Propafenone

Propafenone is an antiarrhythmic Class 1 C agent belonging to a Sodium channel blocker.

Propafenone is used in the treatment of ventricular arrhythmias, Supraventricular arrhythmias, and atrial fibrillation. It is also used as a local anesthetic and nerve-blocking agent.

Propafenone is readily and almost completely absorbed from the gastrointestinal tract with bioavailability of Dose and dosage form dependent. It gets distributed by crossing the placenta and enters breast milk with the volume of distribution: 252 L and Plasma protein binding: >95%, mainly to α1-acid glycoprotein, and gets extensively metabolized in the liver mainly by CYP2D6 isoenzyme into 5-hydroxypropafenone, and to a lesser extent by CYP1A2 and CYP3A4 isoenzymes into N-depropylpropafenone (or propafenone), then to glucuronide or sulfate conjugates and get excreted via urine (<1% as unchanged drug, remainder as glucuronide or sulfate conjugates); feces.

The common side effects are Nausea, vomiting, dry mouth, dysgeusia, constipation, diarrhea, abdominal pain, flatulence, etc.

Propafenone is available in dosage forms such as tablets, capsules, and injections.

Propafenone is available in Italy, Europe, India, the U.S.A

Propafenone is a class 1C antiarrhythmic drug with local anesthetic effects and direct stabilizing activity on myocardial membranes. It inhibits the fast inward Na current and slows the rate of increase of the action potential. Propafenone prolongs the conduction and refractoriness in all areas of the myocardium (with slightly more pronounced activity on intraventricular conduction). It extends the effective refractory period, reduces spontaneous automaticity, and exhibits some β-blockade action.

It works directly on the heart tissue and will slow the nerve impulses in the heart. This helps keep the heart rhythm normal.

The onset of Action of Propafenone was within 2-3 hr.

The Duration of Action of Propafenone was 6 hr.

The Tmax was about 3.5 hours (immediate release); 3-8 hours (extended release). and Cmax was about 150 ng/mL to 1500 ng/mL

Propafenone is available in the form of a dosage form such as tablets, capsules, and injections.

Propafenone is used in the treatment of ventricular arrhythmias, Supraventricular arrhythmias, and atrial fibrillation. It is also used as a local anesthetic and nerve-blocking agent.

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 drug's antiarrhythmic actions.

Propafenone is used in the treatment of ventricular arrhythmias, Supraventricular arrhythmias, and atrial fibrillation. It is also used as a local anesthetic and nerve-blocking agent.

• Ventricular Arrhythmias/Paroxysmal Supraventricular Tachycardia

IR: 150 mg PO q8hr; may increase to 225 mg q8hr after 3-4 days, and, if required, 300 mg q8hr; not to exceed 300 mg q8hr

• Atrial Fibrillation/Flutter
  

IR: 150 mg taken orally at every 8hr; may increase to 225 mg at every 8hr after 3-4 days, and, if required, 300 mg at every 8 hours; not to exceed 300 mg at every 8 hours.

ER: 225 mg taken orally at every 8 hours initially; may increase Dose at every five days to 325 mg taken orally at every 12hr OR 425 mg taken orally at every 12hr, if necessary

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Propafenone is available in various dosage strengths: 150mg, 225mg, 300mg 325mg, 425mg, 35mg/10ml

Propafenone is available in the form of a dosage form such as capsules, tablets, and injections.

Propafenone is used in the treatment of ventricular arrhythmias, Supraventricular arrhythmias, and atrial fibrillation. It is also used as a local anesthetic and nerve-blocking agent.

Ventricular arrhythmias: Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk.

Drinking too much alcohol can increase the risk of developing AFib.It may also trigger AFib episodes in people who already have AFib, especially if patients have existing cardiovascular disease or diabetes.

The dietary restriction should be individualized as per the patient's requirements.

Propafenone may be contraindicated in the following:

• Heart failure
• Cardiogenic shock
• Sinoatrial, atrioventricular and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, AV block) in the absence of an artificial pacemaker
• Known Brugada Syndrome
• Bradycardia
• Marked hypotension
• Bronchospastic disorders or severe obstructive pulmonary disease
• Marked electrolyte imbalance

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Precautions:

• Proarrhythmic Effects

Propafenone has caused new or worsened arrhythmias. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole, and torsade de points. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval. It is therefore essential that each patient is given Propafenone be evaluated electrocardiographically prior to and during therapy to determine whether the response to propafenone supports continued treatment. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret.

In a U.S. uncontrolled, open-label, multicenter trial in patients with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study. However, in 4 of the 9 patients, the ventricular tachycardia was of atrial origin. Six of the nine patients that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all patients had a recurrence of SVT during the study which could have been a change in the patient's arrhythmia behavior or could represent a proarrhythmic event. Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsade de pointes, asystole, and death.

• Unmasking Brugada Syndrome

Brugada Syndrome may be unmasked after exposure to Propafenone. Perform an ECG after initiation of Propafenone, and discontinue the drug if changes are suggestive of Brugada Syndrome

• Patients with pacemakers, and mild to moderate obstructive airway disease (e.g. asthma). May potentially convert paroxysmal atrial fibrillation to atrial flutter with a 2:1 or 1:1 conduction block.

Alcohol consumption with Propafenone may increase the risk of low blood pressure and cause adverse effects, such as Dizziness, fainting, light-headedness, or headache.

Propafenone use in breastfeeding patients is not recommended.

Pregnancy Category C:

There are no adequate and well-controlled studies on pregnant women. Propafenone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Grapefruit or grapefruit juice can increase the amount of propafenone in the body. This can make irregular heart rates worse. Don’t drink grapefruit juice or eat grapefruit while taking this drug.

The adverse reactions related to the molecule Propafenone can be categorized as

• Common Adverse effects:

Cardiac conduction disorder (e.g. slows AV conduction), CNS effects (e.g., dizziness, blurred vision, fatigue), agranulocytosis, elevated antinuclear antibody (ANA) titer, hepatic abnormalities, fulminant hepatitis.

• Less Common adverse effects:

Thrombocytopenia, leucopenia, granulocytopenia. Cardiac disorders: Palpitations, bradycardia, tachycardia, Nausea, vomiting, dry mouth, dysgeusia, constipation, diarrhea, abdominal pain, flatulence.

• Rare adverse effects:

Hypotension, orthostatic hypotension, Erectile dysfunction. Respiratory, thoracic and mediastinal disorders: Dyspnoea.

The clinically relevant drug interactions of Propafenone are briefly summarized here.

CYP2D6 and CYP3A4 Inhibitors

Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, or sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, or grapefruit juice) can be expected to cause increased plasma levels of propafenone. The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with the administration of propafenone may increase the risk of adverse reactions, including proarrhythmia. Therefore, simultaneous use of Proprafenone with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided.

• Amiodarone:

Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended.

• Cimetidine:

Concomitant administration of propafenone immediate-release tablets and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentrations of propafenone.

• Fluoxetine:

Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S-propafenone Cmax and AUC by 39% and 50% and the R propafenone Cmax and AUC by 71% and 50%.

• Rifampin:

Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5-OH-propafenone by 65%. The concentrations of propafenone increased by 30%. In slow metabolizers, there was a 50% decrease in propafenone plasma concentrations and increased the AUC and Cmax of propafenone by 74% and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients: Both the AUC and Cmax propafenone decreased by 84%, with a corresponding decrease in AUC and Cmax of 5-OH-propafenone by 69% and 57%.

• Digoxin

Concomitant use of propafenone and digoxin increased steady-state serum digoxin exposure (AUC) in patients by 60% to 270% and decreased the clearance of digoxin by 31% to 67%. Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed, convulsions, atrioventricular block, and acute circulatory failure.

• Beta-Antagonists

Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at a steady state by 113%. In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at a steady state by 100% to 400%. The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol. In clinical trials using propafenone immediate-release tablets, patients who were receiving beta-blockers concurrently did not experience an increased incidence of side effects.

• Lidocaine

No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms:

Myocardial effects: PQ prolongation, QRS widening, suppression of sinus node automaticity, AV block, ventricular tachycardia, flutter or fibrillation, and hypotension which can lead to CV shock. Non-cardiac effects: Headache, dizziness, blurred vision, tremor, dry mouth, Nausea, constipation. In severe cases, clonic-tonic convulsions, paraesthesia, somnolence, coma, respiratory arrest may occur.

Management:

Symptomatic and supportive treatment. Defibrillation, as well as administration of dopamine or isoproterenol infusion to control rhythm and blood pressure. Administer IV diazepam to alleviate convulsions. May consider mechanical respiratory assistance and external cardiac massage.

Pharmacodynamics:

• Propafenone is a class 1C antiarrhythmic drug with local anesthetic effects and direct stabilizing activity on myocardial membranes. It inhibits the fast inward Na current and slows the rate of increase of the action potential. Propafenone prolongs the conduction and refractoriness in all areas of the myocardium (with slightly more pronounced activity on intraventricular conduction). It prolongs the effective refractory period, reduces spontaneous automaticity, and exhibits some β-blockade action.

Pharmacokinetics:

• Absorption: Readily and almost completely absorbed from the gastrointestinal tract. Bioavailability: Dose and dosage form dependent. Time to peak plasma concentration: 3.5 hours (immediate release); 3-8 hours (extended-release).

• Distribution: Crosses placenta and enters breast milk. The volume of distribution: 252 L. Plasma protein binding: >95%, mainly to α₁-acid glycoprotein.

• Metabolism: Extensively metabolized in the liver mainly by CYP2D6 isoenzyme into 5-hydroxypropafenone, and to a lesser extent by CYP1A2 and CYP3A4 isoenzymes into N-depropylpropafenone (or propafenone), then to glucuronide or sulfate conjugates.

• Excretion: Via urine (<1% as unchanged drug, remainder as glucuronide or sulfate conjugates); feces. Elimination half-life: 2-10 hours (extensive metabolisers); 10-32 hours (poor metabolites).

1. https://reference.medscape.com/drug/Proprafenone -propafenone-342307
2. https://openstreetmap.id/propafenone-medscape-xroe
3. https://go.drugbank.com/drugs/DB01182
4. https://go.drugbank.com/pharmaco/genomics/DBSNPE004766