ANTIARRHYTHMIC DRUGS
QUINIDINE
Quinidine
is an antiarrhythmic agent, whose predominant
electrophysiological effect is the block of the fast
inward sodium channels (Class 1). The drug interacts
with the sodium channel during its open phase and has a
slow dissociation rate during the diastolic phase (Class
IA). This explains why the level of the block increases
at short cardiac cycles (rate-dependent effect). The
drugs even blocks the rapid rectifier potassium
channels (Ikr), in an inverse rate-dependent manner
and slowly inactivates steady-state plateau inward sodium
and calcium currents.
These multiple effects on
transmembrane currents produce: (1) a decrease in the
amplitude and upstroke velocity of the action potential
(rate dependent slowing of conduction); (2) an increase
of the action potential duration (lengthening of the
refractory period) and (3) a slight decrease in
automaticity and excitability.
Moreover,
quinidine has a direct alfa-adrenergic blocking action
and vagolitic effect. Its negative inotropic
effect is partially counterbalanced by the
vasodilating action. The cardiac depressant and
vasodilating action may be profound after intravenous
infusion, virtually precluding this route of
administration.
 Preparation
Quinidine
Sulphate, 200 mg, 300 mg extended release
Quinidine
poligalatturonate, 275 mg
Quinidine
gluconate, 324 mg
Pharmacokinetics
Plasma
peak (oral administration): sulfate 1-2 hours;
poligalatturonate and gluconate 3-4 hours
Bioavailability:
80-90%
Plasma
protein binding: 80-90%
Metabolism:
quinidine undergoes an hepatic oxidative metabolism.
Some metabolites (3-OH-quinidine,
2’oxoquinidine) have a partial pharmacological
activity.
Disposal:
non metabolized quinidine (20 - 30%) and its
metabolites are excreted by the kidney. Urine
alcalinization reduces the elimination of the drugs,
increasing its plasma levels
Distribution
volume: 3 L/Kg
Half
life: 5-8 hours, prolonged in the elderly and in
congestive heart failure.
Drugs
interactions
Coumadin:
increased
anticoagulant effect
Digoxin:
increased
digoxin plasma levels, that may be doubled
Betablockers,
Diltiazem, Verapamil: summation of the hypotensive
effect
Amiodarone,
Verapamil: increased quinidine plasma
levels
Phenobarbital,
Phenytoin; Rifampicine: increased quinidine plasma
levels
Anticholinergic
drugs: additive anticholinergic
effects
Cholinergic
drugs: reduced effects of the drugs
Potassium-wasting
diuretics: hypokalaemia increases the
risk of torsade de pointes
Every
drug lengthening repolarization:
risk of
torsade de pointes
Indications
Quinidine
is effective in every kind of arrhythmia. Today its
use has been virtually abandoned in ventricular
tachyarrhythmias. The drug is effective in the
treatment of atrial fibrillation. It effectively
terminates atrial fibrillation lasting less than 48
hours (efficacy about 75% within 6-12 hours versus
about 50% of placebo) while its efficacy ion
converting chronic atrial fibrillation to sinus
rhythm is in the range of 15-20%. The drug helps
preventing recurrences of the arrhythmia after
cardioversion (efficacy at one year about 50% versus
25% of placebo), but concerns about a possible
increase in mortality by the drug have been raised by
a meta-analysis taking into account the
placebo-controlled trials in this setting. The risk
of increased mortality seems to be particularly
present in patients with heart failure.
Contraindications
Sick
sinus syndrome
Serious
atrioventricular conduction disturbances
Heart
failure
Systemic
hypotension
Severe
hepatic insufficiency
Baseline
long QT
Untoward effect
Quinidine
is frequently ill-tollerated for its systemic side
effects. As with other Class I antiarrhythmic agents,
proarrhythmic effects are likely mainly in patients
with cardiac diseases and heart failure, but torsade
de pointes (potentially lethal) may occur even in
apparently normal hearts.
Cardiac
side effects.
Quinidine
may "organize" atrial fibrillation in
atrial flutter, possibly with a slow cycle, rarely
determining 1:1 atrioventricular conduction.
Worsening of preexisting excitation-conduction
disturbances are possible. The most frequent untoward
effect is torsade de pointes, a peculiar ventricular
tachycardia associated with QT lengthening, usually
self-limiting but sometimes degenerating into
ventricular fibrillation. Its incidence varies
between 1% and 5% of the treated patients. It is more
frequent in females and may be facilitated by
hypokalaemia or bradicardia. Its appearance is not
dose-related and usually appears in the first days of
the treatment, typically - in patients with atrial
fibrillation - after the slowing of heart rate
consequent to the restoration of sinus rhythm. It may
appear even in patients without over cardiac disease
and seems related with latent genetic defects
involving ionic channels. Because of that, quinidine
therapy has to be started in-hospital, under strict
monitoring. Excessive QT lengthening, mainly in case
of frequent ventricular premature beats and marked
repolarization distortion after the postextrasystolic
pause, mandates drug discontinuation. Torsade de
pointes are treated with magnesium sulfate infusion
and, if recurring, with temporary pacing at 100-110
bpm.
Systemic
side effects.
Side
effects necessitating drug discontinuation occur in
20-35% of the patients. The more common are:
diarrhea, nausea and vomiting, followed by central
nervous system disorders (headache, visual
disturbances, tinnitus, confusion and mental
disorders). Hemolytic anemia, trombocytopenia, fever,
arthralgias, skin eruptions are rare.
Dosage
Quinidine
sulfate 600 -
1200 mg divided oral doses.
Quinidine
poligalatturonate 275 mg 3-4 times a day.
Quinidine
gluconate 324
mg 3 times a day.
Given the increased risk of side effects, we
don’t recommend higher dosages or loading doses
anymore.
Leopoldo
Bianconi
Department of Heart Disease - Division
of Cardiology, S. Filippo Neri Hospital - Italy
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