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Adrenoceptor antagonist drugs

Adrenoceptor antagonist drugs. Pawitra Pulbutr M.Sc. In Pharm (Pharmacology). Objectives.

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Adrenoceptor antagonist drugs

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  1. Adrenoceptor antagonist drugs Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

  2. Objectives • นิสิตมีความรู้ความเข้าใจถึงเภสัชวิทยา กลไกการออกฤทธิ์ เภสัชจลนศาสตร์ การใช้ประโยชน์ทางคลินิก การเกิดปฏิกิริยาระหว่างยา ของยาที่ออกฤทธิ์ต้านระบบประสาทซิมพาเทติกทั้งชนิด -receptor antagonist และชนิด -receptor antagonist

  3. Adrenoceptor blocking agent • Affect many physiological & pathophysiological functions • In the past… may be called “Sympatholytics”… Not appropriate • Antagonist or Blocker >>> More appropriate •  blocker… • Pheochromocytoma, Primary hypertension •  blocker… • Hypertension, Ischemic heart disease, Arrhythmia, Other endocrine disorder

  4. Relative selectivity of antagonist for adrenoceptors

  5. Basic Pharmacologyof -blockers • Binding with -receptor • Reversible • Competitive with catecholamine • Phentolamine, Tolazoline, Prazosin, Labetalol • Irreversible • Covalent binding • Phenoxybenzamine • Nitrogen mustard like structure • Form reactive ethyleneimmonium compound

  6. Reversible blocker Irreversible blocker Dose-response curve to NE in the presence of two different -blockers.

  7. Pharmacologic effects • CVS • -receptor control • Arteriolar tone • Venous tone • -receptor antagonist • Decrease peripheral vascular resistance (TPR) • Decreased BP • May cause postural hypotension or reflex tachycardia (esp. if 2 also blocked … increase NE secretion… more tachycardia) • Body compensation in long term use … Increase blood volume

  8. Other -blocking effects • Bladder base & Prostate • -blocker … • Decrease resistance • Increase urine flow • Use in benign prostatic hyperplasia (BPH)

  9. -blockers • Irreversible blockers • Phenoxybenzamine • Reversible blockers • Non-selective blocker • Phentolamine, Tolazoline • Selective 1-blocker • Prazosin family • Doxazosin, Terazosin, Alfuzosin, Tamsulosin • Selective 2-blocker • Yohimbine

  10. Clinical Pharmacology • Pheochromocytoma • Hypertensive emergencies • Chronic hypertension • Peripheral vascular disease • Local vasoconstrictor excess • Urinary obstruction >> BPH • Male sexual dysfunction

  11. Chronic hypertension • Prazosin family • 1-selective blockers • Treatment of mild to moderate hypertension • ADRs • Postural hypotension esp. First dose • Not use non-selective -blocker • 2 blocker … Increase NE release

  12. Urinary obstruction • Benign prostatic hyperplasia (BPH) • Mostly found in elderly male • Treatment • Surgery • Drug therapy • 1-blocker • Partial reversal of smooth muscle contraction at prostate and bladder base • Prazosin, Doxazosin, Terazosin, Tamsulosin • Good effective esp. in hypertensive patients

  13. Basic Pharmacology of -blockers • Competitive binding to -receptor • “Isoproterenol” like structure • Difference affinity to 1 or 2 receptor • Pure antagonist • Pure -blocker • Partial agonist • -blocker with intrinsic sympathomimetic activity (ISA) • Activate -RC… not to maximal response • Interfere endogenous ligand to bind -RC • -blocker with -blocker activity (Mixed) • Labetalol & Carvedilol

  14. Properties of several Beta-blockers

  15. Pharmacological effects • CVS • Decrease BP • Heart • Negative chronotropic & inotropic • Slow arterioventricular conduction • Prolong PR interval (AV node suppression) • Renin Angiotensin Aldosterone (RAA) system… decrease renin release • Vascular resistance • Inhibit 2-mediated vasodilation • Acute effect >>> Vasoconstriction • Prolong action …. Decrease peripheral vascular resistance • Decrease renin (RAA)

  16. Respiratory tract • 2-receptor blocking activity • Bronchoconstriction • Danger in asthmatic patients !! • Should select 1-selective blocker… less bronchoconstriction • Acebutolol, Atenolol, Betaxolol, Bisoprolol, Celiprolol, Esmolol, Metoprolol • Use with caution in asthma

  17. Eyes • -blocker … decrease aqueous humor production …decrease intraocular pressure • Use in glaucoma • Metabolic & endocrine effects • -blocker … Inhibit lipolysis • Inhibit glycogenolysis in liver • May affect hypoglycemia correction ? • Should be use with caution in DM esp. Type 1 • Increase LDL • Decrease HDL • Decrease HDL/ LDL ratio • Increase risk of CVS disease • Partial agonist … less effects • - blockers … No effect

  18. Effects not related to -blockade • Intrinsic sympathomimetic activity of partial agonist • -blocker with ISA (partial agonist) • Acebutolol, Carteolol, Celiprolol, Labetalol, Penbutolol, Pindolol • May be useful in asthmatic & bradycardia patients • Less bronchoconstriction • Less bradycardia

  19. Clinical Pharmacology • Hypertension • Ischemic heart disease • Cardiac arrhythmia • Other CVS disorder • Glaucoma • Hyperthyroidism • Neurologic disease • Miscellaneous

  20. Choice of -blocker • Specific activity of each agent • Benefit or Risk of each agent • 1-selective • Partial agonist • May not be replaced with others • Only pure antagonist is used in hyperthyroidism

  21. ADRs • Propranolol • Rash, Fever, Drug allergy • Sedation, Sleep disturbance, Depression • Less in hydrophillic -blocker…Nadolol, Atenolol • Unwanted -blocking effect • Bronchoconstriction (2)… Asthma • Vasospasm (2)… Peripheral vascular dz. • Use selective 1-blocker

  22. ADRs • Use with caution in CHF patient • Reversal of life threatening -blocker effect • Isoproterenol, Glucagon • Drug Interaction • Ca++ channel blocker • Severe hypotension, Severe bradycardia, Heart failure • Taper dose • Prolong use …“RC upregulation” • Sudden stop … RC over stimulation … Danger ! • Slowly stop using -blocker in ischemic heart disease • Especially in short half-life … propranolol, metoprolol

  23. Use with caution in Type 1 DM • -blocker may interfere hypoglycemia recovery • 2 activation >>> Glycogenolysis • Use selective 1-selective blocker • Mask disease/ symptom manifestation • Mask hypoglycemia sign … tachycardia • Mask hyperthyroidism symptom

  24. -blockers • Pure antagonists • Propranolol, Nadolol, Sotalol, Timolol • Selective 1-antagonists • Metoprolol, Esmolol, Celiprolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol (MEC 2A 2B) • Partial agonist (Blockers with ISA) • Labetalol, Acebutolol, Carteolol, Celiprolol, Penbutolol, Pindolol (LA 2C 2P) • Mixed antagonist ( and -blockers) • Labetalol, Carvedilol

  25. Q & A

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