Pharmacology of the Calcium Channel Blockers

Robert W. Piepho, PhD

Calcium ions play an essential role in regulating skeletal and smooth muscle contractility and in the performance of the normal and diseased heart.1,2 In classifying agents that inhibit the movement and binding of calcium, the World Health Organization has identified two types of calcium channel blocker that are used in clinical situations: those that are selective for L-type (long-lasting, large-current, or slow), voltage-dependent calcium channels, and those that are nonselective.3 The selective calcium channel blockers are by far the most often used in clinical practice.

The selective calcium channel blockers share a similar antihypertensive mechanism of action: they inhibit the influx of extracellular calcium through the L-type channel, resulting in relaxation of vascular smooth muscle and reduction in vascular resistance. They are therefore often assumed to be a homogeneous family of drugs, whereas they are in fact an extremely heterogeneous group of compounds with marked differences in chemical structure, binding sites, tissue selectivity, and, consequently, clinical activity and therapeutic indication.

Selective calcium channel blockers include three discrete chemical types: the phenylalkylamines (eg, verapamil), the benzothiazepines (eg, diltiazem), and the 1,4-dihydropyridines (eg, nifedipine) (Table 1).(Slide 1) The distinct identities of these types are suggested by their chemical structures, shown in Figure 1. Although chemically distinct, the net pharmacologic profiles of verapamil and diltiazem are much closer to one another than either is to the dihydropyridines. For this reason, some authors have recently recommended a new organization of the heterogeneous calcium channel blocker family, which would delineate verapamil and diltiazem as one subgroup and the dihydropyridines as another.4,5

Distinct Binding Sites
 Each of the three types of selective calcium channel blocker interacts with a specific receptor domain found on a large (about 165 kD) membrane-spanning protein that constitutes a substantial portion of the L-type, voltage-dependent calcium channel.(Slide 2) These receptor sites are all located on the alpha1 subunit of the channel. The 1,4-dihydropyridine receptor is the most accessible, located on the surface of the channel. This receptor has therefore been the most widely studied of the three, and such explorations have yielded a relatively large number of dihydropyridine derivatives designed to bind and inhibit (or, in selected cases, stimulate) that site.2,5

There is a complex allosteric relationship among the three calcium channel blocker receptor sites, and each site is also linked allosterically to the gating mechanism of the voltage-dependent calcium channel (Figure 2).2 Thus, drugs binding at the dihydropyridine site appear to increase the affinity of other drugs (eg, diltiazem) for the benzothiazepine site, and vice versa. On the other hand, the binding of verapamil at the phenylalkylamine site appears to reduce the affinities of both diltiazem and the dihydropyridine calcium channel blockers for binding at their respective sites.

Materson suggests that these relations may reflect or perhaps help to explain the fact that diltiazem and nifedipine in combination may be highly effective in selected monotherapy-resistant hypertensive patients, whereas verapamil and nifedipine together have yielded mixed results, and a verapamil-diltiazem combination would be frankly contraindicated.4 Materson further points out that, in this respect, nifedipine and diltiazem complement one another as might agents from fundamentally different drug classes, whereas verapamil and diltiazem, with similar and compounding pharmacologic effects, behave more typically like class-related agents.4

Selectivity of Action
 Binding sites for all three types of calcium channel blocker are found in a variety of tissues, including myocardium, smooth muscle, skeletal muscle, and glandular tissue. Yet this range of target tissues is not necessarily reflected in pharmacologic or therapeutic activity. For example, skeletal smooth muscle is relatively insensitive to calcium channel blockade, as indicated by the fact that calcium channel blocker therapy does not interfere with postural tone. Similarly, experiments involving several dihydropyridine compounds have demonstrated a marked dissociation between binding to cardiac muscle and the ability to elicit a cardiac response.6

Dissociation of binding characteristics and pharmacologic response can be explained by many factors.7,8 Selective calcium channel blockers do not typically elicit pharmacologic responses that are mediated through T- or N-, rather than L-type channels, or those that depend on intracellular calcium mobilization rather than extracellular influx. The activity of a calcium channel blocker in a particular tissue may also be affected by the location of the receptor site and the frequency of channel activity.5 The verapamil and diltiazem binding sites are located internally, deep within the channel. Access to the receptor is therefore enhanced when the channel is open. The rapidly firing tissues of the myocardium and the atrioventricular (AV) node provide ample opportunity for the binding of these agents, which are pharmacologically active in myocardial and cardiac conductive tissues. Dihydropyridine calcium channel blockers are more dependent on the voltage-regulated state of the channel for high-affinity binding. They interact preferentially with vascular smooth muscle, which exists more frequently in a depolarized state than cardiac tissue.5

Pharmacokinetics
 Calcium channel blockers are all well absorbed after oral administration, but there are distinctions in oral bioavailability that relate to differences in first-pass metabolism (Table 2).9,10(Slide 3) Diltiazem, nifedipine, and nicardipine do not undergo extensive first-pass metabolism, whereas verapamil and isradipine undergo fairly extensive first-pass metabolism that may result in wide variations in plasma levels and marked differences between the oral and intravenous doses required to produce a similar physiologic effect.

Protein binding percentages are higher with the dihydropyridines than with either diltiazem or verapamil.9 Furthermore, protein binding with nifedipine and possibly other members of the dihydropyridine class is concentration dependent, theoretically allowing for protein-binding interactions, although none of clinical significance have been reported. With verapamil and diltiazem, protein binding is independent of drug concentrations, making displacement interactions unlikely.9

Because the half-lives of the older calcium channel blockers are relatively short, ranging from approximately 3 to 5 hours, extended-release formulations of these agents (eg, Calan SR, Cardizem CD, Procardia XL) have been developed to permit once-daily administration. Isradipine, felodipine, and amlodipine have substantially longer elimination half-lives, but only amlodipine has a half-life consistent with once-daily administration.11,12

Metabolic Effects
 The calcium channel blockers have few deleterious metabolic effects of clinical consequence.8,13 Unlike the beta blockers and diuretics, calcium channel blockers do not adversely influence insulin secretion, blood glucose levels, or plasma lipoprotein levels, all of which are of potential importance in the frequently comorbid hypertensive population; nor do they affect potassium or magnesium balances.(Slide 4)

Verapamil and diltiazem do not usually affect plasma norepinephrine levels.13,14 Norepinephrine increases have been reported after a single dose of nifedipine, although these catecholamine spikes tend to normalize when nifedipine is administered over an extended period.15 Similarly, plasma renin levels are unaffected by verapamil or diltiazem, but oral nifedipine may produce a transient rise that is apparently related to the reflex sympathetic stimulation induced by the potent hypotensive action of this agent.13,16

Diltiazem, verapamil, and nifedipine all attenuate the pressor effect of norepinephrine, which may account for their effectiveness in the management of hypertensive emergencies. All three types of selective calcium channel blocker also cause transient blockade of the pressor effect of angiotensin II, which may likewise contribute to their acute blood pressure-lowering activity.13

Hemodynamic Differentiation
 The chief hemodynamic feature of the selective calcium channel blockers is vasodilatation of the coronary and peripheral arteries, resulting in a reduction in vascular resistance and an improvement in blood flow (Table 3).(Slide 5)(Slide 6) Nifedipine has a potent vasodilatory effect on both the coronary and peripheral vasculatures, as do the other dihydropyridine agents indicated for the treatment of hypertension. Diltiazem produces coronary vasodilatation similar to that seen with nifedipine but is a less potent peripheral vasodilator than either nifedipine or verapamil. The coronary vasodilatory activity of verapamil is weaker than that of diltiazem or nifedipine, and its effect on the peripheral vasculature is intermediate between the two.17

All calcium channel blockers can produce negative inotropy.18 Although the newer, more vasoselective dihydropyridines are reported to have attenuated cardiac effects, this has not been demonstrated clinically.19 Verapamil is the most potent negative inotrope among the calcium channel blockers, followed by nifedipine.20,21 However, the cardiodepressant effect of nifedipine is largely overcome by reflex sympathetic stimulation, which boosts myocardial contractility and heart rate, at least initially.

Schwinger and Erdmann studied the relationship between vasodilatation and negative inotropic activity in four calcium channel blockers: nifedipine, isradipine, verapamil, and diltiazem.21 The investigators determined the plasma concentration required to achieve vasodilatation with each drug and compared it with the concentration needed to produce a 25% decrease in inotropic activity in human papillary muscle. The ratio of these two concentrations, called the safety factor, provides an index of negative inotropic potential (the lower the safety factor, the greater the negative inotropic potential). The authors determined that the safety factor was approximately 1.1 for verapamil, 2.3 for nifedipine, 22 for diltiazem, and 70 for isradipine.

Verapamil and diltiazem (but not nifedipine or the other dihydropyridine agents) are active in cardiac conductive tissue and thereby modulate heart rate. Verapamil slows conduction through the atrioventricular (AV) node and prolongs the AV node functional recovery period, usually producing a modest decrease in heart rate (although small increases are occasionally reported). Diltiazem has a lesser influence on AV node conduction than verapamil, but has a direct effect on the sinus node that helps to bring about a small but consistent heart rate reduction.7 Intravenous forms of verapamil and diltiazem are indicated for heart rate control in patients with supraventricular tachycardia. In contrast, the dihydropyridine calcium channel blockers do not significantly impact cardiac conduction and have no direct rate-modulating effect. They may, however, indirectly produce an increase in heart rate via reflex activation of sympathetic drive. For this reason, nifedipine and other dihydropyridine agents are contraindicated in patients with tachy-arrhythmias.

Adverse Effects
 Corresponding to the differences in binding, tissue selectivity, and hemodynamics, the three types of selective calcium channel blocker have distinctive adverse effect profiles. (Table 4).(Slide 7)(Slide 8) The most common adverse event reported by patients treated with verapamil is constipation, which is believed to be related to the high affinity of this drug for gastrointestinal smooth muscle.22 The negative inotropic activity of verapamil may precipitate or exacerbate congestive heart failure symptoms in a small percentage of patients. The dampening effect of verapamil on AV node conduction may produce second- or third-degree heart block in some patients.23

Diltiazem, with similar but less potent cardiac effects than verapamil and less dramatic peripheral vasodilatation than nifedipine, is generally considered to be the best tolerated of the original calcium channel blockers.22-24 AV conduction disturbances and heart block may occur with diltiazem, although the risk is lower than in patients receiving verapamil. Vasodilator-type side effects, such as headache, flushing, palpitations, hypotension, and peripheral edema, are less common with diltiazem than with nifedipine.

As a class, the dihydropyridines are associated with the greatest incidence of adverse effects, largely related to their powerful vasodilatory action.25,26 Studies involving short-acting nifedipine demonstrate the highest frequency of such effects, which appear to be less common with the sustained-release nifedipine preparations. Newer dihydropyridines, such as isradipine, felodipine, and amlodipine, also tend to be better tolerated than the conventional formulation of nifedipine.25

Summary
 Important differences separate the three types of selective calcium channel blocker. They bind at different regions of the L-type calcium channel, are pharmacologically active in different cardiovascular tissues, and have different hemodynamic and clinical safety profiles. The dihydropyridines act preferentially on vascular smooth muscle; they have potent peripheral vasodilating effects and their therapeutic benefit is achieved primarily via a reduction in afterload.

Verapamil and diltiazem are less specific for peripheral vascular smooth muscle than the dihydropyridines, but are more active in the myocardium and cardiac conductive tissues. They are effective vasodilators but also decrease myocardial contractility and lower heart rate. Their therapeutic effect reflects a combination of afterload reduction and decreased oxygen consumption, resulting from negative inotropism and lowered heart rate.

On the basis of these differences, some authors have recently recommended a change in the nomenclature describing the calcium channel blocker family. Ferrari refers to the dihydropyridines as "vasodilating" calcium channel blockers and to verapamil and diltiazem as "modulating" calcium channel blockers (in recognition of their cardiac effects).5 Materson advocates that all three types be called "calcium antagonists," but that only verapamil and diltiazem continue to be designated as "calcium channel blockers." He further recommends that nifedipine and its analogues be consistently known as "dihydropyridines" or "DHPs."4 Such distinctions are not merely academic but are practical and evidence-based, and they may assist the clinician in making informed therapeutic choices.

References

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[Introduction | Cardiovascular Risk | Elderly Hypertensives
Information/Questions | Table of Contents ]

[Introduction | Cardiovascular Risk | Elderly Hypertensives | Information/Questions | Table of Contents ]