Adrenergic Antagonist Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture-20 April 03, 2012

Adrenergic Antagonists Bind to adrenoceptors but do not trigger the usual receptor-mediated intracellular effects Act by either reversibly or irreversibly attaching to the receptor Classified according to their relative affinities for α or β receptors in the PNS Types of adrenergic antagonists: α-Adrenergic antagonists β-Adrenergic antagonists Drugs affecting neurotransmitter release and uptake

Adrenergic Antagonists Types of adrenergic antagonists: α-Adrenergic antagonists β-Adrenergic antagonists Drugs affecting neurotransmitter release and uptake

α-Adrenergic Antagonists Drugs that block α-adrenoceptors profoundly affect blood pressure Few α-adrenergic antagonists: Phenoxybenzamine Phentolamine Prazosin Terazosin Doxazosin

Phenoxybenzamine Nonselective, linking covalently to both α1-postsynaptic and α2-presynaptic receptors Block is irreversible and noncompetitive, and the only mechanism the body has for overcoming the block is to synthesize new adrenoceptors Actions last about 24 hrs after a single administration After the drug is injected, a delay of a few hrs occurs before a blockade develops, because the molecule must undergo biotransformation to the active form

Phenoxybenzamine: Therapeutic Use By blocking α receptors, it prevents vasoconstriction of peripheral blood vessels Used in the treatment of pheochromocytoma, a catecholamine-secreting tumor of cells derived from the adrenal medulla Sometimes effective in treating Raynaud's disease Pheochromocytoma-Neuroendocrine tumor of adrenal gland Raynaud’s disease-discoloration of finger, toe or other part of the body Phenoxybenzamine: Adverse Effects Can cause postural hypotension, nasal stuffiness, nausea, and vomiting

Phentolamine Produces a competitive block of α1 and α2 receptors Action lasts for 4 hrs after a single administration Therapeutic use: Short-term management of pheochromocytoma Adverse Effects: Postural hypotension, induces reflex cardiac stimulation and tachycardia, trigger arrhythmias and anginal pain Pheochromocytoma-Neuroendocrine tumor of adrenal gland Arrythmias-Heart rate is too fast or too low or irregular Anginal pain-chest pain

Adrenergic Antagonists Types of adrenergic antagonists: α-Adrenergic antagonists β-Adrenergic antagonists Drugs affecting neurotransmitter release and uptake

β-Adrenergic Blocking Agents β-Blockers are competitive antagonists All β-blockers lower blood pressure in hypertension β-Blockers are effective in treating angina, cardiac arrhythmias, myocardial infarction, congestive heart failure, hyperthyroidism, and glaucoma Myocardial infraction: A heart attack occurs when blood flow to a part of your heart is blocked for a long enough time Glaucoma refers to a group of eye conditions that lead to damage to the optic nerve

Names of β-Adrenergic Antagonists Propranolol Acebutolol Atenolol Metoprolol

Propranolol A nonselective β antagonist and blocks both β1 and β2 receptors Sustained-release preparations for once-a-day dosing are available

Propranolol: Therapeutic Use Hypertension: Lowers blood pressure in hypertension Glaucoma: Effective in diminishing intraocular pressure in glaucoma Migraine: Effective in reducing migraine Angina pectoris Useful in the chronic management of angina Myocardial infarction: Protective effect on the myocardium Myocardium: Muscular tissue of heart

Propranolol: Adverse Effects Bronchoconstriction: Has a serious and potentially lethal side effect when administered to an asthmatic An immediate contraction of the bronchiolar smooth muscle prevents air from entering the lungs Arrhythmias: Treatment with β-blockers must never be stopped quickly because of the risk of precipitating cardiac arrhythmias Disturbances in metabolism: β-Blockade leads to decreased glycogenolysis and decreased glucagon secretion

Propranolol: Drug Interactions Drugs that interfere with the metabolism of propranolol, such as cimetidine, fluoxetine, and paroxetine may potentiate its antihypertensive effects. Conversely, those that stimulate its metabolism, such as barbiturates, and phenytoin can decrease its effects

Acebutolol, Atenolol, Metoprolol Selective β1 antagonists Therapeutic use in hypertension: Useful in hypertensive patients with impaired pulmonary function Useful in diabetic hypertensive patients who are receiving insulin or oral hypoglycemic agents

Adrenergic Antagonists Types of adrenergic antagonists: α-Adrenergic antagonists β-Adrenergic antagonists Drugs affecting neurotransmitter release and uptake

Drugs Affecting Neurotransmitter Release or Uptake These drugs act on the adrenergic neuron, either to interfere with neurotransmitter release or to alter the uptake of the neurotransmitter into the adrenergic nerve Few names Reserpine Guanethidine

Reserpine Guanethidine Blocks the transport of biogenic amines, norepinephrine, dopamine, and serotonin from the cytoplasm into storage vesicles Causes the ultimate depletion of biogenic amines The drug has a slow onset, a long duration of action, and effects that persist for many days after discontinuation Guanethidine Blocks the release of stored NE Leads to gradual depletion of NE in nerve endings Causes orthostatic hypotension