Calcium Channel Blockers:
Introduction
Hundreds of thousands of patients around the world have been treated with drugs
that antagonize the function of calcium channels.
The development of these drugs was based on the remarkable scientific discovery of
calcium channels, the identification of methods to antagonize their effects, and the
development of compounds to block them. As concepts of the pathophysiology and
treatment of hypertension and atherosclerosis evolved in parallel with the science of
calcium channels, an approach to determining whether these therapies have clinical
benefit was developed.
In the treatment of hypertension, the strategy for therapeutic evaluation has been
based on the simple concept that lowering blood pressure will result in a decrease in
the incidence of stroke, myocardial infarction, renal failure, and death. In the
treatment of angina, a more complex set of concepts has prevailed.
Three factors have formed the framework for evaluating therapies for angina: (1) the
role of coronary vasospasm in the production of myocardial ischemia, (2) the belief
that reduction in myocardial ischemia over a specified time interval or improvement in
exercise time on a treadmill provided strong evidence of an overall health benefit, and
(3) more difficult extrapolations related to preservation of cellular function during
myocardial ischemia.
The synthesis of these factors has led to the acceptance of a reduction in frequency
of angina or an improvement in exercise time as adequate evidence of a desirable
clinical benefit of a therapy for angina.
History of Channel Blockers
•1962 - Verapamil reported to possess negative inotropic & chronotropic effects not
seen with other vasodilatory agents such as nitroglycerin (Hass & Hartfelder)
•1967 - Fleckenstein et al. suggest that negative inotropic effect involved reduction of
Ca++ movement into cardiac myocytes
•1972 - Kohlhardt et al. show that D600, a verapamil derivative, blocks Ca++ flux
through the slow channel
•1987 - Sales in U.S. approx. $700 million
•1992 - Sales in U.S. approx. $3 billion
Calcium ions play an essential role in regulating skeletal and smooth muscle
contractility and in the performance of the normal and diseased heart.
In classifying agents that inhibit the movement and binding of calcium, the World
Health Organization has identified two types of calcium channel blocker that are used
in clinical situations:
• those that are selective for L-type (long-lasting, large-current, or slow),
voltage-dependent calcium channels,
• and those that are nonselective..
The selective calcium channel blockers are by far the most often used in clinical
practice.
The selective calcium channel blockers share a similar antihypertensive mechanism of
action: they inhibit the influx of extracellular calcium through the L-type channel,
resulting in relaxation of vascular smooth muscle and reduction in vascular resistance.
They are therefore often assumed to be a homogeneous family of drugs, whereas
they are in fact an extremely heterogeneous group of compounds with marked
differences in chemical structure, binding sites, tissue selectivity, and, consequently,
clinical activity and therapeutic indication.
The major hemodinamic alteration in most patients with chronic essential
hypertension is an increase in peripheral vascular resistance. This increase in the
resistance results from an increase in arteriolar smooth muscle tone that in turn is
dependent upon the intracellular free calcium concentration.
Vascular smooth muscle has low intracellular calcium concentrations and smooth
muscle contraction depends upon an influx of extracellular calcium through calcium
channels located on the cell membrane. The calcium channel blockers inhibit the
movement of extracellular calcium through these calcium channels and result in
arteriolar dilation and a decrease in blood pressure.
It has been proposed that elderly and black patients have greater blood pressure
responses to calcium channel blockers than younger white patients. This has not been
confirmed in all clinical trials.
Calcium channel blockers also appear to slow the progression of renal impairment. The
exact mechanism for this action is still controversial. Some studies have found that
calcium channel blockers dilate the afferent arteriole which would increase glomerular
pressure. Other studies suggest equal vasodilatory effect on the afferent and efferent
arterioles which would decrease intraglomeriolar pressure
Mechanism of action
Normally, an increase in the intracellular Ca++ concentration causes cardiac and
smooth muscle cells to contract.
In smooth muscle, Ca++ binding to calmodulin activates myosin light chain kinase
which in turn phosphorylates the P-light chain of myosin. This triggers contraction (i.
e. actin-myosin interactions), but there appear to be additional Ca++ regulatory
mechanisms.
Channel blockers bind to the L-type channels ("slow channels"), which are abundant in
cardiac and smooth muscle. This may partially explain their rather selective effects on
the cardiovascular system.
Selective calcium channel blockers include three discrete(منفصل) chemical types: the
phenylalkylamines (eg, verapamil), the benzothiazepines (eg, diltiazem), and the 1,4-
dihydropyridines (eg, nifedipine and Amlodipine )
The distinct identities of these types are suggested by their chemical structures,
The net pharmacological profiles of verapamil and diltiazem are much closer to one
another than either is to the dihydropyridines. For this reason, some authors have
recently recommended a new organization of the heterogeneous calcium channel
blocker family, which would delineate(يصف) verapamil and diltiazem as one subgroup
and the dihydropyridines as another.
Distinct Binding Sites
Each of the three types of selective calcium channel blocker interacts with a specific
receptor domain found on a large membrane- spanning protein that constitutes a
substantial (جوهري ) portion of the L-type, voltage-dependent calcium channel.
These receptor sites are all located on the alpha1 subunit of the channel. The 1,4-
dihydropyridine receptor is the most accessible, located on the surface of the channel.
This receptor has therefore been the most widely studied of the three, and such
explorations have yielded a relatively large number of dihydropyridine derivatives
designed to bind and inhibit (or, in selected cases, stimulate) that site.
There is a complex allosteric relationship among the three calcium channel blocker
receptor sites, and each site is also linked allosterically to the gating mechanism of the
voltage-dependent calcium channel
Thus, drugs binding at the dihydropyridine site appear to increase the affinity of other
drugs (eg, diltiazem) for the benzothiazepine site, and vice versa. On the other hand,
the binding of verapamil at the phenylalkylamine site appears to reduce the affinities
of both diltiazem and the dihydropyridine calcium channel blockers for binding at their
respective sites.
Scientists suggests that these relations may reflect or perhaps help to explain the
fact that diltiazem and nifedipine in combination may be highly effective in selected
monotherapy-resistant hypertensive patients, whereas verapamil and nifedipine
together have yielded mixed results, and a verapamil-diltiazem combination would be
frankly contraindicated. Scientists further points out that, in this respect, nifedipine
and diltiazem complement one another as might agents from fundamentally different
drug classes, whereas verapamil and diltiazem, with similar and compounding
pharmacologic effects, behave ((يتصرف more typically like class-related agents.
Selectivity of Action
Binding sites for all three types of calcium channel blocker are found in a variety of
tissues, including myocardium, smooth muscle, skeletal muscle, and glandular tissue.
Yet this range of target tissues is not necessarily reflected in pharmacologic or
therapeutic activity. For example, skeletal smooth muscle is relatively insensitive to
calcium channel blockade, as indicated by the fact that calcium channel blocker therapy
does not interfere with postural tone.
Similarly, experiments involving several dihydropyridine compounds have
demonstrated a marked dissociation between binding to cardiac muscle and the ability
to elicit a cardiac response.
Dissociation (تفكيك ) of binding characteristics and pharmacologic response can be
explained by many factors.
The activity of a calcium channel blocker in a particular tissue may also be affected by
the location of the receptor site and the frequency of channel activity.
The verapamil and diltiazem binding sites are located internally, deep within the
channel. Access to the receptor is therefore enhanced when the channel is open. The
rapidly firing tissues of the myocardium and the atrioventricular (AV) node provide
ample (متسع ) opportunity for the binding of these agents, which are pharmacologically
active in myocardial and cardiac conductive tissues. Dihydropyridine calcium channel
blockers are more dependent on the voltage-regulated state of the channel for high-
affinity binding. They interact preferentially with vascular smooth muscle, which exists
more frequently in a depolarized state than cardiac tissue.
Pharmacokinetics
Calcium channel blockers are all well absorbed after oral administration, but there are
distinctions in oral bioavailability that relate to differences in first-pass metabolism
Diltiazem, nifedipine, and nicardipine do not undergo extensive first-pass metabolism,
whereas verapamil and isradipine undergo fairly extensive first-pass metabolism that
may result in wide variations in plasma levels and marked differences between the oral
and intravenous doses required to produce a similar physiologic effect.
Protein binding percentages are higher with the dihydropyridines than with either
diltiazem or verapamil.
Furthermore, protein binding with nifedipine and possibly other members of the
dihydropyridine class is concentration dependent, theoretically allowing for protein-
binding interactions, although none of clinical significance have been reported. With
verapamil and diltiazem, protein binding is independent of drug concentrations,
making displacement interactions unlikely.
Because the half-lives of the older calcium channel blockers are relatively short,
ranging from approximately 3 to 5 hours, extended-release formulations of these
agents have been developed to permit once-daily administration. Isradipine,
felodipine, and amlodipine have substantially longer elimination half-lives, but only
amlodipine has a half-life consistent with once-daily administration.
Metabolic Effects
The calcium channel blockers have few deleterious(مؤذي) metabolic effects of clinical
consequence. Unlike the beta blockers and diuretics, calcium channel blockers do not
adversely influence insulin secretion, blood glucose levels, or plasma lipoprotein levels,
all of which are of potential importance in the frequently hypertensive population; nor
do they affect potassium or magnesium balances.
Verapamil and diltiazem do not usually affect plasma norepinephrine levels.
Norepinephrine increases have been reported after a single dose of nifedipine,
although these catecholamine spikes tend to normalize when nifedipine is
administered over an extended period.
Similarly, plasma renin levels are unaffected by verapamil or diltiazem, but oral
nifedipine may produce a transient rise that is apparently related to the reflex
sympathetic stimulation induced by the potent hypotensive action of this agent.
Diltiazem, verapamil, and nifedipine all attenuate the pressor effect of norepinephrine,
which may account for their effectiveness in the management of hypertensive
emergencies. All three types of selective calcium channel blocker also cause transient
blockade of the pressor effect of angiotensin II, which may likewise contribute to their
acute blood pressure-lowering activity.
Hemodynamic Differentiation
The chief hemodynamic feature of the selective calcium channel blockers is
vasodilatation of the coronary and peripheral arteries, resulting in a reduction in
vascular resistance and an improvement in blood flow
Nifedipine has a potent vasodilatory effect on both the coronary and peripheral
vasculatures, as do the other dihydropyridine agents indicated for the treatment of
hypertension. Diltiazem produces coronary vasodilatation similar to that seen with
nifedipine but is a less potent peripheral vasodilator than either nifedipine or
verapamil. The coronary vasodilatory activity of verapamil is weaker than that of
diltiazem or nifedipine, and its effect on the peripheral vasculature is intermediate
between the two.
All calcium channel blockers can produce negative inotropy.
Although the newer, more vasoselective dihydropyridines are reported to have
attenuated cardiac effects, this has not been demonstrated clinically. Verapamil is the
most potent negative inotrope among the calcium channel blockers, followed by
nifedipine. However, the cardiodepressant effect of nifedipine is largely overcome by
reflex sympathetic stimulation, which boosts myocardial contractility and heart rate, at
least initially.
Schwinger and Erdmann studied the relationship between vasodilatation and negative
inotropic activity in four calcium channel blockers: nifedipine, isradipine, verapamil, and
diltiazem. The investigators determined the plasma concentration required to achieve
vasodilatation with each drug and compared it with the concentration needed to
produce a 25% decrease in inotropic activity in human papillary muscle.
The ratio of these two concentrations, called the safety factor, provides an index of
negative inotropic potential (the lower the safety factor, the greater the negative
inotropic potential). The authors determined that the safety factor was approximately
1.1 for verapamil, 2.3 for nifedipine, 22 for diltiazem, and 70 for isradipine.
Verapamil and diltiazem (but not nifedipine or the other dihydropyridine agents) are
active in cardiac conductive tissue and thereby modulate heart rate. Verapamil slows
conduction through the atrioventricular (AV) node and prolongs the AV node
functional recovery period, usually producing a modest decrease in heart rate
(although small increases are occasionally reported).
Diltiazem has a lesser influence on AV node conduction than verapamil, but has a
direct effect on the sinus node that helps to bring about a small but consistent heart
rate reduction.
Intravenous forms of verapamil and diltiazem are indicated for heart rate control in
patients with supraventricular tachycardia.
In contrast, the dihydropyridine calcium channel blockers do not significantly impact
(يؤثر في ) cardiac conduction and have no direct rate-modulating effect. They may,
however, indirectly produce an increase in heart rate via reflex activation of
sympathetic drive. For this reason, nifedipine and other dihydropyridine agents are
contraindicated in patients with tachy-arrhythmias.
Adverse Effects
Corresponding to the differences in binding, tissue selectivity, and hemodynamics, the
three types of selective calcium channel blocker have distinctive adverse effect profiles.
The most common adverse event reported by patients treated with verapamil is
constipation, which is believed to be related to the high affinity of this drug for
gastrointestinal smooth muscle. The negative inotropic activity of verapamil may
precipitate or exacerbate congestive heart failure symptoms in a small percentage of
patients. The dampening effect of verapamil on AV node conduction may produce
second- or third-degree heart block in some patients.
Diltiazem, with similar but less potent cardiac effects than verapamil and less dramatic
peripheral vasodilatation than nifedipine, is generally considered to be the best
tolerated of the original calcium channel blockers.
AV conduction disturbances and heart block may occur with diltiazem, although the
risk is lower than in patients receiving verapamil. Vasodilator-type side effects, such
as headache, flushing, palpitations, hypotension, and peripheral edema, are less
common with diltiazem than with nifedipine.
As a class, the dihydropyridines are associated with the greatest incidence of adverse
effects, largely related to their powerful vasodilatory action. Studies involving short-
acting nifedipine demonstrate the highest frequency of such effects, which appear to
be less common with the sustained-release nifedipine preparations. Newer
dihydropyridines, such as isradipine, felodipine, and amlodipine, also tend to be better
tolerated than the conventional formulation of nifedipine.
Summary
Important differences separate the three types of selective calcium channel blocker.
They bind at different regions of the L-type calcium channel, are pharmacologically
active in different cardiovascular tissues, and have different hemodynamic and clinical
safety profiles. The dihydropyridines act preferentially on vascular smooth muscle;
they have potent peripheral vasodilating effects and their therapeutic benefit is
achieved primarily via a reduction in afterload.
Verapamil and diltiazem are less specific for peripheral vascular smooth muscle than
the dihydropyridines, but are more active in the myocardium and cardiac conductive
tissues. They are effective vasodilators but also decrease myocardial contractility and
lower heart rate. Their therapeutic effect reflects a combination of afterload reduction
and decreased oxygen consumption, resulting from negative inotropism and lowered
heart rate.
On the basis of these differences, some authors have recently recommended a
change in the nomenclature describing the calcium channel blocker family. Ferrari
refers to the dihydropyridines as "vasodilating" calcium channel blockers and to
verapamil and diltiazem as "modulating" calcium channel blockers (in recognition of
their cardiac effects). Materson advocates that all three types be called "calcium
antagonists," but that only verapamil and diltiazem continue to be designated as
"calcium channel blockers." He further recommends that nifedipine and its analogues
be consistently known as "dihydropyridines" or "DHPs." Such distinctions are not
merely (فحسب) academic but are practical and evidence-based, and they may assist the
clinician in making informed therapeutic choices.
In some patients, channel blockers (particularly dihydropyridines) may aggravate
anginal symptoms due to reflex increase in sympathetic tone, decreased coronary
perfusion pressure, or coronary steal; this is not usually seen with verapamil or
diltiazem.
Beta-blockers suppress reflex tachycardia induced by som ecalcium antagonists (and
have negative dromotropic, chronotropic, and inotropic effects)
Dihydropyridines will not enhance dromotropic effects of beta-blockers; concurrent
treatment with verapamil or diltiazem is effective, but can lead to AV block, severe
bradycardia, and decreased ventricular function.
Nitrates cause venous dilation and reduce cardiac preload (channel blockers have no
effect on venous return at normal doses)
Unlike other arteriolar vasodilators, channel blockers do not cause fluid retention, and
only the dihydropyridines produce mild to moderate reflex tachycardia.
The channel blockers are all equally effective in treating mild to moderate hypertension
and are as effective as beta-blockers or diuretics.
Channel blockers are well-tolerated; side-effects include dizziness, headache, flushing,
and peripheral edema and are usually associated with dihydropyridines.
Patients with ventricular dysfunction, SA node or AV conduction disturbances, and
systolic blood pressures below 90 mm Hg should not be treated with verapamil or
diltiazem (particularly i.v.).
Some channel blockers (e.g. verapamil) can cause increase in plasma digoxin levels
and are therefore contraindicated for use in treating digitalis toxicity; AV nodal
conduction can also be exacerbated by concurrent treatment with channel blockers
and digitalis.
Cardiovascular Diseases
 |  |
CCBs
