI Effects • Increased secretion • gastric glands • salivary glands • Increased motility - diarrhea

  22. Cholinergic receptors in the brain • Brain has muscarinic receptors • Esters don’t penetrate • Alkaloids penetrate well • Brainstem and spinal cord contain nicotinic receptors • Mild alerting from smoking • Seizures in overdose

  23. Clinical Uses of Cholinergic Agonists • Glaucoma – physostigmine once used • GI and urinary stimulation - bethanechol • myasthenia gravis • edrophonium for diagnosis or testing • pyridostigmine for treatment

  24. SLUDGE: Toxicity • Salivation • Lacrimation • Urination • Defecation • Gastric Emptying

  25. More selective than agonists; may block muscarinic or nicotinic receptors selectively Cholinergic Blockers

  26. Cholinergic Blockers • muscarinic blockers - very useful in medicine • ganglionic blockers - not used much • neuromuscular blockers - used for skeletal muscle relaxation in surgery

  27. Antimuscarinic Drugs • alkaloids – naturally occurring • atropine • scopolamine • tertiary amines • dicyclomine • benztropine • quaternary amines - ipratropium

  28. Antimuscarinic Drugs • tertiary amines & alkaloids • lipid soluble • good absorption from mucous membranes and skin • penetration into brain • wide distribution e.g. brain & periphery • highly selective for muscarinic receptor • quaternary amines - opposite of above

  29. Antimuscarinic Drugs • alkaloids – naturally occurring • atropine • scopolamine • tertiary amines • dicyclomine • benztropine • quaternary amines - ipratropium

  30. Atropine & Scopolamine • plant origin • atropine - Atropa belladonna • scopolamine - Hyoscyamus niger • well absorbed from mucous membranes or skin • competes with Ach for muscarinic receptors • organs differ in sensitivity to these drugs

  31. Atropine • most sensitive • salivary glands • bronchial glands • sweat glands • intermediate sensitivity - heart tissues • least sensitive - parietal cells • highly selective for muscarinic receptors

  32. Atropine - CNS • sedation in therapeutic doses • hallucinations in toxic doses • bradycardia when given parenterally • antimotion sickness effects • antiparkinsonism effects

  33. Atropine - Eye • relaxes pupillary sphincter muscle • unopposed sympathetic effects • mydriasis or dilation • paralysis of the ciliary muscle - cycloplegia • reduction in lacrimal secretion - dry eye

  34. AtropineHeart & Cardiovascular System • initial bradycardia - central effect (?) • tachycardia due to blockade of vagal slowing • Opposes ach effects on SA depolarization • Opposes ach effects on AV conduction • ventricles are less affected • overall - little affect on BP

  35. Atropine • respiratory tract • some bronchodilation • reduction of respiratory secretions • a quaternary drug (Ipatropium) is given as an aerosol to patients with asthma • genitourinary tract - ureter and bladder relaxation • sweat glands - suppressed by atropine

  36. Atropine • dry mouth • slight, if any, decrease in gastric secretion • GI motility decreased • decreased gastric emptying • constipation

  37. Atropine Poisoning • dry as a bone • blind as a bat • red as a beet • very dangerous in children - hyperpyrexia

  38. Therapeutic Uses • antiparkinsonism effects • motion sickness - scopolamine given via transdermal patch • eye examinations - usually something short-acting (e.g. phenylephrine) is used rather than atropine • asthma - ipatropium aerosol • insecticide poisoning

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