indication

Used to prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease. Also used for the treatment of life-threatening documented ventricular arrhythmias, such as sustained ventricular tachycardia.

pharmacology

Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. It is used in the treatment of atrial and ventricular arrhythmias. It works by slowing the influx of sodium ions into the cardiac muscle cells, causing a decrease in excitablity of the cells. Propafenone has local anesthetic activity approximately equal to procaine.

mechanism of action

The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions, which is responsible for the drugs antiarrhythmic actions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy.

toxicity

Symptoms of propafenone overdose (usually most severe within the first 3 hours) may include convulsions (rarely), heartbeat irregularities, low blood pressure, and sleepiness.

biotransformation

Metabolized primarily in the liver where it is rapidly and extensively metabolized to two active metabolites, 5-hydroxypropafenone and N-depropylpropafenone. These metabolites have antiarrhythmic activity comparable to propafenone but are present in concentrations less than 25% of propafenone concentrations.

absorption

Nearly completely absorbed following oral administration (90%). Systemic bioavailability ranges from 5 to 50%, due to significant first-pass metabolism. This wide range in systemic bioavailability is related to two factors: presence of food (food increases bioavailability) and dosage (bioavailability is 3.4% for a 150-mg tablet compared to 10.6% for a 300-mg tablet).

half life

2-10 hours

route of elimination

Approximately 50% of propafenone metabolites are excreted in the urine following administration of immediate release tablets.

drug interactions

Acenocoumarol: Propafenone may increase the anticoagulant effect of acenocoumarol.

Aminophylline: Propafenone increases the effect of theophylline

Anisindione: Propafenone may increase the anticoagulant effect of anisindione.

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Cyclosporine: Propafenone increases the effect and toxicity of cyclosporine

Dicumarol: Propafenone may increase the anticoagulant effect of dicumarol.

Digoxin: Propafenone increases the effect of digoxin

Dihydroquinidine barbiturate: Quinidine increases the effect of propafenone

Duloxetine: Possible increase in the levels of this agent when used with duloxetine

Dyphylline: Propafenone increases the effect of theophylline

Fluoxetine: Additive QTc-prolongation may occur increasing the risk of serious life-threatening arrhythmias. Fluoxetine may also increase the serum concentration of propafenone. Use caution during concomitant therapy and monitor for QTc-prolongation.

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias.

Metoprolol: Propafenone may increase the effect of beta-blocker, metoprolol.

Mexiletine: Propafenone may increase the effect and toxicity of mexilitine.

Oxtriphylline: Propafenone increases the effect of theophylline

Paroxetine: Paroxetine may increase the effect and toxicity of propafenone.

Propranolol: Propafenone may increase the effect of the beta-blocker, propranolol.

Quinidine: Quinidine increases the effect of propafenone

Quinidine barbiturate: Quinidine increases the effect of propafenone

Rifabutin: Rifampin decreases the effect of propafenone

Rifampin: Rifampin decreases the effect of propafenone

Ritonavir: Ritonavir increases the effect and toxicity of propafenone

Sertraline: Fluoxetine increases the effect and toxicity of propafenone

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Propafenone. Consider alternate therapy or monitor for therapeutic/adverse effects of Propafenone if Terbinafine is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias.

Theophylline: Propafenone increases the effect of theophylline

Thiopental: Thiopental may increase the metabolism and clearance of Propafenone. Monitor for decreased therapeutic effect of Propafenone if Thiopental is initiated.

Thioridazine: Increased risk of cardiotoxicity and arrhythmias.

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Tipranavir: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Propafenone. Concomitant therapy is contraindicated.

Tizanidine: Propafenone may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Venlafaxine: Propafenone increases the effect and toxicity of venlafaxine

Voriconazole: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Warfarin: Propafenone may increase the anticoagulant effect of warfarin.

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).