Carvedilol

Carvedilol (brand names Coreg, Coreg CR) is a nonselective beta-adrenergic blocker with additional alpha-1 blocking activity. It is approved by the FDA for several cardiovascular conditions.

It is commonly prescribed for the management of hypertension, congestive heart failure, and left ventricular dysfunction following myocardial infarction. By blocking beta-1 and beta-2 receptors, carvedilol reduces heart rate and force of contraction. Its alpha-1 blockade also causes peripheral vasodilation, lowering systemic vascular resistance.

The combined beta and alpha blockade helps improve cardiac output, decrease blood pressure, and reduce the workload on the heart, making it effective in both acute and chronic cardiac conditions.

CYP2D6 is the primary enzyme responsible for metabolizing carvedilol in the liver. It converts carvedilol into both active and inactive metabolites, influencing overall drug exposure. Genetic variations in CYP2D6 can lead to differences in enzyme activity, ranging from absent function to very high activity.

Variations in CYP2D6 are categorized into phenotype groups based on activity: ultrarapid, normal, intermediate, and poor metabolizers. Individuals with reduced or absent CYP2D6 activity may clear carvedilol more slowly, leading to higher plasma concentrations. Conversely, ultrarapid metabolizers may clear the drug more quickly, potentially reducing therapeutic effect.

Genetic variations in CYP2D6 can significantly influence carvedilol levels. Ultrarapid metabolizers may have lower drug concentrations, risking suboptimal blood pressure control, while poor metabolizers may experience elevated levels, increasing the risk of side effects such as dizziness and bradycardia. Intermediate and normal metabolizers generally have predictable responses, whereas indeterminate cases require standard dosing with careful monitoring.

Ultrarapid Metabolizer

• Effect on drug levels: Lower than expected due to rapid clearance.
• Clinical consequence: Possible reduced efficacy in blood pressure and heart rate control.
• Side effects: Fewer typical side effects (mild and infrequent); may experience reduced dizziness or fatigue.

Normal Metabolizer

• Effect on drug levels: Expected therapeutic concentrations.
• Clinical consequence: Standard balance of efficacy and side effects.
• Side effects: Typical incidence of bradycardia or fatigue (common, mild to moderate).

Intermediate Metabolizer

• Effect on drug levels: Slightly elevated due to reduced clearance.
• Clinical consequence: Mildly enhanced effect; monitor for early signs of over-blockade.
• Side effects: Occasional dizziness or fatigue (mild, infrequent).

Poor Metabolizer

• Effect on drug levels: Significantly elevated due to slow metabolism.
• Clinical consequence: Higher risk of hypotension, bradycardia, and dizziness.
• Side effects: Dizziness, fatigue, hypotension (common, moderate to severe).

Indeterminate/Not Available

• Effect on drug levels: Unknown.
• Clinical consequence: Cannot predict response reliably.
• Side effects: Variable; close clinical monitoring advised.

CYP2D6 Dosing Guidelines

Examples from guidelines include other beta-blockers such as metoprolol or bisoprolol, which may be considered if carvedilol is not tolerated. Dose titration based on clinical response and side effect monitoring is advised. These are illustrative options, not direct medical advice.

• FDA – Table of Pharmacogenetic Associations