QUINIDINE Drug Interactions: What You Need to Know

Drug and Diet Interactions Altered pharmacokinetics of quinidine: Diltiazem significantly decreases the clearance and increases the t ½ of quinidine, but quinidine does not alter the kinetics of diltiazem. 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 P450 IIIA4 . Perhaps because of competition for the P450 IIIA4 metabolic pathway, quinidine levels rise when ketoconazole 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. Hepatic clearance of quinidine is significantly reduced during coadministration of verapamil , with corresponding increases in serum levels and half-life. Grapefruit juice: Grapefruit juice inhibits P450 3A4-mediated metabolism of quinidine to 3-hydroxyquinidine. Although the clinical significance of this interaction is unknown, grapefruit juice should be avoided. Dietary salt: The rate and extent of quinidine absorption may be affected by changes in dietary salt intake; a decrease in dietary salt intake may lead to an increase in plasma quinidine concentrations. 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 digitoxin 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 P450 IID6 is an enzyme critical to the metabolism of many drugs, notably including mexiletine , some phenothiazines , and most polycyclic antidepressants . Constitutional deficiency of cytochrome P450 IID6 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 P450 IID6 -deficient "poor metabolizers" from the majority-phenotype "extensive metabolizers". When drugs whose metabolism is P450 IID6 -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 case of prodrugs whose actions are actually mediated by P450 IID6 -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 P450 IID6 , but therapeutic serum levels of quinidine inhibit the action of cytochrome P450 IID6 , effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450 IID6 . 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 P450 IIIA4 , 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 P450 IIIA4 for metabolism, so similar interactions with quinidine should be anticipated. Altered pharmacodynamics of other drugs: Quinidine's anticholinergic, 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 blocking agents . 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 , felodipine , omeprazole , or quinine . Quinidine's pharmacokinetics are also unaffected by cigarette smoking.

CONTRAINDICATIONS Quinidine is contraindicated in patients who are known to be allergic to it, or who have a history of immune thrombocytopenia or have developed thrombocytopenic purpura during prior therapy with quinidine or quinine (see WARNINGS ). 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.

WARNINGS Mortality: 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 used to prevent or defer recurrence of atrial flutter/fibrillation, the best available data come from a meta-analysis described under 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 meta-analysis, 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. Proarrhythmic effects Like many other drugs (including all other Class Ia antiarrhythmics), quinidine prolongs the QT c interval, and this can lead to torsades de pointes , a life-threatening ventricular arrhythmia (see OVERDOSAGE ). The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia 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 QT c 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 QT c 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. Pharmacokinetic considerations 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 ).

Vagolysis

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.

Thrombocytopenia

Quinidine-induced thrombocytopenia is an immune-mediated disorder characterized by a drug-dependent antibody that is itself nonreactive, but when soluble drug is present at pharmacologic concentrations, binds tightly to specific platelet membrane glycoproteins, causing platelet destruction. 1 Serologic testing for quinidine-specific antibody is commercially available and may be useful for identifying the specific cause of thrombocytopenia in individual cases. Testing is important because a patient with quinidine-dependent antibodies should not be re-exposed to quinidine. A case control study found a 125-fold increased risk of severe thrombocytopenia (platelets<30,000 μL, requiring hospitalization) with quinidine. 2 The incidence of quinidine-induced thrombocytopenia was 1.8 cases per 1,000 patient years of exposure. The incidence of less severe thrombocytopenia may be higher. Typically, a patient with immune thrombocytopenia will have taken drug for about 1 week or intermittently over a longer period of time (possibly years) before presenting with petechiae or bruising. Systemic symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, often may precede bleeding events. Thrombocytopenia may be severe. Patients should have risk/benefit re-evaluated in order to continue treatment with quinidine. If the drug is stopped, symptoms usually resolve within 1 or 2 days and platelet count returns to normal in less than 1 week. If quinidine is not stopped, there is a risk of fatal hemorrhage. The onset of thrombocytopenia may be more rapid upon re-exposure.