Action And Clinical Pharmacology: Quinidine depresses excitability, conduction velocity and contractility of most cardiac tissues by a direct action on cardiac cells. Indirectly, cardiac tissues will also be affected by the anticholinergic and a-adrenoceptor blocking properties of quinidine.
According to Vaughan Williams antiarrhythmic drug classification, quinidine is a Class IA agent. Thus, quinidine reduces the maximal rate of phase 0 depolarization, prolongs repolarization and refractory periods and, in general, decreases automaticity of cardiac cells.
Pharmacokinetics: Absorption of oral quinidine sulfate is assumed to be essentially complete, though bioavailability is approximately 70% due to a first-pass removal by the liver. Peak plasma levels are variable among individuals. After a single dose given orally, quinidine can be detected in blood within 15 minutes and peak concentrations are achieved within 1 to 3 hours. Peak plasma levels during a multiple daily dose regimen may not be reached before the seventh day of administration. 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.
Although quinidine is 80% bound to plasma constituents (mainly a-1 acid glycoprotein), its distribution in the body is predominantly extravascular. The terminal elimination half-life is approximately 7 hours and is primarily associated with its metabolism by the liver (50 to 90% of the dose administered). Quinidine half-life varies considerably between individuals, even among healthy subjects. Total body clearance is approximately 4 mL/kg/min and is also variable. The metabolites may be therapeutically active. Ten to 20% of an administered dose is excreted unchanged in urine. Renal excretion is due to glomerular filtration and secretion by proximal renal tubules and is dependent upon urinary pH; renal clearance diminishes as urinary pH increases. Fecal excretion accounts for less than 5% of the oral dose.
The average therapeutic range is between 6 to 15 mol/L (2 and 5 Âµg/mL) of plasma. Toxic reactions are almost certain to appear at concentrations above 24.7 mol/L (8 g/mL). Levels may differ based on the assay method used.
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.
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, its use should be reserved for patients in whom, in the opinion of the physician, the benefit of treatment clearly outweighs the risks.
For patients with sustained ventricular tachycardia, quinidine therapy should be initiated in the hospital. Hospitalization may 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.
Supraventricular Arrhythmias: Quinidine is also indicated for premature atrial or AV junctional contractions, paroxysmal atrial or AV junctional tachycardia, atrial flutter, atrial fibrillation when this therapy is appropriate and maintenance therapy after electrical conversion of atrial flutter and/or fibrillation to sinus rhythm.
Contra-Indications: Hypersensitivity or idiosyncrasy to quinidine or other cinchona derivatives, history of thrombocytopenic purpura associated with previous quinidine administration, myasthenia gravis, digitalis intoxication manifested by AV conduction disorders, complete AV block with an AV nodal or idioventricular pacemaker, ectopic impulses and rhythms due to escape mechanisms and intraventricular conduction defects (especially with marked widening of the QRS complex).
Manufacturers’ Warnings In Clinical States: Mortality: The results of the Cardiac Arrhythmia Suppression Trial (CAST) in post-myocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in non-fatal cardiac arrest rates 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 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.
Quinidine Cardiotoxicity: Manifestation of quinidine cardiotoxicity, such as excessive prolongation of the QT interval, widening of the QRS complex, and ventricular arrhythmias, mandates immediate discontinuation of the drug and/or close clinical and electrocardiographic monitoring.
Treatment should be discontinued if the duration of the QRS complex increases more than 50% or the P-waves disappear. A significant fall in blood pressure, the onset of ventricular or premature contractions or ventricular tachycardia due to quinidine requires the immediate discontinuation of treatment.
Atrial Flutter Treatment: In the treatment of atrial flutter, reversion to sinus rhythm may be preceded by a progressive reduction in the degree of AV block to a 1:1 ratio, resulting in an extremely rapid ventricular rate. This possible hazard may be reduced by digitalization prior to administration of quinidine.
Cardiac Depression: In predisposed individuals, such as those with marginally compensated cardiovascular disease, quinidine may produce clinically important depression of the cardiovascular system such as hypotension, bradycardia or heartblock. The depressant action of quinidine on cardiac contractility and arterial blood pressure limits its use in congestive heart failure and in hypotensive states unless these conditions are due to or aggravated by the arrhythmia. The potential disadvantages and benefits must be weighed.
Syncopal Episodes: Occasionally, patients taking quinidine have syncopal episodes which usually result from tachycardia or fibrillation. The syndrome has not been shown to be related to dose or plasma levels. Syncopal episodes frequently terminate spontaneously, but sometimes are fatal.
Incomplete AV block: Quinidine should be used with extreme caution in patients with incomplete AV block. This can lead to complete AV block and asystole.
Digitalis Intoxication: Quinidine may cause abnormalities of cardiac rhythm in digitalized patients and, therefore, should be closely monitored. Reports indicate that plasma concentrations of digoxin increase and may even double when quinidine is administered concurrently. Patients on concomitant therapy should be carefully monitored. Reduction of digoxin dosage may have to be considered.
Hepatotoxicity: A few cases of hepatotoxicity, including granulomatous hepatitis, due to quinidine hypersensitivity have been reported in patients taking quinidine. Unexplained fever and/or elevation of hepatic enzymes, particularly in the early stages of therapy, warrant consideration of possible hepatotoxicity. Monitoring of liver function during the first 4 to 8 weeks should be considered. Cessation of quinidine in these cases usually results in the disappearance of toxicity.
Precautions: Test for Hypersensitivity: A test dose of a single tablet of quinidine (275 mg) by mouth should be given initially in order to ascertain any possible hypersensitivity to quinidine. Hypersensitivity to quinidine, although rare, should be constantly considered, especially during the first week of therapy.
Large Doses: Continuous ECG monitoring and determination of plasma quinidine concentrations are indicated when large doses (>2 g/day) are used.
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 the possible hazards.
Pregnancy: It is not known whether quinidine can cause fetal harm when administered to pregnant women. Quinine, the levostereoisomer of quinidine, has caused fetal blindness and has been implicated in congenital deafness. Quinidine should be used during pregnancy only when clearly indicated.
Lactation: Very small quantities pass into breast milk; no effects have been described in infants.
Children: Safety and efficacy of quinidine in children have not been determined.
Adverse Reactions: Quinidine has a low therapeutic index. Adverse effects occur in as many as a third of cases.
The most frequent adverse reactions are gastrointestinal in nature: nausea, vomiting, diarrhea and abdominal pain.
Cinchonism: Symptoms of mild cases include tinnitus, dysphonia and occasionally loss of hearing, some blurring of vision and gastrointestinal upset; more severe cases show headache, photophobia, altered color perception and possibly confusion, delirium and psychosis. Other symptoms observed include palpitations, convulsions, faintness and flushing, localized edema, vertigo, tremor, light-headedness, excitement, apprehension, coma and even death.
Idiosyncratic and Hypersensitivity Reactions: angioedema, febrile reactions, skin eruptions, acute asthmatic episodes, confusion, headache, anorexia, nausea, vomiting, diarrhea, precordial pain, abdominal pain, hepatic toxicity including granulomatous hepatitis, vascular collapse and respiratory arrest.
Cardiovascular: QRS widening, increased QT (and JT) interval, vasculitis, arterial embolism (following conversion of long standing atrial fibrillation to sinus rhythm), decreased cardiac contractility, hypotension (cardiac depression and vasodilatation), syncope (due to paroxysmal ventricular tachycardia or fibrillation), proarrhythmic effects (increased frequency of existing arrhythmia or development of new arrhythmias including ventricular tachycardia, fibrillation or torsades de pointes) and asystole.
Nervous System: apprehension, excitement, psychomotor agitation, hallucinations, delusions or paranoia, delirium, confusion, memory loss, depression, vertigo, disturbed hearing and/or vision.
Hematologic: thrombocytopenia including thrombotic purpura, hemolytic anemia, agranulocytosis, pancytopenia, hypoprothrombinemia and leukopenia.
Liver: moderate increase in enzyme levels, granulomatous hepatitis (see Warnings), hepatocellular necrosis and centrilobular cholestasis.
Kidney: nephrotic syndrome.
Skin: rash, flushing with pruritus, urticaria, photosensitivity and discoloration (bluish-gray).
Musculoskeletal: Very rare cases of lupus erythematosus, carpal tunnel syndrome and arthritis.
Symptoms And Treatment Of Overdose: Symptoms: Large doses may cause cinchonism, ventricular tachycardia, severe hypotension, cardiac standstill and ventricular fibrillation. Serious hypersensitivity reactions are manifested by respiratory embarrassment or cardiovascular collapse.
Treatment: If ingestion is recent, perform gastric lavage or induce emesis. (The use of an emetic may interfere with some of the following procedures.) Administration of 25 to 50 g of activated charcoal is indicated to reduce absorption of any remaining quinidine. Administration of a hypertonic cathartic (30 g sodium sulfate in 250 mL water) will hasten passage of unabsorbed quinidine through the gastrointestinal tract. If the charcoal preparation contains 70% sorbitol, the use of an additional hypertonic saline is not necessary. 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 cardiac standstill should be employed. Refractory bradycardia or heart block that compromises blood pressure may require a temporary pacemaker. Angioneurotic or asthmatic phenomena may require the use of epinephrine and antihistamines. Hemoglobinuria may necessitate blood transfusion and attention to renal function. The use of an alkali to prevent precipitation in the tubules may prove helpful.
Dosage And Administration: Administer a preliminary test dose of a single tablet (275 mg) to determine whether the patient has a quinidine idiosyncrasy. Continuous ECG monitoring is recommended in all cases in which quinidine is used in large doses.
Gastrointestinal symptoms such as nausea, vomiting, diarrhea and colic may be minimized by giving the drug with food.
Dosage should be individualized.
Initially: 275 to 825 mg (1 to 3 tablets) may be used to terminate arrhythmia, and may be repeated in 3 or 4 hours. If, following 3 or 4 equal doses normal rhythm has not been restored, dosage may be increased by 137.5 to 275 mg (1/2 to 1 tablet) and should be administered 3 or 4 times before further dosage increases.
Maintenance: 550 to 825 mg (2 to 3 tablets) daily.
Quinidine polygalacturonate, 275 mg, may be substituted for each 200 mg of quinidine sulfate (or equivalent) previously administered.
Availability And Storage: Each flat, uncoated, scored (one side), off-white tablet on one side and PF on the other, contains: quinidine polygalacturonate 275 mg equivalent in quinidine content to quinidine sulfate 200 mg. Also contains cornstarch 20 mg and lactose 56 mg. Sodium-, sugar- and tartrazine-free. Bottles of 50. Store in tightly-closed, light-resistant containers.
CARDIOQUIN® Purdue Frederick Quinidine Polygalacturonate Antiarrhythmic Agent