CLINICAL PHARMACOLOGY
Electrophysiology/Mechanisms of Action
In animals, Cordarone is effective in the prevention
or suppression of experimentally induced arrhythmias.
The antiarrhythmic effect of Cordarone may be due to at
least two major properties: 1) a prolongation of the myocardial
cell-action potential duration and refractory period and
2) noncompetitive (Ct- and B-adrenergic inhibition.
Cordarone prolongs the duration of the action potential
of all cardiac fibers while causing minimal reduction
of dV/dt (maximal upstroke velocity of the action potential).
The refractory period is prolonged in all cardiac tissues.
Cordarone increases the cardiac refractory period without
influencing resting membrane potential, except in automatic
cells where the slope of the prepotential is reduced,
generally reducing automaticity. These electrophysiologic
effects are reflected in a decreased sinus rate of 15
to 20%, increased PR and QT intervals of about 1 0%, the
development of U-waves, and changes in T-wave contour.
These changes should not require discontinuation of Cordarone
as they are evidence of its pharmacological action, although
Cordarone can cause marked sinus bradycardia or sinus
arrest and heart block. On rare occasions, QT prolongation
has been associated with worsening of arrhythmia (see
WARNINGS).
Hemodynamics
In animal studies and after intravenous administration
in man, Cordarone relaxes vascular smooth muscle, reduces
peripheral vascular resistance (afterload), and slightly
increases cardiac index. After oral dosing, however, Cordarone
produces no significant change in left ventricular ejection
fraction (LVEF), even in patients with depressed LVEF.
After acute intravenous dosing in man, Cordarone may have
a mild negative inotropic effect.
Pharmacokinetics
Following oral administration in man, Cordarone is slowly
and variably absorbed. The bioavailability of Cordarone
is approximately 50%. but has varied between 35 and 65%
in various studies. Maximum plasma concentrations are
attained 3 to 7 hours after a single dose. Despite this,
the onset of action may occur in 2 to 3 days, but more
commonly takes 1 to 3 weeks, even with loading doses.
Plasma concentrations with chronic dosing at 100 to 600
mg/day are approximately dose proportional, with a mean
0.5 mg/L increase for each 100 mg/day. These means, however,
include considerable individual variability.
Cordarone has a very large but variable volume of distribution,
averaging about 60 L/kg, because of extensive accumulation
in various sites, especially adipose tissue and highly
perfused organs, such as the liver, lung, and spleen.
One major metabolite of Cordarone, desethylamiodarone,
has been identified in man; it accumulates to an even
greater extent in almost all tissues. The pharmacological
activity of this metabolite, however, is not known. During
chronic treatment, the plasma ratio of metabolite to parent
compound is approximately one.
The main route of elimination is via hepatic excretion
into bile, and some enterohepatic recirculation may occur.
However, its kinetics in patients with hepatic insufficiency
have not been elucidated. Cordarone has a very low plasma
clearance with negligible renal excretion, so that it
does not appear necessary to modify the dose in patients
with renal failure. In patients with renal impairment,
the plasma concentration of Cordarone is not elevated.
Neither Cordarone nor its metabolite is dialyzable.
In patients, following discontinuation of chronic oral
therapy, Cordarone has been shown to have a biphasic elimination
with an initial one-half reduction of plasma levels after
2.5 to 10 days. A much slower terminal plasma-elimination
phase shows a half-life of the parent compound ranging
from 26 to 107 days, with a mean of approximately 53 days
and most patients in the 4 0 to 55-day range. In the absence
of a loading-dose period, steady state plasma concentrations,
at constant oral dosing, would therefore be reached between
130 and 535 days, with an average of 265 days. For the
metabolite, the mean plasma-elimination half-life was
approximately 61 days. These data probably reflect an
initial elimination of drug from well-perfused tissue
(the 2.5- to 10-day half-life phase), followed by a terminal
phase representing extremely slow elimination from poorly
perfused tissue compartments such as fat.
The considerable intersubject variation in both phases
of elimination, as well as uncertainty as to what compartment
is critical to drug effect, requires attention to individual
responses once arrhythmia control is achieved with loading
doses because the correct maintenance dose is determined,
in part, by the elimination rates. Daily maintenance doses
of Cordarone should be based on individual patient requirements
(see DOSAGE AND ADMINISTRATION).
Cordarone and its metabolite have a limited transplacental
transfer of approximately 10 to 50%. The parent drug and
its metabolite have been detected in breast milk.
Cordarone is highly protein-bound (approximately 96%).
Although electrophysiologic effects, such as prolongation
of QTC, can be seen within hours after a parenteral dose
of Cordarone, effects on abnormal rhythms are not seen
before 2 to 3 days and usually require 1 to 3 weeks, even
when a loading dose is used. There may be a continued
increase in effect for longer periods still. There is
evidence that the time to effect is shorter when a loading-dose
regimen is used. Consistent with the slow rate of elimination,
antiarrhythmic effects persist for weeks or months after
Cordarone is discontinued, but the time of recurrence
is variable and unpredictable. In general, when the drug
is resumed after recurrence of the arrhythmia, control
is established relatively rapidly compared to the initial
response, presumably because tissue stores were not wholly
depleted at the time of recurrence.
Pharmacodynamics
There is no well-established relationship of plasma concentration
to effectiveness, but it does appear that concentrations
much below 1 mg/L are often ineffective and that levels
above 2.5 mg/L are generally not needed. Within individuals
dose reductions and ensuing decreased plasma concentrations
can result in loss of arrhythmia control. Plasma-concentration
measurements can be used to identify patients whose levels
are unusually low, and who might benefit from a dose increase,
or unusually high, and who might have dosage reduction
in the hope of minimizing side effects. Some observations
have suggested a plasma concentration, dose, or dose/duration
relationship for side effects such as pulmonary fibrosis,
liver-enzyme elevations, corneal deposits and facial pigmentation,
peripheral neuropathy, gastrointestinal and central nervous
system effects.
Monitoring Effectiveness
Predicting the effectiveness of any antiarrhythmic agent
in long-term prevention of recurrent ventricular tachycardia
and ventricular fibrillation is difficult and controversial,
with highly qualified investigators recommending use of
ambulatory monitoring, programmed electrical stimulation
with various stimulation regimens, or a combination of
these, to assess response. There is no present consensus
on many aspects of how best to assess effectiveness, but
there is a reasonable consensus on some aspects:
1-If a patient with a history of cardiac arrest does not
manifest a hemodynamically unstable arrhythmia during electrocardiographic
monitoring prior to treatment, assessment of the effectiveness
of Cordarone requires some provocative approach, either
exercise or programmed electrical stimulation (PES).
2-Whether provocation is also needed in patients who do
manifest their life-threatening arrhythmia spontaneously
is not settled, but there are reasons to consider PES or
other provocation in such patients, In the fraction of patients
whose PES-inducible arrhythmia can be made noninducible
by Cordarone (a fraction that has varied widely in various
series from less than 10% to almost 40%, perhaps due to
different stimulation criteria), the prognosis has been
almost uniformly excellent, with very low recurrence (ventricular
tachycardia or sudden death) rates, More controversial is
the meaning of continued inducibility. There has been an
impression that continued inducibility in Cordarone patients
may not foretell a p.o. prognosis but, in fact, many observers
have found greater recurrence rates in patients who remain
inducible than in those who do not. A number of criteria
have been proposed, however, for identifying patients who
remain inducible but who seem likely nonetheless to do well
on Cordarone. These criteria include increased difficulty
of Induction (more stimuli or more rapid stimuli), which
has been reported to predict a lower rate of recurrence,
and ability to tolerate the induced ventricular tachycardia
without severe symptoms, a finding that has been reported
to correlate with better survival but not with lower recurrence
rates. While these criteria require confirmation and further
study in general, easier inducibility or poorer tolerance
of the induced arrhythmia should suggest consideration of
a need to revise treatment. Several predictors of success
not based on PES have also been suggested, including complete
elimination of all nonsustained ventricular tachycardia
on ambulatory monitoring and very low premature ventricular-beat
rates (less than 1 VPB/l,000 normal beats).
While these issues remain unsettled for Cordarone, as
for other agents, the prescriber of Cordarone should have
access to (direct or through referral), and familiarity
with, the full range of evaluatory procedures used in
the care of patients with life-threatening arrhythmias.
It is difficult to describe the effectiveness rates of
Cordarone, as these depend on the specific arrhythmia
treated, the success criteria used, the underlying cardiac
disease of the patient, the number of drugs tried before
resorting to Cordarone, the duration of follow-up, the
dose of Cordarone, the use of additional antiarrhythmic
agents, and many other factors. As Cordarone has been
studied principally in patients with refractory life-threatening
ventricular arrhythmias, in whom drug therapy must be
selected on the basis of response and cannot be assigned
arbitrarily, randomized comparisons with other agents
or placebo have not been possible. Reports of series of
treated patients with a history of cardiac arrest and
mean follow-up of one year or more have given mortality
(due to arrhythmia) rates that were highly variable, ranging
from less than 5% to over 30%, with most series in the
range of 10 to 15%. Overall arrhythmia-recurrence rates
(fatal and nonfatal) also were highly variable (and, as
noted above, depended on response to PES and other measures),
and depend on whether patients who do not seem to respond
initially are included. In most cases, considering only
patients who seemed to respond well enough to be placed
on long-term treatment, recurrence rates have ranged from
20 to 40% in series with a mean follow-up of a year or
more.
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