Adrenergic Blockers PDF

Adrenergic Blockers PHRM 240 Ramzi Sabra, MD, MHPE Learning Outcomes Classify Alpha adrenoceptor antagonists (alpha blockers) based on their mode of action and their selectivity to alpha receptor subtypes Describe and explain the pharmacological effects of alpha blockers on the various orga...

Adrenergic Blockers PHRM 240 Ramzi Sabra, MD, MHPE Learning Outcomes Classify Alpha adrenoceptor antagonists (alpha blockers) based on their mode of action and their selectivity to alpha receptor subtypes Describe and explain the pharmacological effects of alpha blockers on the various organs/systems in the body and differentiate between selective and nonselective blockers Explain why alpha-1 selective agents cause less tachycardia than nonselective alpha blockers Discuss and explain the therapeutic use of alpha agonists in hypertension and in prostatic hypertrophy Identify and explain the major adverse effects of alpha blockers (especially postural hypotension and cardiac stimulation) Specifically explain and why their use in hypovolemic patients with coronary artery disease may be particularly risky Alpha-Adrenergic Blockers 1. Type of blockade Non-competitive – phenoxybenzamine only; slow onset and long duration. Competitive – all the rest- phentolamine, prazosin, yohimbine... 2. Selectivity Nonselective: Phenoxybenzamine and phentolamine alpha-1 selective: Prazosin, terazosin, others alpha-2 selective: Yohimbine alpha/beta blockers: Labetalol Classification of Alpha-receptor Blockers Pharmacological Effects 1. Cardiovascular system Blood pressure: decrease Cardiac Effects: Heart rate and cardiac output: increase (reflex) Organ Blood Flow: increase 2. Urinary bladder: decreased smooth muscle tone in sphincter 3. Inhibition of ejaculation 4. Other effects a. eye - miosis b. lung – bronchodilation - slight c. metabolic - increases insulin secretion Adverse effects Postural hypotension Tachycardia Nasal congestion Impotence (inhibits ejaculation) Miosis Be careful in hypovolemic patients  EPI Receptors no longer % Maximal Increase EPI + Phenoxybenzamine available Phenoxybenzamine alone Decrease in the maximal efficacy of Epi due to a decrease in the number of receptors [Agonist], mg/kg  Alpha-1 selective blockers Prazosin Less cardiac stimulation since it preserves alpha-2 mediated negative feedback + other mechanisms (remember that activation of alpha-2 in CNS decreases sympathetic tone and activation of alpha-2 peripherally inhibits NE release) Used in hypertension as second line drug Adverse effects: First dose phenomenon (hypotension – syncope) Start low dose and increase gradually Favorable effect on plasma lipids: increase HDL/LDL ratio Alpha-2 selective blockers Yohimbine No approved clinical use Important experimental tool Enhances sexual activity in rats – used as aphrodisiac by some Therapeutic Uses of Alpha Blockers Hypertension - alpha-1 selective Increased sympathetic activity – e.g. pheochromocytoma Raynaud’s Disease (Vasospasm in toes & fingers) Benign prostatic hyperplasia: improves symptoms by relaxing the bladder neck Beta-Adrenergic Blockers Propranolol Isoproterenol Learning Outcomes Classify Beta adrenoceptor antagonists (Beta blockers) according to their selectivity and mode of action Discuss the following 3 major properties of Beta blockers and their impact on therapy: cardioselectivity, intrinsic sympathomimetic activity and pharmacokinetic Describe and explain the effects of Beta blockers on the organs/systems of the body List and explain the therapeutic uses of Beta blockers; specifically Clearly explain their mechanism in treating coronary artery disease focusing on their effect on myocardial oxygen demand, Discuss the potential mechanisms for their antihypertensive effect Discuss the major adverse effects to Beta blockers and suggest how selecting the appropriate class of Beta blocker may mitigate some of them Describe and explain the withdrawal syndrome associate with Beta blocker discontinuation  Classification of Beta-adrenergic receptor antagonists. Drugs marked by an asterisk (*) also block α1 receptors Have additional vasodilating effects Important Properties of Beta-blockers Cardioselectivity (Beta-1 selectivity) Intrinsic sympathomimetic activity (partial agonist activity) Lipid solubility – relation to pharmacokinetics Cardioselectivity Where can it be beneficial to leave the Beta-2 receptor free - not blocked? Asthma Diabetes Peripheral vascular disease? Hypertension?  Intrinsic Sympathomimetic Activity (partial agonists) Effect of beta blockers on Heart Rate at Rest and During Exercise Rest Exercise Vehicle 69 70 107 105 Propranolol 61 54* 105 90* Pindolol (+ISA) 67 65 105 91* Beta-Blockers Lipid Solubility and Pharmacokinetics Lipid soluble agents (vs. water soluble) tend to: Be better absorbed Be metabolized in liver Enter the CNS Pharmacological Properties of Non-selective Beta blocker like Propranolol Cardiovascular Cardiac output: decreases Heart rate: decreases Blood pressure: decreases with chronic use due to vasodilation – mechanism not clear Coronary and organ blood flows: decrease Renin-angiotensin system: inhibited Pulmonary bronchoconstriction Metabolic: decreased glycolysis and gluconeogenesis Antihypertensive Effect of Beta Blockers: Proposed Mechanisms 1. Decreased cardiac output (not major cause) 2. Inhibit renin-angiotensin system which constricts arterioles 3. Inhibit central sympathetic outflow 4. Resetting of baroreceptor 5. Others (e.g. vasodilating mechanisms in 3rd generation) Mechanisms for Vasodilation 3rd Generation Drugs 1. Release of vasodilating prostaglandins 2. Production of NO 3. Alpha-receptor blocking activity (e.g. labetalol) 4. Ca channel blockade 5. Opening of K channels  hyperpolarization  vasodilation Pharmacological Properties of Non-selective Beta blocker like Propranolol Cardiovascular Cardiac output: decreases Heart rate: decreases Blood pressure: decreases with chronic use due to vasodilation – mechanism not clear Coronary and organ blood flows: decrease Renin-angiotensin system: inhibited Pulmonary bronchoconstriction Metabolic: decreased glycolysis and gluconeogenesis Beta-Blockers Delay Recovery from Hypoglycemia β-Blocker Insulin Glucose (mmol/L) Control Atenolol (β-1 selective) Propranolol (nonselective) Beta-Blockers - Therapeutic Uses Coronary artery disease – angina and myocardial infarction. Hypertension Arrhythmias Congestive heart failure Dissecting aortic aneurysm Pheochromocytoma Hyperthyroidism Migraine -prophylaxis Essential tremor Anxiety – stage fright Glaucoma (topical) Beta Blockers in Coronary Artery Disease Narrowing of artery with atherosclerosis limits blood flow to heart Under resting conditions no symptoms On exercise, heart needs more blood – more oxygen to meet demands of increased work ( HR, CO, BP) If narrowing, blood flow not enough so get symptoms (angina) Treatment: increase flow (vasodilator) or decrease O2 demand (Beta blocker) Effect of Beta-Blockers during Exercise (relevance to Coronary Artery Disease) Heart Rate Arterial Pressure Cardiac Output Increasing exercise Propranolol No Propranolol Beta-Blockers - Adverse Effects Cardiac (decreased contractility, bradycardia, AV bock) Vascular (decreased perfusion of peripheral tissues) Pulmonary (bronchoconstriction – be careful in asthmatics) Metabolic (delayed recovery from hypoglycemia; be careful in diabetics) Central Nervous System (depression, nightmares, insomnia, etc.) Withdrawal Syndrome: always taper – never stop abruptly because can get rebound over-stimulation of heart – especially worrisome in patients with CAD - and hypertension Cardioselective Beta- Blockers Advantages in: Asthma Diabetes mellitus