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Quinidine preparations have been used for many years, but there are only sparse data from which to estimate the incidence of various adverse reactions. The adverse reactions most frequently reported have consistently been gastrointestinal, including diarrhea, nausea, vomiting, and heartburn/esophagitis. I n one study of 245 adult outpatients who received quinidine to suppress premature ventricular contractions, the incidences of reported adverse experiences were as shown in the table below. The most serious quinidine-associated adverse reactions are described above under WARNINGS.
Adverse Experiences in a 245-Patient PVC Trial
|"upper gastrointestinal distress"||55||(22)|
|change in sleep habits||7||(3)|
Vomiting and diarrhea can occur as isolated reactions to therapeutic levels of quinidine, but they also may be the first signs of cinchonism, a syndrome that also may include tinnitus, reversible high-frequency hearing loss, deafness, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium. Cinchonism is most often a sign of chronic quinidine toxicity, but it may appear in sensitive patients after a single moderate dose.
A few cases of hepatotoxicity, including granulomatous hepatitis, have been reported in patients receiving quinidine. All of these have appeared during the first few weeks of therapy, and most (not all) have remitted once quinidine was withdrawn.
Autoimmune and inflammatory syndromes associated with quinidine therapy have included pneumonitis, fever, urticaria, flushing, exfoliative rash, bronchospasm, psoriasiform rash, pruritus and lymphadenopathy, hemolytic anemia, vasculitis, thrombocytopenic purpura, uveitis, angioedema, agranulocytosis, the sicca syndrome, arthralgia, myalgia, elevation in serum levels of skeletal-muscle enzymes, and a disorder resembling systemic lupus erythematosus.
Convulsions, apprehension, and ataxia have been reported, but it is not clear that these were not simply the results of hypotension and consequent cerebral hypoperfusion. There are many reports of syncope.
Acute psychotic reactions have been reported to follow the first dose of quinidine, but these reactions appear to be extremely rare.
Other adverse reactions occasionally reported include depression, mydriasis, disturbed color perception, night blindness, scotomata, optic neuritis, visual field loss, photosensitivity, and abnormalities of pigmentation.
Read the Quinidine Sulfate (quinidine sulfate tablet, film coated, extended release) Side Effects Center for a complete guide to possible side effects
Drug and Diet Interactions
Altered pharmacokinetics 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 P450MIA4 (P450 3A4).
Perhaps because of competition for the P450 3A4metabolic pathway, quinidine levels rise when ketoconazole is coadministered.
Coadministration of propranolol usually does not affect quinidine pharmacokinetics, but in some studies the (3-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 t½ 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.
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.
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 (P450 2D6) is an enzyme critical to the metabolism of many drugs, notably including mexiletine, some phenothiazines, and most polycyclic antidepressants. Constitutional deficiency of P450 2D6 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 2D6-deficient "poor metabolizers" from the majority-phenotype "extensive metabolizers."
When drugs whose metabolism is P450 2D6-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 2D6-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 P450 2D6, but therapeutic serum levels of quinidine inhibit the action of P450 2D6, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by P450 2D6.
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 P450 3A4, 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 3A4 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 a-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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/29/2008
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