Quinidine - Drug Monograph

Introduction

Quinidine is a class IA antiarrhythmic agent derived from the bark of the Cinchona tree. It has been used clinically for nearly a century and remains an important therapeutic option for certain cardiac arrhythmias despite the development of newer antiarrhythmic drugs. Quinidine is the d-isomer of quinine and possesses both antimalarial and antiarrhythmic properties.

Mechanism of Action

Quinidine exerts its antiarrhythmic effects through multiple mechanisms:

• Sodium channel blockade: Reduces the maximum rate of depolarization (phase 0) of the cardiac action potential
• Potassium channel blockade: Prolongs action potential duration and effective refractory period
• Vagolytic effects: Antagonizes muscarinic receptors, potentially accelerating AV nodal conduction
• Alpha-adrenergic blockade: Causes peripheral vasodilation
• Negative inotropic effect: Reduces myocardial contractility

These combined actions result in decreased automaticity, slowed conduction velocity, and increased refractoriness in cardiac tissue.

Indications

FDA-approved indications:

• Prevention of recurrent atrial fibrillation/flutter
• Suppression of ventricular arrhythmias (including ventricular tachycardia)
• Maintenance of normal sinus rhythm after conversion of atrial fibrillation/flutter

Off-label uses:

• Malaria treatment (particularly chloroquine-resistant Plasmodium falciparum)
• Short QT syndrome management
• Brugada syndrome (investigational)

Dosage and Administration

• Quinidine sulfate: 200-400 mg every 6 hours
• Quinidine gluconate: 324-648 mg every 8-12 hours
• Initial dosing should begin with lower doses with gradual titration

• Renal impairment: Reduce dose by 30-50% in severe renal insufficiency
• Hepatic impairment: Use with caution and consider dose reduction
• Elderly patients: Initiate at lower end of dosing range
• Loading dose: Sometimes used in hospitalized settings with cardiac monitoring

• Therapeutic range: 2-6 μg/mL
• Toxic levels: >6 μg/mL
• Trough levels are most clinically relevant

Pharmacokinetics

• Well absorbed from GI tract
• Bioavailability: 70-80%
• Food may delay but not reduce absorption
• Peak concentrations: 1-3 hours after administration

• Volume of distribution: 2-3 L/kg
• Protein binding: 80-90% (primarily to alpha-1 acid glycoprotein)
• Crosses placenta and enters breast milk

• Extensive hepatic metabolism via CYP3A4
• Forms active and inactive metabolites
• Significant first-pass metabolism

• Half-life: 6-8 hours (prolonged in hepatic impairment)
• Renal excretion: 10-20% as unchanged drug
• Urine acidification enhances renal elimination

Contraindications

• Known hypersensitivity to quinidine or related compounds
• Complete AV block without functioning pacemaker
• History of thrombocytopenia during quinidine therapy
• Myasthenia gravis
• Concurrent use with drugs that prolong QT interval
• Digoxin toxicity
• Bundle branch block
• Severe heart failure

Warnings and Precautions

• Increased mortality shown in patients with non-life-threatening ventricular arrhythmias
• Proarrhythmic effects, including torsades de pointes

• QT interval prolongation: Monitor ECG regularly
• Hypotension: May occur due to alpha-adrenergic blockade
• Cinchonism: Monitor for tinnitus, hearing loss, visual disturbances
• Blood dyscrasias: Regular CBC monitoring recommended
• Hepatitis: Rare but serious hepatic toxicity
• Drug fever: May occur during initial therapy
• Exacerbation of myasthenia gravis or lupus-like syndrome

Drug Interactions

• CYP3A4 inhibitors: Ketoconazole, erythromycin, verapamil (increase quinidine levels)
• CYP3A4 inducers: Rifampin, phenobarbital, phenytoin (decrease quinidine levels)
• Digoxin: Quinidine increases digoxin levels by 50-100%
• Warfarin: Enhanced anticoagulant effect
• Other QT-prolonging drugs: Increased risk of torsades de pointes
• Beta-blockers: Additive cardiac effects
• Calcium channel blockers: Additive effects on AV conduction

• Drugs highly bound to alpha-1 acid glycoprotein may displace quinidine

Adverse Effects

• Diarrhea (30-50%)
• Nausea, vomiting
• Cinchonism (tinnitus, hearing loss, blurred vision)
• Dizziness
• Headache

• Torsades de pointes (2-8%)
• Thrombocytopenia (0.5-1%)
• Hepatitis (<1%)
• Lupus-like syndrome
• Hypotension
• Heart block
• Ventricular arrhythmias
• Hemolytic anemia
• Drug fever

Monitoring Parameters

• ECG: Baseline and regular follow-up (QTc interval)
• Serum drug levels: Especially with dose changes or suspected toxicity
• Blood pressure: During initiation and dose titration
• CBC: Baseline and periodic monitoring
• Liver function tests: Baseline and periodic
• Renal function: Baseline and periodic
• Signs of cinchonism: Regular assessment

• Draw trough levels just before next dose
• Target range: 2-6 μg/mL
• Levels >6 μg/mL associated with increased toxicity risk

Patient Education

• Take medication exactly as prescribed
• Do not stop abruptly without medical supervision
• Report any signs of bleeding or bruising immediately
• Be aware of symptoms of cinchonism (ringing in ears, vision changes)
• Monitor for diarrhea and maintain hydration
• Avoid grapefruit juice during therapy
• Inform all healthcare providers about quinidine use
• Use reliable contraception during treatment
• Seek immediate medical attention for:

- Irregular heartbeat - Fainting or dizziness - Unexplained fever - Yellowing of skin or eyes

• Limit alcohol consumption
• Maintain adequate hydration
• Be cautious with over-the-counter medications
• Regular follow-up appointments are essential

References

1. Roden DM. Antiarrhythmic drugs. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill; 2018. 2. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2014;64(21):e1-e76. 3. Grace AA, Camm AJ. Quinidine. N Engl J Med. 1998;338(1):35-45. 4. FDA prescribing information: Quinidine sulfate tablets. Revised 2019. 5. Woosley RL, Singh SN. Antiarrhythmic drugs. In: Fuster V, Harrington RA, Narula J, Eapen ZJ, eds. Hurst's The Heart. 14th ed. McGraw-Hill; 2017. 6. Lexicomp Online. Quinidine monograph. Wolters Kluwer Clinical Drug Information; 2023. 7. Zimetbaum P. Antiarrhythmic drug therapy for atrial fibrillation. Circulation. 2012;125(2):381-389. 8. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 2013;93(5):402-408.