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. The role of beta-blockers as initial therapy for hypertension, particularly in the absence of compelling indications, has been questioned. Several randomized trials in the 1980s showed a mortality benefit for beta blockers in acute myocardial infarction. 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. In a large randomized trial of over 50,000 patients in the 1990's, Metoprolol was shown to reduce mortality and re-infarction when used chronically after myocardial infarction. Beta blockers have been shown to exert 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. 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.
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 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 is principally excreted via the kidneys. 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. 
Metoprolol may be administered orally or intravenously. The immediate-release oral formulation is to be administered with or immediately following food. The short-acting formulation of metoprolol tartrate is usually taken twice daily. It may be effective for hypertension when taken once per day; however, lower doses may not control blood pressure for 24 hours. The extended-release metoprolol succinate formulation may be administered without regard to meals.
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.
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 must be exercised in patients that have a history of noncompliance as 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 is based 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.
The onset of action for oral immediate-release tablets is within 1 hour with a duration of effect variable depending on the dose given. The extended-release preparation has a similar onset of action and a duration up to 24 hours. Metabolism of metoprolol is hepatic with excretion in the urine. If there is renal impairment, there is no dosage adjustment necessary. If there is a history of hepatic impairment, slowly increasing titrated doses to effect should be used. With the use of intravenous (IV) administration, cardiac monitor including ECG heart rate and blood pressure should be constant. Oral administration heart rate rhythm and blood pressure should be monitored.
Treatment will vary based on the amount of Metoprolol amount taken, comorbidities, age, and other co-investments. On arrival, assess ABCs and monitor appropriate blood work including coingestants, ECG, large bore IVs, and pregnancy status if female. Consult poison control/toxicology early in the course. Treatment choices include volume resuscitation, activated charcoal, whole bowel irrigation, nasogastric lavage, atropine, glucagon, calcium gluconate/calcium chloride, high-dose insulin, vasopressors, Intralipid, transcutaneous or transvenous pacemaker. Cardiac status and a current fluid balance will guide volume resuscitation. Activated charcoal is typically given 1 g/kg and usually only has efficacy if given within 1 to 2 hours of ingestion. If the patient has any altered mentation, caution must be given secondary to the possibility of aspiration. Whole bowel irrigation should be considered for extended release preparations or large quantity ingestion. Nasogastric lavage is usually ineffective with the exception of large quantity ingestions. The clinician may consider atropine use, although it is typically ineffective in moderate-to-severe overdoses. Calcium administration to increase intracellular calcium at a dose of 60 mg/kg over 5 to 10 minutes of calcium gluconate. Calcium chloride at a dose of 10 to 20 mL of a 10% solution can be used if central access is obtained. Glucagon is given at a dose of 50 mcg/kg as a bolus with titration of drip. High-dose insulin at a dose of 1 unit per kilogram bolus followed by 1 unit per kilogram per hour drip. Administration with dextrose with a drip titrating to euglycemia as well as potassium repletion as needed. Vasopressors with epinephrine or norepinephrine titrated rate and blood pressure. Intralipid, IV lipid emulsion therapy can be considered as a lipid sink that extracts the drug from the myocyte. It is also thought to provide free fatty acids as a substrate. It should be noted that the use of this medication will affect some laboratory monitoring. Consider a transcutaneous or transvenous pacemaker. Extracorporeal membrane oxygenation (ECMO) should be considered for refractory cases. If the clinician is concerned about intentional overdose, they should order a mandatory psychiatric evaluation. There may also be a need for the possibility of co-ingestants and treatment of those as well. For non-extended or non-sustained-release preparations, 4 to 6 hours of observation without any derangement of mental status or vital signs is sufficient. Any extended release or sustained release preparation requires 12 to 24 hours of telemetry observation, depending on the preparation. Extra caution should be considered in the pediatric population as very low amounts, including one pill or even one-half pill, can cause cardiovascular collapse and death.
|||Fr�hlich H,Zhao J,T�ger T,Cebola R,Schellberg D,Katus HA,Grundtvig M,Hole T,Atar D,Agewall S,Frankenstein L, Carvedilol Compared With Metoprolol Succinate in the Treatment and Prognosis of Patients With Stable Chronic Heart Failure: Carvedilol or Metoprolol Evaluation Study. Circulation. Heart failure. 2015 Sep [PubMed PMID: 26175538]|
|||Lindholm LH,Carlberg B,Samuelsson O, Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet (London, England). 2005 Oct 29-Nov 4 [PubMed PMID: 16257341]|
|||Khan N,McAlister FA, Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2006 Jun 6 [PubMed PMID: 16754904]|
|||Hjalmarson A,Herlitz J,Holmberg S,Ryd�n L,Swedberg K,Vedin A,Waagstein F,Waldenstr�m A,Waldenstr�m J,Wedel H,Wilhelmsen L,Wilhelmsson C, The G�teborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation. 1983 Jun [PubMed PMID: 6342837]|
|||Intravenous beta-blockade during acute myocardial infarction. Lancet (London, England). 1986 Jul 12 [PubMed PMID: 2873383]|
|||Sleight P, Use of beta adrenoceptor blockade during and after acute myocardial infarction. Annual review of medicine. 1986 [PubMed PMID: 2871805]|
|||Wikstrand J,Warnold I,Tuomilehto J,Olsson G,Barber HJ,Eliasson K,Elmfeldt D,Jastrup B,Karatzas NB,Leer J, Metoprolol versus thiazide diuretics in hypertension. Morbidity results from the MAPHY Study. Hypertension (Dallas, Tex. : 1979). 1991 Apr [PubMed PMID: 2013485]|
|||Freemantle N,Cleland J,Young P,Mason J,Harrison J, beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ (Clinical research ed.). 1999 Jun 26 [PubMed PMID: 10381708]|
|||Remme WJ,Cleland JG,Erhardt L,Spark P,Torp-Pedersen C,Metra M,Komajda M,Moullet C,Lukas MA,Poole-Wilson P,Di Lenarda A,Swedberg K, Effect of carvedilol and metoprolol on the mode of death in patients with heart failure. European journal of heart failure. 2007 Nov [PubMed PMID: 17716943]|
|||Brogden RN,Heel RC,Speight TM,Avery GS, Metoprolol: a review of its pharmacological properties and therapeutic efficacy in hypertension and angina pectoris. Drugs. 1977 Nov [PubMed PMID: 201441]|
|||Kukin ML,Mannino MM,Freudenberger RS,Kalman J,Buchholz-Varley C,Ocampo O, Hemodynamic comparison of twice daily metoprolol tartrate with once daily metoprolol succinate in congestive heart failure. Journal of the American College of Cardiology. 2000 Jan [PubMed PMID: 10636257]|
|||Wikstrand J,Hjalmarson A,Waagstein F,Fagerberg B,Goldstein S,Kjekshus J,Wedel H, Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). Journal of the American College of Cardiology. 2002 Aug 7 [PubMed PMID: 12142116]|
|||Helfand M,Peterson K,Christensen V,Dana T,Thakurta S, . 2009 Jul [PubMed PMID: 21089245]|
|||Ripley TL,Saseen JJ, ?-blockers: a review of their pharmacological and physiological diversity in hypertension. The Annals of pharmacotherapy. 2014 Jun [PubMed PMID: 24687542]|
|||Graudins A,Lee HM,Druda D, Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. British journal of clinical pharmacology. 2016 Mar [PubMed PMID: 26344579]|
|||Stellpflug SJ,Harris CR,Engebretsen KM,Cole JB,Holger JS, Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high-dose insulin. Clinical toxicology (Philadelphia, Pa.). 2010 Mar [PubMed PMID: 20141425]|
|||Walter E,McKinlay J,Corbett J,Kirk-Bayley J, Review of management in cardiotoxic overdose and efficacy of delayed intralipid use. Journal of the Intensive Care Society. 2018 Feb [PubMed PMID: 29456602]|
|||Chenoweth JA,Colby DK,Sutter ME,Radke JB,Ford JB,Nilas Young J,Richards JR, Massive diltiazem and metoprolol overdose rescued with extracorporeal life support. The American journal of emergency medicine. 2017 Oct [PubMed PMID: 28705745]|
|||Euwema MS,Swanson TJ, Toxicity, Deadly Single Dose Agents null. 2018 Jan [PubMed PMID: 28722879]|