Pharmacokinetics and Metabolism

The absolute bioavailability of quinidine from quinidine sulfate tablets is about 70%, but this varies widely (45 to 100%) between patients. The less-than-complete bioavailability is the result of first-pass metabolism in the liver. Peak serum levels generally appear about 2 hours after dosing; the rate of absorption is somewhat slowed when the drug is taken with food, but the extent of absorption is not changed.

The of quinidine is 2 to 3 L/kg in healthy young adults, but this may be reduced to as little as 0.5 L/kg in patients with congestive heart failure, or increased to 3 to 5 L/kg in patients with cirrhosis of the liver. At concentrations of 2 to 5 mg/L (6.5 to 16.2 μmol/L), the fraction of quinidine bound to plasma proteins (mainly to α -acid glycoprotein and to albumin) is 80 to 88% in adults and older children, but it is lower in pregnant women, and in infants and neonates it may be as low as 50 to 70%. Because α -acid glycoprotein levels are increased in response to stress, serum levels of total quinidine may be greatly increased in settings such as acute myocardial infarction, even though the serum content of unbound (active) drug may remain normal. Protein binding is also increased in chronic renal failure, but binding abruptly descends toward or below normal when heparin is administered for hemodialysis. volume of distribution11

Quinidine typically proceeds at 3 to 5 mL/min/kg in adults, but clearance in children may be twice or three times as rapid. The elimination half-life is 6 to 8 hours in adults and 3 to 4 hours in children. Quinidine clearance is unaffected by hepatic cirrhosis, so the increased volume of distribution seen in cirrhosis leads to a proportionate increase in the elimination half-life. clearance

Most quinidine is eliminated hepatically via the action of cytochrome P450IIIA4; there are several different hydroxylated metabolites, and some of these have antiarrhythmic activity.

The most important of quinidine’s metabolites is 3-hydroxyquinidine (3HQ), serum levels of which can exceed those of quinidine in patients receiving conventional doses of quinidine sulfate. The volume of distribution of 3HQ appears to be larger than that of quinidine, and the elimination half-life of 3HQ is about 12 hours.

As measured by antiarrhythmic effects in animals, by QT prolongation in human volunteers, or by various techniques, 3HQ has at least half the antiarrhythmic activity of the parent compound, so it may be responsible for a substantial fraction of the effect of quinidine sulfate in chronic use. Cin vitro

When the urine pH is less than 7, about 20% of administered quinidine appears unchanged in the urine, but this fraction drops to as little as 5% when the urine is more alkaline. Renal clearance involves both glomerular filtration and active tubular secretion, moderated by (pH-dependent) tubular reabsorption. The net renal clearance is about 1 mL/min/kg in healthy adults. When renal function is taken into account, quinidine clearance is apparently independent of patient age.

of serum quinidine levels are widely available, but the results of modern assays may not be consistent with results cited in the older medical literature. The serum levels of quinidine cited in this package insert are those derived from specific assays, using either benzene extraction or (preferably) reverse-phase high-pressure liquid chromatography. In matched samples, older assays might unpredictably have given results that were as much as two or three times higher. A typical “therapeutic” concentration range is 2 to 6 mg/L (6.2 to 18.5 μmol/L). Assays

Mechanisms of Action

In patients with malaria, quinidine acts primarily as an intra-erythrocytic schizonticide, with little effect upon sporozites or upon pre-erythrocytic parasites. Quinidine is gametocidal to and but not to Plasmodium vivaxP. malariae,P. falciparum.

In cardiac muscle and in Purkinje fibers, quinidine depresses the rapid inward depolarizing sodium current, thereby slowing phase-0 depolarization and reducing the amplitude of the action potential without affecting the resting potential. In normal Purkinje fibers, it reduces the slope of phase-4 depolarization, shifting the threshold voltage upward toward zero. The result is slowed conduction and reduced automaticity in all parts of the heart, with increase of the effective refractory period relative to the duration of the action potential in the atria, ventricles, and Purkinje tissues. Quinidine also raises the fibrillation thresholds of the atria and ventricles, and it raises the ventricular fibrillation threshold as well. Quinidine’s actions fall into class 1A in the Vaughan-Williams classification. de

By slowing conduction and prolonging the effective refractory period, quinidine can interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, including atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia.

In patients with the sick sinus syndrome, quinidine can cause marked sinus node depression and bradycardia. In most patients, however, use of quinidine is associated with an increase in the sinus rate.

Quinidine prolongs the QT interval in a dose-related fashion. This may lead to increased ventricular automaticity and polymorphic ventricular tachycardias, including (see ). torsades de pointesWARNINGS

In addition, quinidine has anticholinergic activity, it has negative inotropic activity, and it acts peripherally as an α-adrenergic antagonist (that is, as a vasodilator).

Clinical Effects

In six clinical trials (published between 1970 and 1984) with a total of 808 patients, quinidine (418 patients) was compared to nontreatment (258 patients) or placebo (132 patients) for the maintenance of sinus rhythm after cardioversion from chronic atrial fibrillation. Quinidine was consistently more efficacious in maintaining sinus rhythm, but a meta-analysis found that mortality in the quinidine-exposed patients (2.9%) was significantly greater than mortality in the patients who had not been treated with active drug (0.8%). Suppression of atrial fibrillation with quinidine has theoretical patient benefits ( improved exercise tolerance; reduction in hospitalization for cardioversion; lack of arrhythmia-related palpitations, dyspnea, and chest pain; reduced incidence of systemic embolism and/or stroke), but these benefits have never been demonstrated in clinical trials. Some of these benefits ( reduction in stroke incidence) may be achievable by other means (anticoagulation). Maintenance of sinus rhythm after conversion from atrial fibrillation:e.g.,e.g.,

By slowing the rate of atrial flutter/fibrillation, quinidine can decrease the degree of atrioventricular block and cause an increase, sometimes marked, in the rate at which supraventricular impulses are successfully conducted by the atrioventricular node, with a resultant paradoxical increase in ventricular rate (see ). In studies of patients with a variety of ventricular arrhythmias (mainly frequent ventricular premature beats and non-sustained ventricular tachycardia), quinidine (total N=502) has been compared to flecainide (N=141), mexiletine (N=246), propafenone (N=53), and tocainide (N=67). In each of these studies, the mortality in the quinidine group was numerically greater than the mortality in the comparator group. When the studies were combined in a meta-analysis, quinidine was associated with a statistically significant threefold relative risk of death. WARNINGSNon-life-threatening ventricular arrhythmias:

At therapeutic doses, quinidine’s only consistent effect upon the surface electrocardiogram is an increase in the QT interval. This prolongation can be monitored as a guide to safety, and it may provide better guidance than serum drug levels (see ). WARNINGS

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 ), then quinidine sulfate should be discontinued. DOSAGE AND ADMINISTRATION

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 judgment 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 ( use of other drugs to control the ventricular rate) have been found to be inadequate. e.g.,

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 during therapy, and a single recurrence should not be interpreted as therapeutic failure. will recur

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 judgment of the physician are life-threatening. 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 malaria. Plasmodium falciparum

Mortality

Proarrhythmic effects

Like many other drugs (including all other class IA antiarrhythmics), quinidine prolongs the QT interval, and this can lead to a life-threatening ventricular arrhythmia (see ). The risk of 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 QT interval, and quinidine should be used with extreme care in patients who have preexisting long-QT syndromes, who have histories of of any cause, or who have previously responded to quinidine (or other drugs that prolong ventricular repolarization) with marked lengthening of the QT interval. Estimation of the incidence of in patients with therapeutic levels of quinidine is not possible from the available data. Ctorsades de pointes,OVERDOSAGEtorsadesCtorsades de pointesCtorsades

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 ß-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.

Heart Block

In patients without implanted pacemakers who are at high risk of complete atrioventricular block ( those with digitalis intoxication, second-degree atrioventricular block, or severe intraventricular conduction defects), quinidine should be used only with caution. e.g.,

Drug Interactions

Drugs that alkalinize the urine ( ) reduce renal elimination of quinidine. Altered pharmacokinetics of quinidine:carbonic-anhydrase inhibitors, sodium bicarbonate, thiazide diuretics

By pharmacokinetic mechanisms that are not well understood, quinidine levels are increased by coadministration of or . Very rarely, and again by mechanisms not understood, quinidine levels are decreased by coadministration of . amiodaronecimetidinenifedipine

Hepatic elimination of quinidine may be accelerated by coadministration of drugs ( ) that induce production of cytochrome P450IIIA4. phenobarbital, phenytoin, rifampin

Perhaps because of competition for the P450IIIA4 metabolic pathway, quinidine levels rise when is coadministered. ketaconazole

Coadministration of usually does not affect quinidine pharmacokinetics, but in some studies the ß-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 on quinidine pharmacokinetics have not been adequately studied. propranololother ß-blockers

Hepatic clearance of quinidine is significantly reduced during coadministration of , with corresponding increases in serum levels and half-life. verapamil

Quinidine slows the elimination of 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 are also raised when quinidine is coadministered, although the effect appears to be smaller. Altered pharmacokinetics of other drugs:digoxindigitoxin

By a mechanism that is not understood, quinidine potentiates the anticoagulatory action of , and the anticoagulant dosage may need to be reduced. warfarin

Cytochrome P450IID6 is an enzyme critical to the metabolism of many drugs, notably including , some , and most 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”. mexiletinephenothiazinespolycyclic antidepressants.

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, and , 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. codeinehydrocodone

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 are increased when quinidine is coadministered. haloperidol

Presumably because both drugs are metabolized by cytochrome P450IIIA4, coadministration of quinidine causes variable slowing of the metabolism of . Interactions with other dihydropyridine calcium-channel blockers have not been reported, but these agents (including , , and ) are all dependent upon P450IIIA4 for metabolism, so similar interactions with quinidine should be anticipated. nifedipinefelodipinenicardipinenimodipine

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 are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral α-blockade is sometimes reported. Altered pharmacodynamics of other drugs:verapamil

Quinidine potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing ( -tubocurarine, pancuronium) . These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, addition of quinidine to the serum of pregnant women reduces the activity of pseudocholinesterase, an enzyme that is essential to the metabolism of succinylcholine. dneuromuscular blocking agentsin vitro

Quinidine has no clinically significant effect on the pharmacokinetics of or Non-interactions of quinidine with other drugs:diltiazem, flecainide, mephenytoin, metoprolol, propafenone, propranolol, quinine, timolol,tocainide.

Conversely, the pharmacokinetics of quinidine are not significantly affected by or Quinidine’s pharmacokinetics are also unaffected by cigarette smoking. caffeine, ciprofloxacin, digoxin, diltiazem, felodipine, omeprazole,quinine.

Information for patients

Before prescribing quinidine sulfate as prophylaxis against recurrence of atrial fibrillation, the physician should inform the patient of the risks and benefits to be expected (see ). Discussion should include the facts: CLINICAL PHARMACOLOGY

• that the goal of therapy will be a reduction (probably not to zero) in the frequency of episodes of atrial fibrillation; and

• that reduced frequency of fibrillatory episodes may be expected, if achieved, to bring symptomatic benefit; but

• that no data are available to show that reduced frequency of fibrillatory episodes will reduce the risks of irreversible harm through stroke or death; and in fact

• that such data as are available suggest that treatment with quinidine sulfate is likely to increase the patient’s risk of death.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies to evaluate quinidine’s carcinogenic or mutagenic potential have not been performed. Similarly, there are no animal data as to quinidine’s potential to impair fertility.

Pregnancy

Labor and Delivery

Quinine is said to be oxytocic in humans, but there are no adequate data as to quinidine’s effects (if any) on human labor and delivery.

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.

Geriatric Use

Safety and efficacy of quinidine in elderly patients has not been systematically studied.

Pediatric Use

In antimalarial trials, quinidine was as safe and effective in pediatric patients as in adults. Notwithstanding the known pharmacokinetic differences between children and adults (see ), children in these trials received the same doses (on a mg/kg basis) as adults. CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism

Safety and effectiveness of antiarrhythmic use in pediatric patients have not been established.

Arrhythmias

Serum quinidine levels can be conveniently assayed and monitored, but the electrocardiographic QT interval is a better predictor of quinidine-induced ventricular arrhythmias. C

The necessary treatment of hemodynamically unstable polymorphic ventricular tachycardia (including ) is withdrawal of treatment with quinidine and either immediate cardioversion or, if a cardiac pacemaker is in place or immediately available, immediate overdrive pacing. After pacing or cardioversion, further management must be guided by the length of the QT interval. torsades de pointesC

Quinidine-associated ventricular tachyarrhythmias with normal underlying QT intervals have not been adequately studied. Because of the theoretical possibility of QT-prolonging effects that might be additive to those of quinidine, other antiarrhythmics with Class I (disopyramide, procainamide) or Class III activities should (if possible) be avoided. Similarly, although the use of bretylium in quinidine overdose has not been reported, it is reasonable to expect that the α-blocking properties of bretylium might be additive to those of quinidine, resulting in problematic hypotension. C

If the post-cardioversion QT interval is prolonged, then the pre-cardioversion polymorphic ventricular tachyarrhythmia was (by definition) In this case, lidocaine and bretylium are unlikely to be of value, and other Class I antiarrhythmics (disopyramide, procainamide) are likely to exacerbate the situation. Factors contributing to QT prolongation (especially hypokalemia, hypomagnesemia, and hypocalcemia) should be sought out and (if possible) aggressively corrected. Prevention of recurrent may require sustained overdrive pacing or the cautious administration of isoproterenol (30 to 150 ng/kg/min). Ctorsades de pointes.Ctorsades

Hypotension

Quinidine-induced hypotension that is not due to an arrhythmia is likely to be a consequence of quinidine-related α-blockade and vasorelaxation. Simple repletion of central volume (Trendelenburg positioning, saline infusion) may be sufficient therapy; other interventions reported to have been beneficial in this setting are those that increase peripheral vascular resistance, including α-agonist catecholamines (norepinephrine, metaraminol) and the Military Anti-Shock Trousers.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient. Physicians’ Desk Reference (PDR).

Accelerated removal

Adequate studies of orally-administered activated charcoal in human overdoses of quinidine have not been reported, but there are animal data showing significant enhancement of systemic elimination following this intervention, and there is at least one human case report in which the elimination half-life of quinidine in the serum was apparently shortened by repeated gastric lavage. Activated charcoal should be avoided if an ileus is present; the conventional dose is 1 gram/kg, administered every 2 to 6 hours as a slurry with 8 mL/kg of tap water. Although renal elimination of quinidine might theoretically be accelerated by maneuvers to acidify the urine, such maneuvers are potentially hazardous and of no demonstrated benefit.

Quinidine is not usefully removed from the circulation by dialysis.

Following quinidine overdose, drugs that delay elimination of quinidine (cimetidine, carbonic-anhydrase inhibitors, thiazide diuretics) should be withdrawn unless absolutely required.

Treatment of P. falciparum  malaria

Quinidine sulfate tablets are used in one of the approved regimens for the treatment of life-threatening malaria. The central component of the regimen is Quinidine Gluconate Injection, and the regimen is described in the package insert of Quinidine Gluconate Injection. P. falciparum

Conversion of atrial fibrillation/flutter to sinus rhythm

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Patients with symptomatic atrial fibrillation/flutter should be treated with quinidine sulfate only after ventricular rate control ( with digitalis or ß-blockers) has failed to provide satisfactory control of symptoms. e.g.,

Adequate trials have not identified an optimal regimen of quinidine sulfate for conversion of atrial fibrillation/flutter to sinus rhythm. In one reported regimen, the patient first receives two tablets (400 mg; 332 mg of quinidine base) of quinidine sulfate every six hours. If this regimen has not resulted in conversion after 4 or 5 doses, then the dose is cautiously increased. If, at any point during administration, the QRS complex widens to 130% of its pre-treatment duration; the QT interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension, then quinidine sulfate is discontinued, and other means of conversion ( direct-current cardioversion) are considered. Ce.g.,

Reduction of frequency of release into atrial fibrillation/flutter

In a patient with a history of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy with quinidine sulfate should be an increase in the average time between episodes. In most patients, the tachyarrhythmia during therapy with quinidine sulfate, and a single recurrence should not be interpreted as therapeutic failure. will recur

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Monitoring should be continued for two or three days after initiation of the regimen on which the patient will be discharged.

Therapy with quinidine sulfate should be begun with 200 mg (equivalent to 166 mg of quinidine base) every six hours. If this regimen is well tolerated, if the serum quinidine level is still well within the laboratory’s therapeutic range, and if the average time between arrhythmic episodes has not been satisfactorily increased, then the dose may be cautiously raised. The total daily dosage should be reduced if the QRS complex widens to 130% of its pre-treatment duration; the QT interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension. C

Suppression of ventricular arrhythmias

Dosing regimens for the use of quinidine sulfate in suppressing life-threatening ventricular arrhythmias have not been adequately studied. Described regimens have generally been similar to the regimen described just above for the prophylaxis of symptomatic atrial fibrillation/flutter. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.