Mechanism of Action
At the ionic level, quinidine blocks sodium ($Na^+$) and potassium ($K^+$) channels in cardiomyocytes. This leads to the prolongation of phase 0 (depolarization), phase 3 (repolarization), and phase 4 (diastolic depolarization) of the action potential. In addition to its cardiotropic effects, the drug possesses antimalarial activity through intercalation into parasite DNA via hydrogen bonds, inhibiting transcription and translation.
Furthermore, quinidine acts as a potent inhibitor of P-glycoprotein and hepatic microsomal enzymes (CYP3A4 and CYP2D6), which accounts for its numerous pharmacokinetic drug interactions.
Pharmacological Effects
The direct effect of the drug on the myocardium includes a decrease in automaticity and conductivity, an increase in the effective refractory period of the ventricles, and a moderate negative inotropic effect (decreased contractility). Ectopic pacemakers and AV junction pacemakers are suppressed to a greater extent than the sinus node.
An important component of its action is its vagolytic (anticholinergic) property, which inhibits impulse transmission from the vagus nerve to the heart. This leads to a paradoxical increase in sinoatrial node automaticity and accelerated AV conduction, counteracting the direct depressant effect. Vascular effects include peripheral vasodilation due to adrenoceptor blockade, leading to a moderate decrease in blood pressure.
Indications
According to reference formularies, quinidine is used for the treatment of atrial fibrillation and atrial flutter. The drug is administered orally 1 hour before meals at a dose of 0.2–0.3 g four times a day. The maximum daily dose is 4.0 g.
Historical note: Quinine and quinidine were previously used extensively to treat the erythrocytic stage of malaria, but modern practice utilizes specialized antimalarial drugs for these purposes.
Side Effects and Risks
Toxic effects on the body manifest as a symptom complex known as "cinchonism": this includes tinnitus, deafness, headache, nausea, vomiting, and visual disturbances.
Cardiotoxicity manifests as arrhythmias and QT interval prolongation. The arrhythmogenic effect occurs in approximately 5% of cases and can lead to dangerous ventricular tachyarrhythmias, particularly torsades de pointes. Extracardiac reactions include dyspepsia, neurosensory disturbances, and hematological disorders (thrombocytopenia).
Pharmacokinetic risks: As a P-glycoprotein inhibitor, quinidine prevents the elimination of digoxin from enterocytes, sharply increasing its blood concentration and creating a risk of severe digitalis toxicity. Similarly, P-glycoprotein blockade at the blood-brain barrier can allow peripheral drugs (e.g., loperamide) to penetrate the brain, leading to central nervous system depression.
Administration and Pharmacokinetics
The oral bioavailability of quinidine is 70–80%, peak concentration ($C_{max}$) is reached in 2–3 hours, and plasma protein binding is 60–80%. The drug is metabolized in the liver (including N-oxidation and involvement of CYP3A4 and CYP2D6 isozymes). The elimination half-life ($T_{1/2}$) is 6–7 hours. It is excreted by the kidneys (about 20% unchanged), with excretion significantly enhanced by urine acidification.