Metoprolol

Metoprolol is FDA-approved for the treatment of angina, heart failure, myocardial infarction, atrial fibrillation/flutter, and hypertension. Off-label uses include supraventricular tachycardia and thyroid storm. Both oral and intravenous preparations are available. There are immediate and extended-release preparations available orally. There is controversy regarding the selection of beta-blockers in the management of the above conditions. There also is conflicting evidence regarding the optimal selection of a particular beta-blocker in the treatment of each specific disease.[1] The role of beta-blockers as initial therapy for hypertension, particularly in the absence of compelling indications, has been questioned.[2][3] Several randomized trials in the 1980s showed a mortality benefit for beta-blockers in acute myocardial infarction.[4][5][6] The Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) trial specifically showed a benefit of metoprolol over diuretics regarding sudden cardiac death as well as myocardial infarction.[7] A large randomized trial of over 50,000 patients in the 1990s showed metoprolol to reduce mortality and re-infarction when used chronically after myocardial infarction.[8] Beta-blockers have demonstrated prognostic benefit and reduce mortality in the treatment of chronic heart failure. The carvedilol or metoprolol European trial (COMET) enrolled patients with stable heart failure and compared each drug head-to-head. Carvedilol was associated with a statistically significantly lower risk of all-cause death.[9] However, recent trials have had conflicting evidence on whether selective beta-1 blockers such as metoprolol have any benefit over other beta-blockers like carvedilol.[1]

Metoprolol is a cardioselective beta-1-adrenergic receptor inhibitor that competitively blocks beta1-receptors with minimal or no effects on beta-2 receptors at oral doses of less than 100 mg in adults. It decreases cardiac output by negative inotropic and chronotropic effects. Metoprolol does not exhibit membrane stabilizing or intrinsic sympathomimetic activity. Administration of metoprolol to normal subjects results in a reduction in heart rate and cardiac output; this appears to be related to the dose and concentration of the drug. Metoprolol is mainly lipophilic, and distribution is typical of a basic lipophilic drug. Based on animal studies, it appears to be almost completely absorbed from the gastrointestinal (GI) tract when taken orally. There is significant hepatic first-pass elimination, which results in around 50% of the oral dose reaching the systemic circulation. It is 11% bound to serum albumin. The half-life of metoprolol is about 3 to 4 hours in most patients for non-extended release tabs. Metoprolol excretion principally occurs via the kidneys.[10] Metoprolol succinate produces more level drug concentrations as compared to metoprolol tartrate, which has more peak-to-trough variation. However, despite these differences in pharmacokinetics, studies have concluded that both agents produce similar clinical effects, both acute and chronically.[11]

Metoprolol may administration can be either oral or intravenous. The immediate-release oral formulation is to be administered with or immediately following food intake. The administration of the short-acting formulation of metoprolol tartrate is usually twice daily. It may be effective for hypertension when taken once per day; however, lower doses may not control blood pressure for 24 hours. Patients may take the extended-release metoprolol succinate formulation without regard to meals.[12]

The primary adverse effects of metoprolol include heart failure exacerbation, fatigue, depression, bradycardia or heart block, hypotension, bronchospasm, cold extremities, dizziness, decreased libido, diarrhea, tinnitus, decreased exercise tolerance, glucose intolerance, and may mask hypoglycemia. Abrupt cessation of the drug may lead to a withdrawal syndrome that could cause angina or myocardial infarction. Tachycardia and hypertension are both common in the withdrawal syndrome.[13]

Metoprolol is contraindicated in patients with sick sinus syndrome, second or third-degree heart block (in the absence of pacemaker),  decompensated heart failure, hypotension, and with documented hypersensitivity to the drug or components. Also, caution is necessary for patients that have a history of noncompliance as the abrupt cessation of the drug can lead to withdrawal syndromes, including angina and myocardial infarction. Patients who have ingested cocaine or methamphetamine have traditionally had a contraindication to the use of selective beta-blocker such as metoprolol. This observation has its basis on case reports, and there is no strong evidence that they cause any deleterious effects. Regardless, agents such as labetalol, which have alpha and beta activity, or calcium channel blockers should be used in these cases. Metoprolol is a pregnancy risk factor Category C drug.[14]