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4 In 1960s,Fleckenstein,Godfraind and their
colleagues led to concept that drugs can cardiac and
smooth muscle contraction by blocking the entry of
calcium into myocytes.
4 In 1962, Hass and Hartfelder reported that
verapamil, a putative coronary vasodilator,
possessed inotropic and chronotropic effects.
4 In November 1963 ,it was reported that two new
compounds, the generic names verapamil and
prenylamine, mimicked the cardiac effect of simple
calcium withdrawal in that they diminished
calcium dependent high energy phosphate
utilization, contractile force and oxygen
requirement of the beating.
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4 In 1967, Fleckenstein suggested that negative inotropic
effect result from inhibition of excitation-contraction
coupling and that the mechanism reduced movement of
calcium into myocytes.
4 A derivative of verapamil,gallopamil and other compounds
such as nifedipine,also were shown to block the movement
of calcium through cardiac myocyte calcium channel.
4 In 1969, the term calcium antagonists were given a novel
drug designation.
4 in 1975 ,in an extensive search for other calcium
antagonists, a considerable number of substances were
identified e.g. nifedipine, nimodipine.
4 In 1975, Japanese pharmacologists introduced diltiazem to
this group.
 
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 are often used
to reduce systemic
vascular resistance and
arterial pressure, but are
not used to treat angina.
Example: Aranidipine
Azelnidipine
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Non-Dihydropyridine:

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 are
4 relatively selective for
myocardium
4 reduce myocardial oxygen
demand
4 reverse coronary vasospasm,
and
4 often used to treat angina.
Example: Gallopamil  
   

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 are an
intermediate class between
phenylalkylamine and
dihydropyridines in their
selectivity for vascular
calcium channels.
Example: Diltiazem
 
 

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y èhile most of the agents listed above are relatively
selective, there are additional agents that are
considered nonselective.
y Example: mibefradil, bepridil and fendiline.

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Angina is not a disease itself but is the primary symptom
of coronary artery disease. It is typically experienced as
chest pain, which can be mild, moderate, or severe.
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The probable mechanism by which calcium channel-
blocking agents work in variant angina is the decrease
of the inappropriately stimulated tone of arterial
smooth muscle during coronary vasospasm.
Verapamil, nifedipine and diltiazem are all effective in
treatment of coronary spasm.

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Nifedipine is the safest choice among the calcium channel
blockers for combination with beta blockers. It has also
been shown that nifedipine, along with verapamil and
diltiazem, has additional therapeutic effects when used
with propranolol for patients with chronic stable angina.

-     
 
Studies of the long-term effectiveness of calcium channel
blockers in patients with unstable angina appear to reduce
the number of patients, who require bypass surgery for
relief of angina.
Verapamil has become the treatment of choice in re-entrant
supraventricular tachycardia

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For patients with atrial fibrillation verapamil has been
shown to be effective in controlling the ventricular
response quickly and safely.

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ày prolonging AV nodal conduction in the presence of
supraventricular tachycardia, verapamil may increase
anterograde conduction over the accessory pathway,
raising ventricular rate. Rapid AV conduction can
cause degeneration of atrial fibrillation or flutter into
ventricular fibrillation and sudden death.

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palcium channel blockers are not effective in treating
ventricular arrhythmias except when these arrhythmias
occur in the context of coronary vasospasm with resultant
myocardial ischemia.

       


palcium channel blocking agents are not usually the first
drugs prescribed for the management of hypertension.
Nifedipine is effective in the therapy of chronic arterial
hypertension.
Nifedipine may be of particular value in patients with
hypertension who also have angina or congestive heart
failure.
  

Nifedipine and diltiazem are both widely used for


Raynaud's syndrome.
It is also used for migraine headache prophylaxis,
especially when agents such as propranolol and
amitriptylene have proved ineffective.
Nifedipine has also been used in the setting of
subarachnoid hemorrhage to prevent cerebral
vasospasm.
ppàs are as effective as ApE inhibitors in reducing blood
pressure, but they may not be as effective as ApE
inhibitors in preventing the kidney failure caused by
high blood pressure or diabetes.
Verapamil used to improve left ventricular outflow
obstruction and symptoms in patients with
hypertrophic cardiomyopathy.
   

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palcium channel blockers work by inhibiting pa"+
movement across the cell membrane during
depolarization in smooth and cardiac muscle. This
action blocks muscle contraction and results in
decreased myocardial contractility and decreased
smooth muscle cell tone (vasodilation).1 Generation
and conduction of impulses in the sinoatrial (SA)
and atrioventricular (AV) nodes of the heart depend
on the movement of ca++ through membrane
channels.
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The effects of calcium antagonists are membrane
potential (voltage) dependent. The binding and effects
of calcium antagonists are stereoselective.
èhile the (R)-enantiomers of àay, K-8644 and 202-791
(two recently synthesized experimental 1,4-
dihydropyridine derivatives), act like calcium
antagonists, the (S)-enantiomers are calcium agonists.
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palcium antagonists exhibit different binding affinities.
Depending on the membrane potential (voltage) and the
frequency of channel opening, it is thought that calcium
antagonists bind with highest affinity to channels in the
inactivated state. The channels can exist in one of three
distinct states; mode 0, 1, and 2.
èhen a channel is in mode 0, it does not open in response
to depolarization. In mode 1, depolarization produces a
low opening probability and each opening is brief. In
mode 2, depolarization produces a very high opening
probability and single openings are prolonged.
The different binding sites of ppàs result in differing
pharmacological effects

Use-dependent binding (targets cardiac cells)

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in
 Diltiazem
Verapamil

Voltage-dependent binding (targets smooth muscle)

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-30

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-80 pell Ñ1 Ñ1
mV membrane
in  Nifedipine
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It was found that only the L-type channels were sensitive
to calcium channel-inhibiting drugs. L-type calcium
channels are different in various tissues with respect to
their affinities for calcium antagonists. ppàs bind to
the receptors with higher affinity under depolarized
rather than polarized conditions.
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palcium channel blockers may interact with a number of
other medications.

Diuretics (water pills). This type of medicine may cause


low levels of potassium in the body, which may increase
the chance of unwanted effects from some calcium
channel blockers.

àeta-blockers, such as atenolol ,propranolol, and


metoprolol used to treat high blood pressure, angina,
and other conditions. Taking any of these drugs with
calcium channel blockers may increase the effects of
both types of medicine and may cause problems if either
drug is stopped suddenly.
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Digitalis heart medicines. Taking these medicines
with calcium channel blockers may increase the
action of the heart medication.
Medicines used to correct irregular heart rhythms,
such as quinidine, procainamide. The effects of
these drugs may increase if used with calcium
channel blockers.
Anti-seizure medications such as carbamazepine.
palcium channel drugs may increase the effects of
these medicines.
Grapefruit juice may increase the effects of some
calcium channel blockers.
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