Beta-Adrenergic Blockers  Types of adrenoceptors Alpha-1  Vasoconstriction  Increased peripheral resistance  Increased blood pressure Alpha-2  Inhibition of norepinepherine release  Inhibition of insulin release

Beta-Blockers  Types of Adrenoceptors Beta-1  Tachycardia  Increased lipolysis  Increased myocardial contractility Beta-2  Vasodilation (in skeletal vasculature)  Slightly decreased peripheral resistance  Bronchodilation  Increased muscle and liver glycogenolysis  Increased release of glucagon

Beta-Blockers  Mechanism of Action All clinically available beta-blockers are competitive antagonists  Non-selective act on both B1 and B2 receptors Generally, they antagonize effects of catecholamines on the heart  Effects of beta blockade Angina Tx = decreased myocardial oxygen consumption due to reduced rate and contractility Hypotensive effect = unclear mechanism  Possibilities: diminished CO, decreased NE release at postgang. symp. nerve endings, reduced renin

Beta-Blockers  Effects of beta blockade (contd.) Arrythmia tx = reduces rate of spontaneous depolarization of sinus node, slows conduction in atria tx for symptomatic mgmt. of hyperthyroidism by controlling tachycardias and arrythmias tx of migrane, aortic dissection

Beta-Blockers  pharm properties variations in:  cardioselectivity  membrane-stabilizing effects (local anesthesia)  intrinsic sympathomimetic activity (some are partial agonists)  lipid solubility these variations are generally of little clinical significance  2 important ones are lipid and agonist properties

Beta-Blockers  lipophilic propranolol, metoprolol, oxprenolol, bisoprolol, carevdilol readily absorbed from GI, metabolized in liver large volume of distrib, and penetrate BBB well  hydrophilic acebutolol, atenolol, betaxolol, carteolol, nadolol. sotalol less readily absorbed, not extensively metabolized long plasma half-lives  = hepatic failure prolong t1/2 lipo, renal failure prolongs hydrophilic

Beta-Blockers  B-agonist ( “ intrinsic sympathomim. activity = ISA) pindolol, alprenolol, acebutolol, carteolol, dilevalol, oxprenolol cause little or no resting heart rate depression, but block increased rate due to exercise  useful if patient is naturally bradycardic at rest

Beta-Blockers  Cardioselective metoprolol, esmolol, acebutolol, atenolol, betaxolol relative selectivity for B1 receptor theoretically cause less bronchoconstriction and peri vasodilation  lose selective effects at higher doses

Beta-Blockers  Adverse effects CNS effects (sedation, depression, hallucinations)  seen with hydrophilic as well as lipophiles precipitation of heart failure  if patient relies on increased sympathetic drive for cardiac compensation aggravation of bronchospasm in asthma hypoglycemia in diabetes  due to blockade of catecholamine-mediated counterreg and antagonism of adrenergic warning signs of hypoglycemia) hyperkalemia if K intolerance elevation in 3glycerides, depression HDL

Nitrates  Mechanism cause rapid reduction in myocardial oxygen demand relax vascular smooth muscle  venous more than arterial  cause intracellular conversion to nitrite ions, and then to nitric oxide  this activated guanylate cyclase and increases cell GMP  elevated cGMP = dephosphorylation of myosin light chain = muscle relaxation

Nitrates  Cardiovascular effects 2 major  dilation of large veins, causing pooling of blood  diminishes preload = reduces work of heart  dilates coronary vasculature = increased blood supply to heart muscle Adverse  most common is headache – especially if recovering from long-acting agents  high doses  postural hypotension, flushing, tachycardia

Beta-Blockers and NO  Kalinowski, et. al.  “ Third-Generation ß -Blockers Stimulate Nitric Oxide Release From Endothelial Cells Through ATP Efflux ” A Novel Mechanism for Antihypertensive Action Circulation, May 12, 2003  Abstract 3 rd generation beta-blockers (like Nebivolol and Carvedilol) have endothelium-dependent vasodilating properties specifically related the microcirculation by a molecular mechanism that is not understood yet  classic beta-blockers don ’ t have this effect

Beta-Blockers and NO  Abstract (cont ’ d) Hypothesized mech:  stimulation of NO release from microvascular endothelial cells by extracellular ATP  ATP is known to fxn as autocrine and paracrine signaling factor  Results/Conclusions Contraction and relaxation of renal glomerular vasculature were measured, also active NO and extracellular ATP Results showed that 3 rd gen B-B ’ s induce relaxation of renal glomerular microvasculature through ATP efflux causing NO release from GECs.

References  Harrison ’ s, 15 th Ed.  Lippincott Pharmacology, 2 nd Ed.  Kalinowski et. al., “ Third-Generation ß -Blockers Stimulate Nitric Oxide Release From Endothelial Cells Through ATP Efflux ” Circulation. 2003;107:2747