Pharmacology of Muscarinic Receptor Blockade

1. Pharmacology of Muscarinic Receptor Blockade

2. Acetylcholine is an agonist at both muscarinic and nicotinic receptors The nicotinic actions of acetylcholine remain when muscarinic receptors are blocked

3. X Muscarinic Receptor Blockade Does Not Affect Ganglionic Transmission Muscarinic receptor blockade prevents generation of the IPSP and the sEPSP but not the fEPSP

4. X X Muscarinic receptor blockade does not interfere with transmission at autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers. Sympathetic adrenergic functions are not affected.

5. In Dual Innervated Organs, Muscarinic Receptor Blockade Allows Sympathetic Dominance X

6. Atropine

7. Characteristics of Atropine • Source • Atropa belladonna • Datura stramonium • Known as Jamestown weed or jimsonweed • Chemical nature • An alkaloid • Alternate name is d,l-hyoscyamine • Nature of blockade • Competitive

8. control atropine Response Log dose of acetylcholine Response to ACh in the Presence of Atropine Atropine competitively inhibits muscarinic reponses to ACh

9. Actions of Atropine at Tissue Sites • Eye • Sphincter muscle of the iris: mydriasis • Ciliary muscle: cycloplegia Atropine limits focusing to distant objects Accomodation is blocked by atropine

10. Changes in Accomodation and Pupillary Diameter after Administration of an Antimuscarinic Agent Reproduced from Basic and Clinical Pharmacology

11. Actions of Atropine At Smooth Muscles And Glands • Eye • Lacrimal glands • Mucus glands of the pharynx and nasal cavity • Bronchial smooth muscle • Gastric glands • Intestinal glands • Pancreas • Mucus glands of the respiratory tract • Lacrimal glands • Eccrine sweat glands

12. Cardiovascular Actions of Atropine • Heart rate • Low dose • High dose • Systemic blood vessels • Peripheral resistance • Cutaneous blood vessels

13. Response to Doses of Atropine Reproduced from Basic and Clinical Pharmacology

14. M2 M1 ACh ACh (----) ACh M1Receptor Activation at Parasympathetic Nerve Terminals Exerts A Small Negative Feedback Effect Upon ACh Release in Response to Nerve Impulse Flow postsynaptic fiber cardiac muscle fiber

15. M2 M1 x ACh ACh ACh ACh M1Receptor Blockade Eliminates the Negative Feedback Effect and Increases ACh Release in Response to Nerve Impulse Flow postsynaptic fiber cardiac muscle fiber Pirenzepine is an M1 antagonist

16. i.v. infusion Intravenous infusion of acetylcholine in high doses produces actions at numerous sites. Bradycardia and hypotension are among the results. Such actions are accentuated in the presence of inhibitors of AChE (they also block plasma pseudocholinesterase).

17. x i.v. infusion x x Prior blockade of muscarinic receptors followed by intravenous infusion of a high dose of ACh converts the bradycardiac and hypotensive responses to tachycardia and hypertension, mediated through the nicotinic receptors.

18. Effect Of Atropine in Relation to Dosage ...

19. Dose of Atropine DOSE EFFECT 0.5 mg Slight decline in heart rate Some dryness of mouth Inhibition of sweating

20. Dose of Atropine DOSE EFFECT 1.0 mg Definited dryness of mouth Thirst Inreased heart rate, sometimes preceded by slowing Mild dilatation of pupil

21. Dose of Atropine DOSE EFFECT 2.0 mg Rapid heart rate Palpitation Marked dryness of mouth Dilated pupils Some blurring of near vision

22. Dose of Atropine DOSE EFFECT 5.0 mg All the previous symptoms are marked Difficulty in speaking and swallowing Restlessness and fatigue Headache Dry hot skin Difficulty in micturition Reduced intestinal peristalsis

23. Dose of Atropine DOSE EFFECT 10 mg Previous symtoms are more marked and more Pulse, rapid and weak Iris practically obliterated Vision very blurred Skin flushed, hot, dry, and scarlet Ataxia Restlessness and excitement Hallucinations and delirium Coma

24. The previous five slides are reproduced fromGoodman and Gilman’s The Pharmacological Basis of Therapeutics

25. Scopolamine (1) • Source - Hyoscyamus niger (henbane) • Chemical nature of the molecule • Nature of blockade • Changes in the dose response curve of muscarinic agonists in the presence of scopolamine • Lower doses of scopolamine (0.1 - 0.2 mg) produce greater cardiac slowing than an equivalent dose of atropine. Higher doses produce tachycardia • Low doses of scopolamine produce CNS effects that are not seen with equivalent doses of atropine

26. Scopolamine (2) • Therapeutic doses of scopolamine normally produce CNS depression, manifested as drowsiness, amnesia, fatigue, dreamless sleep, reduction in REM, euphoria • In the presence of pain, the same therapeutic dose occasionally cause excitement, restlessness, hallucinations, or delirium. Such excitement is always seen with large doses, as is also seen with large doses of atropine • Therapeutic use - prophylaxis of motion sickness; an adhesive preparation, the Transderm scop is used

27. Therapeutic Uses of Antimuscarinic Agents

28. Therapeutic Uses of Muscarinic Antagonists (1) • Cardiovascular System - atropine is generally used for the following cases • Improper use of choline esters • Sinus or nodal bradycardia in cases of excessive vagal tone associated with myocardial infarct • Hyperactive carotid sinus (syncope and severe bradycardia) • Second degree heart block

29. Therapeutic Uses of Muscarinic Antagonists (2) • Gastrointestinal Tract • Peptic ulcers • In Europe, Japan, and Canada, M1 muscarinic receptor antagonists such as pirenzepine and telenzepine are used • In the U.S. H2 histamine antagonists such as cimetidine are used • Spasticity of the g.i. tract • M3 muscarinic antagonists are being investigated • Excessive salivation associated with heavy metal poisoning and parkinsonism • Production of partial blockade of salivation in patients unable to swallow

30. Therapeutic Uses of Muscarinic Antagonists (3) • Urinary Bladder • Reverse spasm of the ureteral smooth muscle (renal colic) • Increase bladder capacity in cases of enuresis • Reduce urinary frequency in cases of hypertonic bladder

31. Therapeutic Uses of Muscarinic Antagonists (4) • Central Nervous System • Parkinson’s disease • Motion sickness • Produce tranquilization and amnesia prior to surgery and in certain cases such as labor (not a prominent use anymore) • Anesthesia, to inhibit salivation (not a prominent use anymore) • Prevent vagal reflexes induced by surgical manipulation of organs

32. Therapeutic Uses of Muscarinic Antagonists (5) • Posioning by inhibitors of acetylcholinesterase • Mushroom poisoning due to muscarine • In conjunction with inhibitors of acetylcholinesterase when they are used to promote recovery from neuromuscular blockade after surgery • Injudicious use of choline esters • Prevent vagal reflexes induced by surgical manipulation of visceral organs Atropine is used for the above

33. Toxicity of Atropine

34. Contraindications to the Use Of Antimuscarinic Agents • Narrow Angle Glaucoma

35. Flow of Aqueous and Its Escape From the Eye

36. Contraindications to the Use of Antimuscarinic Agents • Narrow angle glaucoma • Hypertrophy of the prostate gland • Atony of the bladder • Atony of the G.I. Tract

37. Tertiary Muscarinic Antagonists and Their Uses • Ophthalmic applications • Cyclopentolate • Tropicamide • Homatropine • Parkinson’s disease • Benztropine • Trihexphenidyl

38. Tertiary Muscarinic Antagonists and Their Uses • Used for antispasmodic purposes • Flavoxate - urinary bladder • Oxybutynin - urinary bladder • Tolterodine - urinary bladder • Dicyclomine • Oxyphencyclimine In general, they are useful for spasms of the g.t. tract, bile duct, ureters,

39. Tolterodine • Therapeutic use - reduce urinary urgency • Metabolism • Cytochrome P450 • Active metabolite is DD-01 • Drug interactions • Ketoconazole • Erythromycin

40. Quaternary Ammonium Antagonists (1) • General characteristics • Pharmacology and therapeutic uses • Distinct side effects with high and sometimes therapeutic doses

41. Quaternary Ammonium Antagonists (2) • Methantheline (N+) • Propantheline (N +) • Methscopolamine (N +) • Homatropine methylbromide (N +) • Oxyphenonium (N +)

42. Quaternary Ammonium Antagonists (3) • Anisotropine (N+) • Glycopyrrolate (N+) • Isopropamide (N+) • Mepenzolate (N+) • Ipratropium (N+)

43. Ipratropium • Uses • Distinctiveness from atropine

44. M1 Muscarinic Receptor Antagonists • Pirenzepine • Blocks the M1 and the M4 receptor • Its usefulness for peptic ulcer • Telenzepine • Blocks the M1 receptor • Its usefulness for peptic ulcer

45. M2 Muscarinic Receptor Antagonists • Tripitamine • Blocks the M2 receptor • Blocks the action of acetylcholine at cardiac muscle fibers • Gallamine • Blocks M2muscarinic and the NN nicotinic sites

46. M3 Muscarinic Receptor Antagonist • Darifenacin • Blocks the M3 receptor • Blocks the actions of acetylcholine at smooth muscles and glands

47. Drugs of Other Classes With Antimuscarinic Activity (1) • Tricyclic antidepressants • Imipramine • Amitriptyline • Protriptyline • Others

48. Drugs of Other Classes With Antimuscarinic Activity (2) • Phenothiazine Antipsychotic Agents • Chlorpromazine • Thioridazine • Perphenazine • Others

49. Drugs of Other Classes With Antimuscarinic Activity (3) • Dibenzodiazepine antipsychotic agents • Clozapine • Olanzepine • Dibenzoxazepine antipsychotic agents • Loxapine

50. Drugs of Other Classes With Antimuscarinic Activity (4) • H1 Histamine receptor blocking agents • Diphenhydramine • Dimenhydrinate • Promethazine • Carbinoxamine • Dimenhydrinate • Pyrlamine • Tripelennamine • Brompheniramine • Chlorpheniramine • Cyproheptadine