Metoprolol
Metoprolol, sold under the brand names Lopressor and Toprol-XL among others, is a medication used to treat angina, high blood pressure and a number of conditions involving an abnormally fast heart rate. It is also used to prevent further heart problems after myocardial infarction and to prevent headaches in those with migraines. It is a beta blocker, specifically a selective β1 receptor blocker, and is taken by mouth or is given intravenously.
Common side effects include trouble sleeping, feeling tired, feeling faint, and abdominal discomfort. Large doses may cause serious toxicity. Risk in pregnancy has not been ruled out. It appears to be safe in breastfeeding. The metabolism of metoprolol can vary widely among patients, often as a result of hepatic impairment or CYP2D6 polymorphism.
Metoprolol was first made in 1969, patented in 1970, and approved for medical use in 1978. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2023, it was the sixth most commonly prescribed medication in the United States, with more than 59million prescriptions.
Medical uses
Metoprolol is used for a number of conditions, including angina, acute myocardial infarction, high blood pressure, supraventricular tachycardia, ventricular tachycardia, congestive heart failure, and prevention of migraine headaches. It is an adjunct in the treatment of hyperthyroidism. Both oral and intravenous forms of metoprolol are available for administration. The different salt versions of metoprolol – metoprolol tartrate and metoprolol succinate – are approved for different conditions and are not interchangeable.Off-label uses include supraventricular tachycardia and thyroid storm.
Adverse effects
Adverse effects, especially with higher doses, include dizziness, drowsiness, fatigue, diarrhea, unusual dreams, trouble sleeping, depression, and vision problems such as blurred vision or dry eyes. β-blockers, including metoprolol, reduce salivary flow via inhibition of the direct sympathetic innervation of the salivary glands. Metoprolol may also cause the hands and feet to feel cold. Due to the high penetration across the blood–brain barrier, lipophilic beta blockers such as propranolol and metoprolol are more likely than other less lipophilic beta blockers to cause sleep disturbances such as insomnia, vivid dreams and nightmares. Patients should be cautious while driving or operating machinery due to its potential to cause decreased alertness.There may also be an impact on blood sugar levels, and it can potentially mask signs of low blood sugar.
The safety of metoprolol during pregnancy is not fully established.
Precautions
Metoprolol reduces long-term mortality and hospitalisation due to worsening heart failure. A meta-analysis further supports reduced incidence of heart failure worsening in patients treated with beta-blockers compared to placebo. However, in some circumstances, particularly when initiating metoprolol in patients with more symptomatic disease, an increased prevalence of hospitalisation and mortality has been reported within the first two months of starting. Patients should monitor for swelling of extremities, fatigue, and shortness of breath.A Cochrane Review concluded that although metoprolol reduces the risk of atrial fibrillation recurrence, it is unclear whether the long-term benefits outweigh the risks.
This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate. It also may cause some people to become less alert than they are normally, making it dangerous for them to drive or use machines.
Pregnancy and breastfeeding
Risk for the fetus has not been ruled out, per being rated pregnancy category C in Australia, meaning that it may be suspected of causing harmful effects on the human fetus. It appears to be safe in breastfeeding.Overdose
Excessive doses of metoprolol can cause bradycardia, hypotension, metabolic acidosis, seizures, and cardiorespiratory arrest. Blood or plasma concentrations may be measured to confirm a diagnosis of overdose or poisoning in hospitalized patients or to assist in a medicolegal death investigation. Plasma levels are usually less than 200 μg/L during therapeutic administration, but can range from 1–20 mg/L in overdose victims.Pharmacology
Mechanism of action
Metoprolol is a beta blocker, or an antagonist of the β-adrenergic receptors. It is specifically a selective antagonist of the β1-adrenergic receptor and has no intrinsic sympathomimetic activity.Metoprolol exerts its effects by blocking the action of certain neurotransmitters, specifically adrenaline and noradrenaline. It does this by selectively binding to and antagonizing β1 adrenergic receptors in the body. When adrenaline or noradrenaline are released from nerve endings or secreted by the adrenal glands, they bind to β1 adrenergic receptors found primarily in cardiac tissues such as the heart. This binding activates these receptors, leading to various physiological responses, including an increase in heart rate, force of contraction, conduction speed through electrical pathways in the heart, and release of renin from the kidneys. Metoprolol competes with adrenaline and noradrenaline for binding sites on these β1 receptors. By occupying these receptor sites without activating them, metoprolol blocks or inhibits their activation by endogenous catecholamines like adrenaline or noradrenaline.
Metoprolol blocks β1-adrenergic receptors in heart muscle cells, thereby decreasing the slope of phase 4 in the nodal action potential and prolonging repolarization of phase 3. It also suppresses the norepinephrine-induced increase in the sarcoplasmic reticulum Ca2+ leak and the spontaneous SR Ca2+ release, which are the major triggers for atrial fibrillation.
Through this mechanism of selective blockade at β1 receptors, metoprolol exerts the following effects:
- Heart rate reduction, i.e., decrease of the resting heart rate and reduction of excessive elevations resulting from exercise or stress.
- Reduction of the force of contraction, i.e., decrease in contractility, which lessens how hard each heartbeat contracts.
- Decrease in cardiac output, i.e., decrease in both heart rate and contractility within myocardium cells, where β1 is predominantly located, overall blood output per minute lowers called cardiac output/dysfunction, allowing decreased demands placed onto impaired hearts, reducing oxygen demand-supply mismatch.
- Lowering of blood pressure.
- Antiarrhythmic effects, such as supraventricular tachycardia prevention. Metoprolol also prevents electrical wave propagation.
Pharmacokinetics
Metoprolol binds mainly to human serum albumin with an unbound fraction of 0.88. It has a large volume of distribution at steady state, indicating extensive distribution throughout the body. Metoprolol is classified as a moderately lipophilic beta blocker. More lipophilic beta blockers tend to cross the blood–brain barrier more readily, with greater potential for effects in the central nervous system as well as associated neuropsychiatric side effects. The brain-to-blood ratio of metoprolol in humans has been found to be 12:1. For comparison, the brain-to-blood ratio of the highly lipophilic propranolol was 15:1 to 26:1 and of the hydrophilic atenolol was 0.2:1.
Metoprolol undergoes extensive metabolism in the liver, mainly α-hydroxylation and O-demethylation through various cytochrome P450 enzymes such as CYP2D6, CYP3A4, CYP2B6, and CYP2C9. The primary metabolites formed are α-hydroxymetoprolol and O-demethylmetoprolol.
Chemistry
The experimental log P of metoprolol is 1.6 to 2.15.Stereochemistry
Metoprolol contains a stereocenter and consists of two enantiomers. This is a racemate, i.e. a 1:1 mixture of - and the -form:Formulations
Metoprolol was synthesized and its activity discovered 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.Metoprolol tartrate was first developed by Novartis and this dosage form received approval in the US in 1978. The extended-release salt, metoprolol succinate was developed by Astra Pharmaceuticals, and received a US patent in 1992.