Quinidine

Quinidine is a class IA antiarrhythmic derived from cinchona bark and is the dextrorotatory isomer of quinine. It was used widely for atrial fibrillation, ventricular tachycardia and malaria, but it increases mortality in long term use and has largely been replaced. Today it is kept for Brugada syndrome and short QT syndrome under specialist care. In East Africa, it is rarely available, and it must never be confused with quinine, which is used for severe malaria.

Classification. Class IA antiarrhythmic (sodium and potassium channel blocker); cinchona alkaloid.

Mechanism. Blocks fast sodium channels (slowing conduction) and several potassium currents (prolonging repolarisation and the QT interval). It has anticholinergic and alpha blocking effects and inhibits the transient outward potassium current, which explains its benefit in Brugada syndrome.

Pharmacodynamics. Oral onset within 1 to 3 hours, peak at 1 to 2 hours (sulphate) and 3 to 4 hours (gluconate). Prolongs QRS and QT intervals; vagolytic effect can speed atrioventricular conduction in atrial fibrillation (give with a nodal blocker).

Pharmacokinetics. Oral bioavailability 70 to 80%. Half life 6 to 8 hours (longer in older adults, liver and heart failure). Metabolised by CYP3A4 in the liver to active metabolites; about 20% excreted unchanged in urine. Protein bound 80 to 90%. Therapeutic level 2 to 5 mg/L.

Brugada syndrome, adult (specialist). Quinidine bisulphate 300 to 600 mg twice daily (total 600 to 1200 mg daily); titrate to tolerance.

Short QT syndrome and refractory ventricular arrhythmias (specialist), adult. 200 to 400 mg of quinidine sulphate every 6 to 8 hours; maximum 3 g daily.

Atrial fibrillation or flutter (rarely used now), adult. Test dose 200 mg; then 200 to 400 mg of quinidine sulphate every 6 to 8 hours, with a nodal blocker (digoxin or beta blocker) first.

Children (specialist). 30 mg/kg daily of quinidine sulphate in 4 to 5 divided doses.

Contraindications. Heart block without a pacemaker; QT prolongation or history of torsades de pointes; digoxin toxicity; myasthenia gravis; thrombocytopenic purpura related to quinidine; uncorrected hypokalaemia; hypersensitivity (including to quinine); concurrent drugs prolonging the QT interval.

Warnings. Proarrhythmia (torsades de pointes, even at low plasma levels); increased mortality in long term use; quinidine syncope; hypotension; cinchonism (tinnitus, headache, deafness, blurred vision, nausea); thrombocytopenia; haemolysis in glucose 6 phosphate dehydrogenase deficiency; lupus like syndrome; hepatitis.

Adverse effects. Diarrhoea, nausea, vomiting, abdominal pain, tinnitus, rash, light headedness, QT prolongation, torsades de pointes, thrombocytopenia.

Interactions. Digoxin: levels double (halve the dose). Warfarin: INR rises. Amiodarone, macrolides, fluoroquinolones, antimalarials (chloroquine, artemether lumefantrine, mefloquine, quinine), antipsychotics: torsades. Verapamil and cimetidine: raised levels. CYP2D6 substrates (metoprolol, codeine, tricyclic antidepressants): altered effect. Rifampicin and phenytoin: lower levels. Alkalinising agents (antacids, acetazolamide): reduced excretion and higher levels. Grapefruit juice: slower absorption.

Special groups.

• Pregnancy: avoid unless essential; oxytocic effect and thrombocytopenia in the infant.

• Breastfeeding: excreted in milk; avoid.

• Patients of African ancestry: check for glucose 6 phosphate dehydrogenase deficiency before use.

• Older adults: lower doses; accumulation and torsades risk.

• Kidney impairment: reduce the dose by 25% when creatinine clearance is under 10 mL/min.

• Liver impairment: reduce the dose and monitor levels.

Formulations. Quinidine sulphate tablets 200 and 300 mg; quinidine bisulphate and gluconate in some markets (sulphate 200 mg is about equal to gluconate 267 mg).

Administration. Oral with food to reduce nausea. Do not crush modified release tablets.

Baseline. ECG (QTc), potassium, magnesium, full blood count, liver enzymes, glucose 6 phosphate dehydrogenase status, pregnancy test.

Monitoring. ECG at baseline, 2 to 3 days after each dose change and every 6 months (stop if QTc is above 500 ms or increases by more than 25%). Full blood count and liver enzymes at 1 month, 3 months and then yearly. Plasma level if toxicity is suspected. Potassium and magnesium.

Stopping. Taper where possible; stop immediately for torsades, QTc above 500 ms, thrombocytopenia or hepatitis.

Common prescribing errors. Confusing quinidine with quinine or the reverse; using it with other QT prolonging drugs; omitting a nodal blocker in atrial fibrillation; failing to halve digoxin; continuing in a patient with diarrhoea and hypokalaemia.