Cholinoceptor activating drugs

1. Cholinoceptor activating drugs M.R. Zarrindast

2. Cholinergic Receptors: Where are they? • Postganglionic parasympathetic neuroeffector junctions • All autonomic ganglia • At the neuromuscular endplate

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

4. Subtypes and characteristic of cholinoceptors

8. Muscarinic receptors(Stimulated by muscarine) • on cells innervated by PNS • smooth muscle • heart • exocrine glands • endothelial cells of the vascular beds (even though these are not innervated) • brain

9. Nicotinic receptors(Stimulated by nicotine) • autonomic ganglia - CNS & PNS • neuromuscular junction (somatic nerves) • brain – esp. the spinal cord

10. The major groups of cholinoceptor-activating drugs

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

12. Esters of Choline

13. 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

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

15. Properties of choline esters

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

18. Nicotinic to depolarizing blockade receptors are susceptible • depolarizes ganglion cell or neuromuscular endplate • if present in high concentration, they produce a “depolarizing block” • neuron or endplate stays depolarized • skeletal muscle relaxation • ganglia of both PNS & SNS systems may be paralyzed

19. Effects of Muscarinic Agonists • Eye • Cardiovascular system • Heart • Blood vessels • Respiratory tract • Gastrointestinal tract

20. Effect of direct-acting cholinoceptor stimulants

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

25. 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

26. 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)

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

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

29. 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

30. Nicotine • Complex effects on receptors • Agonist effects • brain nicotinic receptors • ganglionic nicotinic receptors – turns on both PNS and SNS • neuromuscular nicotinic receptors – only in overdose • Blockade - may produce a “depolarizing block” of nicotinic receptors in high doses

31. Nicotine • Organ effects • Determined by predominate branch of the autonomic nervous system in that organ • CV effects - largely sympathetic • Increased HR, SV, CO • Vasoconstriction of vascular beds • GI & Urinary - largely parasympathetic • Chronic toxicity is the most serious from a societal point of view

32. Indirect-Acting Agents • inhibit Ach’esterase • buildup of Ach at ganglia, neuroeffector and neuromuscular junctions • amplify effects of endogenous Ach • chief use: insecticides

33. Acetylcholinesterase Inhibitors 1. simple alcohols (edrophonium) 2. carbamic acid esters (neostigmine) 3. organophosphates (isoflurophate)

34. Enzyme Binding • simple alcohols - bind to enzyme reversibly (edrophonium) • carbamates - bond with Ach’ase more long-lasting e.g. 30 mins • organophosphates - bond irreversibly; very long acting

35. Duration of Action of Cholinesterase Inhibitors • Determined mostly by length of binding to enzyme • simple alcohols - short • carbamates - intermediate • organophosphates - very long

36. Therapeutic uses and durations of action of cholinesterase inhibitors

38. Edrophonium (Tensilon) • Short acting alcohol type • Uses • Diagnosis of myasthenia gravis* • Muscle strength tested after administration • Marked improvement is a positive test • Adequacy of treatment *Look up the pathogenesis of myasthenia gravis

39. Edrophonium (Tensilon) • Test adequacy of treatment with longer acting agents (e.g. pyridostigmine) • Improvement means dose of long acting agent too low • No improvement or worsening indicates “depolarizing block” by long-acting agent. Lower dose indicated.

40. Organophosphates • phosphorylates Ach’esterase enzyme • covalent phosphorus-enzyme bond strong • After time the bond “ages” or gets stronger • enzyme may be rejuvenated with pralidoxime, esp. before “aging”

41. Signs and symptoms of organophosphate poisoning

42. Some Insecticides • Organophosphates • chlorpyrifos (Dursban) • malathion • diazinon • Carbamate • Carbaryl (Sevin)

43. Cholinesterase Inhibitors • CNS - may cause convulsions • GI, respiratory, urinary – stimulatory, like direct-acting agents

44. Cholinesterase Inhibitors • Cardiovascular • both sympathetic & parasympathetic stimulation • parasympathetic predominate • bradycardia, decreased CO, modest fall in BP

45. Cholinesterase Inhibitors • Skeletal muscle • therapeutic doses - • moderately prolong Ach • intensify Ach actions • toxic doses • fibrillation of muscle fibers • depolarizing blockade and muscle paralysis

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

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

48. Cholinesterase Inhibitor Toxicity • approximately 100 organophosphates & 20 carbamate insecticides available • SLUDGE • convulsions in bad toxicities • depolarizating nmj blockade

49. Cholinergic Blockers More selective than agonists; may block muscarinic or nicotinic receptors selectively M.R. Zarrindast

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