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Adrenoceptor Blocking Agents

Adrenoceptor Blocking Agents. Subat Turdi . Adrenergic Blocking Agents. Alpha Adrenoceptor Blocking Agents. Beta Adrenoceptor Blocking Agents. Non-Selective Propranolol ( Prototype) Nadolol Timolol *Pindolol *Carteolol. Non-Selective Phenoxybenzamine Phentolamine.

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Adrenoceptor Blocking Agents

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  1. Adrenoceptor Blocking Agents Subat Turdi

  2. Adrenergic Blocking Agents Alpha Adrenoceptor Blocking Agents Beta Adrenoceptor Blocking Agents Non-Selective Propranolol (Prototype) Nadolol Timolol *Pindolol *Carteolol Non-Selective Phenoxybenzamine Phentolamine Alpha-one Selective Prazosin Terazosin Tamsulosin (1A) Doxazosin Cardioselective Atenolol *Acebutolol Metoprolol Betaxolol Ergot Alkaloids Ergotamine Ergonovine Alpha-two Selective Yohimbine Very Short Acting Esmolol Alpha and Beta Blocker Labetalol

  3.  -Adrenergic Receptor Antagonists • Receptor Blockers • Phenoxybenzamine - irreversiblea1 & a2 blocker • Phentolamine - prototype reversible a1 & a2 blocker • Prazosin - selective a1 blocker • Tamsulosin – selective a1A blocker • Yohimbine - selective a2 blocker

  4.  -Adrenergic Receptor Antagonists • Phenoxybenzamine = noncompetitve, irreversible • Phentolamine = competitive, reversible Both bind both 1 &  receptors • very low potency at -receptors

  5. Alpha Adrenergic Blockers • Non-selective blockers: Block both alpha-one and alpha-two adrenergic receptors. • Alpha blockers are antagonists (they have nointrinsic activity but do produce pharmacological changes). • ’ cause they block the effects of endogenous agonists (epinephrine; norepinephrine)

  6. Phenoxybenzamine (Dibenzyline) • Mechanism. Binds covalently to alpha-1 and alpha-2 adrenergic receptors. i.e. non-selective, irreversible, alpha blocker. Onset is slow requiring 10-20 minutes for formation of covalent linkages. Offset is even slower with a t1/2 of 24 hours. Terminated by metabolism and new receptor synthesis. Called non-equilibrium or non-competitive blocker.

  7. Phenoxybenzamine • New receptors must be synthesized to overcome the blockade • Several (2-5) days to regenerate • “Dirty” drug - also blocks histamine, acetylcholine, & serotonin receptors

  8. Effect of NE to contract vascular smooth muscle in the presence of increasing doses of phenoxybenz-amine.

  9. Phenoxybenzamine:Pharmacological Effects. 1. Vascular. Dependent on the degree of sympathetic tone. i.e., blocks the effects of endogenous NE. See reduced blood pressure. Orthostatic hypotension.

  10. Phenoxybenzamine:Pharmacological Effects 2. Cardiac. Reflex tachycardia from reducing BP, which enhances NE release. Because alpha-2 receptors on adrenergic nerves are also blocked, this further increases NE release at the heart, where it can act on beta-1 receptors.

  11. Phenoxybenzamine: Effects 3. CNS. lipophilic agent which can cross the blood brain barrier. Nausea, vomiting and weakness may be signs of non-specific effects. 4. Others: miosis, inhibition of ejaculation, stuffy nose (all alpha1 blockade).

  12. Phenoxybenzamine: Clin. Uses 1. Pheochromocytoma: Pre-operative management to treat vascular effects of high circulating catecholamines. 2. Peripheral Vascular Disease. Raynaud’s syndrome where sympathetic tone to peripheral vasculature is high. Acrocyanosis from frost bite.

  13. Reversible Alpha Blockers • Competitive blockers. Rapid onset of blockade. Surmountable by high concentrations of alpha-1 agonists • Phentolamine and Tolazoline (Imidazoline derivatives). Non-selective for alpha-1 and alpha-2 receptors. Duration of several hours. They also activate histamine receptors (adverse effect).

  14. Phentolamine: Clinical Uses 1. Pheochromocytoma. Acute hypertensive crisis. 2. Clonidine withdrawal 3. Treat necrosis due to vasoconstrictors such as NE and phenylephrine. 4. For erectile dysfunction (ED) – has been replaced by drugs with less severe side-effects. • Side effects: tachycardia, nausea, diarrhea, orthostatic hypotension.

  15. Alpha-1 Selective Blockers • Block alpha-1 but not alpha-2 adrenergic receptors. • Generally reflex tachycardia is less prevalent than with non-selective alpha blockers. • Syncope is noted when first administered in a large group of patients. Caution patients to avoid sudden postural changes. • Agents: PRAZOSIN, TERAZOSIN, DOXAZOSIN • Uses: Hypertension, benign prostatic hypertrophy

  16. Alpha-One Selective Blockers • Prazosin (Minipress) (prototype) • Terazosin (Hytrin) • Doxazosin (Cardura) • Selective block for 1 receptor; 2 intact • Clinical Uses: • Hypertension • Benign prostatic hypertrophy - reverses smooth muscle contraction

  17. Other -Blockers • Yohimbine • a2 & 5-HT blocker • aphrodisiac, improves erectile function • Viagra will replace • Ergot Alkaloids • Ergotamine, Ergonovine • originally found in spoiled rye (fungus), caused abortions, gangrene, convulsions • used to treat migraine (also 5-HT agonists)

  18. Receptor Antagonists Blockers • Nonselective = both 1 and 2 • Propranolol (prototype) • Timolol • Pindolol • partial agonist, ISA • Nadolol

  19. Blockers • Cardioselective = 1-selective • Atenolol (prototype) • Others • Acebutolol • partial agonist, ISA • Metoprolol • Betaxolol

  20. Blockers • Very short acting - Esmolol • Alpha and beta Blocker - Labetolol - Carvedilol

  21. Beta Adrenergic Receptor Blockers. A. Propranolol (Inderal) is the prototype • mechanism. Non-selective competitive antagonist at beta-1 and beta-2 receptors. High therapeutic doses may also have a non-receptor related quinidine-like or membrane-stabilizing effects. Relatively high lipid solubility allows distribution to the CNS (some drowsiness)

  22. Propranolol: Pharmacological Effects • The effect of antagonists is due to blocking existing tone. Effects are greater if sympathetic tone is high. 1. Heart. decreases HR, CO, and pacemaker activity. 2. Blood vessels. Slow developing decrease in peripheral resistance. Possibly due to: central reduction in sympathetic tone and reduction in renin release (beta-1 effect)

  23. Propranolol • Pharmacological Effects - depend on existing sympathetic tone • Heart: •  heart rate and cardiac output • exercise tolerance • rate of depolarization of ectopic pacemakers •  O2 demand •  AV nodal conduction •  infarct size & re-infarction- prevent sudden death

  24. Propranolol: Pharmacological Effects. 3. Bronchial Smooth Muscle. 4. Metabolic. Blocks beta receptor effects on lipolysis and glycogenolysis. 5. Quinidine-like effect.

  25. Propranolol: Metabolism • Well absorbed following oral administration. • Up to 2/3 may be inactivated by first pass metabolism. There is large inter-individual variation. Variation is relatively constant for a given patient. Must titrate the dose upward for each patient.

  26. Propranolol: Clinical Uses 1. Angina pectoris. Reduces cardiac work and O2 consumption. 2. Hypertension. Decreases CO and produces slow decrease in peripheral resistance due to blockade of renin release. May see Na+ and water retention with prolonged use because of reduced CO. 3. Migraine headache (Prophylactic treatment)

  27. Propranolol: Clinical Uses 4. Arrhythmias: sinus tachycardia and supraventricular ectopic beat • Recurrent VT, VF - especially when due to ischemia 5. Pheochromocytoma

  28. Propranolol: Clinical Uses • Thyrotoxicosis: • hyperthyroid patients have receptor sensitivity • Adjuntive treatment for anxiety (panic) attacks • reduces peripheral sympathetic signs and symptoms, e.g., palpitations • MI & Post-MI prophylaxis • protects against arrhythmias & limits infarct size • Acute MI: assess LV function • 5-12 days after MI, reduces O2 demand & spread of infarct zone

  29. Congestive Heart Failure • Congestive Heart Failure • Dramatic results in recent clinical trials • Beta blockers prevent HF in >50%, strokes reduced by >38%, occurrence of CAD and other CV events significantly decreased • Mortality rate reduced 65% by carvedilol, 34% by metoprolol, 33% by bisoprolol • Beta blockers increase LVEF, cause beneficial remodeling of heart • Use only in stable CHF (class II &III), gradually titrate dose • Patients also treated with diuretic, ACE inhibitors, & digoxin

  30. Propranolol: Side Effects • Common: • dizziness, fatique, diarrhea, constipation, nausea, depression • Severe • purpura, rash, fever • Interferes with SGOT and BUN tests • Chronic use (hypertension)  VLDL & HDL

  31. Propranolol: Side Effects • Use with caution in diabetics • inhibits compensatory response to hypoglycemia (glucagon release & glycogenolysis) • masks signs of hypoglycemia (tachycardia) that are important “clues” to diabetic patient • Contraindicated in most asthmatics and COPD • Sudden withdrawal syndrome: • rebound hypertension, anginal attack & possibly MI if drug suddenly withdrawn after chronic therapy

  32. Propranolol: • Sudden Withdrawal. rebound hypertension and possibly anginal attacks. Beta receptor synthesis is increased by beta blocker use. Example of receptor up-regulation. • Other Contraindications. Acute treatment of heart failure; 2nd and 3rd degree heart block, and cardiogenic shock.

  33. Propranolol: Drug Interactions • Other hypotensive medications • reserpine, guanethidine, methyldopa • Other anti-arrhthymic agents • calcium channels blockers • lidocaine • Insulin and oral hypoglycemic drugs • prolongs hypoglycemia and masks signs • Masks symptoms of hyperthyroidism

  34. Other Nonselective  Blockers • Nonselective Blockers • Nadolol (Corgard) - longer acting; once-per-day dosing • Timolol (Blocadren) - more potent than propranolol • Timolol (Timoptic) - • lowers IOP in glaucoma • reduces aqueous humor production • Pindolol (Visken) - partial agonist; partial blockade • less incidence of rebound hypertension • less bradycardia • Carteolol - like pindolol

  35. 1-Selective Blockers • All are more potent at 1 than 2 receptors • at higher doses, block 2 as well • lessen risk of bronchospasm -still contraindicated in asthmatic • do not prolong hypoglycemia • Atenolol(Tenormin) prototype • Acebutolol (Sectral) - partial agonist, hypertension, dysrhythmias • Metoprolol(Lopressor, Topral XL) – hypertension, CHF • Betaxolol (Betoptic) – glaucoma • Bisoprolol (Zebeta) - CHF

  36. Labetolol (Trandate) • Selective 1 blocker • Nonselective 1 & 2 blocker • Clinical Uses: • hypertension • pheochromocytoma

  37. Cardio- or Beta-1 Selective • Metoprolol-hypertension • Atenolol-hypertension, stable angina • Acebutolol-hypertension, dysrhythmias • Betaxolol-glaucoma, hypertension They must be used very cautiously if at all in patients with reactive (asthma) airways.

  38. Esmolol (Brevibloc) • Very rapid onset & short duration of action • 1-selective • Used as IV infusion for peri-operative tachycardia and hypertension, arrhthymias • Used in electroconvulsive therapy

  39. Beta-Blockers with Partial Agonist Activity • Pindolol • Acebutolol No demonstrated therapeutic advantage over pure antagonists. Lessened bradycardia, better lipid profile ? ISA (Intrinsic sympathomimetic activity)

  40. Carvedilol (Coreg) • Nonselective b-blocker + a-blocker • Very lipid soluble • Also has antioxidant properties • Very dramatic results in CHF clinical trials • Decreased mortality by 65%

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