Side Effects of Quinidine Injection

Quinidine is an antiarrhythmic agent and antimalarial drug used to treat abnormal heart rhythms such as

• atrial fibrillation,
• atrial flutter, and
• ventricular arrhythmias such as paroxysmal ventricular tachycardia.

Quinidine injection is also used to treat malaria. 

Common side effects of quinidine injection include

• vomiting,
• heartburn,
• rash,
• fever,
• dizziness,
• fatigue,
• weakness, and
• headache.

Serious side effects of quinidine injection include

• irregular heartbeat,
• chest pain,
• skin rash,
• hearing changes (ringing or loss of hearing),
• vision changes (blurred vision or light sensitivity), and
• unusual bleeding.

Drug interactions of quinidine injection include azole antifungals and protease inhibitor/antiretroviral drugs because their concomitant use can increase quinidine levels and thus increase the risk of quinidine toxicity and cardiac arrhythmias.

Phenothiazines and tricyclic antidepressants should not be used with quinidine since they can cause cardiac arrhythmias, and their use with quinidine increases the risk of cardiac arrhythmias.

Quinidine increases the action of the blood thinner warfarin and can lead to excessive blood thinning and bleeding.

Blood levels of digoxin are raised by quinidine due which can give rise to intoxication with digoxin.

Removal of quinidine by the liver is accelerated by

• phenobarbital,
• phenytoin, and
• rifampin.

Amiodarone may decrease the removal of quinidine by the kidneys or liver giving rise to elevated quinidine blood levels, which may result in life-threatening arrhythmias, including torsades de pointes.

Cimetidine increases quinidine levels by decreasing the elimination of quinidine giving rise to elevated quinidine serum levels that may lead to quinidine toxicity.

Safety and efficacy of quinidine has not been established in pregnant women. Quinidine can enter breast milk and should be avoided by breastfeeding mothers.

The most common side effects are:

• Vomiting
• Heartburn
• Rash
• Fever
• Dizziness
• Fatigue
• Weakness
• Headache

Other important side effects include:

• Irregular heartbeat
• Chest pain
• Skin rash
• Hearing changes (ringing or loss of hearing)
• Vision changes (blurred or light sensitivity)
• Unusual bleeding

If patients experience any of the above side effects, they should call their doctor immediately.

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.

In 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 in the prescribing information.

Adverse Experiences in a 245–Patient PVC Trial

Intramuscular injections of quinidine gluconate (injection) are typically followed by moderate to severe local pain. Some patients will develop tender nodules at the site of injection that persist for several weeks.

Vomiting and diarrhea can occur as isolated reactions to therapeutic levels of quinidine, but they may also be the first signs of cinchonism, a syndrome that may also 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

• fever,
• urticaria,
• flushing,
• exfoliative rash,
• bronchospasm,
• pneumonitis,
• 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 was 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.

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 of 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.

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 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 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–phenotype “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 cyctochrome P450IIIA4, 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 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.
• Diltiazem significantly decreases the clearance and increases the t½ of quinidine, but quinidine does not alter the kinetics of diltiazem.

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.