PM716 Pharmacology I - NE Blockers PDF

PM716 Pharmacology I Chapter 10 NE Blockers Sympatholytics RMRocco, PhD PM716 C10 Adrenoceptor Blockers 1  Case Study 46 year old female with headache and palpitations, drenching sweats, BP 150/90 mmHg, heart rate 88 bpm. Palpation of abdomen caused BP t...

PM716 Pharmacology I Chapter 10 NE Blockers Sympatholytics RMRocco, PhD PM716 C10 Adrenoceptor Blockers 1  Case Study 46 year old female with headache and palpitations, drenching sweats, BP 150/90 mmHg, heart rate 88 bpm. Palpation of abdomen caused BP to rise to 210/120 mm Hg, bpm 122. Cause? Treatment? PM716 C10 Adrenoceptor Blockers 2  Case Study Patient has a pheochromocytoma. Examination set off another episode of catecholamine release. Treat pre-op to stabilize with phenoxybenzamine or phentolamine. PM716 C10 Adrenoceptor Blockers 3 Sympatholytics (Adrenoceptor Antagonists) PM716 C10 Adrenoceptor Blockers 4  Sympatholytics Adrenergic receptor blockers of alpha and beta receptors mainly in the PNS. Adrenergic antagonists block endogenous catecholamines and related agonist drugs. Blockade of PNS dopamine receptors has no major clinical use (CNS antagonism is of major clinical importance). PM716 C10 Adrenoceptor Blockers 5  Sympatholytics Clinical Uses Include: Nonselective alpha antagonists: pheochromocytoma Alpha1 selective antagonists: hypertension and benign prostatic hyperplasia (BPH) Beta antagonists: hypertension, ischemic heart disease, neurological disorders etc. PM716 C10 Adrenoceptor Blockers 6  Pheochromocytoma Tumor derived from the neural crest cells of the sympathetic nervous system. Cause of ~ 2% of all hypertension. Tumor releases NE and EP which causes palpitations, sweating, headaches, hypertension. 85% of tumors in adrenal, rest outside. Surgical treatment following phenoxybenzamine. PM716 C10 Adrenoceptor Blockers 7  Sympatholytics Alpha Antagonist Types: (Based on type of binding to their receptors) Reversible: duration of action related to t1/2 or length of time Cp stays elevated. Irreversible: drugs forms covalent bond with receptor. Drug action continues for days after the drug clears the plasma. New receptor synthesis required to restore physiological function (takes days). PM716 C10 Adrenoceptor Blockers 8  Sympatholytics Alpha Antagonists Reversible: phentolamine tolazoline prazosin labetalol Irreversible: phenoxybenzamine PM716 C10 Adrenoceptor Blockers 9  Adrenergic Alpha 1 selective Antagonists Prazosin Terazosin doxazosin Non-Selective Alpha Phentolamine phenoxybenzamine Beta 1 Selective Acebutolol Atenolol Bisoprolol metoprolol Non-Selective Beta Carteolol Bucindolol Nadolol Penbutolol timolol PM716 C10 Adrenoceptor Blockers 10  Main Mechanisms of Sympathetic Block (1) Decrease sympahetic outflow from brain. (2) Supress release of NE from neuron terminals. (3) Block postsynaptic receptors. PM716 C10 Adrenoceptor Blockers 11  Concepts to Remember Alpha 2 AGONISTS (clonidine) reduces sympathetic activity. An Agonist drug that acts Antagonistically at Alpha 2 receptors (clonidine) Used to treat hypertension. Alpha 2 activation inhibits sympathetic outflow from brain and release of NE from neuron terminals (PNS). PM716 C10 Adrenoceptor Blockers 12  Sympatholytics Alpha Antagonists Alpha receptors mostly on vascular smooth muscle, antagonism lowers BP. Epinephrine (EP) Reversal: a condition in which activation of alpha and beta receptors located in the same tissue leads to opposite effects. EP activates alpha and beta to increase BP, selective alpha1 antagonist blocks BOTH alpha and beta agonist actions of EP and BP is lowered. PM716 C10 Adrenoceptor Blockers 13  Sympatholytics Alpha Antagonists Phentolamine: alpha 1 and 2 antagonist used to lower BP; also used to treat pheochromocytoma (neural crest cell tumor of the sympathetic nervous system. Tumor produces NE and EP and induces hypertensive crisis. Cause of up to 2% of all hypertension. Tumor most often located in the adrenal gland. PM716 C10 Adrenoceptor Blockers 14  Sympatholytics Alpha Antagonists Phenoxybenzamine: irreversible alpha blocker, 14-48+ h duration of action. Prazosin: Alpha 1 selective, low incidence of tachycardia due to selectivity. Terazosin: reversible alpha 1 antagonist, used to treat BP and BHP. Doxazosin: used for BP and BHP with long half life (22 h). Tamsulosin(tam SOO loe sin): Used for BP and BHP, long half life 9-15 h, alpha 1 blocker. PM716 C10 Adrenoceptor Blockers 15  Sympatholytics Alpha Antagonists Ergot Derivatives: reversible alpha blockers, use in migraine due to serotonin (5HT) blocking not alpha effects. PM716 C10 Adrenoceptor Blockers 16  Alpha Blockers Most cause vasodilation and that means lowered BP. (Alpha agonists cause vasoconstriction) POSTURAL HYPOTENSION: Standing requires more NE to control BP Less NE required to control BP when lying. Alpha blockers have greater effect when NE is highest (standing) = Postural Hypotension. PM716 C10 Adrenoceptor Blockers 17  Alpha Blockers Side Effects Postural hypotension Reflex tachycardia. PM716 C10 Adrenoceptor Blockers 18  Sympatholytics Alpha Antagonists Pheochromocytoma: adrenal medulla tumor (usual location) releases NE and EP with high BP, sweating, palpitations, headache due to catecholamine excess. Diagnose with urinary NE, EP metabolites (VMA), CT, MRI. Phenoxybenzamine and phentolamine drugs of choice pre and post op. PM716 C10 Adrenoceptor Blockers 19  Sympatholytics Alpha Antagonists Hypertensive Emergencies: limited use, (beta blockers most often used) Chronic Hypertension: prazosin and other alpha 1 selective blockers. Urinary Obstruction: drug treatment for BPH (rather than surgery), drugs block smooth muscle contraction in enlarged prostate. Prazosin, doxazocin, terazosin. PM716 C10 Adrenoceptor Blockers 20  Sympatholytics Beta Antagonists (Beta Blockers) Drugs block catecholamine (NE, EP) actions at beta receptors. All bind competitively (not irreversible). Most are pure antagonists (no partial activation of the receptor). Some are partial antagonists (inhibit in presence of endogenous agonists, stimulate in absence of endogenous agonists, EP, NE). Drugs differ in selectivity for beta 1 and 2, none have absolute specificity. PM716 C10 Adrenoceptor Blockers 21  Sympatholytics Beta Antagonists Propranolol Nadolol Pindolol Acebutolol Metoprolol Timolol Atenolol Labetalol PM716 C10 Adrenoceptor Blockers 22  Agonists and Antagonists Sympath Sympath Parasymp Alpha Beta Muscarinic NE +++ + -------- EP + +++ -------- Ach ------- ------ +++ Agonists Phenylephrine Isoproterenol Muscarine methoxamine Dobutamine pilocarpine Albuterol terbutaline Antagonists Phentolamine Propranolol Atropine Prazosin Pindolol scopolamine Ergots timolol terazosin PM716 C10 Adrenoceptor Blockers 23 Chapter 10 Adrenoceptor Antagonist Drugs PM716 C10 Adrenoceptor Blockers 24 © The McGraw-Hill Companies, Inc, Chapter 10 Adrenoceptor Antagonist Drugs PM716 C10 Adrenoceptor Blockers 25 © The McGraw-Hill Companies, Inc,  Agonists Clinical Effects Sympath Sympath Parasym Alpha Beta Muscarinic Heart Increase rate Decrease rate Increase Decrease contraction contraction Blood Vessels constriction dilation dilation Intestines Dec motility Dec motility Increase motility PM716 C10 Adrenoceptor Blockers 26  Sympatholytics Beta Antagonists Well absorbed after po dosing. F of drugs varies widely with some first pass effects. Drugs have large Vd, t1/2 is 3 - 10 h, most cross the BBB (lipophilic). Genetic variation in CYP 2D6 accounts for variation in response. PM716 C10 Adrenoceptor Blockers 27  Sympatholytics Beta Antagonists Cardiovascular: Lower BP due to multiple effects in CNS, suppression of renin angiotensin system, blood vessels. Negative inotropic and chronotropic effects on the heart. Respiratory System: Block B2 in smooth muscle causes constriction in airway, beta 1 selective (metoprolol, atenolol) more specific for cardiac with less effect on lung. PM716 C10 Adrenoceptor Blockers 28  The Eye Increased intraocular pressure (glaucoma) can lead to nerve and retina damage with blindness. Open angle glaucoma is treated with drugs by either reducing aqueous humor secretion or enhancing humor outflow. PM716 C10 Adrenoceptor Blockers 29 Chapter 10 Adrenoceptor Antagonist Drugs PM716 C10 Adrenoceptor Blockers 30 © The McGraw-Hill Companies, Inc,  Sympatholytics Beta Antagonists EYE: reduce intraocular pressure in glaucoma. Metabolic and Endocrine: inhibit lipolysis, used with caution in diabetes because beta 2 selective beta blockers reduce glycogenolysis in liver. PM716 C10 Adrenoceptor Blockers 31  Sympatholytics Beta Antagonists Propranolol: first drug in the beta blocker class, non selective, numerous CNS effects. Metoprolol and Atenolol: Beta 1 selective. Nadolol: long duration of action. Timolol: nonselective, used topically for glaucoma. PM716 C10 Adrenoceptor Blockers 32  Sympatholytics Beta Antagonists HYPERTENSION: combined with a diuretic and/or vasodilator. ISCHEMIC HEART DISEASE: reduce frequency of angina episodes, improve exercise tolerance. CARDIAC ARRHYTHMIAS: treat both supraventricular and ventricular arrhythmias. PM716 C10 Adrenoceptor Blockers 33  Sympatholytics Beta Antagonists GLAUCOMA: reduce intraocular pressure, topical application blocks aqueous humor production. HYPERTHYROIDISM: excess hormone produces elevated EP, NE levels. NEUROLOGIC DISEASE: propranolol used for migraine. PM716 C10 Adrenoceptor Blockers 34  Agonists: Clinical Uses EP sc, iv for anaphylatic shock iv cardiac arrest sc with local anesthetic to delay absorption B2 Agonists inhalation for asthma Phenylephrine intranasal to reduce nasal congestion PM716 C10 Adrenoceptor Blockers 35  Antagonists: Clinical Uses Prazosin (A1) hypertension Phenoxybenzamine (non-selective) to treat pheochromocytoma Atenolol, metoprolol, propranolol hypertension Timolol eye drops for glaucoma PM716 C10 Adrenoceptor Blockers 36 Beta Blockers Music college teacher in Memphis fired for recommending propranolol to her students who suffered from stage fright. Drug blocks sympathetic outflow which accounts for fear in perceived danger (classic concert). Estimates are that 27% of classical musicians use beta blockers for stage fright. PM716 C10 Adrenoceptor Blockers 37  Sympatholytics Beta Antagonists CNS effects: sedation, sleep disturbance, depression found with non-selectives (propranolol) and high lipid solubility beta antagonists. Non-selective drugs block Beta 2 receptors in lung and worsen asthma conditions. Cardiac function requires sympathetic drive which if blocked by beta antagonists in cardiac diseased patients can provoke cardiac failure. Beta blockers exacerbate hypoglycemia in insulin dependent patients. PM716 C10 Adrenoceptor Blockers 38  Summary (1) Clinical uses of antagonists (alpha and beta) (2) pheochromocytoma (3) reversible vs irreversible drugs (4) antagonist drugs (5) alpha blocker drugs (6) beta blocker drugs (7) clinical uses of blocker (antagonist) drugs. PM716 C10 Adrenoceptor Blockers 39