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Beta-Adrenergic Blockers

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

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Beta-Adrenergic Blockers

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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 • 3rd 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

  13. 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 renalglomerular vasculature were measured, also active NO and extracellular ATP • Results showed that 3rd gen B-B’s induce relaxation of renal glomerularmicrovasculature through ATP efflux causing NO release from GECs.

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

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