Quinidine

QUINIDINE

General Monograph,

Quinidine

Antiarrhythmic – Antimalarial

Action And Clinical Pharmacology: Quinidine is a class IA antiarrhythmic agent according to the Vaughan-Williams classification. It depresses most cardiac tissues by a direct action on cardiac cells.

Quinidine depresses the rapid inward depolarizing sodium current, thereby reducing the amplitude of the action potential without affecting the resting potential. The slope of the slow depolarization phase of Purkinje fibres is reduced, and the threshold voltage for reactivation is increased by an effect on the sodium current. The result is a reduction in excitability, conduction velocity and contractility in most parts of the heart, with an increase in the refractory periods and duration of action potential in the atria, ventricles and Purkinje tissues. Quinidine also raises the ventricular defibrillation threshold.

Quinidine also has anticholinergic activity, and acts peripherally as an a-adrenergic antagonist (i.e., a vasodilator).

By slowing conduction and prolonging the effective refractory period, quinidine can interrupt or prevent re-entrant arrhythmias, including atrial flutter, atrial fibrillation and paroxysmal supraventricular tachycardia.

In patients with sick sinus syndrome, quinidine may cause marked sinus node depression and bradycardia. In most patients, however, quinidine is associated with an increase in sinus rate and AV conduction, presumably through the combination of its anticholinergic effects and reflex increases in sympathetic activity.

Quinidine prolongs the QT interval in a dose-related fashion. At high serum levels, and especially in the presence of hypokalemia, this may lead to increased ventricular automaticity and polymorphic ventricular tachycardias, including torsades de pointes.

In patients with normal conduction time, a 50% increase in QRS duration is dangerous, and therefore, the increase in the QRS interval should not exceed 25% of the control value.

Quinidine has antimalarial activity and is used i.v. to treat severe and complicated P. falciparum malaria. It has been associated with clearing of parasitemia and high rates of survival. Although quinidine and its optical isomer, quinine, are both effective, i.v. quinine is an emergency release drug and may not be readily available.

Pharmacokinetics: Each salt dissociates in the gastrointestinal tract to release quinidine base, which is rapidly and almost completely absorbed from the small intestine. Extended-release formulations and the different salts of the drug are absorbed at different rates. Quinidine concentrations are generally higher and appear earlier when the drug is administered on an empty stomach, but the amount of drug absorbed is not diminished by the presence of food in the digestive tract. Extended-release preparations are generally preferred as the plasma concentration profile is smoother, and doses can be given at 8- to 12-hour intervals compared to the usual 6-hour dosing schedule for regular-release formulations.

All salts and formulations have approximately the same bioavailability of 70%. Peak plasma levels will vary among individuals primarily as a result of individual variations in first pass metabolism. Quinidine is widely distributed to all tissues except the brain. Quinidine crosses the placenta and is distributed into breast milk. At therapeutic plasma concentrations, the plasma protein binding of quinidine is 70 to 90% in adults and older children, but in infants and neonates it may be as low as 50 to 70%.

The elimination half-life is approximately 6 to 8 hours in adults and 3 to 4 hours in children but varies considerably among individuals. Quinidine is metabolized in the liver via the action of cytochrome-P450. Some of its metabolites may be therapeutically active. Decreased liver function does not seem to significantly affect the plasma clearance of the drug. Approximately 10 to 50% is excreted unchanged in the urine within 24 hours. Renal excretion is by glomerular filtration and secretion by proximal renal tubules. Renal clearance diminishes as urinary pH increases. Fecal excretion accounts for less than 5% of the oral dose.

The average therapeutic range is 6 to 15 µmol/L (2 to 5 µg/mL) of plasma. However, levels differ based on the assay method used. Currently available methods which are more specific than older methods report lower plasma quinidine concentrations. Toxicity is almost certain at concentrations above 25 µmol/L (8 µg/mL). The concentration necessary to produce a therapeutic effect will depend on the individual as well as the type, severity and duration of the arrhythmia. When efficacy is established, a serum drug concentration should be determined against which future levels should be compared if arrhythmia recurs or modifications made to the formulation or salt. Sampling is usually done just prior to the next dose.

Small amounts of quinidine are removed by hemodialysis; the drug is not removed by peritoneal dialysis.

Indications And Clinical Uses:

No antiarrhythmic drug has been shown to reduce the incidence of sudden death in patients with asymptomatic ventricular arrhythmias. Most antiarrhythmic drugs have the potential to cause dangerous arrhythmias; some have been shown to be associated with an increased incidence of sudden death. In light of the above, physicians should carefully consider the risks and benefits of antiarrhythmic therapy for all patients with ventricular arrhythmias.

Supraventricular Arrhythmias: Quinidine is the drug of choice for new onset (less than 1 year) atrial fibrillation or flutter when direct current cardioversion is undesirable. Ventricular rate should be controlled first with an agent that inhibits AV node conduction such as digoxin, beta-blockers or verapamil. Conversion of atrial fibrillation may be associated with embolism; therefore, anticoagulant treatment may be necessary before administration of quinidine. Quinidine is also the drug of choice for maintenance of sinus rhythm after cardioversion in patients with atrial fibrillation or flutter and for prevention of recurrent atrial fibrillation or flutter although this latter role is being re-evaluated.

Quinidine may also be used for prevention of paroxysmal atrial tachycardia due to AV nodal re-entry in patients with structural heart disease when digoxin or beta-blockers have failed or cannot be used.

Quinidine is not recommended to be used for atrial fibrillation or flutter of longer than 1 year’s duration or in patients with an enlarged left atrium as successful conversion is very unlikely.

Ventricular Arrhythmias: For the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. Quinidine may also be used for the treatment of patients with documented symptomatic ventricular arrhythmias when the symptoms are of sufficient severity to require treatment. Because of the proarrhythmic effects of quinidine, its use should be reserved for patients in whom the benefit of treatment clearly outweighs the risks.

For patients with sustained ventricular tachycardia, quinidine therapy should be initiated in the hospital. Hospitalization may also be required for certain other patients depending on their cardiac status and underlying cardiac disease.

The effects of quinidine in patients with recent myocardial infarction have not been adequately studied and, therefore, their use in this condition cannot be recommended.

Parenterally, quinidine may be used in the treatment of the above conditions when oral therapy is not feasible or when rapid therapeutic effect is required.

P. falciparum Malaria: I.V. quinidine is indicated for the treatment of life-threatening P. falciparum malaria.

Contra-Indications: Second-degree or complete atrioventricular block, junctional or idioventricular conduction disturbance that might be aggravated by quinidine, uncompensated heart failure, digitalis intoxication, prolonged QT interval (see also Warnings); patients manifesting clinical signs or having a past history of idiosyncrasy or hypersensitivity to quinidine or other cinchona derivatives (e.g., febrile reactions, skin eruptions, thrombocytopenic purpura, SLE syndrome); history of drug-induced torsades de pointes; myasthenia gravis. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Mortality: The results of the Cardiac Arrhythmia Suppression Trial (CAST) in postmyocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in nonfatal cardiac arrest rate in patients treated with encainide or flecainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine and placebo arms only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine treated group.

The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present it is prudent to consider these results when using any antiarrhythmic agent.

Patients with non-life-threatening arrhythmias received quinidine or a class IB or IC antiarrhythmic in a series of unrelated clinical trials. In a meta-analysis of these trials, mortality was greatest among the patients who had received quinidine.

Quinidine should be used with extreme caution in the presence of: incomplete AV block (since a complete block and asystole may result); digitalized patients (quinidine may cause unpredictable abnormalities of rhythm); partial bundle branch block; severe congestive heart failure, cardiogenic shock, severe bradycardia and hypotensive states (quinidine may have a depressant effect on myocardial contractility and arterial pressure); hepatic and renal insufficiency (especially renal tubular acidosis, because of the potential for quinidine accumulation).

In the treatment of atrial fibrillation or flutter, conversion to sinus rhythm may be preceded by an extremely rapid ventricular rate as the degree of AV block is progressively reduced. Agents which inhibit AV node conduction such as digoxin, beta-blockers or verapamil, should be used prior to the initiation of quinidine therapy for atrial fibrillation or flutter.

Cardiotoxicity: Quinidine cardiotoxicity may be manifested by increased PR and QT intervals, 50% widening of QRS, ventricular ectopic beats or tachycardia. Appearance of these toxic signs during quinidine administration mandates immediate discontinuation of the drug and close clinical and ECG monitoring.

Syncopal Episodes: Quinidine syncope may occur as a complication of long-term therapy. It is manifested by sudden loss of consciousness and ventricular arrhythmias with bizarre QRS complexes of the torsades de pointes type. This syndrome does not appear to be related to dose or plasma levels, but occurs more often with prolonged QT intervals. Syncopal episodes frequently terminate spontaneously, but sometimes are fatal. If quinidine-induced syncope occurs, the drug should be discontinued immediately.

Vagal Stimulation: Because quinidine antagonizes the effect of vagal excitation upon the atrium and the AV node, the administration of parasympathomimetic drugs or the use of any other procedure to enhance vagal activity may fail to terminate paroxysmal supraventricular tachycardia in patients receiving quinidine.

Digitalis Intoxication: Quinidine slows the elimination of digoxin and simultaneously reduces digoxin’s apparent volume of distribution. As a result, serum digoxin levels may double or even triple. When used concurrently, digoxin dosage should be reduced by approximately 50%, plasma concentrations should be monitored and patients observed closely for digoxin toxicity.

Hepatotoxicity: A few cases of hepatotoxicity, including granulomatous hepatitis, due to quinidine hypersensitivity have been reported. Unexplained fever and/or elevation of hepatic enzymes, particularly in the early stages of therapy, warrant consideration of possible hepatotoxicity. Cessation of quinidine in these cases usually results in the disappearance of toxicity.

Precautions: Proarrhythmic effects, or worsening of arrhythmias, can occur and are more likely in patients with sustained ventricular arrhythmias and left ventricular dysfunction.

A test dose of quinidine (orally or i.m.) should be given initially in order to identify possible hypersensitivity to quinidine. Although rare, the possibility of hypersensitivity should be constantly considered, especially during the first week of therapy.

When initiating therapy, hospitalization for close clinical observation, ECG monitoring and plasma level monitoring is indicated when large doses (i.e., >2 g/day) are used, or in patients at increased risk such as those with a history of syncope or presyncope due to ventricular arrhythmias.

Serum Potassium: Quinidine’s activity is enhanced by potassium and reduced if hypokalemia is present.

Established Atrial Fibrillation: The use of quinidine in established atrial fibrillation is controversial. Weigh the benefits of such use in each patient against possible hazards.

Parenteral Administration: Overly rapid infusion of quinidine may cause peripheral vascular collapse and severe hypotension. Blood pressure and ECG should be monitored continuously during i.v. administration; quinidine administration should be discontinued if there is a significant fall in blood pressure. Because the kinetics of absorption may vary with the patient’s peripheral perfusion, i.m. injection of quinidine is not recommended. I.M. injections are typically followed by moderate to severe local pain. Some patients will develop tender nodules at the site of injection that persist for several weeks.

P. falciparum Malaria: Complicated P. falciparum infection represents a medical emergency, and prompt administration of a schizonticidal drug is essential. All patients with severe P. falciparum malaria requiring i.v. administration of quinidine should be treated in an intensive care facility where hemodynamic and ECG monitoring is available. Even in patients without pre-existing cardiac disease, antimalarial use of quinidine has occasionally been associated with hypotension, QT prolongation, and cinchonism.

Pregnancy: It is not known whether quinidine can cause fetal harm when administered to pregnant women. There have been no teratogenic effects reported since the introduction of the drug, although quinine, the levostereoisomer of quinidine, has caused fetal blindness and has been implicated in congenital deafness. No clinical or epidemiologic studies have, however, been done. Quinidine should be used during pregnancy only when clearly indicated.

Lactation: Quinidine is present in breast milk at levels slightly lower than those in maternal serum. If possible, administration of quinidine should be avoided in nursing women.

Children: Safety and efficacy of antiarrhythmic use of quinidine in children has not been established. In antimalarial trials, quinidine was as safe and effective in pediatric patients as in adults. Children in these trials received the same doses (on a mg/kg basis) as adults.

Adverse Reactions: Gastrointestinal: The most frequent adverse reactions occurring in approximately 30% of patients are gastrointestinal disorders (diarrhea, nausea, vomiting and anorexia). These can occur as isolated reactions to therapeutic levels of quinidine, but they may also be the first signs of cinchonism. Gastrointestinal side effects may be less severe with extended-release formulations or the polygalacturonate salt.

Cinchonism is most often a sign of chronic toxicity but may appear in sensitive patients after a single dose. Symptoms include tinnitus and other hearing disturbances, nausea, diarrhea, vertigo, blurred vision, headache, dizziness, confusion and tremor.

Cardiac: Ventricular tachycardia (most frequently torsades de pointes or ventricular fibrillation), decreased contractility, reduction in blood pressure, syncope and ECG abnormalities (marked increase in PR, QRS and QT intervals) can occur.

Hypersensitivity: fever, urticaria, flushing, exfoliative rash, bronchospasm, psoriasiform rash, photosensitivity, pruritus, lymphadenopathy, vasculitis, thrombocytopenic purpura, uveitis, angioedema, the sicca syndrome and SLE-like syndrome. Serious reactions are manifested by respiratory arrest or cardiovascular collapse.

Hematologic: hemolytic anemia, aplastic anemia, thrombocytopenia, neutropenia, leukocytosis, leukopenia, agranulocytosis, hemolysis in patients with G6PD deficiency.

CNS: headache, vertigo, apprehension, excitement, confusion, delirium, ataxia, mental depression.

Ophthalmic: mydriasis, blurred vision, disturbed color perception, photophobia, diplopia, night blindness, scotomata, reduced visual fields, optic neuritis.

Musculoskeletal: arthralgia, myalgia, increased serum skeletal muscle creatine phosphokinase.

Hearing: tinnitus, decreased auditory capacity, transitory deafness.

Liver: increased hepatic enzyme levels, hepatitis (see Warnings).

Symptoms And Treatment Of Overdose: Symptoms: Large doses may cause ataxia, respiratory distress, apnea, vomiting, diarrhea, severe hypotension, syncope, anuria, tachyarrhythmias, depressed automaticity and conduction, heart block, heart failure, irritability, lethargy, seizures, paresthesia, coma and death. Symptoms of cinchonism have also occurred. tag_Treatment

Treatment: If ingestion is recent, gastric lavage and/or administration of activated charcoal with sorbitol may reduce absorption and hasten the passage of any remaining unabsorbed quinidine through the gastrointestinal tract. Avoid the use of charcoal if ileus is present. Maintain body temperature. Monitor electrolytes, especially potassium, calcium and magnesium. Support blood pressure and maintain renal function. Phenytoin or lidocaine may be used to control arrhythmias. Ventricular tachycardia may require DC cardioversion or pacing. Standard therapy for asystole should be employed. Refractory bradycardia or heart block that compromises blood pressure may require a temporary pacemaker. Torsades de pointes may require electrical conversion, treatment with magnesium or isoproterenol, or atrial or ventricular overdrive pacing. Angioneurotic or asthmatic phenomena may require the use of epinephrine and antihistamines.

Dosage And Administration:

Oral: Dosage based on quinidine sulfate equivalent. Administer a preliminary test dose of a single tablet of quinidine sulfate to determine whether the patient has a quinidine idiosyncrasy. Continuous or frequent ECG monitoring is desirable when quinidine therapy is initiated, especially if using large doses, i.e., >2 g quinidine sulfate daily. Gastrointestinal symptoms such as nausea, vomiting, diarrhea and colic may be minimized by giving the drug with food.

Premature Atrial and Ventricular Contractions: 200 to 300 mg of quinidine sulfate 3 or 4 times daily. Alternatively, a loading dose of 12 mg/kg, followed by a maintenance dose of 6 mg/kg every 4 to 6 hours has been recommended.

Paroxysmal Supraventricular Tachycardia: 400 to 600 mg of quinidine sulfate every 2 or 3 hours until the paroxysm is terminated.

Atrial Fibrillation or Flutter: Various schedules of quinidine administration have been utilized. One widely used technique is to give 200 mg of quinidine sulfate orally every 2 or 3 hours for up to 8 doses, with subsequent daily increase of the individual dose until sinus rhythm is restored or toxic effects occur. The total daily dose should not exceed 3 to 4 g of quinidine sulfate in any regimen.

The patient should be anticoagulated before conversion of atrial fibrillation. Ventricular rate should be brought under control with digoxin, verapamil or b-blockers. Congestive heart failure should be controlled if present. Patients should be digitalized before quinidine administration for atrial flutter.

Maintenance Therapy: 200 to 300 mg of quinidine sulfate 3 or 4 times daily.

Extended-release tablets may be given every 8 to 12 hours.

Parenteral: Dosage based on quinidine gluconate equivalent. If the patient has not received quinidine before and time permits, an initial dose of 200 mg of quinidine gluconate may be give i.m. as a test for idiosyncrasy. The test dose is given i.m. regardless of whether subsequent administration is to be i.m. or i.v.

The patient must be under close clinical observation. Frequent or continuous ECG and frequent measurement of blood pressure are recommended, especially during i.v. injection, to detect any change in rate or rhythm. I.V. administration of the drug must be stopped when any one of the following occurs: severe adverse effects, restoration of sinus rhythm, prolongation of QRS complex in excess of 25% beyond that observed prior to the injection, disappearance of P waves, or if the patient develops significant tachycardia, symptomatic bradycardia or hypotension.

I.M.: Because the kinetics of absorption may vary with the patient’s peripheral perfusion, intramuscular injection of quinidine is not recommended, except as a test dose.

I.V.: In about 50% of patients who respond successfully to quinidine, arrhythmias can be terminated by a total dose of less than 5 mg/kg of quinidine gluconate but some patients may require up to 10 mg/kg. If conversion to sinus rhythm has not been achieved after infusion of 10 mg/kg, the infusion should be discontinued and other means of conversion considered.

For i.v. administration, dilute 10 mL of quinidine gluconate 80 mg/mL injection to 50 mL with 5% dextrose for injection. Infusions of quinidine must be delivered slowly, preferably under control of a volumetric pump, no faster than 0.25 mg/kg/min (or 1 mL/kg/hour of the diluted solution).

Treatment of P. falciparum Malaria: 2 regimens have been empirically shown to be effective, with or without concomitant exchange transfusions. As soon as practical, standard oral antiplasmodial therapy should be instituted.

a) Continuous I.V. Infusion: loading dose of 10 mg/kg of quinidine gluconate (6.2 mg/kg base) in a volume of 250 mL normal saline infused over 1 to 2 hours, followed immediately by maintenance infusion of 0.02 mg/kg/min of quinidine gluconate (0.0125 mg/kg/min base) for up to 72 hours, or until oral therapy can be instituted to complete 7 days of treatment.

b) Intermittent I.V. Infusion: loading dose of 24 mg/kg of quinidine gluconate (15 mg/kg base) in a volume of 250 mL normal saline infused over 4 hours followed by maintenance infusion, beginning 8 hours after the beginning of the loading dose, of 12 mg/kg of quinidine gluconate (7.5 mg/kg base) infused over 4 hours, every 8 hours until the patient can swallow. Oral therapy can then be substituted to complete 7 days of treatment.

QUINIDINE General Monograph, Quinidine Antiarrhythmic – Antimalarial

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