are usually less than 200 μg/L during therapeutic administration, but can range from 1–20 mg/L in overdose victims. Pharmacology A general pharmacological description of the characteristics and activities of metoprolol includes: it is moderately lipophilic; it has weak membrane stabilizing activity; it is β1 adrenergic receptor-selective; it is without intrinsic sympathomimetic activity; and it decreases heart rate, contractility, and cardiac output, thereby decreasing blood pressure. Mechanism of action Metoprolol blocks β1 adrenergic receptors in heart muscle cells, thereby decreasing the slope of phase 4 in the nodal action potential (reducing Na+ uptake) and prolonging repolarization of phase 3 (slowing down K+ release). It also suppresses the norepinephrine-induced increase in the sarcoplasmic reticulum (SR) Ca2+ leak and the spontaneous SR Ca2+ release, which are the major triggers for atrial fibrillation. Pharmacokinetics Metoprolol undergoes α-hydroxylation and O-demethylation as a substrate of the cytochrome liver enzymes CYP2D6. Chemistry Metoprolol was synthesized and its activity discovered by Bengt Ablad and Enar Carlsson in 1969. The specific agent in on-market formulations of metoprolol is either metoprolol tartrate or metoprolol succinate, where tartrate is an immediate-release formulation and the succinate is an extended-release formulation (with 100 mg metoprolol tartrate corresponding to 95 mg metoprolol succinate). Stereochemistry Metoprolol contains a stereocenter and consists of two enantiomers. This is a racemate, i.e. a 1:1 mixture of (R)- and the (S)-form: Regulatory status Application by Validus Pharms for Lopressor (metoprolol tartrate), 50 and 100 mg tablet formulations, was first approved in the U.S. by the Food and Drug Administration (FDA) in August 1978. As of 2022, metaprolol formulations are FDA-approved in the U.S. for treatment of angina, heart failure, myocardial infarction, atrial fibrillation/flutter, and hypertension. Metaprolol is approved for use within the UK, with classification as a prescription-only drug in the beta blocker class, as regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). Off-label uses Off-label uses include supraventricular tachycardia and thyroid storm. Generic approvals Metoprolol tartrate, a generic version of Lopressor, was licensed and authorized in June 1997 to Novartis Pharmaceuticals. In September 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) granted the Intas Pharmaceuticals Limited marketing authorization (licences) for metoprolol tartrate (50 mg and 100 mg tablets) for medicinal prescription only; this was after it was established that there were no new or unexpected safety concerns and that the benefits of metoprolol tartrate were greater than the risks. In sport Because beta blockers can