Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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. In general, calcium channel antagonists are contraindi[11] Welling A, Kwan E, Bosse V et al. Sub unit-dependent cated in heart failure. For example, in the study of modulation of recombinant L-type calcium channels. MolecuElkayam et a/.[48], chronic therapy with nifedipine lar basis for dihydropyridine tissue selectivity. Circ Res 1993; 73: 974-80. capsules had adverse effects when compared with isosorbide dinitrate in the treatment of chronic congestive [12] Johansson B, Somlyo AP. Electrophysiology and excitationcontraction coupling. In: Bohr DF, Somlyo AP, Sparks HV, heart failure. In the DAVIT-II study, the reduction of eds. The Handbook of Physiology. The Cardiovascular postinfarct death and reinfarction was obtained in System, Vascular Smooth Muscle, Volume 2. American patients who did not have overt clinical failure (defined Physiological Society, Washington DC, 1980: 301-24. as those requiring furosemide 160 mg or more daily). In [13] Levick JR. Vascular smooth muscle. In: An Introduction to Cardiovascular Physiology. London: Butterworths, 1991: the postinfarct diltiazem studies, diltiazem had no over171-5. all beneficial effect but did decrease cardiac events in patients without heart failure (defined by an ejection [14] Bolton TB. Mechanisms of action of transmitters and other substances on smooth muscle. Physiol Rev 1979; 59: 606-718. fraction below 40%), whereas diltiazem increased car- [15] Van Zwieten PA, van Meel CA, Timmermans BMWM. diac events in patients with a decreased ejection fraction. Functional interaction between calcium channel antagonists In the specific case of amlodipine, studies by and the vasoconstriction by the stimulation of postsynaptic alpha-adrenoceptors. Circ Res 1983; 5 (Suppl I): 77-80. Packer et al.[49] show that this agent, which does not have abrupt vasodilatory properties, was safe when [16] Godfraind T, Salomone S, Dessy C et al. Selectivity scale of calcium antagonists in the human cardiovascular system based added to existing antifailure therapy in patients with on in vitro studies. J Cardiovasc Pharmacol 1992; 20 (Suppl congestive heart failure (New York Heart Association 5): S34-S41. Categories III and IV) and in patients with ischaemic [17] Cheng C-P, Noda T, Nordlander M et al. Comparison of effects of dihydropyridine calcium antagonists on left vencardiomyopathy. In similar patients with 'dilated cardiotricular systolic and diastolic performance. J Pharmacol Exp myopathy' (non-ischaemic from the clinical point of Ther 1994; 268: 1232^1. view), amlodipine may have decreased morbidity and [18] Ardissino D, de Servi S, Salerno JA et al. Efficacy, duration mortality. Of interest is the concept that amlodipine and mechanism of action of nifedipine in stable exercisemay be acting to limit cytokine-induced damage in the induced angina pectoris. Eur Heart J 1983; 4: 873-81. case of dilated cardiomyopathy (Matsumori, personal [19] Thaulow E, Guth BD, Ross J Jr. Role of calcium channel blockers in experimental exercise-induced ischemia. Cardiocommunication). vasc Drugs Ther 1987; 1: 503-12. [20] Gage JE, Jess DM, Murakami T et al. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients References with classic angina pectoris: reversibility by nitroglycerin. Circulation 1986; 73: 865-76. [1] Yatani A, Bahinski A, Mikala G et al. Single amino acid [21] Lichtlen PR, Engel H-J, Rafflenbeul W. Calcium entry substitutions within the ion permeation pathway alter singleblockers, especially nifedipine, in angina of effort: Possible channel conductance of the human L-type cardiac Ca2+ mechanisms and clinical implications. In: Opie LH, eds. channel. Circ Res 1994; 75: 315-23. Calcium Antagonists and Cardiovascular Disease. New York: [2] Pragnell M, De Waard M, Mori Y et al. Calcium channel Raven Press, 1984: 221-36. beta-subunit binds to a conserved motif in the I—11 cytoplasm [22] Kaufmann P, Vassalli G, Utzinger U, Hess OM. Coronary mic linker of the alpha 1-subunit. Nature 1994; 368: 67-70. vasomotion during dynamic exercise: influence of intravenous [3] Opie LH, Buhler FR, Fleckenstein A et al. International and intracoronary nicardipine. J Am Coll Cardiol 1995; 26: Society and Federation of Cardiology: Working Group on 624-31. Classification of Calcium Antagonists for Cardiovascular [23] Bellet M, Sassano T, Guyenne P el al. Converting-enzyme Disease. Am J Cardiol 1987; 60: 630-2. inhibition buffers the counter-regulatory response to acute [4] Spedding M, Paoletti R. Classification of calcium channels administration of nicardipine. Br J Clin Pharmacol 1987; 24: and calcium antagonists: progress report. Cardiovasc Drugs 465-72. Ther 1992; 6: 35-9. [24] Redfield MM, Neumann A, Tajik AJ et al. Effect of long[5] Striessnig J, Murphy BJ, Catterall WA. Dihydropyridine acting oral felodipine and nifedipine on left ventricular conreceptor of L-type Ca2+ channels: identification of binding tractility in patients with systemic hypertension: differentiation domains for [3H]( + )-PN200-l 10 and [3H]azidopine within between reflex sympathetic and direct contractile responses the alpha 1-subunit. Proc Natl Acad Sci USA 1991; 88: (Abstr). J Am Coll Cardiol 1994; 23: 348A. 10769-73. [6] Kalasz H, Watanabe T, Yabana H et al. Identification of [25] Muiesan G, Agabiti-Rosei E, Romanelli G el al. Adrenergic activity and left ventricular function during treatment of 1,4-dihydropyridine binding domains within the primary essential hypertension with calcium antagonists. Am J Cardiol structure of the alpha 1-subunit of the skeletal muscle L-type 1986; 57: 44D-49D. calcium channel. FEBS J 1993; 331: 177-81. [7] Watanabe K, Kalasz H, Yabana H et al. Azidobutyryl [26] Phillips RA, Ardeljan M, Shimabukuro S et al. Normalization of left ventricular mass and associated changes in neurohorclentiazem, a new photoactivatable diltiazem analog, labels mones and atrial natriuretic peptide after 1 year of sustained benzothiazepine binding sites in the alpha 1-subunit of the nifedipine therapy for severe hypertension. J Am Coll Cardiol skeletal muscle calcium channel. FEBS J 1993; 334: 261-4. 1991; 17: 1595-1602. [8] Striessnig J, Glossmann H, Catterall WA. Identification of a phenylalkylamine binding region within the alpha 1-subunit of [27] Leenen FHH, Holliwell DL. Antihypertensive effect of felodipine associated with persistent sympathetic activation skeletal muscle Ca2+ channels. Proc Natl Acad Sci USA 1990; and minimal regression of left ventricular hypertrophy. Am J 87:9108-112. Cardiol 1992; 69: 639^*5. [9] Glossman H, Ferry DR, Goll A et al. Calcium channels: basic properties as revealed by radioligand binding studies. [28] Waters D. Proischemic complications of dihydropyridine calcium channel blockers. Circulation 1991; 84: 2598-2600. J Cardiovasc Pharmacol 1985: 7 (Suppl 6): S2O-S30. Calcium channel antagonists in heart failure Eur Heart J, Vol. 18, Suppl A 1997 Pharmacology of calcium antagonists [29] Baumgart D, Ehring T, Heusch G. A proischemic action of nisoldipine: relationship to a decrease in perfusion pressure and comparison to dipyridamole. Cardiovasc Res 1993; 27: 1254-9. [30] Thadani U, Zellner SR, Glasser S et al. Double-blind, doseresponse, placebo-controlled multicenter study of nisoldipine. A new second-generation calcium channel blocker in angina pectoris. Circulation 1991; 84: 2398-2408. [31] Glasser S, Ripa S, MacCarthy EP for the Nisoldipine CC Multicenter Study Group. Efficacy and safety of extended release nisoldipine as monotherapy for chronic stable angina pectoris (Abstr). J Am Coll Cardiol 1994; 23: 267A. [32] Kleinbloesem CH, van Brummelen P, Danhof M et al. Rate of increase in the plasma concentration of nifedipine as a major determinant of its hemodynamic effects in humans. Clin Pharmacol Ther 1987; 41: 26-30. [33] Gustafsson D. Microvascular mechanisms involved in calcium antagonist edema formation. J Cardiovasc Pharmacol 1987; 10(Suppl 1): S121-S131. [34] Hammond JJ, Cutler SA. A comparison of isradipine and felodipine in Australian patients with hypertension: focus on ankle oedema. Blood Pressure 1993; 2: 205-11. [35] Guazzi MD, De Cesare N, Galli C et al. Calcium-channel blockade with nifedipine and angiotensin converting enzyme inhibition with captopril in the therapy of patients with severe primary hypertension. Circulation 1984; 70: 279-84. [36] Visser CA, Koolen JJ, Van Wezel H et al. Hemodynamics of nicardipine in coronary artery disease. Am J Cardiol 1987; 59: 9J-12J. [37] Ruddy TD, Wright JM, Savard D et al. Comparison of the efficacy and safety of once daily vs twice daily formulations of diltiazem in the treatment of systemic hypertension. Cardiovasc Drug Ther 1995; 9: 799-807. [38] Opie LH. Calcium channel antagonists. Part IV. Side effects and contraindications. Drug interactions and combinations. Cardiovasc Drugs Ther 1988; 2: 177-89. [39] Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the secondary Danish Verapamil Infarction Trial (DAVIT II) and other recent studies. Am J Cardiol 1991; 67: 1295-1297. [40] Fischer Hansen J. Postinfarct prophylaxis by calcium antagonists. In: Opie LH, ed. Myocardial Protection by Calcium Antagonists. New York: Authors' Publishing House-Wiley Liss, 1994: 98-111. [41] MDPIT study —Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988; 319: 385-92. A79 [42] Furberg CD, Psaty BM, Meyer JV. Nifedipine dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326-31. [43] Opie LH, Messerli FH. Nifedipine and mortality: Grave defects in the dossier. Circulation 1995; 92: 1068-1073. [44] Opie LH, Frishman WH, Thadani U. Calcium channel antagonists (calcium entry blockers). In: Opie LH, ed. Drugs Tor the Heart, 4th edn. Philadelphia: W. B. Saunders, 1995: 50-82. [45] DAVIT-II study-Danish Study Group on Verapamil in Myocardial Infarction. Effect of verapamil on mortality and major events after acute myocardial infarction (The Danish Verapamil Infarction Trial II-DAVIT II). Am J Cardiol 1990; 66: 779-85. [46] Dargie HJ, Ford I, Fox KM, on behalf of the TIBET Study Group. Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. Eur Heart J 1996; 17: 104-12. [47] Rehnqvist N, Hjemdahl P, Billing E et al. Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur Heart J 1996; 17: 104-12. [48] Elkayam U, Amin J, Mehra A et al. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990; 82: 195461. [49] Packer M, Nicod P, Khandheria BR et al. Randomized multicenter, double-blind, placebo-controlled evaluation of amlodipine in patients with mild-to-moderate heart failure (Abstr). J Am Coll Cardiol 1991; 17: 274A. [50] Ljung B. Vascular selectivity of felodipine. Drugs 1985; 29 (Suppl 2): 46-58. [51] Opie LH. The Heart: Physiology, metabolism, pharmacology and therapy. London and Orlando: Grune and Stratton, 1984. [52] Frishman WH, Sonnenblick EH. Calcium channel blockers. In: Schlant RC, Alexander RW, eds. The Heart: Arteries and Veins, 8th edn. New York: McGraw-Hill Inc, 1994: 1291— 1308. [53] Opie LH. Calcium channel antagonists. Part VIII. Current developments. In: Clinical Use of Calcium Channel Antagonist Drugs, Second edition. Boston: Kluwer Academic Publishers, 1990: 286-307. Eur Heart J, Vol. 18, Suppl A 1997