QUINIDINE GLUCONATE- quinidine gluconate tablet, extended release
Watson Laboratories, Inc.
Quinidine is an antimalarial schizonticide and an antiarrhythmic agent with Class Ia activity; it is the d-isomer of quinine, and its molecular weight is 324.43. Quinidine gluconate is the gluconate salt of quinidine; its chemical name is cinchonan-9-ol, 6’-methoxy-, (9S)-, mono-D-gluconate. The structural formula is represented below:
C20 H24 N2 O2 •C6 H12 O7 M.W. 520.58
Quinidine gluconate contains 62.3% of the anhydrous quinidine alkaloid, whereas quinidine sulfate contains 82.86%. In prescribing Quinidine Gluconate Extended-release Tablets, this factor should be considered.
Each tablet, for oral administration, contains 324 mg of quinidine gluconate (202 mg of quinidine base) in a matrix to provide extended-release.
Quinidine Gluconate Extended-release Tablets contain the following inactive ingredients: carnauba wax, ethylcellulose, magnesium stearate and povidone.
This product meets USP Drug Release Test 1.
The absolute bioavailability of quinidine from quinidine gluconate is 70 to 80%. Relative to a solution of quinidine sulfate, the bioavailability of quinidine from quinidine gluconate is reported to be 1.03. The less-than-complete bioavailability is thought to be due to first-pass elimination by the liver. Peak serum levels generally appear 3 to 5 hours after dosing; when the drug is taken with food, absorption is increased in both rate (27%) and extent (17%). The rate and extent of absorption of quinidine from quinidine gluconate are not significantly affected by the coadministration of an aluminum-hydroxide antacid. The rate of absorption of quinidine following the ingestion of grapefruit juice may be decreased.
The volume of distribution 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 α1 -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 α1 -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.
Quinidine clearance 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.
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-hydroxy-quinidine (3HQ), serum levels of which can approach those of quinidine in patients receiving conventional doses of quinidine gluconate. 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 on animals, by QTc prolongation in human volunteers, or by various in vitro 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 gluconate in chronic use.
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.
Assays 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).
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 Plasmodium vivax and P. malariae, but not to 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 de fibrillation threshold as well. Quinidine’s actions fall into Class Ia in the Vaughn-Williams classification.
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.
Like other antiarrhythmic drugs with Class Ia activity, quinidine prolongs the QT interval in a dose-related fashion. This may lead to increased ventricular automaticity and polymorphic ventricular tachycardias, including torsades de pointes (see WARNINGS).
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).
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 (e.g., 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 (e.g., reduction in stroke incidence) may be achievable by other means (anticoagulation).
By slowing the atrial rate in 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 WARNINGS).
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 with 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.
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).
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