Adrenergic Antagonists.pdf

Adrenergic Antagonists Alpha Adrenergic Blockers Actions • Decrease sympathetic tone of blood vessels • Results in decrease in TPR • May provoke reflex tachycardia • Baroreceptors in Carotid body Peripheral resistance • Compensatory HR and force of contraction Phenoxybenzamine • An haloalkylam...

Adrenergic Antagonists Alpha Adrenergic Blockers Actions • Decrease sympathetic tone of blood vessels • Results in decrease in TPR • May provoke reflex tachycardia • Baroreceptors in Carotid body Peripheral resistance • Compensatory HR and force of contraction Phenoxybenzamine • An haloalkylamine • Binds irreversibly to α-adrenergic receptors • Leads muscle relaxation and a widening of the blood vessels • Vasodilation results in • lowering of blood pressure • increased blood flow to the skin, mucosa and abdominal viscera • Used to control of episodes of hypertension in pheochromocytoma prior to Sx Phentolamine • Competitive reversible antagonist of alpha-1 (duration of 4 hrs) • Induces vasodilatation of vascular smooth muscle • Used as adjunct Tx for pheochromocytomectomy IV/IM 5 mg (pre-op 1-2 hrs) • Also used (off-label) for hypertensive crisis 5mg IV q 10 min • Also, competitively inhibits the inhibitory activity of alpha-2 adrenergic receptors • Blocks alpha-1 adrenergic receptors of iris dilator, thus reduces diameter of the pupil (miosis) • Ryzumvi 0.75% ophthalmic solution to reverse mydriasis induced by muscarinic antagonists Quinazoline – Based drugs • Compound made up of two fused six-member simple aromatic rings • Display hypotensive and anticancer activity • α1-AR blockers • Relaxation of smooth muscle of peripheral vasculature results in hypotensive effect by decreased TPR • Relaxation of smooth muscle in the prostate and bladder sphincter decreases resistance to urinary flow, reduces discomfort associated with BPH • Some studies have found to have antitumor efficacy through the induction of apoptosis in benign and malignant prostate cells – reduce to reduce tumor growth Quinazoline – Based drugs • Primary use for BPH** and HTN* • Prazosin (Minipress) * • Terazosin (Hytrin) ** • Doxazosin (Cardura)* • Tamsulosin (Flomax) ** - linked to intraoperative floppy iris syndrome (IFIS), a risk factor for complications during cataract surgery, interferes with pupillary dilation • Facilitates passage of kidney stones (ureterolithiasis) – off label • First dose phenomenon – orthostatic hypotension, dizziness reflex tachycardia effect Drugs Affecting Neurotransmitter Release Reserpine (Serprasil ®) Anti-hypertensive effect is by blocking the transport and storage of biogenic amines (dopamine, serotonin, NE)) causing depletion of norepinephrine from central and peripheral synapses Also reduces HR and contractility Drugs Affecting Neurotransmitter Release Reserpine (Serprasil ®) • Also been used for relief of psychotic symptoms by reducing dopamine levels in the brain (positive symptoms) Guanethidine (Ismelin®) • Blocks release of storage norepinephrine Drugs Affecting Neurotransmitter Release Guanethidine • Mechanism: Depletes the nerve ending of NE in the PNS • Main effects: decrease in PVR and decrease in HR → decrease in BP • Adverse effects: Orthostatic hypotension, Na+ and water retention; no CNS effects • Pharmacokinetics: Poorly absorbed from the G.I. Onset slow (1-2 weeks). Metabolites excreted in urine • Not used anymore; severe side effects Classification • Nonselective (1st generation) • Some with intrinsic sympathomimetic activity (ISA) * • Cardio-selective (b-1 selective, 2nd generation) • Hybrid antihypertensive drugs (Beta and Alpha blocking CV actions (3rd generation) Proposed mechanisms • Block cardiac 1 receptors → Lower HR → lower CO • Block renal 1 receptors → lower renin, lower PVR • Oppose action of NE released (ISA) * A group of β blockers that can stimulate β-adrenergic receptors and release NE (agonist effect) and oppose the stimulating effects of the NE released (antagonist effect) in a competitive way; they don't reduce the resting cardiac output and heart rate as effectively as Beta-blockers without ISA Beta-Adrenergic Blocking Agents 1st Generation Non-Selective • Propranolol • Timolol • *Pindolol • *Penbutolol 2nd Generation B1-Selective • *Carteolol • Metoprolol • *Acebutolol • Atenolol (hydrophylic) • Betaxolol • Bisoprolol (Diabetics on insulin and Asthmatics ) 3rd Generation (Hybrids) • Labetalol ( & )* • Carvedilol ( & ) *ISA Clinical Uses Hypertension - Reduce cardiac output and renin secretion. Arrythmia prophylaxis after a myocardial infarction and Tx of Supraventricular tachycardias • Propranolol, metropolol esmolol acebutolol and timolol - Block β1 receptors in the heart → reduce the sympathetic effect on the heart causing : • Decrease automaticity of S.A. node and ectopic pacemakers • Prolong refractory period ( slow conduction ) of the A.V node Clinical Uses Angina pectoris - propranolol nadolol and other B blockers reduce heart rate and force of contraction Glaucoma - timolol and other B blockers reduce secretion of aqueous humor Migraine - propranolol provides prophylactic effect. Thyrotoxicosis - propranolol reduces cardiac rate and potential for arrythmias Labetalol (Trandate) • A combined alpha-1, beta-1, and beta-2 blocker. Beta blocking action is more prominent. It also has some ISA property. • Can be given i.v. for hypertensive emergencies Carvedilol (Coreg) • Nonselective beta blocker and alpha-1 blocker • BB of choice in the treatment of CHF Side Effects Arrhythmias Bronchoconstriction Sexual dysfunction