Pharmacokinetics and Metabolism
After intramuscular injection of quinidine gluconate (quinidine gluconate (quinidine gluconate injection) injection) , peak
serum levels of quinidine are achieved in a little less than two hours. This time
to peak levels is identical to the time measured when quinidine salts are
The volume of distribution of quinidine is typically 2–3
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 3–5 L/kg in patients
with cirrhosis of the liver. At concentrations of 2–5 mg/L (6.5–16.2 μmol/L), the fraction of quinidine bound to
plasma proteins (mainly to α1–acid glycoprotein and to albumin) is 80– 88%
in adults and older children, but it is lower in pregnant women, and in infants
and neonates it may be as low as 50–70%. 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 3–5 mL/min/kg in
adults, but clearance in pediatric patients may be twice or three times as rapid.
The elimination half–life is about 6–8 hours in adults and 3–4 hours in
pediatric patients. 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 (quinidine gluconate (quinidine gluconate injection) injection) . 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 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 (quinidine gluconate (quinidine gluconate injection) injection) in
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 2–6 mg/L (6.2 – 18.5 μmol/L).
Mechanisms of Action
In patients with malaria, quinidine acts primarily as an
intraerythrocytic schizonticide, with little effect upon sporozoites 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 defibrillation threshold as well.Quinidine's actions fall into
class Ia in the Vaughan–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 sinus rate.
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 a–adrenergic antagonist
(that is, as a vasodilator).
Intravenous quinidine has been associated with clearing of parasitemia and
high rates of survival in patients with severe P. falciparum malaria
and hyperparasitemia. Placebo–controlled trials have not been performed,
but clearing of these levels of parasitemia is unprecedented in the absence
of effective therapy. Use of quinidine in patients infected with chloroquine–sensitive
malaria or in chloroquine–resistant non–falciparum malaria has not been reported.
Maintenance of sinus rhythm after conversion from atrial fibrillation
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 (eg, 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 (eg,
reduction in stroke incidence) may be achievable by other means
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 WARNINGS).
Non–life–threatening ventricular arrhythmias
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.
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).