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Adrenoceptor Blocking Agents Subat Turdi Adrenergic Blocking Agents Alpha Adrenoceptor Blocking Agents Non-Selective Phenoxybenzamine Phentolamine Alpha-one Selective Prazosin Terazosin Beta Adrenoceptor Blocking Agents Non-Selective Propranolol (Prototype) Nadolol Timolol *Pindolol *Carteolol Ergotamine Ergonovine Cardioselective Atenolol *Acebutolol Metoprolol Betaxolol Alpha-two Selective Yohimbine Very Short Acting Esmolol Tamsulosin (1A) Doxazosin Ergot Alkaloids Alpha and Beta Blocker Labetalol -Adrenergic Receptor Antagonists Receptor Blockers - irreversible 1 & 2 blocker Phentolamine - prototype reversible 1 & 2 blocker Prazosin - selective 1 blocker Tamsulosin – selective 1A blocker Yohimbine - selective 2 blocker Phenoxybenzamine -Adrenergic Receptor Antagonists Phenoxybenzamine = noncompetitve, irreversible Phentolamine = competitive, reversible Both bind both 1 & receptors very low potency at -receptors Alpha Adrenergic Blockers Non-selective blockers: Block both alpha-one and alpha-two adrenergic receptors. Alpha blockers are antagonists (they have no intrinsic activity but do produce pharmacological changes). ’ cause they block the effects of endogenous agonists (epinephrine; norepinephrine) 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 noncompetitive blocker. Phenoxybenzamine New receptors must be synthesized to overcome the blockade Several (2-5) days to regenerate “Dirty” drug - also blocks histamine, acetylcholine, & serotonin receptors Effect of NE to contract vascular smooth muscle in the presence of increasing doses of phenoxybenzamine. 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. 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. 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). 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. 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 alpha2 receptors. Duration of several hours. They also activate histamine receptors (adverse effect). 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 sideeffects. Side effects: tachycardia, nausea, diarrhea, orthostatic hypotension. 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 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 Other -Blockers Yohimbine 2 & 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) Receptor Antagonists Blockers Nonselective = both 1 and 2 Propranolol (prototype) Timolol Pindolol partial Nadolol agonist, ISA Blockers Cardioselective = 1-selective Atenolol (prototype) Others Acebutolol partial agonist, ISA Metoprolol Betaxolol Blockers Very short acting - Esmolol Alpha and beta Blocker - Labetolol - Carvedilol 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 nonreceptor related quinidine-like or membranestabilizing effects. Relatively high lipid solubility allows distribution to the CNS (some drowsiness) 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) 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 Propranolol: Pharmacological Effects. 3. Bronchial Smooth Muscle. 4. Metabolic. Blocks beta receptor effects on lipolysis and glycogenolysis. 5. Quinidine-like effect. 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. 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) Propranolol: Clinical Uses 4. Arrhythmias: sinus tachycardia and supraventricular ectopic beat Recurrent VT, VF - especially when due to ischemia 5. Pheochromocytoma 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 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 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 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 Propranolol: Sudden Withdrawal. rebound hypertension and possibly anginal attacks. Beta receptor synthesis is increased by beta blocker use. Example of receptor upregulation. Other Contraindications. Acute treatment of heart failure; 2nd and 3rd degree heart block, and cardiogenic shock. 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 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 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 Labetolol (Trandate) Selective 1 blocker Nonselective 1 & 2 blocker Clinical Uses: hypertension pheochromocytoma 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. 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 Beta-Blockers with Partial Agonist Activity Pindolol Acebutolol No demonstrated therapeutic advantage over pure antagonists. Lessened bradycardia, better lipid profile ? ISA (Intrinsic sympathomimetic activity) Carvedilol (Coreg) Nonselective -blocker + -blocker Very lipid soluble Also has antioxidant properties Very dramatic results in CHF clinical trials Decreased mortality by 65%