Mechanism of action
At the ionic level, quinidine blocks sodium ($Na^+$) and potassium ($K^+$) channels of 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 action, the drug exhibits antimalarial activity due to intercalation into the DNA of Plasmodium via hydrogen bonds, which inhibits 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 consists of decreased automaticity and conduction, an increased 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 the vagolytic (anticholinergic) property, which inhibits the transmission of impulses from the vagus nerve to the heart. This leads to a paradoxical increase in sinoatrial node automaticity and acceleration of AV conduction, counteracting the direct depressant effect. On the vascular side, peripheral vasodilation is observed due to adrenoceptor blockade, leading to a moderate decrease in blood pressure.
Indications for use
According to the prescription reference guide, quinidine is used to treat atrial fibrillation and flutter. The drug is prescribed orally 1 hour before meals at a dose of 0.2–0.3 g 4 times a day. The maximum daily dose (MDD) is 4.0 g.
Historical background: Previously, quinine and quinidine were actively used to treat the erythrocytic stage of malaria; however, in modern practice, specialized antimalarial agents are used for these purposes.
Side effects and risks
The toxic effect of the drug on the body manifests as a complex of symptoms known as "cinchonism": this includes tinnitus, deafness, headache, nausea, vomiting, and vision disturbances.
Cardiotoxicity is manifested by the occurrence of arrhythmias and prolongation of the QT interval. The arrhythmogenic effect occurs in approximately 5% of cases and can lead to dangerous ventricular tachyarrhythmias, specifically "torsades de pointes" (torsades de pointes). Extracardiac reactions include dyspepsia, neurosensory disturbances, and hematological disorders (thrombocytopenia).
Pharmacokinetic risks: As a P-glycoprotein inhibitor, quinidine prevents the excretion of digoxin from enterocytes, sharply increasing its concentration in the blood and creating a risk of severe cardiac glycoside intoxication. Similarly, blockade of P-glycoprotein at the blood-brain barrier can lead to the penetration of peripheral drugs (e.g., loperamide) into the brain with the development of CNS depression.
Administration features and pharmacokinetics
The bioavailability of quinidine when taken orally is 70–80%, the maximum 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 the involvement of CYP3A4 and CYP2D6 isoenzymes). The elimination half-life ($T_{1/2}$) is 6–7 hours. It is excreted by the kidneys (about 20% unchanged), and excretion is significantly enhanced by urine acidification.
Briefly: answers to topical questions
What ECG changes are caused by the toxic effect of quinidine?
The toxic effect of quinidine on the heart is manifested by prolongation of the QT interval on the ECG. This is due to the blockade of potassium channels and prolongation of the repolarization phase. This change is associated with the risk of developing ventricular tachyarrhythmias, particularly torsades de pointes (torsades de pointes).
In what rhythm disorders is the use of quinidine indicated?
The use of quinidine is indicated for the treatment of a wide range of ventricular and supraventricular arrhythmias. This antiarrhythmic drug is primarily used in clinical practice for the following rhythm disorders:
- Supraventricular arrhythmias — primarily atrial fibrillation.
- Frequent extrasystole — for effective suppression of ectopic excitation foci.
What hematological side effects are characteristic of quinidine?
Quinidine is characterized by the development of several serious hematological side effects. The main blood disorders associated with this drug include:
- Thrombocytopenia — may manifest as thrombocytopenic purpura developing via a cytolytic type of allergic reaction.
- Hemolytic anemia — occurs as a result of erythrocyte hemolysis in patients with a genetic deficiency of the enzyme glucose-6-phosphate dehydrogenase.
With which drugs does quinidine enter into clinically significant interactions due to P-glycoprotein inhibition?
Due to the inhibition of the P-glycoprotein transport protein, quinidine enters into clinically significant interactions with digoxin and loperamide.
- Digoxin (Digoxinum) — quinidine disrupts its excretion from enterocytes into the intestinal lumen, which increases the concentration of digoxin in the blood and creates a risk of cardiac glycoside intoxication.
- Loperamide (Loperamidum) — blockade of P-glycoprotein at the blood-brain barrier leads to the penetration of loperamide into the brain and increases the risk of developing severe central nervous system adverse reactions.
QUINIDINE: Q — Cinchona (source), U — Inhibitor of CYP3A4 and P-glycoprotein, N — Sodium channel blocker, I — Intercalation into DNA (in malaria), D — Long QT interval (arrhythmogenicity).
Class and exam questions
To which class of antiarrhythmic drugs does quinidine belong, and what is its mechanism at the ionic level?
Quinidine belongs to subclass IA (quinidine-like agents). Its mechanism consists of blocking sodium ($Na^+$) and potassium ($K^+$) channels, which prolongs phases 0, 3, and 4 of the action potential.
Why is the simultaneous administration of quinidine and digoxin dangerous?
Quinidine is a potent P-glycoprotein inhibitor. It blocks the efflux of digoxin from the intestine back into the lumen, leading to a sharp increase in the concentration of the cardiac glycoside in the blood and severe intoxication.
What is included in the classical symptom complex of quinidine poisoning ("cinchonism")?
"Cinchonism" manifests as tinnitus, deafness, headache, nausea, vomiting, and visual disturbances, as well as cardiotoxic effects with QT interval prolongation.
How does urine pH affect the excretion of quinidine from the body?
Renal excretion of the drug is significantly enhanced by urine acidification (shifting its reaction to the acidic side).
What else to study on this topic
- Comparative pharmacodynamics of subclass IA (quinidine, procainamide, disopyramide)
- The role of P-glycoprotein in pharmacokinetics and overcoming blood-tissue barriers
- The mechanism of development of torsades de pointes ventricular tachycardia during QT prolongation
- Interaction of CYP3A4 substrates and hepatic enzyme inhibitors
- Features of the antimalarial action of cinchona alkaloids
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