Quinidine

Drug Interactions 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 P450 IIIA4 .

Perhaps because of competition for the P450 IIIA4 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 t 1/2 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 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-pheno-type “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 cases 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 IID6 , 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 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 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, diltiazem, felodipine, omeprazole , or quinine .

Quinidine’s pharmacokinetics are also unaffected by cigarette smoking.

Pregnancy Pregnancy Category C Animal reproductive studies have not been conducted with quinidine. There are no adequate and well-controlled studies in pregnant women. Quinidine should be given to a pregnant woman only if clearly needed. Human placental transport of quinidine has not been systematically studied. In one neonate whose mother had received quinidine throughout her pregnancy, the serum level of quinidine was equal to that of the mother, with no apparent ill effect. The level of quinidine in amniotic fluid was about three times higher than that found in serum.

In another case, the levels of quinidine and 3-hydroxyquinidine in cord blood were about 30% of simultaneous maternal levels.

Nursing Mothers Quinidine is present in human milk at levels slightly lower than those in maternal serum; a human infant ingesting such milk should (scaling directly by weight) be expected to develop serum quinidine levels at least an order of magnitude lower than those of the mother. On the other hand, the pharmacokinetics and pharmacodynamics of quinidine in human infants have not been adequately studied, and neonates’ reduced protein binding of quinidine may increase their risk of toxicity at low total serum levels. Administration of quinidine should (if possible) be avoided in lactating women who continue to nurse.