Calcium channel blockers

1. 19 Calcium Channel Blockers
Vijay C. Swamy and David J. Triggle
DRUG LIST
GENERIC NAME PAGE GENERIC NAME PAGE
Amlodipine 218 Nifedipine 218
Diltiazem 218 Nimodipine 218
Felodipin 218 Nisoldapine 218
Isradipine 220 Verapamil 218
Nicardipine 218
The agents commonly called the calcium channel ine (Cardene), felodipine (Plendil), nisoldipine (Sular),
blockers comprise an increasing number of agents, includ- and amlodipine (Norvasc). These agents differ from
ing the prototypical verapamil (Calan, Isoptin), nifedipine nifedipine principally in their potency, pharmacokinetic
(Adalat, Procardia), and diltiazem (Cardizem). These characteristics, and selectivity of action. Nimodipine has
agents are a chemically and pharmacologically heteroge- selectivity for the cerebral vasculature; amlodipine ex-
neous group of synthetic drugs, but they possess the com- hibits very slow kinetics of onset and offset of blockade;
mon property of selectively antagonizing Caϩϩ move- and felodipine and nisoldipine are vascular-selective
ments that underlie the process of excitation–contraction 1,4-dihydropyridines.
coupling in the cardiovascular system. The primary use of
these agents is in the treatment of angina, selected cardiac
arrhythmias, and hypertension.
CALCIUM ANTAGONISM
Although the Caϩϩ channel blockers are potent va-
sodilating drugs, they lack the fluid-accumulating prop- The concept of calcium antagonism as a specific mech-
erties of other vasodilators and the persistent activation anism of drug action was pioneered by Albrecht
of the sympathetic and renin–angiotensin–aldosterone Fleckenstein and his colleagues, who observed that ve-
axes. Furthermore, the broad potential range of activi- rapamil and subsequently other drugs of this class
ties, both within and without the cardiovascular system, mimicked in reversible fashion the effects of Caϩϩ
suggests that they may be clinically useful in disorders withdrawal on cardiac excitability. These drugs inhib-
from vertigo to failure of gastrointestinal smooth mus- ited the Caϩϩ component of the ionic currents carried
cle to relax . in the cardiac action potential. Because of this activity,
A number of second-generation analogues are these drugs are also referred to as slow channel block-
known, particularly in the nifedipine (1,4-dihydropyri- ers, calcium channel antagonists, and calcium entry
dine) series, including nimodipine (Nimotop), nicardip- blockers.
218

2. 19 Calcium Channel Blockers 219
The actions of these drugs must be viewed from the Site II Site I
perspective of cellular Caϩϩ regulation (Fig. 19.1). Caϩϩ
1,4-DHP
is fundamentally important as a messenger, linking cel- Site
ϩ
lular excitation and cellular response. This role is made Diltiazem
Activator
possible by the high inwardly directed Caϩϩ concentra-
Antagonist
tion and electrochemical gradients, by the existence of
Ϫ Ϫ
specific high-affinity Caϩϩ binding proteins (e.g.,
ϩ
calmodulin) that serve as intracellular Caϩϩ receptors,
and by the existence of Caϩϩ-specific influx, efflux, and Ca2ϩ
sequestration processes. Calcium, in excess, serves as a Channel
mediator of cell destruction and death during myo-
Ϫ Ϫ
cardial and neuronal ischemia, neuronal degeneration,
and cellular toxicity. The control of excess Caϩϩ mobi-
Ϫ
lization is thus an important contributor to cell and tis-
sue protection.
The available Caϩϩ channel blockers exert their ef-
fects primarily at voltage-gated Caϩϩ channels of the
Verapamil/D600
plasma membrane. There are at least several types of
channels—L, T, N, P/Q and R—distinguished by their
electrophysiological and pharmacological characteris-
tics. The blockers act at the L-type channel at three dis- Site III
tinct receptor sites (Fig. 19.2). These different receptor
FIGURE 19.2
interactions underlie, in part, the qualitative and quan-
The principal receptors or drug binding sites at the calcium
titative differences exhibited by the three principal channel. These sites are linked to the opening and closing
classes of channel blockers. of the channel and to each other by activating (ϩ) or
Cellular stimuli that involve Caϩϩ mobilization by inhibiting (Ϫ) allosteric mechanisms. The 1,4-DHP site is a
processes other than that at the L-type voltage-gated receptor site for a number of 1,4-dihydropyridine
channels will be either completely or relatively insensi- compounds; D600 is the designation for a close chemical
tive to the channel blockers. This differential sensitivity relative of verapamil.
contributes to the variable sensitivity of vascular and
nonvascular smooth muscle to the actions of these
extracellular drugs, for example, the regional vascular selectivity and
intracellular 7 the general lack of activity of these agents in respiratory
Ca2؉
MITO ATP Ca2؉ or gastrointestinal smooth muscle disorders.
1
Na؉ CM
Na؉
8 The Selectivity of Action of Calcium
9
Ca2؉ Channel Blockers
ROC
Ca2؉ Ca2؉ Although the available Caϩϩ channel blockers exert
2
SR their effects through an interaction at one type of chan-
5 nel, they do so at different sites. Figure 19.2 shows that
ATP
Ca2؉
VGC the channel blockers act at three discrete receptor sites
Ca2؉ 3 6 to mediate channel blockade indirectly rather than by a
direct or physical channel block. The existence of the
4 different receptor sites is one basis for the different
Ca2؉ Ca2؉ pharmacological profiles exhibited by these agents.
The activity of the Caϩϩ channel blockers increases
with increasing frequency of stimulation or intensity
FIGURE 19.1
and duration of membrane depolarization. This use-
Cellular calcium regulation. Depicted are several sites that
dependent activity is consistent with a preferred interac-
control calcium entry, efflux, and sequestration. 1. Naϩ,
Caϩϩ exchange. 2. Receptor-operated channels. 3. Voltage- tion of the antagonists with the open or inactivated states
gated channels. 4. Leak pathways. 5, 6. Entry and efflux of the Caϩϩ channel rather than with the resting state. This
in sarcoplasmic reticulum. 7. Plasma membrane pump. activity is not shared equally by all Caϩϩ blockers and
8, 9. Entry and efflux in mitochondria. ATP adenosine
, so may provide a further basis for the therapeutic dif-
triphosphate; CM, cell membrane. ferences between them. For example, verapamil and

3. 220 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM
diltiazem are approximately equipotent in cardiac and tribute to the recently described antiatherogenic actions
vascular smooth muscle, whereas nifedipine and all seen in experimental and clinical states.
other agents of the 1,4-dihydropyridine class are signifi-
cantly more active in vascular smooth muscle.
Furthermore, different members of the 1,4-dihydropyri- PHARMACOLOGICAL EFFECTS ON THE
dine class have different degrees of vascular selectivity. CARDIOVASCULAR SYSTEM
These differences are broadly consistent with the obser-
The effects of the prototypical calcium channel blockers
vation that verapamil and diltiazem act preferentially
are seen most prominently in the cardiovascular system
through the open channel state, and nifedipine and its
(Table 19.1), although calcium channels are widely dis-
analogues act through the inactivated state.
tributed among excitable cells. The following calcium
The clinically available calcium channel antagonists
channel–blocking drugs are clinically the most widely
have also proved to be invaluable as molecular probes
used compounds in this very extensive class of pharma-
with which to identify, isolate, and characterize calcium
cological agents: amlodipine, diltiazem, isradipine,
channels of the voltage-gated family. In particular, the
nifedipine, nicardipine, nimodipine, and verapamil.
1,4-dihydropyridines with their high affinity, agonist–
antagonist properties, and selectivity have become de-
fined as molecular markers for the L-type channel. Vascular Effects
Synthetic drugs of comparable selectivity and affin- Vascular tone and contraction are determined largely
ity to the 1,4-dihydropyridines do not yet exist for the by the availability of calcium from extracellular sources
other channel types, T, N, P/Q, and R; these remain char- (influx via calcium channels) or intracellular stores.
acterized by complex polypeptide toxins of the aga- and Drug-induced inhibition of calcium influx via voltage-
conotoxin classes. Neuronal pharmacology, including gated channels results in widespread dilation and a de-
that of the central nervous system (CNS), is dominated crease in contractile responses to stimulatory agents. In
by the N, P/Q, and R channels. This underscores the general, arteries and arterioles are more sensitive to
normally weak effect of L-channel antagonists on the relaxant actions of these drugs than are the veins,
CNS function. Drugs that act at the N, P, and R channels and some arterial beds (e.g., coronary and cerebral ves-
with comparable selectivity and affinity to the 1,4- sels) show greater sensitivity than others. Peripheral
dihydropyridines may be expected to offer major po- vasodilation and the consequent fall in blood pressure
tential for a variety of CNS disorders, including neu- are commonly accompanied by reflex tachycardia
ronal damage and death from ischemic insults. when nifedipine and its analogues are used; this is in
The Caϩϩ channel blockers also differ in the extent of contrast to verapamil and diltiazem, whose effects on
their additional pharmacological properties. Verapamil peripheral vessels are accompanied by cardiodepres-
and to a lesser extent diltiazem possess a number of re- sant effects.
ceptor-blocking properties, together with Naϩ and Kϩ
channel–blocking activities, that may contribute to their
Cardiac Effects
pharmacological profile. Nifedipine and other 1,4-dihy-
dropyridines are more selective for the voltage-gated Calcium currents in cardiac tissues serve the functions
Caϩϩ channel, but they may also affect other pharmaco- of inotropy, pacemaker activity (sinoatrial (SA) node),
logical properties because their nonpolar properties and conduction at the atrioventricular (A-V) node. In
may lead to cellular accumulation. Together with their principle, the blockade of calcium currents should result
channel-blocking properties, these properties may con- in decreased function at these sites. In clinical use, how-
TA B L E 1 9 . 1 Cardiovascular Effects of Calcium Channel Blockers*
Nifedipine Diltiazem Verapamil
Blood pressure Ϫ Ϫ Ϫ
Vasodilation ϩϩϩ ϩϩ ϩϩ
Heart rate ϩϩ Ϫ Ϯ
Contractility 0/ϩ 0 0/Ϫ
Coronary vascular resistance Ϫ Ϫ Ϫ
Blood flow ϩϩϩ ϩϩϩ ϩϩ
Key: ϩ ϭ increase; Ϫ ϭ decrease; 0 ϭ no significant effect.
*Changes are those seen commonly following oral doses used in therapy of hypertension or angina.
The magnitude of response is indicated by number of symbols.

4. 19 Calcium Channel Blockers 221
ever, dose-dependent depression is seen only with vera- Their antihypertensive efficacy is comparable to that
pamil and diltiazem and not with nifedipine, reflecting of ␤-adrenergic blockers and angiotensin-converting
mainly differences in the kinetics of their interaction at enzyme (ACE) inhibitors. The choice of a calcium chan-
calcium channels (see section on calcium antagonism). nel blocker, especially for combination therapy, is
Characteristic cardiac effects include a variable slowing largely influenced by the effect of the drug on cardiac
of the heart rate, strong depression of conduction at the pacemakers and contractility and coexisting diseases,
A-V node, and inhibition of contractility, especially in the such as angina, asthma, and peripheral vascular disease.
presence of preexisting heart failure.
Ischemic Heart Disease
The effectiveness and use of calcium channel blockers
THERAPEUTIC APPLICATIONS
in the management of angina are well established (see
The calcium channel–blocking drugs have been investi- Chapter 17); their benefit in postinfarction stages is less
gated for an unusually wide number of clinical applica- certain. Efficacy in angina is largely derived from their
tions. Verapamil-induced improvement of diastolic func- hemodynamic effects, which influence the supply and
tion has proved to be beneficial in the treatment of demand components of the ischemic balance (1) by in-
hypertrophic cardiomyopathy. Vasodilatory properties of creasing blood flow directly or by increasing collateral
these drugs are used in the treatment of peripheral vaso- blood flow and (2) by decreasing afterload and reducing
constrictive disorders (Raynaud’s disease) and in reliev- oxygen demand. All three agents are useful in the man-
ing vasospasm following subarachnoid hemorrhage. agement of stable exertional angina, with their vasodila-
There is ongoing interest in investigating protective ef- tory and cardiac effects making beneficial contributions.
fects on renal function and in the ability to reduce dele- Given the differences in their relative effects (Table
terious vascular changes in diabetes mellitus. Similarly, 19.1), the response of the patient can vary with the
the potential benefit afforded by their selective vasodila- agent used and the preexisting cardiac status.
tory action (especially the second-generation agents) in All agents are also effective in the control of variant
the management of heart failure is an area of interest. (Prinzmetal’s) angina, in which spasm of the coronary
These drugs are of some benefit in a variety of noncar- arteries is the main factor. Their usefulness in the more
diovascular conditions characterized by hyperactivity of complex unstable (preinfarction) angina is less definite,
smooth muscle (e.g., achalasia). However, their main ap- depending on the hemodynamic status and the suscep-
plications are as follows. tibility of the patient to infarction.
Hypertension Cardiac Arrhythmias
The calcium channel–blocking drugs are effective anti- The prominent depressant action of verapamil and dil-
hypertensive agents and enjoy widespread use as single tiazem at the SA and A-V nodes finds use in specific ar-
medication or in combination. Their effectiveness is re- rhythmias. They are of proven efficacy in acute control
lated to a decrease in peripheral resistance accompanied and long-term management of paroxysmal supraventric-
by increases in cardiac index. The magnitude of their ef- ular tachycardia (see Chapter 16). Their ability to inhibit
fects is determined partly by pretreatment blood pres- conduction at the A-V node is employed in protecting
sure levels; maximum blood pressure lowering gener- ventricles from atrial tachyarrhythmias, often in combi-
ally is seen 3 to 4 weeks after the start of treatment. nation with digitalis or propranolol.
These drugs possess some distinct advantages relative
to other vasodilators, including the following:
PHARMACOKINETICS
1. Their relaxant effect on large arteries results in A comparison of the pharmacokinetic properties of
greater compliance, which is beneficial in older these agents is listed in Table 19.2. All three drugs are
persons. well absorbed following oral administration. Verapamil
2. Tolerance associated with renal retention of fluid and diltiazem undergo greater first-pass metabolism rel-
does not occur; an initial natriuretic effect is often ative to nifedipine, resulting in lower bioavailability of
observed, especially with the nifedipine group of the former two drugs. Hepatic metabolism of nifedipine
blockers. is complete, yielding inactive metabolites; this is unlike
3. They do not have significant effects on the re- verapamil and diltiazem, whose metabolites have phar-
lease of renin or cause long-term changes in lipid macological activity. Verapamil is metabolized stereose-
or glucose metabolism. lectively in favor of the more active (Ϫ) enantiomer,
4. Postural hypotension, first-dose effect, and re- thus requiring higher plasma concentrations after oral
bound phenomenon are not commonly seen. administration.

5. 222 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM
TA B L E 1 9 . 2 Pharmacokinetics of Calcium Channel Blockers
Verapamil Nifedipine Diltiazem
Absorption, oral (%) Ͼ90 Ͼ90 Ͼ90
Bioavailability (%) 20 60–80 ~40
Onset of action: oral (min) 90–120 Ͻ20 Ͻ30
Peak effect 5 hr 1–2 hr 3–5 hr
Protein binding (%) 90 90 90
Plasma half-life 4–8 hr 5 hr* 5 hr
Metabolism 80% 1st-pass active metabolites Inactive metabolites 60% of 1st dose: 10% steady state
Excretion
Renal (%) 70 90 30
Fecal (%) 15 10 70
*Six to 11 hours after oral tablets: above value for capsules.
TOXICITY
The common side effects seen in chronic therapy (Table enhancement of the action of other cardiodepressant
19.3) are mostly related to vasodilation—headaches, drugs. Their use is generally contraindicated in obstruc-
dizziness, facial flushing, hypotension, and so forth. High tive conditions (e.g., aortic stenosis). No consistent or
doses of verapamil in elderly patients are known to significant changes in lipid and glucose levels have been
cause constipation. Serious side effects, especially fol- reported with chronic therapy. Non–sustained release
lowing the intravenous use of verapamil, include formulations of nifedipine are contraindicated in hyper-
marked negative inotropic effects and depression of tension because of sympathetic rebound that may ag-
preexisting sick sinus syndrome, A-V nodal disease, and gravate existing left ventricular dysfunction.
TA B L E 1 9 . 3 Adverse Effects of Calcium Channel Blockers
Verapamil Diltiazem Nifedipine
Tachycardia 0 0 ϩ
Decreased heart rate* ϩ ϩ 0
Depressed A-V nodal conduction* ϩϩϩ ϩϩ 0
Negative inotropy ϩϩ ϩ 0
Vasodilation (flushing, edema, hypotension, headaches) ϩ ϩ/0 ϩϩϩ
Constipation, nausea ϩϩ ϩ ϩ/0
Key: ϩ ϭ increase; 0 ϭ no change.
*Marked effect in presence of sick sinus syndrome and A-V nodal disease.

6. 19 Calcium Channel Blockers 223
Study Questions
1. Which of the following statements most accurately ANSWERS
characterize the cellular action of the calcium chan- 1. C. The available blockers act primarily at voltage-
nel blockers? gated calcium channels of the L type. The three pro-
(A) Their interaction with membrane phospho- totypes, verapamil, nifedipine, and diltiazem, act at
lipids results in a nonselective decrease of ion trans- three discrete sites at this channel.
port. 2. B. The other three drugs (dihydropyridines) are
(B) They inhibit the Naϩ–Caϩϩ exchanger in car- characterized by relatively selective vasodilator ef-
diac and smooth muscle. fects with little if any cardiac effects at doses em-
(C) They interact at three distinct sites at the L- ployed clinically for hypertension or angina.
type voltage-gated calcium channels. 3. D. The vasodilatory effects of nifedipine are largely
(D) Their interaction with the sodium pump results restricted to arteries (and consequently the after-
in an inhibition of calcium transport. load). It does not alter venous tone (and thus pre-
2. Which of the following calcium channel blockers load) significantly.
would be most likely to suppress atrial tach- 4. C. Since they are metabolized in the liver, hepatic
yarrhythmias involving the A-V node? cirrhosis can be expected to alter their half-life.
(A) Nifedipine 5. A. Skeletal muscles depend on the mobilization of
(B) Verapamil intracellular stores of calcium for their contractile
(C) Nicardipine responses rather than transmembrane flux of cal-
(D) Amlodipine cium through the calcium channels. Therefore,
3. All of the following statements are applicable with skeletal muscle weakness is not likely to occur.
regard to the systemic effects caused by nifedipine
EXCEPT: SUPPLEMENTAL READING
(A) It typically causes peripheral vasodilation. Abernathy DR and Schwartz JB. Calcium-antagonist
(B) It often elicits reflex tachycardia. drugs. N Engl J Med 1999;34:1447–1457.
(C) It causes coronary vasodilatation and an in- Epstein M (Ed.). Calcium Antagonists in Clinical
crease in coronary blood flow. Medicine (3rd Ed.). Philadelphia: Hanley & Belfus,
(D) Its benefit in the management of angina is re- 2002.
lated to the reduction in preload that it induces. Kizer JR and Kimmel SE. Epidemiologic review of the
4. All of the following statements regarding the phar- calcium channel blocker drugs: An up-to-date per-
macokinetics of calcium channel blockers are cor- spective on the proposed hazards. Arch Intern Med
rect EXCEPT 2001;161:1145–1158.
(A) They are characterized by significant amount Taira N. Differences in cardiovascular profile among
(~ 90%) of protein binding. calcium antagonists. Am J Cardiol 1987;59:24B–29B.
(B) They undergo significant first-pass metabolism. Triggle DJ. Mechanisms of action of calcium channel
(C) Their half-life is not altered by hepatic cirrho- antagonists. In Epstein EM (Ed.). Calcium
sis. Antagonists in Clinical Medicine (3rd Ed.).
(D) They can be administered orally. Philadelphia: Hanley & Belfus, 2002.
5. All of the following adverse effects are likely to oc- Tulenko TN et al. The smooth muscle membrane dur-
cur with long-term use of calcium channel blockers ing atherogenesis: A potential target in atheropro-
EXCEPT tection. Am Heart J 2001;141(2Suppl): S1–S11.
(A) Skeletal muscle weakness
(B) Flushing
(C) Dizziness
(D) Headache

7. 224 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM
Case Study Nifedipine-Induced Vasodilatation
A 65-year-old recently retired man is being
evaluated for elevated blood pressure. He
occasionally has angina precipitated by physical
ANSWER: Nifedipine, unless formulated for slow,
sustained release, is characterized by relatively
rapid onset of vasodilatory effects. This man’s side
exertion and rapidly controlled by sublingual use of effects reflect the rapid and intense fall in blood
nitroglycerin. His blood pressure is 160/100 mm Hg. pressure and consequent reflex increases in
He is advised to take nifedipine 80 mg/day, which sympathetic tone. The increase in anginal episodes
he does, in divided doses of 20 mg (capsules). He also is a result of drug-induced periodic increases in
develops flushing, dizziness, and nervousness shortly heart rate.
(Ͻ30 minutes) after taking the drug, and these
symptoms persist for approximately 1 hour. The
number of anginal episodes have increased during
this period. QUESTION: How do the properties of
nifedipine relate to the above development?