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Disopyramide

Disopyramide: A Comprehensive Overview

Introduction

Disopyramide is a class Ia antiarrhythmic agent used in the treatment of certain types of cardiac arrhythmias, particularly ventricular arrhythmias and atrial fibrillation. As a sodium channel blocker, it affects the electrical conduction within the heart, making it useful in stabilizing abnormal heart rhythms. Marketed under several brand names including Norpace, Disopyramide has been in clinical use since the 1970s.

Chemical and Pharmacological Profile

  • Chemical Name: 4-diisopropylamino-2-phenyl-2-(2-pyridyl)butyramide

  • Molecular Formula: C21H29N3O

  • Class: Class Ia antiarrhythmic

  • Mechanism of Action: Disopyramide blocks fast sodium channels in the cardiac cells, slowing conduction and prolonging the action potential duration. It also exhibits anticholinergic activity, which can influence heart rate and conduction through the AV node.

Indications and Usage

Disopyramide is primarily indicated for:

  • Ventricular Tachycardia: Particularly in patients unresponsive to other antiarrhythmics.

  • Atrial Fibrillation/Flutter: As a rhythm control agent in certain cases.

  • Prevention of Recurrence: In patients with recurrent arrhythmias.

It is often reserved for patients who cannot tolerate or have failed other antiarrhythmic agents.

Formulations and Dosing

Disopyramide is available in two primary forms:

  • Immediate-release capsules (Norpace): 100 mg and 150 mg

  • Extended-release capsules (Norpace CR): 100 mg, 150 mg, and 200 mg

Typical Adult Dosage:

  • Immediate-release: 100-150 mg every 6 hours

  • Extended-release: 200-300 mg every 12 hours

Dose adjustments are necessary in patients with renal or hepatic impairment.

Pharmacokinetics

  • Absorption: Well absorbed orally with bioavailability around 80%.

  • Distribution: Widely distributed with a volume of distribution of ~2 L/kg.

  • Metabolism: Hepatically metabolized, primarily via CYP3A4.

  • Elimination: Renal excretion of both unchanged drug and metabolites.

  • Half-life: Approximately 6-8 hours (immediate-release), up to 12 hours for extended-release.

Mechanism of Action in Detail

Disopyramide exerts its antiarrhythmic effects by:

  1. Sodium Channel Blockade: Slows Phase 0 depolarization in cardiac cells.

  2. Prolonged Repolarization: Increases effective refractory period.

  3. Decreased Automaticity: Reduces abnormal ectopic pacemaker activity.

These effects are particularly beneficial in treating tachyarrhythmias.

Anticholinergic Activity

One unique aspect of disopyramide is its strong anticholinergic (antimuscarinic) effect. This leads to:

  • Dry mouth

  • Urinary retention

  • Constipation

  • Blurred vision

However, in some cases, this property can be therapeutically advantageous (e.g., in vagally mediated atrial fibrillation).

Clinical Studies and Efficacy

Disopyramide has been evaluated in multiple studies for its antiarrhythmic efficacy:

  • Ventricular Arrhythmias: Shown to be effective in reducing PVCs and sustained VT episodes.

  • Hypertrophic Cardiomyopathy: Used off-label to reduce left ventricular outflow tract obstruction due to its negative inotropic effects.

Long-term studies suggest moderate effectiveness in rhythm control but with notable adverse effect profiles compared to newer agents.

Adverse Effects

Common side effects include:

  • Anticholinergic symptoms (dry mouth, urinary retention, constipation)

  • Negative inotropic effects (may exacerbate heart failure)

  • QT prolongation and proarrhythmia (torsades de pointes)

Rare but serious adverse effects:

  • Agranulocytosis

  • Hepatotoxicity

  • Seizures (at high doses or with overdose)

Contraindications

Disopyramide is contraindicated in:

  • Second- or third-degree AV block (without pacemaker)

  • Cardiogenic shock

  • Congenital long QT syndrome

  • Severe heart failure

Drug Interactions

  • CYP3A4 inhibitors (e.g., ketoconazole, erythromycin): Can increase disopyramide levels

  • Other QT-prolonging drugs: Risk of torsades de pointes

  • Beta-blockers/Calcium channel blockers: Additive negative inotropic and chronotropic effects

Monitoring Parameters

  • ECG monitoring: QT interval, PR and QRS duration

  • Serum drug levels: Therapeutic range typically 2-4 mcg/mL

  • Renal and hepatic function: Dose adjustments needed

Use in Special Populations

  • Elderly: Increased sensitivity to anticholinergic effects; cautious use

  • Pregnancy: Category C – only if benefits outweigh risks

  • Lactation: Excreted in breast milk; not recommended

  • Renal/Hepatic Impairment: Dose reduction necessary

Patient Counseling Information

Patients should be advised to:

  • Take the medication exactly as prescribed

  • Report any signs of dizziness, syncope, or palpitations

  • Avoid other QT-prolonging agents

  • Maintain hydration to avoid urinary retention

Alternatives and Comparisons

Other Class Ia agents include:

  • Quinidine: Similar mechanism but with more gastrointestinal side effects

  • Procainamide: More frequently associated with lupus-like syndrome

Other class antiarrhythmics for comparison:

  • Class Ic (e.g., Flecainide, Propafenone): Used in structurally normal hearts

  • Class III (e.g., Amiodarone, Sotalol): Broader efficacy but different side effect profiles

Current Guidelines and Positioning

According to AHA/ACC guidelines:

  • Disopyramide is considered a second-line or adjunctive agent for atrial fibrillation

  • Preferred in hypertrophic cardiomyopathy with obstructive physiology when beta-blockers or verapamil are not tolerated or sufficient

Research and Emerging Uses

  • Hypertrophic Cardiomyopathy (HCM): Increasing interest due to its negative inotropic effects

  • Atrial Fibrillation in Vagal Tone-Driven Arrhythmias: May be beneficial due to its anticholinergic activity

Storage and Handling

  • Store at room temperature

  • Protect from moisture and light

  • Keep out of reach of children

Conclusion

Disopyramide remains a valuable agent in the management of certain arrhythmias, especially in patients who have failed other therapies or those with specific indications like obstructive hypertrophic cardiomyopathy. While its use has declined with the advent of newer agents, its unique pharmacological profile continues to serve a role in specialized cardiac care. Proper monitoring and patient selection are key to maximizing therapeutic benefit while minimizing adverse effects.

References

  1. ACC/AHA/HRS Guidelines on the Management of Patients With Atrial Fibrillation

  2. Goodman & Gilman's: The Pharmacological Basis of Therapeutics

  3. Drugs.com, FDA Prescribing Information for Disopyramide

  4. Journal of the American College of Cardiology (JACC), Clinical Updates in Arrhythmia Management

  5. UpToDate: Disopyramide Drug Monograph.