Calcium Antagonists

I. MECHANISM OF ACTION
Calcium movement into cells is mediated by several
mechanisms. Albrecht Fleckenstein showed that the
calcium channels can be selectively blocked by a class
of agents. He called these agents calcium antagonists.
Calcium movement into the cells is mediated by several
mechanisms. Calcium antagonists act at the plasma
membrane to inhibit calcium entry into cells by blocking
voltage-dependent calcium channels.

Calcium ions play an important role in the contraction
of cardiac, skeletal, and smooth muscle. Myoplasmic
calcium depends on calcium entry into the cell. Calcium
binds to the regulatory protein troponin, removing the
inhibitory action of tropomyosin. In the presence of
adenosine triphosphate this allows the interaction between
myosin and actin with consequent contraction of the
muscle cell.

There are at least three different types of calcium
channels designated as L, T, and N types. The L-type
channels, once activated, remain for a long period of time
and have a large calcium-carrying capacity. The T channels
have a brief opening time and N channels have
characteristics that are neither of the L nor T type. Only
the L-type channels are sensitive to the action of calcium
antagonists. The effect of the calcium antagonists is to
restrict calcium entry, and over a given period of time
fewer calcium ions are available for participation in
intracellular events such as muscle contraction and neuronal
activity. Thus some have labeled these compounds
calcium channel blockers, calcium channel antagonists,
calcium entry blockers, and slow calcium blockers.
Calcium antagonists differ from one another in terms
of their potency, tissue selectivity, and duration of action.
The calcium antagonists available for clinical use are
mainly L-type channel blockers. The T channel appears at
more negative potentials and seems to play a role in the
initial depolarization of the sinus node and atrioventricular
(AV) node tissue. Mibefradil, a T channel blocker, caused
bradycardia and a host of adverse effects that caused the
drug’s premature withdrawal from the market.

The three major calcium antagonists include nifedipine,
diltiazem, and verapamil (see Fig. 1 for their structural
formulas). Dihydropyridine, the prototype of which
is nifedipine, appears to act by plugging the calcium
channels. These agents cause dilation of coronary arteries
and marked peripheral arteriolar dilatation resulting in a
profound fall in blood pressure. There is little or no action
on the sinoatrial (SA) node and conducting tissue.

Verapamil and diltiazem are phenylalkylamines and
benzothiazepines. They cause distortion of calcium channels
and coronary artery dilation, but there are additional
effects on the SA and AV nodes. These agents also have a
negative inotropic effect and decrease myocardial contractility.
Thus, the dihydropyridines, phenylalkylamines, and
benzodiazepines have vastly different actions. For example,
only amlodipine and felodipine, of the dihydropyridine
family, have proved relatively safe in patients with left
ventricular dysfunction and heart failure. Other agents
may precipitate heart failure.

II. AVAILABLE CALCIUM ANTAGONISTS
A. Dihydropyridines
These agents cause dilation of arteries throughout the
body including mild dilatation of coronary arteries. They
also cause a variable decrease in myocardial contractility
that may lead to heart failure in susceptible individuals.
Dihydropyridines include amlodipine, felodipine, and,
nifedipine. They are indicated for the management of
hypertension. They may also be used for the treatment
of stable angina, but only in combination with a betablocking
drug that prevents an increase in heart rate and
the increase in cardiac workload that may be caused by
dihydropyridines. The common adverse effects include
edema of the ankles, flushing, headaches, and rarely,
hypertrophy of the gums. Other dihydropyridines include
isradipine, nicardipine, nimodipine, nitrendipine, and
niludipine.

1. Amlodipine (Norvasc)
This dihydropyridine has a long half-life of 35–50 h and
peak blood levels are reached after 6–12 h. Amlodipine is
an effective antihypertensive agent that is used worldwide.
It has a good safety profile but pulmonary edema (heart
failure) may be precipitated in patients with severe left
ventricular dysfunction and ejection fraction of less than
30%. Edema of the ankles, feet, and lower leg may be
bothersome in about 10% of treated patients. This drug is
often combined with a beta-blocker in the management
of angina. The dose for angina or hypertension is 5–10 mg
once daily.

2. Felodipine (Plendil)
This dihydropyridine has actions, effects, and indications
that are similar to amlodipine. The dose for hypertension
is 2.5–5 mg daily with a maximum dose of 10 mg.

3. Nifedipine (Procardia, Adalat XL)
Nifedipine is the first calcium antagonist used in clinical
practice. It was introduced during the early 1980s for the
management of hypertension, angina, and particularly
coronary artery spasm (variant angina) and is still used
worldwide. The drug is an excellent antihypertensive
agent. Headache, edema of the ankles, and facial flushing
occur in about 15% of patients. Although introduced for
the management of angina, like other dihydropyridines,
the drug should be used only for stable angina in patients
who are also administered a beta-blocker. For the management
of coronary artery spasm (Prinzmetal variant
angina), the drug can be used without beta-blockers, which
are contraindicated in this condition.

Short-acting capsule or tablet formulations of nifedipine
are no longer recommended because an increase in
morbidity and mortality has been reported in patients with
coronary artery disease. The slow-release once daily
formulation is now used worldwide at a dose of 30–60
mg once daily. The maximum dose of 90 mg should be
used with caution.

B. Benzothiazepines
1. Diltiazem
Diltiazem is a mild arteriolar vasodilator. It is a widely used
calcium antagonist because its safety profile is good. The
blood pressure lowering effect of this benzothiazepine is
not as powerful as the dihydropyridines, and a large dose
is usually required to obtain a satisfactory antihypertensive
effect. Diltiazem has a milder action than the dihydropyridines
and causes less vasodilatation of arteries; thus it
is a week antihypertensive agent. The drug causes some
decrease in myocardial contractility and heart failure may
be precipitated in patients with left ventricular dysfunction
or in patients who are administered a beta-blocking drug
concomitantly.

Most important, the drug inhibits electrical conduction
through the AV node. It is useful for the management of
supraventricular tachycardias by slowing rapid heart rates
that may occur with atrial fibrillation.

Unfortunately, this drug causes some suppression of the
sinus node and normal pacemaker activity and may cause
bradycardia. It should be avoided in patients with sick
sinus syndrome and heart failure. Adverse effects include
increased liver function tests, increased transaminases, and
constipation, but headache and edema of the ankles are less
common than with the dihydropyridines.
Important interactions occur with digoxin, and digoxin
levels may be increased by about 33%. Diltiazem combined
with amiodarone may produce deleterious effects
on the sinus pacemaker causing arrest and hypotension.
Interactions have been noted with cyclosporine, cimetidine,
and carbamazepine.

The short-acting tablet formulation of diltiazem is not
recommended. Long-acting and slow-release formulations
are administered 180 mg to a maximum of 300 mg once
daily.

C. Phenylalkylamines
1. Verapamil
Verapamil is a moderately potent vasodilator. Two major
differences between the actions of verapamil and the
dihydropyridines include a major depressant effect on the
AV node and a mild depressant effect on the SA node.
Also, depression of myocardial contractility for verapamil
is considerably more than the maximum effect observed
for dihydropyridines. This marked negative inotropic
effect may precipitate heart failure in patients with left
ventricular dysfunction and an ejection fraction less than
40%. Because of this effect, verapamil should not be
combined with a beta-blocking agent.

The electrophysiologic effect of mild depression of
conduction through the AV node makes the drug effective
in the management of supraventricular tachycardia. Given
intravenously, verapamil was used worldwide for the
management of this condition from 1984 to 1996 and
has now been relegated to second choice behind adenosine.
Verapamil is indicated for the management of hypertension
and for angina, particularly when beta-blockers
are contraindicated. It is also used for the management
of coronary artery spasm. The intravenous preparation
is indicated for supraventricular tachycardia. Doses of
120–240 mg sustained-release, long-acting preparations
are advised once daily.

Verapamil is contraindicated in patients with bradycardia
( a heart rate of <60) style="font-weight: bold;">III. THERAPEUTIC BENEFITS
Calcium antagonists are indicated for the conditions
outlined below.

Isolated hypertension without organ damage or coexisting
disease benefits from calcium antagonists.

These agents are particularly useful for isolated
hypertension in older people of African origin and
usually achieve the blood pressure goal; they have been
shown in randomized clinical trials to be more effective
than ACE inhibitors, beta-blockers, and diuretics.

In younger people of African origin a clinical study
showed that diltiazem was effective in 64% compared
with 47% for atenolol and 40% for diuretics.

Patients with severe stage II and III hypertension
require the combination of several antihypertensive
agents and calcium antagonists are appropriate except
in patients with left ventricular dysfunction.

Calcium antagonists are a critical part of combination
therapy in hypertensive patients with a variety of underlying
disorders (comorbidities) in whom blood pressure
control at more aggressive goals has been deemed
essential but remains elusive.

Calcium antagonists are used to treat hypertension
associated with renal disease or renal failure if ACE
inhibitors are contraindicated or poorly effective.

Calcium antagonists have shown benefits in hypertensive
diabetic patients; the large SYST-EUR and the
Systolic Hypertension in China (SYST-China) trials
demonstrated more than a 50% reduction in total
mortality in the diabetic subgroup.

In patients with stable angina the addition of a calcium
antagonist, particularly a dihydropyridine or diltiazem,
has been shown in clinical trials to cause significant
amelioration of recurrent chest pain.

In patients with severe aortic regurgitation, the
unloading effect of nifedipine has been shown in a
clinical trial to cause significant reversal of the left
ventricular dilatation and hypertrophy, and surgical
therapy may be appropriately delayed from 1 to 2
years.

Patients with cold fingers and Raynaud’s phenomenon
may find some benefit with calcium antagonists.

The dihydropyridine nimodipine, in a clinical trial, was
shown to be useful in the management of cerebral
arterial spasm caused by subarachnoid hemorrhage with
controlled blood pressure.

Following coronary artery bypass graft using the radial
artery as a conduit, dihydropyridine calcium antagonists
are used for an indefinite period to prevent spasm
and occlusion of the arterial graft.

IV. NEXT GENERATION AGENTS
Several dihydropyridine calcium antagonists have been
introduced during the past 25 years. First degeneration
dihydropyridines are the naturally short-acting agents that
include felodipine, isradipine, nifedipine, and nitrendipine.
These rapid-acting vasodilators are powerful antihypertensive
agents, but their fast onset of action results in
marked vasodilation that causes reflex stimulation of the
sympathetic nervous system and hemodynamic adverse
effects that include increased heart rate, increased cardiac
workload, and an increased incidence of heart failure in
patients with left ventricular dysfunction. These adverse
effects have become controversial and the short-acting
formulations of dihydropyridines such as verapamil and
diltiazem are no longer recommended. They have largely
been removed from the marketplace.

Second generation agents such as verapamil SR,
nifedipine XL, felodipine ER, and diltiazem SR and CD
were developed with modified release properties to slow
their onset of action. Adverse effects are still high, particularly
edema and constipation, and heart failure is precipitated,
albeit rarely.

Third generation agents include amlodipine. These
agents have a naturally occurring long plasma half-life
(over 24 h) but are washed out from the receptor relatively
fast. Equilibrium is essentially between the plasma proteinbound
drug and the calcium L channel. Amlodipine moves
quickly onto the calcium channel to provide a quick onset
of action and thus vasodilatation, which results in modest
sympathetic stimulation and unwanted mild tachycardia
or an increase in heart rate of about 10 beats per minute
from baseline. These agents may precipitate pulmonary
edema in patients with left ventricular dysfunction.
Next generation agents include lercanidipine, lacidipine,
and manidipine. These dihydropyridines have important
and subtle differences when compared with second and
third generation dihydropyridine calcium antagonists.
Lercanidipine has been shown to have major advantages
over amlodipine. Because the drug dilates both afferent
and efferent arterioles, the high incidence of peripheral
edema caused by older calcium antagonists is reduced
more than 50%. The balanced effect of lercanidipine and
manidipine on efferent and afferent arterioles is important
in renal protection. The older calcium antagonists listed
above dilate only afferent arterioles. The COHORT study
of elderly hypertensive patients concluded that lercanidipine
and lacidipine are much better tolerated than
amlodipine.

Recent investigations indicate that lercanidipine administered
to hypertensive diabetic patients is more effective
than the angiotensin receptor blocker, losartan, in reducing
left ventricular hypertrophy and left ventricular mass.
These third generation dihydropyridines represent an
important addition to the therapeutic armamentarium.
Their place in clinical practice will increase further if
they are shown to be devoid of the major adverse effect
of all calcium antagonists — the precipitation of
heart failure in patients with significant left ventricular
dysfunction.

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