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Mechanism of Action
Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. 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. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity.
Studies in anesthetized dogs and isolated organ preparations show that propafenone has beta-sympatholytic activity at about 1/50 the potency of propranolol. Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a betaadrenergic blocking potency (per mg) about 1/40 that of propranolol in man. In clinical trials, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range. 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. Moreover, propafenone inhibits a variety of cardiac potassium currents in in vitro studies (i.e. the transient outward, the delayed rectifier, and the inward rectifier current). Propafenone has local anesthetic activity approximately equal to procaine. Compared to propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and calcium channel activity, but about 10 times less beta-blocking activity (Ndepropylpropafenone has weaker sodium channel activity but equivalent affinity for betareceptors).
Electrophysiology studies in patients with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His- Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged. In patients with Wolff-Parkinson-White syndrome, RYTHMOL reduces conduction and increases the effective refractory period of the accessory pathway in both directions.
Propafenone slows prolongs the PR and QRS intervals. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval.
Table 2: Mean Changes in Electrocardiogram Intervalsa
|Interval||Total Daily Dose (mg)|
|337.5 mg||450 mg||675 mg||900 mg|
|a Change and percent change based on mean baseline values for each treatment group.|
In any individual patient, the above ECG changes cannot be readily used to predict either efficacy or plasma concentration.
RYTHMOL causes a dose-related and concentration-related decrease in the rate of single and multiple premature ventricular contractions (PVCs) and can suppress recurrence of ventricular tachycardia. Based on the percent of patients attaining substantial (80% to 90%) suppression of ventricular ectopic activity, it appears that trough plasma levels of 0.2 to 1.5 μg/mL can provide good suppression, with higher concentrations giving a greater rate of good response.
When 600 mg/day propafenone was administered to patients with paroxysmal atrial tachyarrhythmias, mean heart rate during arrhythmia decreased 14 beats/min and 37 beats/min for paroxysmal atrial fibrillation/flutter (PAF) patients and paroxysmal supraventricular tachycardia (PSVT) patients, respectively.
Studies in humans have shown that propafenone HCl exerts a negative inotropic effect on the myocardium. Cardiac catheterization studies in patients with moderately impaired ventricular function (mean C.I. = 2.61 L/min/m²) utilizing intravenous propafenone infusions (loading dose of 2 mg/kg over 10 min followed by 2 mg/min for 30 min) that gave mean plasma concentrations of 3.0 μg/mL (a dose that produces plasma levels of propafenone greater than does recommended oral dosing) showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances and depression of cardiac output and cardiac index.
Propafenone HCl is nearly completely absorbed after oral administration with peak plasma levels occurring approximately 3.5 hours after administration in most individuals. Propafenone exhibits extensive saturable presystemic biotransformation (first pass effect) resulting in a dose dependent and dosage form dependent absolute bioavailability; e.g., a 150 mg tablet had absolute bioavailability of 3.4%, while a 300 mg tablet had absolute bioavailability of 10.6%. A 300 mg solution which was rapidly absorbed had absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability increases still further.
Propafenone HCl follows a nonlinear pharmacokinetic disposition presumably because of saturation of first pass hepatic metabolism as the liver is exposed to higher concentrations of propafenone and shows a very high degree of interindividual variability. For example, for an increase in daily dose from 300 to 900 mg/day there is a 10-fold increase in steady-state plasma concentration. The top 25% of patients given 337.5 mg/day, however, had a mean concentration of propafenone larger than the bottom 25%, and about equal to the second 25%, of patients given a dose of 900 mg. Although food increased peak blood level and bioavailability in a single dose study, during multiple dose administration of propafenone to healthy volunteers food did not change bioavailability significantly.
Following intravenous administration of propafenone, plasma levels decline in a bi-phasic manner consistent with a 2 compartment pharmacokinetic model. The average distribution half-life corresponding to the first phase was about 5 minutes. The volume of the central compartment was about 88 liters (1.1 L/kg) and the total volume of distribution about 252 liters.
In serum, propafenone is greater than 95% bound to proteins within the concentration range of 0.5 to 2 μg/mL.
There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination halflife from 2 to 10 hours. These patients metabolize propafenone into two active metabolites: 5- hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone (norpropafenone) which is formed by both CYP3A4 and CYP1A2.
In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed. In these patients, the estimated propafenone elimination half-life ranges from 10 to 32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with a diminished ability to metabolize debrisoquine and a variety of other drugs (such as encainide, metoprolol, and dextromethorphan) whose metabolism is mediated by the CYP2D6 isozyme. In these patients, the N-depropylpropafenone metabolite occurs in quantities comparable to the levels occurring in extensive metabolizers.
There are significant differences in plasma concentrations of propafenone in slow and extensive metabolizers, the former achieving concentrations 1.5 to 2.0 times those of the extensive metabolizers at daily doses of 675 to 900 mg/day. At low doses the differences are greater, with slow metabolizers attaining concentrations more than five times that of extensive metabolizers. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxy metabolite in the slow metabolizers, and because steady-state conditions are achieved after 4 to 5 days of dosing in all patients, the recommended dosing regimen is the same for all patients. The greater variability in blood levels require that the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity [see DOSAGE AND ADMINISTRATION].
Stereochemistry: RYTHMOL is a racemic mixture. The R- and S-enantiomers of propafenone display stereoselective disposition characteristics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of S-propafenone to Rpropafenone at steady state. Both enantiomers have equivalent potency to block sodium channels; however, the S-enantiomer is a more potent β-antagonist than the R-enantiomer. Following administration of RYTHMOL immediate-release tablets, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. In addition, no difference in the average values of the S/R ratios is evident between genotypes or over time.
Hepatic Impairment: Decreased liver function increases the bioavailability of propafenone. Absolute bioavailability of RYTHMOL immediate-release tablets is inversely related to indocyanine green clearance, reaching 60-70% at clearances of 7 mL/min and below. Protein binding decreases to about 88% in patients with severe hepatic dysfunction. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction [see WARNINGS AND PRECAUTIONS].
Animal Toxicology and/or Pharmacology
Renal changes have been observed in the rat following 6 months of oral administration of propafenone HCl at doses of 180 and 360 mg/kg/day (about 2 and 4 times, respectively, the MRHD on a mg/m² basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for 6 weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone HCl at a dose of 270 mg/kg/day (about 3 times the MRHD on a mg/m² basis). There were no renal or hepatic changes at 90 mg/kg/day (equivalent to the MRHD on a mg/m² basis).
In two randomized, crossover, placebo-controlled, double-blind trials of 60 to 90 days duration in patients with paroxysmal supraventricular arrhythmias [paroxysmal atrial fibrillation/flutter (PAF), or paroxysmal supraventricular tachycardia (PSVT)], propafenone reduced the rate of both arrhythmias, as shown in Table 3.
Table 3: Reduction of Arrythmias in Patients with PAF
|Study 1||Study 2|
|PAF||n = 30||n = 30||n = 9||n = 9|
|Percent attack free||53%||13%||67%||22%|
|Median time to first recurrence||> 98 days||8 days||62 days||5 days|
|PSVT||n = 45||n = 45||n = 15||N = 15|
|Percent attack free||47%||16%||38%||7%|
|Median time to first recurrence||> 98 days||12 days||31 days||8 days|
The patient population in the above trials was 50% male with a mean age of 57.3 years. Fifty percent of the patients had a diagnosis of PAF and 50% had PSVT. Eighty percent of the patients received 600 mg/day propafenone. No patient died in the above 2 studies.
In U.S. long-term safety trials, 474 patients (mean age: 57.4 ± 14.5 years) with supraventricular arrhythmias [195 with PAF, 274 with PSVT and 5 with both PAF and PSVT] were treated up to 5 years (mean: 14.4 months) with propafenone. Fourteen of the patients died. When this mortality rate was compared to the rate in a similar patient population (n = 194 patients; mean age: 43.0 ± 16.8 years) studied in an arrhythmia clinic, there was no age-adjusted
difference in mortality. This comparison was not, however, a randomized trial and the 95% confidence interval around the comparison was large, such that neither a significant adverse or favorable effect could be ruled out.
Last reviewed on RxList: 6/7/2013
This monograph has been modified to include the generic and brand name in many instances.
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