Propafenone

Propafenone (brand name Rythmol SR) is an oral antiarrhythmic medication classified as a class Ic agent. It works by blocking sodium channels in cardiac cells, which slows conduction and helps restore normal heart rhythm.

Propafenone is used to treat atrial fibrillation, atrial flutter, and certain ventricular arrhythmias. By stabilizing the cardiac action potential, it reduces episodes of rapid or irregular heartbeats.

In addition to sodium‐channel blockade, propafenone has mild β‐adrenergic receptor–blocking activity, which contributes to its antiarrhythmic effects and may help control heart rate.

The primary gene influencing propafenone metabolism is CYP2D6, a member of the cytochrome P450 enzyme family in the liver. CYP2D6 converts propafenone into its active and inactive metabolites. Variations in this gene alter enzyme activity and influence how quickly the drug is cleared from the body.

Genetic variants in CYP2D6 are grouped into metabolizer phenotypes—from ultrarapid to poor—based on the number and function of gene copies. An ultrarapid metabolizer has extra functional copies and processes the drug quickly, while a poor metabolizer has little or no enzyme activity and clears the drug slowly.

CYP2D6 phenotype influences propafenone plasma levels and the risk of arrhythmia. Ultrarapid and normal metabolizers generally achieve expected drug concentrations with standard dosing, while intermediate and poor metabolizers may have higher exposures that increase the risk of adverse cardiac events.

Ultrarapid Metabolizer

• Effect on drug levels: Increased metabolism leading to potentially lower propafenone plasma concentrations
• Clinical consequence: Possible reduced therapeutic effect
• Side effects: Similar to normal dosing; no increased risk identified

Normal Metabolizer

• Effect on drug levels: Expected normal propafenone plasma concentrations
• Clinical consequence: Standard efficacy and safety profile
• Side effects: Typical effects such as dizziness or taste disturbances; incidence as per normal dosing

Intermediate Metabolizer

• Effect on drug levels: Reduced metabolic clearance leading to higher plasma concentrations
• Clinical consequence: Increased risk of adverse reactions, including proarrhythmia
• Side effects: Greater likelihood of arrhythmias; monitor for cardiovascular side effects

Poor Metabolizer

• Effect on drug levels: Significantly reduced clearance resulting in substantially elevated plasma concentrations
• Clinical consequence: High risk of adverse reactions, especially arrhythmias; avoid use with CYP3A4 inhibitors
• Side effects: Severe proarrhythmia risk; serious cardiovascular side effects

Indeterminate/Not available

• Effect: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring

CYP2D6 Dosing Guideline

While the FDA guideline does not specify pharmacogenetic‐guided alternatives for propafenone, clinicians may consider other class Ic agents such as flecainide or class III agents like amiodarone based on clinical judgment and patient characteristics.

• FDA – Table of Pharmacogenetic Associations