Beta Blockers ============= Medical Letter Vol. 43 (Issue 1097) February 5, 2001 WHICH BETA-BLOCKER? Some classes of drugs include so many agents that hospital formulary committees, managed care organizations and individual practitioners may find it difficult to choose among them. Fifteen beta-adrenergic receptor antagonists (beta-blockers) are now marketed for systemic use in the USA. One or more have been approved by the FDA for use in hypertension and eight other indications listed in the table on page 10. Differences in indications between drugs are sometimes due to differences in properties, but may also reflect manufacturers' lack of interest in seeking FDA approval for additional indications. PROPERTIES - Cardioselective beta-blockers, which have a greater affinity for cardiac beta -adrenergic receptors than for beta 2-receptors in bronchi and peripheral blood vessels, at doses lower than those generally used in clinical practice are less likely than nonselective beta-blockers to cause bronchospasm; at higher doses much of this cardiac selectivity is lost. Beta-blockers that act as beta-agonists, but still block the more significant agonist effects of endogenous catecholamines, have intrinsic sympathomimetic activity (ISA) and tend to slow heart rate less. Beta-blockers with ISA are less likely to increase serum triglyceride concentrations or decrease HDL cholesterol. Beta-blockers with lower lipid solubility do not enter the brain as readily and might have a lower incidence of adverse effects on the central nervous system, but this has never been demonstrated clinically. Carvedilol and labetolol have alphaas well as beta-blocking activity. Sotalol is not only a beta-blocker but also a potassium-channel blocker. HYPERTENSION - All beta-blockers except esmolol and sotalol are marketed for oral treatment of hypertension and appear to be about equally effective (JNC VI, Arch Intern Med 1997; 157:2413). Beta-blockers with ISA should not be used for hypertensive patients with a prior myocardial infarction. ANGINA PECTORIS - Beta-blockers, along with nitrates and aspirin, are commonly used for treatment of angina pectoris. Many small trials have demonstrated similar efficacy among beta-blockers for this indication, including some with ISA, but Medical Letter consultants advise against using beta-blockers with ISA for treatment of angina. ARRHYTHMIAS All beta-blockers are similarly effective in preventing and treating ventricular arrhythmias and in slowing the rapid ventricular rate associated with atrial tachyarrhythmias. Only sotalol, which delays ventricular repolarization, has been shown to be effective for maintenance of sinus rhythm in patients with chronic atrial fibrillation. Esmolol is often used for rate control in patients with atrial arrhythmias after cardiac surgery because it is given intravenously and has an elimination half?life of about 9 minutes; its therapeutic and adverse effects usually disappear within 30 minutes of stopping an infusion. Drug Dosage[1] Cost[2] Cardio selectivity ISA[3] Lipid Solubility FDA-Approved Indications Acebutolol 200?1200 mg yes yes low Hypertension,ventriculararrhythmias average generic price $21.30 Sectral (Wyeth?Ayerst) 37.50 Atenolol 25?100 mg yes no low Hypertension,angina pectoris,myocardialinfarction average generic price 8.70 Tenormin (Astra Zeneca) 32.40 Betaxolol ? average generic price 5?40 mg 24.60 yes no low Hypertension Kerlone (Searle) 28.80 Bisoprolol ? average generic price 5?20 mg 36.30 yes no low Hypertension Zebeta (Lederle) 37.80 Carteolol ? Cartrol (Abbott) 2.5?10 mg 35.70 no yes low Hypertension Carved i1014 ? Coreg (SK Beecham) 12.5?50 mg 92.40 no no high Hypertension,congestiveheart failure Esmolol ? Brevibloc (Baxter) ??? ??? yes no low Supraventriculartachycardia,intra? or postoperativehypertension Labetolol[4] 200?1200 mg no no moderate Hypertension average generic price 24.60 Normodyne (Schering?Plough) 34.80 Metoprolol tartrate 50?200 mg yes no moderate Hypertension,angina pectoris,myocardialinfarction average generic price 7.80 Lopressor (Novartis) 21.90 Metoprolol succinate[5] long?acting ? Toprol XL (AstraZeneca) 50?400 mg 19.50 Nadolol 20?240 mg no no low Hypertension,angina pectoris average generic price 18.30 Corgard (Bristol?Myers Squibb) 41.10 Penbutolol ? Levatol (Schwarz Pharma) 20 mg 42.90 no yes high Hypertension Pindolol 10?60 mg no yes moderate Hypertension average generic price 21.60 Visken (Novartis) 63.00 Propranolol 40?240 mg no no high Hypertension,angina, cardiacarrhythmias, postmyocardial infarction, migraine average generic price 8.40 Inderal (Wyeth?Ayerst) 21.60 long?acting ? average generic price 60?240 mg 27.60 Inderal LA (Wyeth?Ayerst) 33.90 Sotalol ??? ??? no no low Ventriculararrhythmias,atrial fibrillation Betapace (Berlex) and others Betapace AF Timolol 10?40 mg no no low?moderate Hypertension, postmyocardial infarction, migraineprophylaxis average generic price 16.20 Blocadren (Merck) 31.80 1. For hypertension. 2. Average cost to the patient for 30 days' treatment of hypertension with lowest daily dosage or the smallest size tablet, based on data from retail pharmacies nationwide provided by Scott?Levin's Source? Prescription Audit (SPA), December 1999?November 2000. 3. Intrinsic sympathomimetic activity. 4. Both carvedilol and labetolol have alpha?blocking activity. 5. Metoprolol succinate is not approved for myocardial infarction. 6. Also essential tremor, hypertrophic cardiomyopathy, pheochromocytoma. Long?acting propranolol has not been approved for all of these indica tions. POST MYOCARDIAL INFARCTION ? Use of beta blockers after myocardial infarction has been associated not only with increased survival but also with lower rates of hospital readmission for heart failure (PA Rochon et al, Lancet 2000; 356:639). In large randomized clinical trials after a myocardial infarction, atenolol and metoprolol decreased early mortality, and propranolol and timolol decreased late mortality. A meta?analysis showed less mortality reduction post myocardial infarction when beta?blockers with ISA were used (N Freemantle et al, BMJ 1999; 318:1730). HEART FAILURE ? Bisoprolol, carvedilol and metoprolol have been shown to decrease the risk of hospitalization and to lower mortality in patients with mild, moderate or severe heart failure (Medical Letter 2000; 42:54). Four small trials compared carvedilol with metoprolol. Two trials found that carvedilol led to a greater increase in ejection fraction and a greater decrease in left ventricular size than metoprolol (A Di Lenarda et al, J Am Coll Cardiol 1999; 33:1926; M Metra et al, Circulation 2000; 102:546). The other two trials found no difference between the two drugs (ML Kukin et al, Circulation 1999; 99:2645; JE Sanderson et al, J Am Coll Cardiol 1999; 34:1522). MIGRAINE ? Although only propranolol and timolol have been approved by the FDA for migraine prevention, metoprolol, nadolol and atenolol have also been shown to be effective in preventing migraine (Drugs of Choice from The Medical Letter, 1999, page 120). OTHER USES ? Perioperative use of various beta?blockers (without ISA) can protect patients at high risk for myocardial ischemia or infarction during and after major surgery (DT Mangano, N Engl J Med 1996; 335:1713; D Poldermans et al, N Engl J Med 1999; 341:1789). This use has not been approved by the FDA. Propranolol has been FDA?approved for treatment of essential tremor, hypertrophic cardiomyopathy and pheochromocytoma and is widely used, although not FDA?approved, to prevent symptoms of stage fright. ADVERSE EFFECTS ? Beta?blockers have many adverse effects, but most can be minimized by starting with a low dose and gradually increasing the dose over several weeks. All beta?blockers can cause symptomatic hypotension, bradycardia/heart block, bronchospasm, and aggravation of congestive heart failure. They may mask some of the symptoms of hypoglycemia in diabetics, and may promote development of type 2 diabetes in some patients with hypertension (TW Gress et al, N Engl J Med 2000; 342:905). Beta?blockers also decrease exercise tolerance and can cause fatigue, depression, impotence, Raynaud's phenomenon, insomnia and delirium. Abrupt withdrawal of a beta?blocker can precipitate myocardial ischemia. Labetalol has been associated with hepatic toxicity. CONCLUSION ? All beta?blockers appear to be equally effective for treatment of hypertension, preventing and treating ventricular arrhythmias, and slowing the rapid ventricular rate associated with atrial tachyarrhythmias. Bisoprolol, carvedilol or metoprolol are preferred for treatment of heart failure. Beta?blockers with intrinsic sympathomimetic activity should not be used for angina pectoris, for cardiac protection during surgery, or after a myocardial infarction. There is no convincing evidence that less lipid?soluble beta?blockers have fewer adverse effects on the central nervous system.