Conversion of atrial fibrillation/flutter
In patients with symptomatic atrial fibrillation/flutter whose symptoms are not adequately controlled by measures that reduce the rate of ventricular response, quinidine sulfate is indicated as a means of restoring normal sinus rhythm. If this use of quinidine sulfate does not restore sinus rhythm within a reasonable time (see DOSAGE AND ADMINISTRATION), then quinidine sulfate should be discontinued.
Reduction of frequency of relapse into atrial fibrillation/flutter
Chronic therapy with quinidine sulfate is indicated for some patients at high risk of symptomatic atrial fibrillation/flutter, generally patients who have had previous episodes of atrial fibrillation/flutter that were so frequent and poorly tolerated as to outweigh, in the judgement of the physician and the patient, the risks of prophylactic therapy with quinidine sulfate. The increased risk of death should specifically be considered. Quinidine sulfate should be used only after alternative measures (e.g., use of other drugs to control the ventricular rate) have been found to be inadequate.
In patients with histories of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy should be an increase in the average time between episodes. In most patients, the tachyarrhythmia will recur during therapy, and a single recurrence should not be interpreted as therapeutic failure.
Suppression of ventricular arrhythmias
Quinidine sulfate is also indicated for the suppression of recurrent documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgement of the physician are lifethreatening. Because of the proarrhythmic effects of quinidine, its use with ventricular arrhythmias of lesser severity is generally not recommended, and treatment of patients with asymptomatic ventricular premature contractions should be avoided. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.
Antiarrhythmic drugs (including quinidine sulfate) have not been shown to enhance survival in patients with ventricular arrhythmias.
Treatment of malaria
Quinidine sulfate is also indicated in the treatment of life-threatening Plasmodium falciparum malaria.
Quinidine is contraindicated in patients who are known to be allergic to it, or who have developed thrombocytopenic purpura during prior therapy with quinidine or quinine.
In the absence of a functioning artificial pacemaker, quinidine is also contraindicated in any patient whose cardiac rhythm is dependent upon a junctional or idioventricular pacemaker, including patients in complete atrioventricular block.
Quinidine is also contraindicated in patients who, like those with myasthenia gravis, might be adversely affected by an anticholinergic agent.
In many trials of antiarrhythmic therapy for non-life-threatening arrhythmias,active antiarrhythmic therapy has resulted in increased mortality; the risk of active therapy is probably greatest in patients with structural heart disease.
In the case of quinidine usedto prevent or defer recurrence of atrial flutter/fibrillation,the best available data come from a metaanalysis CLINICAL PHARMACOLOGY /Clinical Effects above. In the patients studied in the trials there analyzed, the mortality associated with the use of quinidine was more than three times as great as the mortality associated with the use of placebo.
Another metaanalysis, also described under CLINICAL PHARMACOLOGY/Clinical Effects, showed that in patients with various non-life-threatening ventricular arrhythmias, the mortality associated with the use of quinidine was consistently greater than that associated with the use of any of a variety of alternative antiarrhythmics.
Like many other drugs (including all other class IA antiarrhythmics), quinidine prolongs the QTC interval, and this can lead to torsadesde pointes, a life-threatening ventricular arrhythmia (see OVERDOSAGE). The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, or high serum levels of quinidine, but it may appear in the absence of any of these risk factors. The best predictor of this arrhythmia appears to be the length of the QTC interval, and quinidine should be used with extreme care in patients who have preexisting long- QT syndromes, who have histories of torsades de pointes of any cause, or who have previously responded to quinidine (or other drugs that prolong ventricular repolarization) with marked lengthening of the QTC interval. Estimation of the incidence of torsades in patients with therapeutic levels of quinidine is not possible from the available data. Other ventricular arrhythmias that have been reported with quinidine include frequent extrasystoles, ventricular tachycardia, ventricular flutter, and ventricular fibrillation.
Paradoxical increase in ventricular rate in atrial flutter/fibrillation
When quinidine is administered to patients with atrial flutter/fibrillation, the desired pharmacologic reversion to sinus rhythm may (rarely) be preceded by a slowing of the atrial rate with a consequent increase in the rate of beats conducted to the ventricles. The resulting ventricular rate may be very high (greater than 200 beats per minute) and poorly tolerated. This hazard may be decreased if partial atrioventricular block is achieved prior to initiation of quinidine therapy, using conduction-reducing drugs such as digitalis, verapamil, diltiazem, or a β-receptor blocking agent.
Exacerbated bradycardia in sick sinus syndrome
In patients with the sick sinus syndrome, quinidine has been associated with marked sinus node depression and bradycardia.
Renal or hepatic dysfunction causes the elimination of quinidine to be slowed, while congestive heart failure causes a reduction in quinidine’s apparent volume of distribution. Any of these conditions can lead to quinidine toxicity if dosage is not appropriately reduced. In addition, interactions with coadministered drugs can alter the serum concentration and activity of quinidine, leading either to toxicity or to lack of efficacy if the dose of quinidine is not appropriately modified. (See PRECAUTIONS /Drug Interactions.)
Because quinidine opposes the atrial and A-V nodal effects of vagal stimulation, physical or pharmacological vagal maneuvers undertaken to terminate paroxysmal supraventricular tachycardia may be ineffective in patients receiving quinidine.
In patients without implanted pacemakers who are at high risk of complete atrioventricular block(e.g., those with digitalis intoxication, second-degree atrioventricular block, or severe intraventricular conduction defects), quinidine should be used only with caution.
Altered pharmacokinetics of quinidine
Drugs that alkalinize the urine (carbonic-anhydrase inhibitors, sodium bicarbonate,thiazide diuretics) reduce renal elimination of quinidine.
By pharmacokinetic mechanisms that are not well understood, quinidine levels are increased by coadministration of amiodarone or cimetidine. Very rarely, and again by mechanisms not understood, quinidine levels are decreased by coadministration of nifedipine.
Hepatic elimination of quinidine may be accelerated by coadministration of drugs (phenobarbital,phenytoin, rifampin) that induce production of cytochrome P450IIIA4 .
Perhaps because of competition for the P450IIIA4 metabolic pathway, quinidine levels rise when ketaconazole is coadministered.
Coadministration of propranolol usually does not affect quinidine pharmacokinetics, but in some studies the β-blocker appeared to cause increases in the peak serum levels of quinidine, decreases in quinidine’s volume of distribution, and decreases in total quinidine clearance. The effects (if any) of coadministration of other β-blockers on quinidine pharmacokinetics have not been adequately studied.
Diltiazem significantly decreases the clearance and increases the t1/2 of quinidine, but quinidine does not alter the kinetics of diltiazem. Hepatic clearance of quinidine is significantly reduced during coadministration of verapamil , with corresponding increases in serum levels and half-life.
Altered pharmacokinetics of other drugs
Quinidine slows the elimination of digoxin and simultaneously reduces digoxin’s apparent volume of distribution. As a result, serum digoxin levels may be as much as doubled. When quinidine and digoxin are coadministered, digoxin doses usually need to be reduced. Serum levels of digoxin are also raised when quinidine is coadministered, although the effect appears to be smaller.
By a mechanism that is not understood, quinidine potentiates the anticoagulatory action of warfarin , and the anticoagulant dosage may need to be reduced. Cytochrome P450IID6 is an enzyme critical to the metabolism of many drugs, notably including mexiletine , some phenothiazines , and most polycyclic antidepressants. Constitutional deficiency of cytochrome P450IID6 is found in less than 1% of Orientals, in about 2% of American blacks, and in about 8% of American whites. Testing with debrisoquine is sometimes used to distinguish the P450IID6 -deficient “poor metabolizers” from the majority-pheno-type “extensive metabolizers”.
When drugs whose metabolism is P450IID6-dependent are given to poor metabolizers, the serum levels achieved are higher, sometimes much higher, than the serum levels achieved when identical doses are given to extensive metabolizers. To obtain similar clinical benefit without toxicity, doses given to poor metabolizers may need to be greatly reduced. In the cases of prodrugs whose actions are actually mediated by P450IID6 -produced metabolites (for example, codeine and hydrocodone , whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in poor metabolizers.
Quinidine is not metabolized by cytochrome P450IID6 , but therapeutic serum levels of quinidine inhibit the action of cytochrome P450IID6 , effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450IID6 .
Perhaps by competing for pathways of renal clearance, coadministration of quinidine causes an increase in serum levels of procainamide.
Serum levels of haloperidol are increased when quinidine is coadministered.
Presumably because both drugs are metabolized by cytochrome P450IID6 , coadministration of quinidine causes variable slowing of the metabolism of nifedipine. Interactions with other dihydropyridine calcium-channel blockers have not been reported, but these agents (including felodipine , nicardipine , and nimodipine) are all dependent upon P450IIIA4 for metabolism, so similar interactions with quinidine should be anticipated.
Altered pharmacodynamics of other drugs
Quinidine’s anitcholinergic, vasodilating, and negative inotropic actions may be additive to those of other drugs with these effects, and antagonistic to those of drugs with cholinergic, vasoconstricting, and positive inotropic effects. For example, when quinidine and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral α-blockade is sometimes reported.
Quinidine potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (d -tubocurarine, pancuronium) neuromuscular blockingagents. These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, in vitro addition of quinidine to the serum of pregnant women reduces the activity of pseudocholinesterase, an enzyme that is essential to the metabolism of succinylcholine.
Non-interactions of quinidine with other drugs
Quinidine has no clinically significant effect on the pharmacokinetics of diltiazem,flecainide, mephenytoin,metoprolol, propafenone, propranolol,quinine, timolol, or tocainide.
Conversely, the pharmacokinetics of quinidine are not significantly affected by caffeine, ciprofloxacin,digoxin, diltiazem,felodipine, omeprazole, or quinine. Quinidine’s pharmacokinetics are also unaffected by cigarette smoking.
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