Diversity of calcium antagonists

CLINICALTHER4PEUTICSVVOL.19, SUPPL.A, 1997

Diversity of Calcium Antagonists Bertram Pitt, MD Department

of Medicine, University of Michigan Medical Centel; Ann Arbor, Michigan

ABSTRACT Calcium antagonists (CAs) are widely used in the management of hypertension and chronic stable angina pectoris. Currently available CAs fall into three distinct structural classes-the dihydropyridines, the benzothiazepines, and the phenylalkylamines. The diversity of these agents, even among drugs within a structural group, is apparent in their pharmacology, physiologic effects, and therapeutic uses. Traditional CAs produce their effects through blockade of the L-type calcium channel. Recently, a new CA has been developed. Mibefradil, the first member of a new class of CAs, is a tetralol derivative. It is characterized by its selective blockade of T-type calcium channels. It differs from existing CAs and may offer important therapeutic advantages. Key words: calcium antagonists, antihyperten0149-291&97/$3.50

sive agents, mibefradil, calcium channel blockers, pharmacology. INTRODUCTION Since their introduction more than 20 years ago, calcium antagonists (CAs) have been widely used for the treatment of patients with hypertension, angina, and certain cardiac arrhythmias. Despite their categorization as a single drug class, considerable heterogeneity exists among these agents, as reflected in their pharmacologic and therapeutic diversity. Currently available CAs fall into three distinct structural classes: the dihydropyridines, including nifedipine and amlodipine; the phenylalkylamines, such as verapamil; and the benzothiazepines, represented by diltiazem.’ Recently, mibefradil, a tetralol derivative, was developed and recognized as the prototype drug in a new class of CAs (figure). 3

CLINICALTHERAPEUTICS’

Nifedlpine (a diWropyrldW

Diltiazem (a knzothiazaphe) lW

Verapamil (a phenylalkylamlne) Pr’

ME

Mibefradil (a tetralol detivaUve)

.P(CI H

Figure. Structural formulas for nifedipine, diltiazem, and verapamil, representatives of the dihydropyridine, benzothiazepine, and phenylalkylamine classes of calcium antagonists, respectively, and mibefradil, a new calcium antagonist that is a tetralol derivative.

Consideration of the differences between these agents is particularly relevant in view of the recent concern about the safety of the short-acting CAs. Specifically, some reports2-4 suggested that patients with cardiovascular disease who are treated with short-acting CAs are at increased risk for mortality. Some of the proposed mechanisms for this increased risk include pro-ischemic and negative inotropic effects and neurohormonal activation.3 In contrast, some studies5-’ have suggested that long-acting CAs are not associated with an increased 4

risk of myocardial infarction or mortality, and even that they may be superior to diuretics and beta-blockers in treating patients with cardiovascular disease. Further long-term studies are required to reach a conclusion concerning the safety of these agents. The disparate reports in the literature reflect the diversity of pharmacologic and structural properties among the CAs and their subsequently distinct physiologic effects and clinical uses. This paper reviews the diversity of the CAs and discusses the therapeutic implications of their differences.

B. PITT

MECHANISM OF ACTION Fundamental to understanding the pharmacology of the CAs is an appreciation of their mechanism of action. The calcium ion (Ca2+) is an important signal transducer and participates in excitation and contraction of cardiac and vascular smooth muscle.8 In addition, Ca2+ currents are required for the pacemaker activity of sinoatrial (SA) node cells and for conduction through the atrioventricular (AV) node. The passage of Ca2+ from the extracellular space into the cell interior is made possible by the opening of ion-selective channels; this opening allows Ca2+ to diffuse passively across the plasma membrane. In cardiovascular tissues, there are two types of Ca2+ channels-the well-described L-type and the more recently discovered T-type Ca2+ channel. The L- and T-type Ca2+ channels differ in terms of gating threshold and expression within various cardiovascular tissues, which implies that these two types of channels have different physiologic roles.9 T-type Ca2+ channels are less prevalent than L-type Ca2+ channels and are found in low density in cardiac muscle and in relatively high density in spontaneously active vascular muscle.8,10*11T-type Ca2+ channels do not normally exist in ventricular myocytes except under certain conditions such as hypertrophic growth.12 However, the T-type Ca2+ channel is found in the SA node and generally is considered to have a role in automaticity.i3 In addition, T-type Ca2+ channels are found in other types of excitable cells such as neurosecretory cells, the cells of the adrenal cortex and medulla, and the juxtaglomerular cells of the kidney. 14*15Because T-type Ca2+ channels are overexpressed in rapidly proliferating cells and hypertro-

phied myocytes, they are thought to promote cell growth and proliferation.12J6 The basic mechanism of action of CAs is the blockade of Ca2+ entry into myocardial and vascular smooth muscle through the Ca2+ channels. Despite their different chemical structures, phenylalkylamine, benzothiazepine, and dihydropyridine CAs act by blocking L-type Ca2+ channels. Mibefradil selectively blocks T-type Ca2+ channels and, to a lesser degree, L-type Ca2+ channels.17*18 PHARMACOKINETIC DIFFERENCES CAs are all highly protein bound and are subject to differing degrees of first-pass metabolism. Their bioavailability varies widely from 20% to 90% (Table I).19 Because of their short half-lives, the firstgeneration CAs verapamil, diltiazem, and nifedipine need to be administered three or four times daily and are sometimes associated with fluctuations in blood pressure. Sustained-release drug delivery systems that use diffusion, bioerosion or biodegradation, and generation of osmotic pressure have been developed. Compared with standard formulations, these galenicaliy manipulated formulations decrease variations in drug concentrations in plasma and allow relatively short-acting drugs to be administered once or twice daily with comparable efficacy and sometimes fewer adverse reactions. l9 Newer compounds such as amlodipine and mibefradil have intrinsically long half-lives and allow once-daily dosing without galenic manipulation (Table I).2os2* The pharmacokinetics of some CAs are affected-by the age of the patient and the presence of concomitant disease. These issues can complicate the treatment of hy5

Higher plasma levels but similar t,,

ttR may be increased as result of decreased clearance

t,, may be increased as result of decreased clearance

GlTS = gastrointestinal therapeutic system; SR = sustained release; t,, = half-life. *Repeat dosing. Adapted from Frishman.‘g

Elderly

tlR may be prolonged

None

None

Slight delay in absorption

Bioavailability decreased

Effect of food

Renal

Renal

Renal

Renal

inactive metabolites

Excretion

No change

Hepatic (75%)

Esterase-catalyzed hydrolysis and cytochrome P-450-mediated oxidation to weak or inactive metabolites

Hepatic to weak or

Hepatic to weak or inactive metabolites

Hepatic with active metabolite.

Hepatic with active metabolite

Metabolism

90

60-65

85

40

20-35

(%)

17-25

35-50

2

Bioavailability

5-7 (SR)

4~5-12~

Mibefradil

GITS

Amlodipine

Nifedipine

Plasma t,, (h)

Diltiazem

of different calcium antagonists.

Verapamil

Table 1. Pharmacokinetics

B. PITT

pertension or angina for particular subgroups of patients. For example, the pharmacokinetics of verapamil and diltiazem are not significantly altered in patients with renal disease,22-24but the pharmacokinetic profiles of the dihydropyridine CAs vary in patients with renal disease. The plasma concentration-time curves of orally administered nifedipine do not differ between patients with renal disease and healthy volunteers.25~26The pharmacokinetics of other dihydropyridines such as nicardipine, isradipine, and nimodipine (but not amlodipine, nisoldipine, or nitrendipine) are affected by the presence of renal impairment. 27-32 In patients with chronic renal failure, steady-state plasma concentrations of mibefradil are independent of the degree of renal impairment, and dosage adjustment is not required. The clearance of CAs is reduced in elderly patients. This effect is thought to be responsible for the altered pharmacokinetic profiIes of verapamil, diltiazem, and nifedipine in these patients. Amlodipine, nitrendipine, isradipine, and felodipine also show a reduction in the metabolic clearance rate in this population.3”5 Dose adjustments of mibefradil, however, are not necessary in elderly patients.36

PHARMACOLOGIC ACTIONS Clear differences in tissue selectivity exist among the CAs. The dihydropyridines are more selective for vascular smooth muscle than for cardiac tissue. Verapamil and diltiazem have almost equipotent selectivity for the myocardium, the SA and AV conducting tissue, and the vasculature.37-39 Mibefradil is selective for the vasculature rather than the myocardium and for the coronary rather than peripheral vessels.40 Because of their different tissue selectivity, the CAs have different electrophysiologic, hemodynamic, and inotropic effects4rA7 These differences have important clinical implications. Although all CAs are arterial vasodilators, their pharmacologic effects on peripheral and coronary artery beds, SA and AV nodes, and myocardial contractility vary considerably (Table II). The dihydropyridines are the most potent systemic vasodilators and are associated with baroreceptor-mediated reflex sympathetic activation. At therapeutic doses, nifedipine does not affect AV node conduction. Verapamil and diltiazem have weaker peripheral vasodilating actions than the dihydropyridines and, therefore,

Table II. Cardiovascular effects of different calcium antagonists. Coronary

systemic

Vasodilation

Vasodilation

Myocardial Contractility

Heart Rate

Atrioventricular Node Conduction

Amlodipine

tt

IT

0 or k

0 or t

0

Nifedipine Verapamil

7-r tt

tT t

0 11 or 4,

0 41 or t

P

Diltiazem

7-l‘

t

4

4

1

Mibefradil

tt

tt

0

11

1

? = increase; 1 = decrease; 0 = no change.

7

CLINICALTHERAPEUTICS’

cause less reflex cardiac stimulation. Verapamil depresses SA node automaticity and slows AV node conduction. The effect of diltiazem on AV node conduction is between that of the dihydropyridines and verapamil.42*48Mibefradil slows SA node activity, resulting in a slight decrease in heart rate; has a small but significant effect on AV nodal conduction, causing an increase in the AV nodal refractory period, and slightly prolongs the PR inter~al.~~ In humans, mibefradil causes peripheral vasodilation but is not associated with reflex tachycardia.50 Verapamil, diltiazem, and the dihydropyridines also affect myocardial contractility differently. Verapamil and, to a lesser extent, diltiazem have a direct depressant effect on myocardial contractility. In vitro studies show that the dihydropyridines differ from the other classes in their negative inotropic properties.43 The dihydropyridines have intrinsic negative-inotropic properties, but their overall cardiovascular effect is dominated by their vasodilator properties, which result in reflex cardiac activation.48 Data from preclinical models and human trials suggest that mibefradil has a distinct pharmacologic profile. Like other CAs, mibefradil is a potent arterial vasodilator and lowers heart rate, but, unlike verapamil and diltiazem, it is not associated with negative inotropic effects.51-S4 EFFECTS ON RENAL FUNCTION CAs differ in their effects on proteinuria and microscopic albuminuria and in their ability to slow the rate of progression toward end-stage renal disease in both diabetic and nondiabetic patients with hypertension. Available data suggest that 8

dihydropyridines may not be as beneficial as benzothiazepines or phenylalkylamines.55”7 The effect of CAs on renal function is particularly important, as systemic hypertension often develops in patients with chronic renal failure; in addition, hypertension itself can adversely affect renal function.58-60 The effects of CAs on the progression of renal disease vary depending on the patient population and drug studied. Clinical trials with nifedipine,61 diltiazem,62 amlodipine,63 and verapamila have shown short-term favorable effects on renal function in patients with essential hypertension and mild renal insufficiency. Long-term studies with diltiazem in patients with essential hypertension and normal renal function have demonstrated no adverse effects of diltiazem on creatinine levels.65,66Similarly, in a 3-year, randomized, controlled trial comparing sustained-release nifedipine with captopril in hypertensive patients with chronic renal failure, the progression of renal insufficiency was similar in both groups.67 Most studies of the effects of CAs on proteinuria were done in patients with diabetic nephropathy, and the drugs showed variable effects on proteinuria and progression of renal insufficiency. One study68 comparing the effects of nifedipine, captopril, and placebo in patients with insulin-dependent diabetes mellitus showed a 40% increase in albumin excretion in the nifedipine group and a 40% decrease in the same in the captopril group. However, studies comparing diltiazem with lisinopril in patients with non-insulin-dependent diabetes mellitus and nicardipine with enalapril in patients with non-insulin-dependent diabetes mellitus and microalbuminuria have revealed

B.

PITT

similar decreases in protein excretion with the CAs compared with the angiotensinconverting enzyme (ACE) inhibitors.69~70 A prospective crossover trial assessing the effects of diltiazem and nifedipine on proteinuria in diabetic patients with renal insufficiency showed that diltiazem decreased urinary protein excretion (from 2.7 g/d at baseline to 1.3 g/d) and nifedipine increased urinary protein excretion (2.8 g/d at baseline to 5.3 g/d). Mibefradil is not as well studied in humans, but in stroke-prone spontaneously hypertensive rats, it dramatically decreased urinary protein excretion compared with control animals given placebo.71 Differences in CA effects on renal function may result from differences in the types of Ca2+ channels in the kidney, in patients or disease processes, and in the intrinsic properties of the CAs. One mechanism that may account, at least in part, for the various effects of the CAs on renal function is their varying effects on renal blood flow. Clinical studies61,‘ssp72*73 have demonstrated, for example, that diltiazem increases renal blood flow but verapamil and nifedipine do not. Moreover, data from human and animal studies61*74-76 suggest that intrarenal hemodynamics are affected differently by different CAs-diltiazem is associated with both afferent and efferent glomerular arteriolar dilation, whereas nifedipine appears to dilate afferent arterioles only. EFFECT ON ATHEROGENESIS Atherosclerosis of the coronary and peripheral arteries is a major cause of cardiovascular disease. CAs inhibit the atherosclerotic process, at least in animal models.77-79 They affect a number of processes, including the hydrolysis of cho-

lesterol esters, lipoprotein uptake, smoothmuscle migration, and cell proliferation and mitosis. In animal models, the dihydropyridine CAs nifedipine and nilvadipine were more effective than verapamil and diltiazem in inhibiting cell proliferation and chemoattractant-induced migration of rat aortic smooth-muscle cells.77 Studies with verapamil in the Watanabe rabbit, which lacks low-density lipoprotein (LDL) receptors, showed that there was no protection against the development of atherosclerosis, suggesting that the presence of LDL receptors might be important in mediating the effects of verapamil.78 In rats, mibefradil inhibited smooth-muscle cell growth in the neointima after vascular injury. Neither verapamil nor amlodipine had this effect, although each agent reduced blood pressure significantly.79 Clinical studies have suggested that CAs, particularly dihydropyridines, inhibit the development or retard the progression of atherosclerotic lesions.80*81 Data from the International Nifedipine Trial on Atherosclerosis demonstrated no significant effect of nifedipine on coronary lesion progression or regression; however, there were fewer new lesions in the nifedipine-treated group.*O In patients with new-onset angina, the effects of 2 years of treatment with nifedipine, propranolol, or isosorbide dinitrate on the development and progression of coronary lesions were compared using angiography. Thirty-one percent of nifedipine-treated patients had progression of lesions compared with 53% of those receiving propanolol and 47% of those receiving isosorbide dinitrate.*l However, this study had relatively few patients, and the findings will need to be confirmed. 9

CLINICAL THERAPEUTICS’

CLINICAL USES In addition to their differences in structure, pharmacology, and effects on physiologic and pathophysiologic disease processes, the diversity of the CAs is apparent in their clinical uses. All of the CAs are effective antihypertensive agents. With the dihydropyridines, the effect is mediated solely by their action on vascular smooth muscle. With verapamil and diltiazem, the reduction in blood pressure may be due to a combination of peripheral vasodilation and a reduction in cardiac contraction. Mibefradil lowers blood pressure through its effects on peripheral vasculature. Because they reduce ventricular afterload and myocardial wall tension, CAs are useful in the treatment of patients with angina. Verapamil and diltiazem may provide some advantage over the dihydropyridines in reducing oxygen consumption because they have negative inotropic effects and lower heart rate. Mibefradil is a potent dilator of the coronary vascular bed, is associated with a slight reduction in heart rate without negative inotropic effects,** and is effective and well tolerated in patients with chronic stable angina pectoris.ss CAs are used in the treatment and prophylaxis of cardiac arrhythmias. Verapamil and diltiazem prolong AV node conduction time and lengthen the refractory period. Intravenous verapamil terminates most episodes of paroxysmal supraventricular tachycardia and is a treatment of choice for terminating sustained SA nodal reentry, AV nodal reentry, and reciprocating tachycardia associated with WolffParkinson-White syndrome (after simple vagal maneuvers have failed).1,19*47 Diltiazem has not been approved for the treat10

ment of arrhythmias. Mibefradil produces an increase in corrected SA node recovery time and a small increase in the AV nodal refractory period.49 Certain CAs, such as nimodipine, are used mainly as cerebrovascular vasodilators.84 Other therapeutic uses for CAs include migraine, Raynaud’s phenomenon, and coronary vasospasm.19 ADVERSEEFFECT PROFILES AND LIMITATIONS The adverse-effect profiles of the CAs are as diverse as their therapeutic uses. Vasodilative adverse effects such as flushing, headache, and dizziness have been reported with each of the CAs but are more frequent with dihydropyridines because of their potent systemic vasodilation. These vasodilative side effects are particularly noticeable with the short-acting preparations and have for the most part been overcome by sustained-release formulations and by development of dihydropyridines with longer half-lives and gradual onsets of action, Pedal edema, likewise, is more commonly observed with the dihydropyridines. However, the incidence of pedal edema does not appear to diminish with sustained-release preparations or with dihydropyridines with longer half-lives.1*42 In a placebo-controlled trial,5Omibefradil has been shown to be well tolerated, with a low incidence of leg edema at the 50and lOO-mg doses versus placebo (O%, 3%, and 5%, respectively). Verapamil and diltiazem may produce symptomatic sinus bradycardia and AV block, especially when combined with beta-blockers or digoxin, or when used in patients with preexisting SA or AV node dysfunction. Therefore, high-grade AV block, sick sinus syndrome, and sinus

B. PI-IT

bradycardia are relative contraindications for these CAs. The dihydropyridines may be less desirable as antianginal agents because of the intense peripheral vasodilation associated with their use. This effect may provoke increased catecholamine levels and reflex tachycardia, which may increase myocardial oxygen demand and possibly provoke angina or arrhythmias. However, their use in combination with beta-blockers may offset these undesirable effects. Mibefradil has a gradual onset of action and does not provoke reflex tachycardia.83,85Moreover, both preclinical and clinical studiess4s6 have shown that mibefradil has no stimulatory effect on neurohormone levels in patients with preserved systolic function or in those with left ventricular ejection fractions <40%. The vasodilator effects of the CAs and their ability to reduce afterload would be expected to improve cardiac performance in patients with congestive heart failure (CHF). However, studies of nifedipine, diltiazem, and verapamil have produced disappointing results in patients with CHF. For example, in a subgroup of patients with pulmonary congestion in the longterm Multicenter Diltiazem Postinfarction Tria1,87treatment with diltiazem was associated with an increased incidence of cardiac events compared with placebo. The Danish Study Group on Verapamil in Myocardial Infarction88 found that in patients who had myocardial infarctions and showed evidence of CHF, the incidence of major cardiac events after treatment with verapamil was similar to that observed with placebo. Negative inotropy and neurohormonal activation may be implicated in the exacerbation of heart failure reported with nifedipine, diltiazem, and verapamil. The

cardiac depressant properties of verapamil and beta-blockers may be responsible for the deleterious effects of administering verapamil or diltiazem in combination with a beta-blocker to patients with CHF. Several lines of evidence suggest that the newer CAs, including mibefmdil, may be safer in patients with left ventricular dysfunction. The Prospective Randomized Amlodipine Survival Evaluation89 investigated the effects of adding amlodipine to usual therapies (digitalis, diuretic, or an ACE inhibitor) in patients with severe chronic heart failure. Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. In a subgroup of patients with nonischemic dilated cardiomyopathy, survival may have been prolonged. This result is currently being reassessed in a second trial. The Vasodilator Heart Failure Trial IIJW a prospective, randomized, doublemasked, placebo-controlled study, compared the effects of the extended-release (ER) formulation of felodipine (felodipine ER) with placebo when added to a stable regimen of enalapril and loop diuretics with and without digoxin in patients with New York Heart Association (NYHA) functional class II or III CHF. A preliminary analysis failed to show a clear-cut benefit for felodipine ER therapy. On the other hand, there was no increase in overall mortality or norepinephrine levels among patients treated with felodipine ER compared with placebo. In preclinical models, mibefradil has lesser negative inotropic effects than verapamil, diltiazem, and amlodipine.51*91In an ischemic rat model of CHF (Pfeffer model), mibefradil improved survival to the same extent as the ACE inhibitor cilazapril without impairing left ventricular function,92 an effect that had not been 11

CLINICAL THERAPEUTICS”

previously demonstrated in a CA. In a short-term study of 10 patients with CHF (NYHA functional class II or III), mibefradil caused no worsening of systolic function and preserved diastolic function. Definitive determination of the efficacy and safety of mibefradil in patients with U-IF awaits the completion of the Mortality Assessment in Congestive Heart Failure (MACH-l), a large, prospective, multicenter, double-masked, placebo-controlled morbidity and mortality trial. CONCLUSIONS four classes of CAs, there are meaningful differences in mechanisms of action at the Ca*+ channel level, in pharmacokinetic profiles, and in pharmacologic properties. These differences are reflected in the clinical uses, the relative contraindications, and the types of adverse effects associated with each class. Mibefradil, the first member of a new class of CAs that selectively block T-type Ca*+ channels, has several properties that differentiate it from previous CAs. These properties may extend its efficacy and safety compared with those of existing CAs. Among

the

Address correspondence to: Bertram Pitt, MD, 1500 East Medical Center Drive, 3910 Taubman Center, Ann Arbor, MI 48109-0366.

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