Quinidine

Overview

Quinidine is a class IA antiarrhythmic drug used in dogs for the treatment of ventricular and supraventricular arrhythmias and for conversion of atrial fibrillation to sinus rhythm. Its use for long-term control of ventricular arrhythmias and supraventricular tachycardia in dogs has declined as other antiarrhythmic agents are considered more effective.

Quinidine is nearly completely absorbed from the gastrointestinal tract after oral administration, although a hepatic first-pass effect reduces the amount that reaches the systemic circulation, and it is distributed rapidly to all body tissues except the brain. It is metabolized in the liver, primarily by hydroxylation, and approximately 20% of a dose may be excreted unchanged in the urine within 24 hours of dosing.

Mechanism of Action (MOA): Quinidine blocks fast sodium channels during phase 0 of the cardiac action potential. It depresses myocardial excitability, conduction velocity, and contractility while prolonging the action potential duration and effective refractory period. These effects help prevent reentry phenomena and increase cardiac conduction times. Quinidine also possesses anticholinergic activity that decreases vagal tone and may facilitate AV conduction.

Indications

Quinidine is used in dogs for the management of selected ventricular and supraventricular arrhythmias and for cardioversion of atrial fibrillation.

• Ventricular arrhythmias: Treatment of premature ventricular contractions (PVCs) and ventricular tachycardia.
• Supraventricular tachycardia: Management of refractory supraventricular tachycardias, tried when the drugs of first choice such as diltiazem have been ineffective, or when the tachycardia is thought to arise from an automatic rather than a reentrant focus.
• WPW-associated arrhythmias: Treatment of supraventricular arrhythmias associated with anomalous conduction in Wolff-Parkinson-White (WPW) syndrome, in which class I agents are more effective than when the tachycardia has another mechanism.
• Atrial fibrillation: Conversion of atrial fibrillation to sinus rhythm in dogs without underlying heart disease.

Dosage (Reference)

Dog

Quinidine may be used for the treatment of ventricular arrhythmias or for conversion of atrial fibrillation to sinus rhythm in selected canine patients.

Cat

Oral quinidine therapy is generally not used in cats.

Warnings & Precautions

Quinidine has a narrow therapeutic margin and should be used cautiously in patients with pre-existing cardiac disease, electrolyte abnormalities, or impaired hepatic or renal function.

• Hypersensitivity: Contraindicated in patients with a known hypersensitivity to quinidine.
• AV conduction disorders: Contraindicated in complete AV block with an AV junctional or idioventricular pacemaker, intraventricular conduction defects, aberrant ectopic impulses, and abnormal rhythms secondary to escape mechanisms.
• Myasthenia gravis: Contraindicated in patients with myasthenia gravis.
• Digitalis toxicity: Contraindicated in patients with digitalis intoxication associated with arrhythmias or AV conduction disorders. Use extreme caution in any form of AV block, or if any clinical signs of digoxin toxicity are present.
• Electrolyte and acid-base abnormalities: Use cautiously in patients with uncorrected hypokalemia, hypoxia, or acid-base imbalances; hypokalemia and hypomagnesemia also blunt the response to class I antiarrhythmic drugs.
• QT prolongation: Quinidine may prolong the QT interval, which can potentially lead to torsades de pointes; in people the risk is increased by bradycardia, hypokalemia, hypomagnesemia, hypocalcemia and high serum concentrations, and torsades may appear without any of them.
• Hepatic or renal insufficiency: Use cautiously, as drug accumulation and toxicity may occur.
• Congestive heart failure: Use with caution because reduced volume of distribution may increase the risk of toxicity. Dose reduction may be necessary.
• Pregnancy and lactation: Safety has not been established in animals. Use only when the maternal benefits outweigh the potential risks to offspring.
• Therapeutic monitoring: Consider monitoring blood concentrations, particularly in patients showing signs of toxicity or inadequate response; the canine therapeutic range is reported both as 2.5 to 5 µg/mL and as 2 to 7 µg/mL, and concentrations above 10 µg/mL are considered toxic.
• Sick sinus syndrome: Use quinidine with particular caution when this rhythm disturbance is present; marked depression of the sinus node and bradycardia have been reported in people with it.
• Mortality data in people: Deaths in human trials were three times as frequent with quinidine as with placebo when it was used to prevent recurrence of atrial flutter or fibrillation, and the risk of antiarrhythmic therapy appears greatest in patients with structural heart disease; the significance of these findings for veterinary patients is unclear.
• Vagal maneuvers: Quinidine’s anticholinergic action opposes the atrial and atrioventricular effects of vagal stimulation, so vagal maneuvers used to terminate a supraventricular tachycardia may be ineffective in a patient receiving it.

Drug Interactions

Quinidine has numerous clinically significant drug interactions that may affect serum concentrations, cardiac conduction, or the risk of toxicity. Careful monitoring is recommended when used concurrently with the following medications.

• Acetazolamide: May reduce quinidine clearance.
• Amiodarone: May significantly increase quinidine concentrations and the risk of cardiotoxicity.
• Antacids containing aluminum, calcium, or magnesium: May delay oral absorption; administer doses separately.
• Anticholinesterases (e.g., pyridostigmine, neostigmine): Quinidine may antagonize the effects of anticholinesterases in patients with myasthenia gravis.
• Antihypertensive agents (e.g., amlodipine, enalapril, sildenafil, telmisartan): Quinidine may potentiate hypotensive effects.
• Aurothioglucose: May increase the risk of blood dyscrasias.
• Azole antifungals (e.g., fluconazole, itraconazole, ketoconazole): May increase the risk of cardiotoxicity; the combination is contraindicated in humans.
• Cimetidine: May increase quinidine concentrations by inhibiting hepatic microsomal enzymes.
• Cisapride: May increase the risk of QT interval prolongation.
• Colchicine: Quinidine may increase colchicine concentrations.
• Dexamethasone: In dogs, dexamethasone increased the volume of distribution of quinidine by 49% to 78% and prolonged its elimination half-life by 1.5 to 2.3 times.
• Digoxin: Serum concentrations may rise considerably in a patient already stabilized on digoxin; some cardiologists recommend halving the digoxin dose when quinidine is added, and monitoring the concentrations of both drugs may be warranted. This matters when digoxin is also being used to slow the ventricular response during conversion of atrial fibrillation.
• Diltiazem and verapamil: Both may reduce quinidine clearance and prolong its elimination half-life, and verapamil additionally increases the risk of hypotension.
• Other drugs that prolong the QT interval: Hydroxyzine, methadone, metronidazole, ondansetron, sotalol, trazodone, procainamide and tricyclic antidepressants such as amitriptyline, clomipramine, doxepin and imipramine can also prolong the QT interval, and the effect is additive.
• Macrolide and fluoroquinolone antibiotics: Concurrent use with clarithromycin, erythromycin, ciprofloxacin or enrofloxacin carries an increased risk of cardiotoxicity.
• Lidocaine and mexiletine: Concurrent use with these class I antiarrhythmics may increase the risk of cardiotoxicity.
• Neuromuscular blocking agents: Quinidine may increase the effect of succinylcholine, tubocurarine and atracurium.
• Hepatic enzyme inducers (phenobarbital, primidone, rifampin): Quinidine’s serum half-life may be halved, which can cause loss of arrhythmia control.
• Phenothiazines (e.g., acepromazine): Additive cardiac depressant effects may be seen.
• Urinary acidifiers and alkalinizers: Methionine and ammonium chloride acidify the urine, which increases quinidine excretion and lowers its serum concentration; carbonic anhydrase inhibitors, thiazide diuretics, sodium bicarbonate and antacids alkalinize it, which reduces excretion and prolongs the half-life.
• Warfarin: Coumarin anticoagulants given with quinidine may increase the likelihood of bleeding problems.
• Doxorubicin, morphine, paroxetine and vincristine: Concurrent use may increase exposure to each of them. Quinidine interferes with membrane channels and increases concentrations of some coadministered drugs.

Side Effects & Overdose

Side Effects

Adverse effects of quinidine in dogs are primarily gastrointestinal and cardiovascular in nature and may be associated with excessive serum concentrations or rapid administration.

• Gastrointestinal effects: Anorexia, vomiting, and diarrhea may occur during treatment.
• Weakness: Generalized weakness has been reported.
• Hypotension: May occur, particularly following overly rapid IV administration.
• Negative inotropism: Quinidine may reduce myocardial contractility.
• ECG changes: Widening of the QRS complex and prolongation of the QT interval may occur.
• AV block: Impaired atrioventricular conduction may develop during therapy.
• Ventricular tachyarrhythmias: Multiform ventricular tachycardias have been reported.
• Tachycardia: The heart rate may increase, because the drug opposes vagal tone; use it cautiously in animals with heart disease.
• Neurologic signs: Ataxia and seizures have been reported when high oral doses are used for conversion to sinus rhythm.

Overdose

Quinidine overdose can result in serious cardiovascular and neurologic toxicity. Cardiovascular effects typically occur before central nervous system signs, although neurologic signs may persist after cardiovascular abnormalities begin to resolve.

• CNS effects: Depression, lethargy, confusion, and seizures may occur.
• Renal effects: Oliguria may develop in severely affected patients.
• Cardiac toxicity: Depressed automaticity, impaired cardiac conduction, and tachyarrhythmias may occur.
• Management: Recent oral ingestions may benefit from gastrointestinal decontamination and supportive care, and consultation with a 24-hour poison control center that provides veterinary-specific information is recommended.
• Enhanced elimination: Forced diuresis with fluids and diuretics, along with urinary acidification, may increase renal excretion of the drug.
• Advanced support: Temporary cardiac pacing may be required in cases of severe AV block. Hemodialysis can effectively remove quinidine, but peritoneal dialysis will not.
• Anticonvulsant therapy: Intravenous diazepam controls the seizures caused by quinidine toxicity, and the other signs abate within several hours of stopping the drug.
• Cardiovascular support: Intravenous fluids with metaraminol or norepinephrine may be used to treat hypotension, and a one-sixth molar intravenous infusion of sodium lactate may be used in an attempt to reduce the cardiotoxic effects.

Key Notes

Practical clinical points that may help optimize the use of quinidine in dogs, in which it is now used less often than other class I antiarrhythmic drugs:

• High protein binding: Quinidine is extensively bound to plasma proteins (approximately 82%–92%).
• Placental transfer: Quinidine crosses the placenta and is also distributed into maternal milk.
• Urinary pH effect: Acidic urine (pH < 6) increases renal excretion of quinidine and may shorten its serum half-life.
• Pharmacokinetics in dogs: The reported volume of distribution in dogs is approximately 2.9 L/kg, with a serum half-life of approximately 5.6 hours.
• Extended-release tablets: The 324 mg tablet is unscored, but the dose may be titrated by breaking a tablet in half; crushing or chewing destroys the extended-release properties.
• Administration with food: Gastrointestinal upset such as anorexia, vomiting or diarrhea may be reduced if the drug is given with food.
• P-glycoprotein inhibition: The ABCB1 (MDR1) transporter is inhibited by quinidine, which can raise the concentrations of drugs that depend on it, and that is the mechanism behind several of its interactions; its own oral absorption in collies was not altered by P-glycoprotein deficiency.
• Storage and appearance: All quinidine salts darken on exposure to light and should be stored in light-resistant, well-closed containers; a salt that has taken on a dark color should not be used.
• Treating asymptomatic ectopy: Antiarrhythmic therapy in an animal with no clinical signs is controversial. Human studies of asymptomatic ventricular premature complexes after myocardial infarction found a high incidence of sudden death when class I antiarrhythmics were started, and no comparable veterinary studies have been done.