Metoprolol

Metoprolol is a selective β₁-adrenergic receptor blocker commonly prescribed under brand names such as Lopressor and Toprol XL.

It is indicated for the treatment of hypertension, angina pectoris, heart failure, and for the prevention of further cardiovascular events after myocardial infarction.

Metoprolol works by selectively inhibiting β₁-receptors in the heart, reducing heart rate, myocardial contractility, and cardiac output, which lowers blood pressure and decreases cardiac workload.

The primary gene influencing metoprolol metabolism is CYP2D6, a liver enzyme responsible for converting metoprolol into inactive metabolites. Variations in CYP2D6 activity can alter how quickly the drug is cleared from the body.

Genetic differences in CYP2D6 are classified into functional groups (e.g., ultrarapid, normal, intermediate, poor metabolizers) based on inherited variants. These groups help predict an individual’s capacity to process metoprolol safely and effectively.

CYP2D6 metabolizer status determines metoprolol exposure: ultrarapid metabolizers may clear the drug too quickly, risking reduced efficacy; poor metabolizers may have high circulating levels, increasing the chance of bradycardia and hypotension. Intermediate and normal metabolizers typically have predictable responses within the expected therapeutic range.

Genetic differences in CYP2D6 activity can lead to variations in metoprolol exposure and clinical response as detailed below.

Ultrarapid Metabolizer

• Effect: Rapid clearance results in decreased metoprolol levels.
• Clinical consequence: Potential reduced blood pressure and heart rate control.
• Side effects: Side effects are uncommon; monitoring for insufficient response is advised.

Normal Metabolizer

• Effect: Expected metoprolol levels with standard clearance.
• Clinical consequence: Typical therapeutic response achieved with standard dosing.
• Side effects: Common side effects include fatigue and dizziness at normal frequency.

Intermediate Metabolizer

• Effect: Moderately increased drug levels due to slower clearance.
• Clinical consequence: Generally well tolerated; may have slightly prolonged effect.
• Side effects: Infrequent mild bradycardia or fatigue; monitor as needed.

Poor Metabolizer

• Effect: Markedly increased metoprolol levels from very slow clearance.
• Clinical consequence: Higher risk of excessive heart rate and blood pressure reduction.
• Side effects: Frequent bradycardia and hypotension; requires dose adjustment or monitoring.

Indeterminate / Not Available

• Effect: Unknown impact on metoprolol levels.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Uncertain; monitor patient response per usual clinical practice.

CYP2D6 Dosing Guidelines

Examples of alternative beta-blockers less dependent on CYP2D6 metabolism include atenolol and bisoprolol. These may be considered if metoprolol is not recommended due to genetic variation.

• CPIC – Guideline for Beta-Blockers Based on CYP2D6 Genotype