Download Pharmacological differences between calcium antagonists

European Heart Journal (1997) 18 (Supplement A), A71-A79
Pharmacological differences between calcium
antagonists
L. H. Opie
Ischaemic Heart Disease Research Unit of the Medical Research Council, University of Cape Town
Medical School, Cape Town, South Africa
The calcium channel antagonists are not an homogeneous
group. From both pharmacological and clinical points of
view, they can be divided into those of the dihydropyridine
family like nifedipine, and those of the non-dihydropyridine
family like verapamil and diltiazem. These families bind at
different sites to the calcium channel, which may explain
some of the clinical differences. The dihydropyridines are
more vascular selective and the non-dihydropyridines are
more myocardial selective and tend to reduce the heart rate.
Further important differences are between short- and longacting forms of the calcium channel antagonists. From the
clinical point of view, these agents are most used in angina
pectoris and hyertension. Emerging studies suggest that in
angina of effort these agents have a safety record somewhat
similar to that of /?-blockers. In congestive heart failure,
these agents, as a group, are contraindicated.
(Eur Heart J 1997; 18 (Suppl A): A71-A79)
Calcium channel structure and binding
sites
the results are thought to be applicable to the heart and
vascular smooth muscle. The calcium channel in the
heart is a complex protein found especially in the
membranes of the sarcolemma including the T-tubules.
This channel is composed of four subunits (a,, a2, P, S)
with a total molecular weight of about 222 000 daltons
(d). In skeletal muscle, there is an additional gamma
subunit, not expressed in the heart or in vascular smooth
muscle.
Of the four channel subunits, the major one that
actually contains the calcium channel pores is the a,
subunit (molecular weight 165 000 d). This subunit contains four transmembrane repeat domains, very similar
to each other in structure, each consisting of six helices.
Each of the four domains of the a\ subunit has a
pore, thought to lie between helices S5 and S6, that
potentially admits calcium ions. In reality, each of the
four domains of the a, subunit appears to be folded in
on itself, so that each of the four pores (S5-S6) of each
of the domains contributes structurally to form one
functioning pore per four domains. Ionic selectivity
appears to be conferred by the amino acid structure of
the S5-S6 linker region1'1.
A point of potential confusion is that the term 'calcium
channel' is applied by molecular biologists to the whole
protein structure including all the subunits concerned
with regulation of calcium ion entry. In contrast, the
actual 'channel' through which calcium ion flow occurs
can also be called the 'calcium channel', meaning the
calcium-permeable pore of the calcium channel. The
term 'calcium channel' best refers to all the calcium
channel proteins taken together, that is the large
molecular conglomerate of 4-5 subunits and the term
'calcium channel pore' best refers to that part of the
structure that allows the actual inflow of calcium ions.
The major functional differences between the fast
sodium and slow calcium channels are well known to
clinicians. From the molecular point of view, however
there is a surprising degree of overlap and homology.
This may explain why calcium channels also have the
capacity to admit sodium ions in certain experimental
conditions. These two channels clearly belong to the
same superfamily, concerned with voltage-induced ion
entry into cells. The structure of the calcium channel has
been best studied in skeletal muscle preparations, and
Key Words: Calcium channel structure, binding
sites, vascular selectivity, anti-anginal effects, calcium
antagonists.
Other subunits
Correspondence: Professor L. H. Opie, Ischaemic Heart Disease
Research Unit of the Medical Research Council, University of
Cape Town Medical School, Observatory, 7925 Cape Town,
South Africa.
0195-668X/97/OA0071+09 S18.00/0
The functions of the a2, /?, and 8 subunits are still not
clarified. Nonetheless, the presence of the /? subunit
greatly increases the activity of the a, subunit, acting on
1997 The European Society of Cardiology
A72
L. H. Opie
Table 1 Binding sites for calcium antagonists and their clinical correlates
Site
DHP binding
Site 1A
Non-DHP binding
Site IB, diltiazem;
Site 1C, verapamil
Clinical correlate
Drug example
vascular selectivity
10 x
100 x
1000 x
1. myocardial selectivity
2. nodal selectivity
nifedipine, amlodipine
nicardipine, isradipine, felodipine
nisoldipine
verapamil, diltiazem
verapamil, diltiazem
DHP = dihydropyridine.
For data on selectivity, see'16'.
the linker chain between domains I and II as it runs
through the cytoplasm'21. In other words, the /? subunit
helps powerfully to 'open' the calcium channel.
originally used by Fleckenstein (nifedipine, verapamil
and diltiazem) has its own particular binding site. Therefore, these sites have been called the N, V and D sites'31,
although their technical names are more complex'41.
Phosphorylation of a, subunit
The a, subunit also contains phosphorylation sites that
gain the phosphate moiety in response to /?-adrenergic
activity, when the intracellular cyclic AMP level rises
and activates protein kinase A. The latter enzyme
promotes the phospborylation, thereby enhancing the
probability of the channel being in the open state.
When /?-adrenergic stimulation 'opens' the
channel, any given degree of voltage depolarization will
allow more calcium ions to flow inwards. It is this
enhanced 'opening' of the calcium channels in the cells
of the sinus node, the atrioventricular node, and the
contractile myocardium that accounts at least in part for
the chronotropic, dromotropic, and inotropic effects of
catecholamine /?-adrenergic effects.
Class 1A binding site, the dihydropyridine or
N site
Nifedipine and all the many other dihydropyridines bind
in a highly specific way to this site. Some of these agents
have additional pharmacological properties such as
longer half-lives or enhanced vascular selectivity that
differ substantially from nifedipine. The dihydropyridine
site appears to be on the calcium channel pore, probably
on S6 extending into the channel pore on the S6 side'51.
The binding sites may be found on three of the four
transmembrane spanning domains, I, III, and IV'61. One
of the dihydropyridines, amlodipine, appears to have
somewhat different binding characteristics in that the
onset and offset of binding is slower.
Binding sites for calcium channel antagonists
The L-(long lasting) channels account for the later
phases of calcium channel opening at less negative
voltages. It is on this type of calcium channel that the
calcium channel antagonists act by altering the pattern
of channel opening from long duration to short duration
bursts. In technical terms, the calcium channel antagonists alter the pattern of L-channel opening towards
a preponderance of mode 1 (short duration) openings
and fewer mode 2 (long duration ) openings. Calcium
channel antagonists thereby reduce the rate at which
calcium ions enter through the L-channel. Thus these
agents do not actually block but rather partially reduce
calcium channel opening rates. The calcium channel
antagonists bind to the a, subunit S5-S6 pores, thereby
exerting calcium channel antagonism. Because none of
the major classes of calcium channel antagonists bind to
all of the S5-S6 structures of the a, subunit, it is clear
that total channel blockade cannot be achieved by these
drugs.
From the pharmacological point of view, each
of the three prototype calcium channel antagonists
Eur Heart J. Vol. 18. Suppl A 1997
Class IB binding site, the benzothiazepine or
D site
Agents such as diltiazem have a distinct binding site on
the a, subunit171- This s 'te is probably allosterically linked
to the dihydropyridine site (for review, see'31). In the
presence of diltiazem, binding of the dihydropyridines to
their specific site is promoted, so that these two types of
calcium channel antagonists could theoretically be used
together.
Class 1C binding site, the phenylalkylamine
or V site
Phenylalkylamines bind to the a, subunit, in the neighbourhood of the C-terminal chain and the adjacent S6
helix'8'. Verapamil, in contrast to diltiazem, inhibits
rather than promotes the binding of labelled dihydropyridine'91, which is further evidence for separate V and
D sites.
Pharmacology of calcium antagonists
Clinical application of binding sites
In general, agents binding to the dihydropyridine (1A)
site have characteristics rather different from those
that do not (Classes IB and C), so that the latter are
termed the non-dihydropyridines (Table 1). Among the
differences are (1) greater vascular selectivity of the
dihydropyridines and (2) absence of clinical effect of
the dihydropyridines on nodal tissue. Thus the dihydropyridines tend to be less negatively inotropic. Also
by vigorous peripheral vasodilation they tend reflexly
to increase the heart rate, whereas the nondihydropyridines tend to be more negatively intropic
and chronotropic. The clinical similarities between the
two non-dihydropyridines, verapamil and diltiazem,
could not be predicted from their very different
molecular structure and different binding sites.
The concept is that the actual aperture or pore of
the calcium channel consists of the four S5-S6 spans of
each of the four domains of the a, subunit. With this
subunit folded on itself the four S5-S6 spans make the
single pore of the calcium channel. Unless the calcium
channel antagonists bind to all of the S5-S6 spans
(which they do not), there will be some possibility for
residual calcium ion entry. Therefore, the use of these
drugs does not cause total arrest of myocardial contraction, or complete inhibition of the sinus node, or complete peripheral arteriolar relaxation. Rather, there is an
in-built safety factor.
Tissue selectivity of calcium
antagonists
Calcium channel in vascular smooth muscle
The a, subunit of vascular smooth muscle is very
similar to that of the heart1'01, although there are
critical molecular differences to explain why the dihydropyridines are vascular selective[H1. In this subunit,
there are, again, four transmembrane domains. The
calcium channel pore is also situated in the a, subunit
which again contains the binding sites for the calcium
channel antagonists. Electrophysiologically, the isolated smooth muscle a, subunit of the channel protein
carries calcium currents that are indistinguishable from
those of the cardiac channel. An important difference
is that the fast sodium channel appears to be absent
or quiescent in vascular smooth muscle. The source of
the depolarization required to open the voltageoperated channels (also called depolarization-operated
channels) is not yet fully understood, but includes the
following.
First, spontaneous slow depolarization occurs in
some blood vessels in regular bursts with a distant
resemblance to cardiac pacemaker activity. In larger
vessels, there may be multiple sites of such 'pacemaker'
activity'121. Second, receptor-operated channels may
exist. For example, norepinephrine released from termi-
A73
nal adrenergic neurones can increase vascular tone by
two mechanisms1'31. First, a,-adrenergic activity can
result in depolarization, smooth muscle contraction, and
increased vascular tone[14l It is open to question
whether these receptor-operated channels are in reality a
different population from the voltage-operated channels.
In some studies calcium channel antagonists are able to
block norepinephrine-mediated vasoconstriction or at
least the a2-receptor component thereoftl5). Thus a simplifying hypothesis is that both voltage depolarization
and receptor-operated signal systems ultimately open
the same L-type calcium channels in vascular smooth
muscle.
Secondly, pharmacomechanical coupling is the
process whereby pharmacologically active agents such as
norepinephrine can induce vascular contraction by a
process totally independent of depolarization. Hypothetically, stimulation of the a-receptor by norepinephrine calls into action an internal signalling system
(inositol trisphosphate, IP3) that liberates calcium from
the saj;coplasmic reticulum. The consequent rise in
cytosolic calcium triggers contraction.
Role of calcium channel antagonists in
modulating vascular contraction
Because the response to sympathetic stimulation by
norepinephrine varies so greatly from vessel to vessel,
and because calcium channel opening is not the only
mechanism of norepinephrine-induced vasoconstriction, it is difficult to predict which blood vessels will
be relaxed by calcium channel antagonists. It is
pragmatically known that the vessels most sensitive
are the arterioles that generate the systemic vascular
resistance.
The vasoconstrictive mechanisms that could
respond to calcium channel antagonists include (1) the
ill-defined entity of spontaneous slow depolarization,
and (2) the calcium channel linked components of
vasoconstriction mediated by norepinephrine, endothelin and angiotensin-II. Calcium channel antagonists
will, however, not influence the receptor signalling
path leading directly from the receptors to the calcium
channel via G-proteins, or the formation of IP 3 and
subsequent calcium release from the sarcoplasmic reticulum. Thus, in conditions of intense stimulation
by any one or more of the vasoconstrictors such
as norepinephrine, endothelin or angiotensin-II, the
calcium channel antagonists by themselves cannot
be expected to be as effective as the specific receptor blocker. The latter is able to inhibit both the
vasoconstrictor pathways involving G-proteins and the
calcium channel, and the one resulting from IP 3
formation. When, however, the exact receptor involved
in vasoconstriction is not known, then calcium channel
antagonists are likely to act at least against one of the
pathways of each of the major vasoconstrictors.
Eur Heart J, Vol. 18, Suppl A 1997
A74
L. H. Opie
Table 2 Relative effects of calcium antagonists in experimental preparations compared with therapeutic levels in
humans
Condition and level
Therapeutic level in humans (ng . ml ')
molecular weight (d)
molar value
protein binding
molar value, corrected for protein binding
Isolated coronary artery contraction
50% inhibition
Myocardial depression
40% depression of contractile force
Fast sodium current depression
Alpha-blockade, Ki (myocardium)
Slowing of heart rate by 20%
Relative effect on AV node vs contractile force
Inhibition of enzyme release from infarcting myocardium
Inhibition of ventricular automaticity
(ventricular fibrillation threshold in coronary ligated rat heart)
Ratio vascular vs myocardial effects
animal data1501
.
.
[16]
human data
Verapamil
Nifedipine
Diltiazem
80-400
455
2-8 x 1 0 " 7 M
about 90%
2-8 x 1 0 " 8 M
25-100
346
0-5-2 x 1 0 " 7 M
about 95%
0-3-1 x 10~ 8 M
50-300
415
1-7 x 1 0 " 7 M
about 85%
1-5 x 1O~8 M
10" 7 M
10~ 8 M
10~ 7 M
5x 1 0 " 6 M
IO" 4 M
5x 1 0 " 7 M
10" 6 M
6-5:1
2x 1 0 " 7 M
5 x 10"7M
no effect
4x 10"6M
10" 5 M
1:1
10" 7 M
5 x 10"4 M
7 x 10" 6 M
1-7 x 1 0 " 4 M
10"8 M
20:1
10" M
10~ 7 M
10" 6 M
5 x 10"6
1-4
1
14
10
7
1
M
A V = atrioventricular.
For references, see [51].
Calcium channels in pacemaker and in
atrioventricular nodal cells
Certain calcium channel antagonists, notably verapamil
and diltiazem, have prominent effects on nodal tissue
(Table 2). These drugs do not, however, totally stop
depolarization because they only block the L-type channels. In nodal tissues, the T-(transient) channels may be
responsible for the first phase of depolarization. These
T-channels do not interact with standard calcium channel antagonists which, therefore, cannot spontaneously
interfere with the initiation of the heart beat. In pacemaker cells, diastolic activation of the T-channels leads
to progressive depolarization until the threshold of
activation of the L-channels is reached, whereupon the
latter channels open to admit the bulk of calcium ions
concerned with the more rapid phase of pacemaker
depolarization. Such pacemaking depolarization is
not, however, only achieved by L-type calcium channel
activity, but also by other depolarizing currents, such as
If (a sodium carrying current), as well as decay of the
outward potassium current, Ik. Thus, ultimately, even
the non-dihydropyridine calcium channel antagonists,
such as verapamil and diltiazem, cannot totally arrest
the pacemaker cells of the sinus node. An exception to
this statement would be the situation in which there is
added nodal disease (as in the sick sinus syndrome) or
added nodal inhibition by other drugs, such as
/?-blockers or digoxin. In isolated hearts, high concentrations of nifedipine and other dihydropyridines also
inhibit nodal tissue. Yet, in practice, the dihydropyridines tend to increase rather than to decrease the heart
rate, because their more prominent peripheral vasoEur Heart J. Vol. 18, Suppl A 1997
dilation leads to reflex sympathetic stimulation of the
sinoatrial and atrioventricular nodes.
To explain the prominent inhibition of atrioventricular nodal tissue by verapamil and diltiazem in
paroxysmal supraventricular tachycardia, it is proposed
that these agents have a use-dependent (also called
frequency-dependent) effect. The hypothesis is that these
agents best enter the pores of the calcium channel in
atrioventricular nodal cells when the channel is in the
open state, thereby reaching the binding site. The more
frequently the calcium channels open, the better the
penetration to the binding sites. This postulate may
explain why, in clinical practice, only verapamil and
diltiazem but not dihydropyridines are able to inhibit
supraventricular tachycardias that have a re-entry
circuit through the atrioventricular node.
Calcium channels in skeletal muscle
Although the sarcolemma of skeletal muscle is rich in
calcium channels and has a high density of binding sites,
in practice calcium channel antagonists do not alter
skeletal muscle power. The explanation for this important point is complex, but includes the fact that skeletal
muscle cells are very large and do not rely on calcium
entry from the outside to achieve an increase of cytosolic
calcium sufficiently large to trigger contraction. Calcium
for this purpose is derived almost exclusively from the
sarcoplasmic reticulum by a process not involving the
sarcolemmal calcium channels. For practical purposes,
calcium channel antagonists have no effect on skeletal
muscle.
Pharmacology of calcium antagonists
Myocardial versus vascular selectivity
The ratio of the potency of calcium channel antagonists
on vascular smooth muscle compared with that in the
myocardium is an index of their vascular selectivity. It is
difficult to define such characteristics with exactness in
intact humans. Nonetheless, observations have been
made on isolated human papillary muscles and on
coronary arteries obtained at operation. According to
the analysis of Godfraind et a/.'161, diltiazem and verapamil are about equipotent in their negative inotropic
effects on isolated human papillary muscle and in their
vasodilatory effects on human coronary arteries, i.e.
neither is vascular selective. Some animal data suggest
that diltiazem is somewhat more vascular selective than
verapamil, and a common clinical impression (not supported by firm data) is that verapamil is the most
negatively inotropic of the calcium channel antagonists.
Nifedipine and amlodipine are approximately 10 times
more vascular than myocardial selective, and, at the
other end of the scale, nisoldipine is about 1000 times
more selective'161. It is sometimes incorrectly thought
that all second-generation dihydropyridines, including
amlodipine, are highly vascular selective.
One hypothesis is that vascular selectivity is a
desirable quality allowing, for example, coronary or
peripheral vasodilation in the absence of significant
myocardial depression. It should be recalled, however,
that among the most successful antianginal agents are
the /?-adrenergic blockers which have a prominent negative inotropic effect. A reasonable possibility is that the
calcium channel antagonists are most effective against
effort angina when there is at least some negative
inotropic effect, as in the case of the modestly vascular
selective dihydropyridines, such as nifedipine and
amlodipine1171, and especially in the case of the nonselective agents, such as verapamil and diltiazem. It does
not necessarily follow that the non-vascular selective
agents, such as verapamil and diltiazem, are by virtue of
their greater negative inotropic effects better antianginal
agents than nifedipine, amlodipine, and other dihydropyridines. The latter agents may compensate for their
relative lack of negative inotropic effects by more
powerful vasodilation, thus increasing coronary blood
flow and reducing the afterload. On the other hand,
greatly increased vascular selectivity may be counter
productive in the treatment of angina by more readily
evoking a reflex adrenergic discharge with tachycardia
and an increased oxygen demand.
Mechanism of antianginal and related
protective effects of calcium channel
antagonists
The mechanism of the antianginal effects is complex,
multifactorial and probably at least to some extent
different between the dihydropyridines and other types
of calcium channel antagonists.
A75
Coronary vasodilation and increased oxygen
supply
Because the calcium channel antagonists as a group are
major vasodilators, they should improve myocardial
oxygen delivery'181. Experimentally, coronary vasoconstriction induced by norepinephrine during exercise is
improved by calcium channel antagonists, which increase the blood flow particularly in the subendocardial
zones'191. Such vasoconstriction represents increased
coronary vascular tone and should be distinguished
from focal spasm. In addition, the lumen area at the site
of coronary stenosis decreases during exercise'20'. In
patients with coronary artery disease, regional myocardial blood flow falls during rapid atrial pacing. Calcium
channel antagonists restore the flow towards normal'211.
Likewise, exercise-induced vasoconstriction of the
stenotic site is relieved by the dihydropyridine agent,
nicardipine'221. Thus, there is reasonable evidence that
calcium channel antagonists could act by increasing
coronary blood flow, especially of coronary resistance
vessels and that calcium channel antagonists relieve
the additional decrease in stenosis size caused by exercise, as do the nitrates'201. Effects of calcium channel
antagonists and nitrates on exercise-induced coronary
vasoconstriction may be additive'221.
Decreased myocardial oxygen demand
Three of the major determinants of the myocardial
oxygen uptake are heart rate, blood pressure, and the
contractile state of the myocardium. Calcium channel
antagonists can influence each of these but variably.
First, peripheral vasodilation reduces the blood pressure
and this effect appears to be common to all calcium
channel antagonists. Second, some agents, especially
diltiazem and verapamil tend to reduce the heart rate.
In contrast, short-acting nifedipine tends reflexly to
increase the heart rate which is generally an unwanted
effect in the therapy of angina. Third, verapamil and
diltiazem exert a direct negative inotropic effect, thereby
reducing the oxygen demand and having a/?-blocker-like
beneficial action. The effects of acute and chronic
therapy by calcium channel antagonists may differ,
particularly with the dihydropyridines in which the
initial tachycardia appears to become less with time. In
addition, in the case of the dihydropyridines, the truly
long-acting preparations will not cause acute repetitive
vasodilation and should therefore avoid repetitive reactive tachycardia. Due to these differing effects on the
balance between the myocardial oxygen demand and
supply, it is not possible to generalize concerning the
antianginal mechanisms of the major types of calcium
channel antagonists. Nonetheless, it is clear that verapamil and diltiazem act to reduce myocardial oxygen
demand (heart rate and blood pressure decrease, contractility less), whereas the dihydropyridines have more
variable effects.
Eur Heart J, Vol. 18, Suppl A 1997
A76
L. H. Opie
Table 3 Pharmacological half-lives and duration of action of dihydropyridine calcium antagonists
Drug category
Short-acting
(dose three times daily)
Medium duration
(dose twice daily)
Ultralong-acting
(dose once daily)
Possible side-effects
Reflex adrenergic and
neurohormonal activation
Lessened but still significant
adrenergic activation
Subclinical adrenergic activationi
uncovered by ^-blockade
Drug example
Nifedipine
(capsules)
Nicardipine
(capsules)
Nicardipine
(SR)*
Isradipine*
Amlodipine
Felodipine-ER*
Nifedipine-CC*
Nifedipine-XL
Elimination tl/2
Duration of action
0-5 h' 5 2 '
4ha
20 min-6 h[53]
1 ha
4-5 h'"i
20 min-8 ha
, _ 4 hI52]
9ha
20min-12ha
1-5 hu
6-12 ha
2-5-5 ha
2-5-5 ha
8h a
'max
6ha
a
30-50 h
ll-16h a
7h a
4-17 hi52'
2-12 ha
24h+i"l
24 ha
24 ha
24 ha
*Not approved for angina in the U.S.A; tmax = time to maximal plasma level; tl/2=elimination half-life; SR = sustained-release capsules;
ER = extended release; CC=core-coat.
"Manufacturers' data in Physicians Desk Reference.
Counter-productive adrenergic activation
In response to acute hypotension, such as that induced
by rapid-release nifedipine capsules, baroreceptors are
activated to evoke reflex adrenergic stimulation that in
turn causes tachycardia and peripheral vasoconstriction
(Table 3). There is also /?-adrenergic-mediated release of
renin with ultimate formation of vasoconstrictory
angiotensin-II as well as increased levels of aldosterone.
Concomitant therapy by converting enzyme inhibition
buffers this counter-regulatory response'231, as also does
therapy by /?- blockade'241. Thus, it can be expected that
rapidly acting nifedipine is more likely to increase renin
activity and catecholamines levels than slower onset
verapamil'25'. By contrast, in the case of extended-release
nifedipine, plasma catecholamine levels may stay steady
although the mean levels of renin still tend to rise'26'.
There is, nonetheless, some masked reflex adrenergic
activation, as shown by the uncovering of the direct
negative inotropic effect when simultaneous ^-blockade
is added to extended-release nifedipine'24'.
One current hypothesis is that repetitive acute
vasodilation by shorter acting dihydropyridine-type calcium channel antagonists might have adverse effects
resulting from repeated reflex adrenergic stimulation.
Thus the antianginal effects could be blunted or angina
could be precipitated. It is also proposed that regression
of hypertensive left ventricular hypertrophy is impaired
by repetitive sympathetic activation as shown with
the use of twice daily felodipine'271. The combination
of adrenergic activation with a reduced coronary perfusion pressure, as the blood pressure falls, may explain
the proischaemic complications of the short-acting
dihydropyridines'28-291.
Therefore, on present evidence, it is difficult to
avoid the conclusion that ultralong-acting dihydropyridines, such as amlodipine or extended-release nifedipine or other similar long-acting preparations, such as
once-daily isradipine or felodipine, are preferable to
short-acting agents such as standard preparations of
nifedipine or nicardipine, provided that all other factors
Eur Heart J, Vol. 18. Suppl A 1997
are equal. One specific example of the importance of
duration of action is the ultra-vascular selective dihydropyridine nisoldipine. When given as a twice daily tablet,
the antianginal effect is modest or feeble'30'. In contrast,
when given as the ultralong-acting core-coat preparation, the antianginal effect becomes evident'3'1.
Pharmacological basis of side-effect
profile
The dihydropyridines
Acute vasodilatory side-effects are in part the result of
reflex adrenergic activation (tachycardia and flushing)
and in part the result of a rapid blood pressure fall
(dizziness). The rate of rise of blood dihydropyridine
levels determines the side-effects'32', so that the slower
rise in the blood level with nifedipine in the ultralongacting formation explains the lower incidence of these
side-effects with these preparations.
Headaches also result from vasodilation. Although there is a clinical impression that the ultralong-acting calcium channel antagonists with a slower
rise of blood dihydropyridine levels may cause less
headache, there appear to be no good studies using the
same patients as their own controls. There is some
indication that headaches may be less with amlodipine
with its very slow mode of onset than with other
dihydropyridines, but again the evidence is not firm.
Ankle oedema is caused by precapillary vasodilation and not by salt and water retention'33'. There is
no suggestion that this side-effect is lessened by the use
of long-acting preparations, nor related to the adrenergic activation of short-acting dihydropyridines. The
package insert for nifedipine-XL makes it clear that at
high doses (180 mg daily) 30% of patients can develop
oedema. Unexpectedly, one second-generation dihydropyridine, isradipine, has a lower incidence of ankle
oedema than does another, felodipine, both being given
twice daily'34'. The comparison is somewhat clouded
Pharmacology of calcium antagonists
because 35% of patients in the isradipine group and only
24% in the felodipine had an added ACE inhibitor
known to diminish ankle oedema'351.
Negative inotropic effects of dihydropyridines
are generally masked by peripheral vasodilation. In
the case of preexisting depression of left ventricular
function, cautious use of a highly vascular selective
dihydropyridine, such as nicardipine'361 or felodipine'171,
may be considered in the presence of standard antifailure measures.
Verapamil
Even with the standard formulation of verapamil,
vasodilatory side-effects including tachycardia, flushing,
headache, and oedema are more rare than with the
dihydropyridines. In contrast, there is a high rate of
constipation, up to 30%, presumably due to a specific
interaction of verapamil with the calcium channel in
smooth muscle of the gut. Although constipation has
been reported with diltiazem, it is much less common
than with verapamil. Also of interest is that a verapamillike compound, gallopamil, appears not to cause constipation. Especially in the presence of atrioventricular
nodal disease or concurrent administration of other
drugs inhibiting nodal tissue, such as /?-blockers, verapamil significantly depresses sinoatrial nodal function
and causes high degree atrioventricular nodal block.
Diltiazem
Although high doses of diltiazem can cause dose-related
side-effects including oedema, yet in lower doses the
incidence of side-effects is low, as in the case of verapamil. The conspicuous difference is the absence of
constipation with diltiazem. With the use of ultralongacting diltiazem (diltiazem CD or XR), the incidence of
side-effects is claimed by the manufacturers to be close
to that of placebo. Therefore, it seems as if antianginal
and antihypertensive effects can be obtained even
though vasodilatory side-effects are few. Nonetheless, in
practice, headaches and oedema do occur'371 especially
at high doses'381. The reason why oedema is relatively
less common with diltiazem and verapamil than with the
dihydropyridines is not clear, but may lie in a more
vigorous dilation of the precapillary sphincters by the
dihydropyridines. Like verapamil, diltiazem may precipitate severe SA nodal inhibition or high degree atrioventricular block when other circumstances predispose.
Long-term safety of calcium channel
antagonists
Post-infarct trials
Much has been made of the fact that calcium antagonists as a group do not confer postinfarct protection
A77
according to a meta-analysis'391. Yet the overall data
are skewed by inclusion of the SPRINT (Secondary
Prevention Reinfarction Israeli Nifedipine Trial) postinfarct trial which used rapidly acting nifedipine in a
fixed dose and which was entirely negative'401. The
meta-analysis did not separately exclude patients with
a history of prior heart failure, an important proviso
built into the protocol of the Danish Verapamil
Infarction Trial-II (DAVIT-II trial'401). Speculatively,
had the nifedipine study been carried out with an
ultralong-acting preparation, then reflex adrenergic
activation might have been avoided with possibly a
more favourable result. Of note is the finding that with
diltiazem too, there is postinfarct protection, provided
that patients with depressed left ventricular function
are retrospectively excluded, as in the MDPIT
study'411.
Recently, there have been further questions
raised about the long-term safety of calcium antagonists
as a result of the meta-analysis by Furberg, recently
published'421. Almost all the studies analysed related to
the use of nifedipine in its short-acting form. It is,
however, claimed by Opie and Messerli'431 that the
meta-analysis is statistically faulty. It is clear that the use
of high-dose nifedipine capsules for patients with unstable angina or acute myocardial infarction (in the
absence of concurrent ^-blockade) is no longer clinically
acceptable. In the meta-analysis of Yusuf et alP9\ it
appears to be incorrect to include in the same metaanalysis the relatively small number of postinfarct
patients studied with verapamil together with the much
larger number studied with short-acting nifedipine'391.
Furthermore, there may be important differences
between the dihydropyridine and non-dihydropyridine
calcium antagonists'441.
Rather, the DAVIT-II study'451 suggests an encouraging trend for the benefit of calcium antagonist
therapy in postinfarct patients. In Scandinavian
countries, verapamil is now registered for postinfarct
use.
Calcium channel antagonists versus
fi-blockers in angina of effort
A related safety issue, also not yet entirely settled, is
the safety of calcium antagonists vs /?-blockers in
angina pectoris. In the TIBET study, nifedipine tablets
were as safe as atenolol in the long-term treatment of
patients with chronic stable angina. Both showed the
same incidence of hard end-points which included
unstable angina, myocardial infarction, and cardiac
death1461. In the APSIS study, verapamil over 3-4 years
(median time) was as safe as metoprolol, as judged by
the death rate, the incidence of acute myocardial infarction, severe angina, or a cerebrovascular incident'471. Nonetheless, in general, more long-term safety
studies on more patients are required for calcium
antagonists in patients with ischaemic heart disease.
Eur Heart J, Vol. 18, Suppl A 1997
A 78
L. H. Opie
[10] Hullin R, Biel M, Flockerzi V, Hofmann F. Tissue-specific
expression of calcium channels. Trends Cardiovasc Med 1993;
3: 48-53.
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cated in heart failure. For example, in the study of
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73: 974-80.
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eds. The Handbook of Physiology. The Cardiovascular
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In the specific case of amlodipine, studies by
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