CLINICAL PHARMACOLOGY
Nifedipine is a calcium ion influx inhibitor (slow-channel
blocker or calcium ion antagonist) and inhibits the transmembrane
influx of calcium ions into cardiac muscle and smooth
muscle. The contractile processes of cardiac muscle and
vascular smooth muscle are dependent upon the movement
of extracellular calcium ions into these cells through
specific ion channels. Nifedipine selectively inhibits
calcium ion influx across the cell membrane of cardiac
muscle and vascular smooth muscle without changing serum
calcium concentrations.
Mechanism of Action
The precise means by which this inhibition relieves angina
has not been fully determined, but includes at least the
following two mechanisms.
Relaxation and Prevention of Coronary Artery
Spasm
Nifedipine dilates the main coronary arteries and coronary
arterioles, both in normal and ischemic regions, and is
a potent inhibitor of coronary artery spasm, whether spontaneous
or ergonovine-induced. This property increases myocardial
oxygen delivery in patients with coronary artery spasm,
and is responsible for the effectiveness of nifedipine
in vasospastic (Prinzmetal's or variant) angina. Whether
this effect plays any role in classical angina is not
clear, but studies of exercise tolerance have not shown
an increase in the maximum exercise rate-pressure product,
a widely accepted measure of oxygen utilization. This
suggests that, in general, relief of spasm or dilation
of coronary arteries is not an important factor in classical
angina.
Reduction of Oxygen Utilization
Nifedipine regularly reduces arterial pressure at rest
and at a given level of exercise by dilating peripheral
arterioles and reducing the total peripheral resistance
(afterload) against which the heart works. This unloading
of the heart reduces myocardial energy consumption and
oxygen requirements, and probably accounts for the effectiveness
of nifedipine in chronic stable angina.
Electrophysiologic Effects
Although, like other members of its class, nifedipine
decreases sinoatrial node function and atrioventricular
conduction in isolated myocardial preparations, such effects
have not been seen in studies in intact animals or in
man. In formal electrophysiologic studies, predominantly
in patients with normal conduction systems, nifedipine
has had no tendency to prolong atrioventricular conduction,
prolong sinus node recovery time, or slow sinus rate.
Additional Information for Immediate Release
Capsules
Hemodynamics: Like other slow-channel
blockers, nifedipine exerts a negative inotropic effect
on isolated myocardial tissue. This is rarely, if ever,
seen in intact animals or man, probably because of reflex
responses to its vasodilating effects. In man, Nifedipine
causes decreased peripheral vascular resistance and a
fall in systolic and diastolic pressure, usually modest
(5-10mm Hg systolic), but sometimes larger. There is usually
a small increase in heart rate, a reflex response to vasodilation.
Measurements of cardiac function in patients with normal
ventricular function have generally found a small increase
in cardiac index without major effects on ejection fraction,
left ventricular end diastolic pressure (LVEDP) or volume
(LVEDV). In patients with impaired ventricular function,
most acute studies have shown some increase in ejection
fraction and reduction in left ventricular filling pressure.
Pharmacokinetics and Metabolism: Nifedipine
is rapidly and fully absorbed after oral administration.
The drug is detectable in serum 10 minutes after oral
administration, and peak blood levels occur in approximately
30 minutes. Bioavailability is proportional to dose from
10 to 30 mg; half-life does not change significantly with
dose. There is little difference in relative bioavailability
when nifedipine capsules are given orally and either swallowed
whole, bitten and swallowed, or, bitten and held sublingually.
However, biting through the capsule prior to swallowing
does result in slightly earlier plasma concentrations
(27 ng/ml 10 minutes after 10 mg) than if capsules are
swallowed intact. It is highly bound by serum proteins.
Nifedipine is extensively converted to inactive metabolites
and approximately 80% of nifedipine and metabolites are
eliminated via the kidneys. The half-life of nifedipine
in plasma is approximately 2 hours. Since hepatic biotransformation
is the predominant route for the disposition of nifedipine,
the pharmacokinetics may be altered in patients with chronic
liver disease. Patients with hepatic impairment (liver
cirrhosis) have a longer disposition half-life and higher
bioavailability of nifedipine than healthy volunteers.
The degree of serum protein binding of nifedipine is high
(92-98%). Protein binding may be greatly reduced in patients
with renal or hepatic impairment.
Additional Information for Extended Release Tablets
Hypertension
The mechanism by which nifedipine reduces arterial blood
pressure involves peripheral arterial vasodilatation and
the resulting reduction in peripheral vascular resistance.
The increased peripheral vascular resistance that is an
underlying cause of hypertension results from an increase
in active tension in the vascular smooth muscle. Studies
have demonstrated that the increase in active tension
reflects an increase in cytosolic free calcium.
Nifedipine is a peripheral arterial vasodilator which
acts directly on vascular smooth muscle. The binding of
nifedipine to voltage-dependent and possibly receptor-operated
channels in vascular smooth muscle results in an inhibition
of calcium influx through these channels. Stores of intracellular
calcium in vascular smooth muscle are limited and thus
dependent upon the influx of extracellular calcium for
contraction to occur. The reduction in calcium influx
by nifedipine causes arterial vasodilation and decreased
peripheral vascular resistance which results in reduced
arterial blood pressure.
Pharmacokinetics and Metabolism
Nifedipine is completely absorbed after oral administration.
Plasma drug concentrations rise at a gradual, controlled
rate after a nifedipine extended release tablet dose and
reach a plateau at approximately 6 hours after the first
dose. For subsequent doses, relatively constant plasma
concentrations at the plateau are maintained with minimal
fluctuations over the 24 hour dosing interval. About a
four-fold higher fluctuation index (ratio of peak to trough
plasma concentration) was observed with the conventional
immediate release nifedipine capsule at tid dosing than
once daily nifedipine extended release tablet. At steady-state
the bioavailability of nifedipine extended release tablets
is 86% relative to nifedipine capsules. Administration
of the nifedipine extended release tablets in the presence
of food slightly alters the early rate of drug absorption,
but does not influence the extent of drug bioavailability.
Markedly reduced GI retention time over prolonged periods
(i.e., short bowel syndrome), however, may influence the
pharmacokinetic profile of the drug which could potentially
result in lower plasma concentration. Pharmacokinetics
of nifedipine extended release tablets are linear over
the dose range of 30-180 mg in that plasma drug concentrations
are proportional to dose administered. There was no evidence
of dose dumping either in the presence or absence of food
for over 150 subjects in pharmacokinetic studies.
Nifedipine is extensively metabolized to highly water-soluble,
inactive metabolites accounting for 60-80% of the dose
excreted in the urine. The elimination half-life of nifedipine
is approximately 2 hours. Only traces (less than 0.1%
of the dose) of unchanged form can be detected in the
urine. The remainder is excreted in the feces in metabolized
form, most likely as a result of biliary excretion. Thus,
the pharmacokinetics of nifedipine are not significantly
influenced by the degree of renal impairment. Patients
in hemodialysis or chronic ambulatory peritoneal dialysis
have not reported significantly altered pharmacokinetics
of nifedipine. Since hepatic biotransformation is the
predominant route for the disposition of nifedipine, the
pharmacokinetics may be altered in patients with chronic
liver disease. Patients with hepatic impairment (liver
cirrhosis) have a longer disposition half-life and higher
bioavailability of nifedipine than healthy volunteers.
The degree of serum protein binding of nifedipine is high
(92-98%). Protein binding may be greatly reduced in patients
with renal or hepatic impairments.
Hemodynamics
Like other slow-channel blockers, nifedipine exerts a
negative inotropic effect on isolated myocardial tissue.
This is rarely, if ever, seen in intact animals or man,
probably because of reflex responses to its vasodilating
effects. In man, nifedipine decreases peripheral vascular
resistance which leads to a fall in systolic and diastolic
pressures, usually minimal in normotensive volunteers
(less than 5-10 mm Hg systolic), but sometimes larger.
With nifedipine extended release tablets, these decreases
in blood pressure are not accompanied by any significant
change in heart rate. Hemodynamic studies in patients
with normal ventricular function have generally found
a small increase in cardiac index without major effects
on ejection fraction, left ventricular end diastolic pressure
(LVEDP) or volume (LVEDV). In patients with impaired ventricular
function, most acute studies have shown some increase
in ejection fraction and reduction in left ventricular
filling pressure.
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