A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rythmol Pharmacology, Pharmacokinetics, Studies, Metabolism - Propafenone
Rythmol Pharmacology, Pharmacokinetics, Studies, Metabolism - Propafenone
CLINICAL PHARMACOLOGY
Mechanism of Action
RYTHMOL (propafenone HCl) is a Class 1C antiarrhythmic
drug with local anesthetic
effects, and a direct stabilizing action
on myocardial membranes.
The electrophysiological effect
of RYTHMOL manifests itself in a reduction of upstroke velocity
(Phase 0) of the monophasic action
potential. In Purkinje fibers,
and to a lesser extent myocardial
fibers, RYTHMOL reduces the fast inward current
carried by sodium ions.
Diastolic excitability
threshold is increased and effective refractory
period prolonged. Propafenone
reduces spontaneous automaticity
and depresses triggered activity.
Studies in anesthetized dogs and isolated organ
preparations show that
RYTHMOL has beta- sympatholytic
activity at about 1/
50 the potency of propranolol.
Clinical studies employing isoproterenol challenge
and exercise testing after single doses of propafenone indicate
a beta- adrenergic
blocking potency (per mg) about 1/ 40 that of propranolol in man.
In clinical
trials, resting heart
rate decreases of about
8% were noted at the higher end
of the therapeutic
plasma concentration
range. At very high concentrations
in vitro, propafenone can inhibit the slow
inward current carried
by calcium but this calcium
antagonist effect
probably does not contribute to antiarrhythmic
efficacy. Propafenone has local
anesthetic activity
approximately equal to procaine.
Electrophysiology
Electrophysiology studies in patients with ventricular
tachycardia have
shown that RYTHMOL prolongs atrioventricular
conduction while
having little or no effect
on sinus node
function. Both AV nodal
conduction time
(AH interval) and His Purkinje conduction
time (HV interval) are
prolonged. Propafenone has little or no
effect on the atrial
functional refractory
period, but AV nodal functional
and effective refractory
periods are prolonged. In patients with WPW, RYTHMOL reduces conduction
and increases the effective refractory period
of the accessory pathway
in both directions. Propafenone slows conduction
and consequently produces dose
related changes in the PR interval
and QRS duration. QTc interval
does not change.
Mean Changes in ECG
Intervals*
|
Total Daily Dose (mg)
|
|
337.5 mg
|
450 mg
|
675 mg
|
900 mg
|
| Interval |
msec
|
%
|
msec
|
%
|
msec
|
%
|
msec
|
%
|
| RR |
-14.5
|
-1.8
|
30.6
|
3.8
|
31.5
|
3.9
|
41.7
|
5.1
|
| PR |
3.6
|
2.1
|
19.1
|
1.6
|
28.9
|
17.8
|
35.6
|
21.9
|
| ORS |
5.6
|
6.4
|
5.5
|
6.1
|
7.7
|
8.4
|
15.6
|
17.3
|
| QTc |
2.7
|
0.7
|
-7.5
|
-1.8
|
5.0
|
1.2
|
14.7
|
3.7
|
Change and percent change
based on mean baseline
values for each treatment group.
In any individual patient,
the above ECG changes cannot
be readily used to predict either efficacy
or plasma concentration.
RYTHMOL causes a dose-related and concentration-related decrease
in the rate of single and
multiple PVCs and can
suppress recurrence
of ventricular tachycardia. Based on the percent
of patients attaining substantial (80-90%) suppression of ventricular
ectopic activity, it
appears that trough plasma
levels of 0.2 to 1.5 pg/mL can provide good suppression,
with higher concentrations giving a greater rate
of good response.
When 600 mg/day propafenone was administered to patients with paroxysmal
atrial tachyarrhythmias, mean
heart rate
during arrhythmia
decreased 14 beats/ mm and
37 beats/mm for PAF patients
and PSVT patients, respectively.
Hemodynamics
Sympathetic stimulation
may be a vital component
supporting circulatory function in patients with congestive heart
failure, and its inhibition by the beta
blockade produced by
RYTHMOL may in itself aggravate congestive heart failure. Additionally,
like other Class 1C antiarrhythmic
drugs, studies in humans have shown that RYTHMOL exerts a negative
inotropic effect on
the myocardium. Cardiac catheterization
studies in patients with moderately impaired ventricular
function (mean C.I.=
2.61 mm/m2) utilizing intravenous propafenone infusions
(2 mg/kg over 10 min+ 2 mg/mm for 30 min) that gave mean
plasma concentrations
of 3.0 pg/mL (well above the therapeutic range
of 0.2-1.5 pg/mL) showed significant
increases in pulmonary capillary wedge
pressure, systemic
and pulmonary vascular
resistances and depression of cardiac
output and cardiac
index.
Pharmacokinetics and Metabolism
RYTHMOL is nearly completely absorbed after oral
administration
with peak plasma levels
occurring approximately 3.5 hours after administration in most individuals.
Propafenone exhibits extensive saturable presystemic biotransformation
(first pass effect) resulting in a dose
dependent and dosage
form dependent absolute
bloavailability, e.g., a 150 mg
tablet had absolute
bioavailability of 3.4%, while a 300 mg
tablet had absolute
bioavailability
of 10.6%. A 300 mg solution
which was rapidly absorbed, had absolute
bioavailability of 21.4%. At
still larger doses, above those recommended, bioavailability increases
still further. Decreased liver
function also increases
bioavailability; bioavailability is inversely related to indocyanine
green clearance
reaching 60-70% at clearances of 7 mL/min and below. The clearance
of propafenone is reduced and the elimination
half-life increased
in patients with significant hepatic dysfunction
(see PRECAUTIONS).
RYTHMOL follows a nonlinear pharmacokinetic disposition
presumably due to saturation
of first pass hepatic
metabolism as the
liver is exposed to higher
concentrations of propafenone and shows a very high degree
of interindividual variability. For example, for a three-fold increase
in daily dose from 300
to 900 mg/day there is a ten-fold increase in steadystate plasma
concentration. The top 25% of patients given 375 mg/day, however,
had a mean concentration
of propafenone larger than the bottom 25%, and about equal to the
second 25%, of patients given a dose
of 900 mg. Although food increased peak blood
level and bioavailability
in a single dose study,
during multiple dose
administration
of propafenone to healthy
volunteers food did not change bioavailability
significantly.
There are two genetically determined patterns of propafenone metabolism.
In over 90% of patients, the drug
is rapidly and extensively metabolized with an elimination
half-life from 2-10
hours. These patients metabolize propafenone into two active metabolites:
5- hydroxypropafenone and N-depropylpropafenone. In vitro
preparations have shown these two metabolites to have antiarrhythmic
activity comparable to propafenone but in man
they both are usually present in concentrations less than 20% of
propafenone. Nine additional metabolites have been identified, most
in only trace amounts.
It is the saturable hydroxylation pathway that is responsible for
the nonlinear pharmacokinetic disposition.
In less than 10% of patients (and in any patient
also receiving quinidine, see PRECAUTIONS),
metabolism of propafenone
is slower because the 5-hydroxy metabolite
is not formed or is minimally formed. The estimated propafenone
elimination half-life
ranges from 10-32 hours. Decreased ability
to form the 5-hydroxy metabolite
of propafenone is associated with a diminished ability
to metabolize debrisoquine
and a variety of other
drugs (encainide, metoprolol, dextromethorphan). In these patients,
the N-depropylpropafenone occurs in quantities comparable to the
levels occurring in extensive metabolizers. In
slow metabolizers propafenone
pharmacokinetics
are linear.
There are significant
differences in plasma
concentrations of propafenone in slow
and extensive metabolizers, the former achieving concentrations
1.5 to 2.0 times those of the extensive metabolizers at daily doses
of 675-900 mg/day. At low
doses the differences are greater, with slow
metabolizers attaining concentrations more than five times that
of extensive metabolizers. Because the difference decreases at high
doses and is mitigated
by the lack of the active 5-hydroxy metabolite
in the slow metabolizers,
and because steady-state conditions are achieved after 4-5 days
of dosing in all patients, the recommended dosing regimen
is the same for all patients. The greater variability in blood
levels require that the drug
be titrated carefully in patients with close attention
paid to clinical and
ECG evidence
of toxicity (See DOSAGE AND ADMINISTRATION).
Clinical Trials
In two randomized, crossover, placebo-controlled, double-blind
trials of 60-90 days duration
in patients with paroxysmal
supraventricular
arrhythmias [paroxysmal atrial
fibrillation/ flutter
(PAF), or paroxysmal
supraventricular tachycardia (PSVT)], propafenone reduced the rate
of both arrhythmias, as shown in the following table:
| |
Study 1
|
Study 2
|
|
Propafenone
|
Placebo
|
Propafenone
|
Placebo
|
| PAF |
n= 30
|
n= 30
|
n= 9
|
n= 9
|
| Percent attack
free |
53%
|
13%
|
67%
|
22%
|
| Median
time to
first recurrence
|
>98 days
|
8 days
|
62 days
|
5 days
|
| PSVT |
n= 45
|
n= 45
|
n= 15
|
n= 15
|
| Percent attack
free |
47%
|
16%
|
38%
|
7%
|
| Median
time to
first recurrence
|
>98 days
|
12 days
|
31 days
|
8 days
|
The patient population
in the above trials was 50% male
with a mean age of 57.3 years. Fifty percent
of the patients had a diagnosis
of PAF and 50% had PSVT. Eighty percent
of the patients received 600 mg/day propafenone. No patient
died in the above 2 studies.
In the U. S. long-term safety trials, 474 patients (mean age: 57.4
± 14.5 years) with supraventricular
arrhythmias [195 with PAF, 274 with PSVT and 5 with both PAF
and PSVT] were treated up to 5 years (mean: 14.4 months) with propafenone.
Fourteen of the patients died. When this mortality
rate was compared to the rate
in a similar patient
population (n= 194
patients; mean age: 43.0 ± 16.8 years) studied in an arrhythmia
clinic, there was no age-adjusted
difference in mortality. This comparison was not, however, a randomized
trial and the 95% confidence interval
around the comparison was large, such
that neither a significant
adverse or favorable effect could be ruled out.
Animal Toxicology
Renal changes have been observed in the rat
following 6 months of oral administration of propafenone at doses
of 180 and 360 mg/kg/day (12-24 times the maximum
recommended human dose)
but not 90 mg/kg/day. Both inflammatory and non-inflammatory changes
in the renal tubules with
accompanying interstitial nephritis were observed. These lesions
were reversible in
that they were not found in rats treated at these dosage
levels and allowed to recover for 6 weeks. Fatty degenerative changes
of the liver were found
in rats following chronic
administration
of propafenone at dose
levels 19 times the maximum
recommended human dose.
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