Calcium-channel blockers in systemic hypertension

William H. Frishman, M.D., is Director of Medicine at The Hospital of the Albert Einstein College of Medicine and Professor of Medicine at The Albert Einstein College of Medicine in the Bronx. He is a graduate of the Bron,x High School of Science and the (i-Year combined Liberal ArtsMedical Program at Boston University. He completed his postgraduate training in medicine and cardiology at the Einstein afiliated hospitals (Mont&ore Hospital, Hospital of the Albert Einstein College of Medicine, and the Bronx Municipal Hospital Center), and Cornell-New York Hospital. Dr. Frishman is a former Teaching Scholar of the American Heart Association and a previous recipient of the Preventive Cardiology Academic Award of the National Heart, Lung, and Blood Institute. He is a coprincipal investigator of the lo-year NZH-sponsored Bronx Longitudinal Aging Study, and a coinvestigator in the Systolic Hypertension in the Elderly Program (SHEP) and the Study of Left Ventricular Dysfunction (SOLID) cardiovascular trials. His major research interests are in cardiovascular pharmacology medical education, and cardiovascular disease prevention. He has authored and edited si,x books in the area of cardiovascular pharmacology, including a text titled Calcium Channel Antagonists in Cardiovascular Disease, which was published in 1984. He serves on the editorial board of many cardiovascular journals, and is the founding coeditor of the Journal of Clinical Hypertension.

Jack A. Stroh, M.D., is a Senior Associate Resident in the Evans Memorial Department of Medicine, University Hospital, at the Boston University Medical Center in Boston. He is a graduate of the Yeshiva University High School and College in New York City. He received his medical degree with Special Distinction for Research in Cardiology from the Albert Einstein College of Medicine in the Bronx He will commence his training in cardiology this July at New York University Medical Center. 290

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Steven M. Greenberg, M.D., is currently a cardiovascular research fellow at the Albert Einstein College of Medicine in the BronF, New York. He did his undergraduate training at the State University of New York at Stony Brook. He received his medical degree from the Albany Medical College, where he was elected to A.O.A. He completed an internship and internal medicine residency at the Bronx Municipal Hospital Center, a division of the Albert Einstein College of Medicine. During his residence training, he was a recipient of the Leo DavidoflAward for Clinical Teaching. He is a coinvestigator in several multicenter clinical trials involving experimental antihypertensive and antianginal agents. He is also a member of the Bronx Aging Study group. Dr. Greenberg has developed particular interests in cardiovascular pharmacology, cardiac gerontology, and states of unstable angina.

Theresa Suarez received a B.A. in history from Sarah Lawrence College and is currently in her final year at the Albert Einstein College of Medicine. She is working this year with Dr. Frishman in his cardiovascular research program. Her future plans include an internal medicine residency and possible specialization in cardiology. Her interests include cardiovascular research and infectious disease. Curr

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Adam tarp graduated with a BA. in chemistry, Summe cum Laude, from Yeshiva University. He is currently in his jinal year at the Albert Einstein College of Medicine and will be doing an internal medicine residency at Maimonides Medical Center. His interests include cardiovascular pharmacology and primary care medicine.

Harry B. Peled, M.D., is a senior resident in medicine at the Mont&ore Hospital in the Bronx He graduated from Rutgers College in 1989 with highest honors and from the Albert Einstein College of Medicine with distinction for research in cardiology. He completed an internship and junior residency in medicine at University Hospital in Boston. He will be starting his cardiology fellowship at Albert Einstein this July. Curr

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CALCIUM-CHANNEL BLOCKERS IN SYSTEMIC HYPERTENSION

Calcium-channel blockers are a distinct group of compounds that interfere with the normal transmembrane flux of extracellular calcium ions on which vascular tissue depends for contraction or impulse generati0n.l The drugs reduce the contractile activity of the heart, and promote coronary and systemic vasodilatation. These effects provide the clinical rationale for using calcium antagonists in the management of ischemic heart disease, hypertrophic cardiomycan opathy, and certain arrhythmias.2’3 Since systemic vasodilatation be expected to reduce elevated arterial blood pressure (BP), interest has been focused on the use of the calcium-channel blockers in the medical management of systemic hypertension.4-6 In this report, we will explore the scientific rationale for use of the calcium-channel blockers in the treatment of systemic arterial hypertension and review the clinical experiences with three prototype agents: nifedipine, verapamil, and diltiazem, and two new dihydropyridine drugs, nitrendipine, and nicardipine. CHEMICAL STRUCTURE OF ACTION STRUCTURE

OF THE

AND BASIC

CALCIUM-CHANNEL

MECHANISMS BLOCKERS

The structures of the three slow-channel blockers approved by the Food and Drug Administration are shown in Figure 1. Diltiazem is a benzothiazepine derivative that is structurally unrelated to other vasodilators.7 Nifedipine is a dihydropyridine derivative unrelated to the nitrates, and is lipophilic and inactivated by light.‘,’ Several other dihydropyridine derivatives (nivaldipine, nimodipine, amlodipine, nitrendipine, isradipine and nicardipine) are now under investigation. Verapamil has some structural similarity to papaverine. DIFFERENTIAL

EFFECTS

ON SLOW

CHANNELS

The predominant effect of calcium antagonist channels of the cell membrane. These calcium Curr

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drugs is on the slow channels permit en293

A

DILTIAZEM

NIFEDIPINE

VERAPAMIL

FIG 1. Chemical structures of diltiazem dine derivative), and verapamil

(a benzothiazepine (structurally similar

derivative), to papaverine).

nifedipine

(a dihydropyri-

try of some sodium in addition to calcium, and are activated much slower than the fast channels through which sodium predominantly enters to cause the initial rapid rise in the action potential. Nifedipine has been shown to depress the slow inward calcium ion current in a dose-dependent manner in isolated cat papillary muscles under voltage clamp conditions. At concentrations of lop7 to lOA'M, there is no effect on the fast inward Na+ current or on the rate of activation, inactivation, or recovery of the slow currents.~ll This action of nifedipine is similar to that of tetrodotoxin on the sodium channels, and thus, nifedipine is thought to “plug” the Ca”’ ion channels, leaving their control mechanisms unaffected, thus explaining its dose-dependent effect. However, further research is required to define the specific site of action of nifedipine. Verapamil is a racemic mixture of the (R) ( + )-enantiomer and the 6) ( - )-enantiomer, each having different electrophysiologic effects.8 The ( + )-isomer depresses the maximal rate of rise of the action potential and has additional effects on the plateau phase and overall shape of the action potential, The ( - j-isomer depresses the plateau phase of the action potential. Both of these effects are frequencydependent, being much more pronounced at a stimulus rate of 90 per minute than at 15 per minute.” These effects are markedly enhanced by increasing the length of exposure to the drug.13 In contrast to nifedipine, verapamil alters the kinetics of the slow channels, slowing both activation and more markedly, recovery from inactivation.14 The effects of verapamil are thus quite complex, since it is a mixture of ( + 1 and ( - )-enantiomers, each with different actions. The 234

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drug cannot be thought of as only a selective blocker of the slow inward current.15 Diltiazem lowers the plateau and shortens the duration of the action potential.16 High concentrations also reduce the maximal rate of rise of the action potential, suggesting that diltiazem is primarily an inhibitor of the slow channel at low concentrations (2.2 X 10W6M), but exerts fast (sodium) channel inhibitory effects at higher concentrations (2.2 X lo-‘Ml. It has been proposed that there are two sets of calcium channels: potential-operated channels and receptor-operated channels (Fig 21.l’ These two sets of channels are believed to exist because of their selective sensitivities to D-600 (a verapamil analog) and because they are additive. There is also thought to be a passive influx of calcium into smooth muscle (most noticeable in sodium-free medial, which is insensitive to D-600. Diltiazem does not seem to inhibit calcium extrusion from the cell, but does inhibit calcium entry through both types of calcium channe1s.l’ Each of these calcium-channel blockers differs in apparent mode of action, time course of action, concentration-effect relation, and pharmacologic action in different tissues.’ INTRACELLULAR

EFFECTS

In addition to their effects on the slow channels, calcium-channel antagonists can inhibit the availability of calcium ions for excitation

FIG 2. Calcium ion-dependent regulation of muscle tone in vascular smooth muscle. Calcium ions (Ca”) entry can occur in response to electrical stimulation through the voltagedependent channel, or receptor activation through the adrenergic receptor-mediated channel, or both. On entry in the cell, the cellular-free calcium ions bind to the calciumbinding protein, calmodulin. This calmodulin-calcium ion complex, in turn, activates myosin kinase. which causes the phosphorylation of myosin’s light chain. Phosphorylation then activates the binding of actin to myosin and leads to contraction. Intracellular calcium ion levels are reduced through energy-dependent membrane pumps, which promote calcium eff Iux. which involves sodium-calcium countertransport Cur

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29.5

coupling at intracellular sites. Such an interaction may take place at the inner surface of the sarcolemma, sarcoplasmic reticulum, mitochondria, or at any site where calcium may be made available as an excitation-response messenger.8J’g SCIENTIFIC BLOCKERS

RATIONALE FOR IN HYPERTENSION

CALCIUM-CHANNEL

BLOCKERS

USE

OF

CALCIUM-CHANNEL

AS VASODZLATORS

The beneficial effects of the calcium-channel blockers in hypertension relate to their ability to induce systemic arterial vasodilation.‘j In isolated human blood vessels, nifedipine has been demonstrated to produce concentration-dependent relaxation of noradrenaline or adrenaline-induced constriction of arteries and veins.” In clinical use, the partial venodilator effects of nifedipine are usually overcome by the sympathetic reflex activity elicited by the drug, leaving arterial dilatation as the predominant vascular effect.‘l The P-adrenergic stimulating responses elicited by nifedipine can also result in increases in heart rate and myocardial contractility.’ Investigations of verapamil have found the drug to produce little change in heart rate or cardiac output.2’22 Like nifedipine, the principal hypotensive action of verapamil is mediated by peripheral vasodilation with reduction in peripheral vascular resistance. However, with verapamil, the reflex sympathetic stimulation noted with nifedipine and other vasodilators, is blunted due to the drug’s concomitant negative inotropic and chronotropic effects. Administration of diltiazem also produces little change in heart rate or cardiac output .Z,23 The comparative hemodynamic and electrophysiologic effects of the various calcium blockers discussed in this report are shown in Table 1. THE

CONCEPT

OF HYZ’ERCALCEMZC

ZfYPERTENSZON

Hypertension frequently complicates the course of both acute and chronic hypercalcemic states. The rapid intravenous (IV) administration of calcium causes an elevation of BP that varies directly with the increments in serum calcium ion concentrationz4,” Among 600 patients enrolled in a hypertension clinic, the incidence of hypercalcemia was 0.6% .26 This is approximately 80 to 160 times that of the general population. The pathogenesis of this so called hypercalcemic hypertension is not totally understood, but several observations have been made: 1. Calcium has been demonstrated to have direct vasoconstrictive effects in peripheral arterioles.27 Such pressor effects have been shown in vessels of adult forearm and on renal arterioles.28 In vitro 296

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TABLE

1.

Pharmacologic

*Downward sinoatrial

Effects

of the Calcium-Channel

arrow indicates decrease; node; and AV, artdoventricular

upward arrow, node.

Blockers*

increase;

minus

sign,

no change;

V, variable;

SA,

studies have documented that high concentrations of calcium cause smooth-muscle contractionzg 2. In addition to direct vasoconstrictive effects, calcium has also been reported to promote catecholamine release from the adrenal medulla.30 The pressor effects of calcium have not been associated with renin-aldosterone activation.24 3. Renal insufficiency seems to sensitize patients to the effect of acute calcium elevation or infusion.25 An unanswered question is whether calcium plays a role in development of increased vascular tone seen in hypertension. If so, it is interesting to speculate whether the effectiveness of the calciumchannel blockers in the treatment of hypertension may be due, in part, to specific antihypertensive actions at the molecular level. THE

UNIFIED

HYPOTHESIS

Smooth-muscle fibers maintain a large electrochemical gradient across the cell membrane, favoring inward calcium movement.3*‘32 To maintain themselves in a noncontracted state, these fibers must extrude calcium ions, a process that requires ener@. It has been suggested that extracellular concentrations of sodium ions play a central role in this extrusion: sodium entering the cell moves down an electrochemical gradient, the energy thereby released being tapped to transport calcium ions out of the cell. Consequently, a change in the ratio of intracellular to extracellular sodium ions can alter the concentration of calcium ions within the cell. Investigators have linked sodium balance in vascular tissues and calcium ion flux with alterations in BP.31,32 They have surmised that changes in vascular tone reflect changes in the intracellular calcium ion concentration and that a rise in the mean intracellular calcium ion concentration may be the mechanism by which most hypertensive states are produced. It is proposed that the ingestion of a salt load leads to a decreased gradient and thereby less energy to transport calcium ions out of the cell. The higher intracellular calcium ion concentraCurr

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tion results in increased peripheral vascular resistance. Although this “unified hypothesis” remains to be proven, it suggests that calcium ion fluxes may play a pivotal role in the cellular basis of BP control. CALCIUM

CONCENTRATION

AND

KINETICS

IN HYPERTENSZON

The role of calcium in contractile processes led to speculation regarding a potential role in hypertension as well. Investigators have increased intracellular calcium concentrations in spontaneously hypertensive rats33’ 34 and in the adipose tissue of patients with essential hypertensjon.35 More recently, an increased free calcium concentration in the. platelets of patients with borderline and established hypertension has been demonstrated.36 A circulating plasma factor has been found to cause this increased platelet calcium uptake.“’ Investigators have also studied calcium kinetics in the belief that such kinetics may be deranged in the hypertensive state. Using the spontaneously hypertensive rat, Zsoter et al.37 reported diminished uptake and enhanced efflux of calcium ions in the aorta of experimental animals. They suggested that such findings were likely due to diminished calcium ion binding by the membrane and sarcoplasmic reticulum due to a “leak” of calcium ions when traveling from these structures to contractile proteins. These investigators also speculated that this leak may be a fundamental defect in hypertensive blood vessels, and thus, may be responsible for the high resting vascular tone. In contrast, other researchers studying the aortas of spontaneously hypertensive rats have reported decreased rates of calcium efflux from vascular smooth-muscle cells, a finding to explain the slower rates of relaxation of hypertensive vascular tissue.38’ 3s b GA. BELIER: Very small changes in cytoplasmic calcium appear to have a large effect on smooth muscle contractile force. It has not yet been definitively ascertained whether there is an increased sensitivity to calcium or an elevated intracellular concentration of calcium contributing to the etiology of hypertension. Regardless of the mechanism, if myogenic tone is raised in hypertension, the calcium-blocking drugs should be effective in lowering blood pressure.

ZXZ’ERZMENTAL HWERTENSZVE

USE OF CALCIUM-CHANNEL ANIMALS

BLOCKERS

IN

Nifedipine has been used as an antihypertensive agent in rats with spontaneous hypertension, renovascular hypertension, deoxycorticosterone-induced hypertension, and chronic neurogenic hypertensionPO Significant and dose-related decreases in BP were seen in all experimental models. Nifedipine has also been compared with hydralazine in the rat modelP’ Both drugs effectively reduced BP and 286

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increased heart rate, but the tachycardia was less pronounced with nifedipine than with hydralazine. In conscious hypertensive rats, the use of diltiazem has been demonstrated to produce dose-related decreases in BP and increases in heart rate4’; the latter was attenuated by pretreatment with propran0101, suggesting that reflex sympathetic stimulation was likely the cause of diltiazem-induced tachycardia. Long-term oral administration of diltiazem to these experimental animals prevented the expected progressive increase in BP typical of this breed. In another study,43 long-term administration of diltiazem to young, spontaneously hypertensive rats initially brought BP to normal levels, but later had only weak effects in reducing BP. This loss of BP control may have reflected an inadequate long-term dosing regimen. There are other possible antihypertensive effects of calcium-channel blockers (Table 2). Although the major effects of these drugs in hypertension are related to their vasodilator properties, there is evidence that some calcium-entry blockers have mild direct antiadmay be rerenergic effects.@ Some of their activity in hypertension lated to a mild myocardial depressant effect. Calcium-entry blockers have natriuretic effects that may be related to their dilator actions on the renal blood suppl~.~~,~~ Calcium-entry blockers appear to also interfere with the actions of angiotensin II on aldosterone release.& CLINICAL EXPERIENCE WITH IN SYSTEMIC HYPERTENSION

CALCIUM-CHANNEL

BLOCKERS

NIFEDIPINE Hemodynamic Eficts Detailed clinical investigations have documented the hemodynamic effects of nifedipine in hypertensive patients.47 In one study,48 a single lo-mg oral dose of nifedipine in 27 hypertensive patients reduced mean arterial pressure by 21% from control with an average fall of 28 mm Hg; the hemodynamic response to nifedipine was charTABLE Mechanisms Antagonists

2. by Which Calcium Reduce Blood Pressure

Definite Mechanism Peripheral vasodllation Possible Mechanisms Mild antiadrenergic activity Mild myocardial depressant effect Natriuretic effects withotit diuresis Interference with angiotensin II actions

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acterized by a reduction in peripheral vascular resistance and a concomitant rise in cardiac output. After the initial hemodynamic assessment, patients were treated with nifedipine for a three-week period; during this time, BP remained well controlled with 10 mg administered every six hours for three weeks. The hemodynamic effects of nifedipine recorded after three weeks of treatment were similar to the responses seen during acute administration of the drug. At the end of the trial, substitution of placebo for nifedipine caused a return of arterial BP to pretreatment levels within two days. Similar results have been reported by Murakami et a14’ From these studies, it would seem that the negligible effects of nifedipine on capacitance vessels do not cause venous pooling because, although cardiac output increases, right atrial pressure usually does not change. This is consistent with the findings of Mostbeck et al.?’ who performed whole-body scanning with a gamma camera after an IV injection of ‘-Tc labeled human albumin, and found that no shift in fluid volume from the limbs to the trunk occurred after nifedipine administration. Guazzi et al.48 attributed the tendency of some patients to have edema after nifedipine to arteriolar vasodilatation without venous vasodilatation, effects that could increase capillary pressure and result in edema. The effect of nifedipine treatment on cerebral blood flow was investigated using xenon 133 in ten hypertensive patients randomly allocated to receive either oral nifedipine or IV clonidine.50 Before treatment, global cerebral blood flow was normal in all ten patients tested. Oral nifedipine and IV clonidine were equally effective in lowering BP, but significantly different changes in cerebral blood flow were observed between the two groups. Cerebral blood flow increased in four of the five patients treated with nifedipine; the fifth patient showed a slight decrease. This observation is consistent with findings of animal experiments that have demonstrated a selective increase in cardiac and cerebral blood flow after vasodilatation with nifedipine.51 Intravenous administration of clonidine significantly reduced cerebral blood flow by as much as 28%. The decline noted with clonidine is probably related to a decrease in cardiac output and a slight concomitant increase in peripheral vascular resistance.52 Eflects on Plasma Renin Activity and Aidosterone There is no consensus as to the effect of nifedipine on plasma renin activity.5s57 In a study by Pedersen et al.F4 plasma renin activity increased after short-term administration of nifedipine, the most marked increases being seen in those patients with the highest plasma renin levels prior to treatment. However, long-term administration of nifedipine for six weeks produced no humoral changes. Thibonnier et al.55 were unable to demonstrate an alteration of plasma renin activity after short-term administration of nifedipine. 300

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Olivari et al.56 observed no change in plasma renin activity after three weeks of drug administration. Clearly, methodologic differences (e.g., the times at which plasma renin activity was measured, the assay system employed, the baseline renin level of the subjects, and the size of the study group) may explain much of the discrepant data, and further research should help resolve these questions. Insofar as calcium is important for the proper functioning of the feedback loop of the macula densa, which mediates renin release, calcium-channel blockers may inhibit this humoral loop and thereby inhibit renin release, despite significant vasodilation and reduction of systemic levels have arterial pressure.56J 58 No changes in plasma aldosterone been observed with nifedipine, and the drug appears to have an acute natriuretic effect. Monotherapy

Nifedipine monotherapy in the treatment of systemic hypertension has been actively investigated.478”gG1 Beer et al.” evaluated the short-term use of nifedipine in BP control in 43 patients with either moderate or severe hypertension. In the severely hypertensive patients, single 20-mg sublingual doses of nifedipine led to reductions in systolic and diastolic BPS of 44 and 31 mm Hg, respectively (Fig 3). In patients with moderate hypertension, 10 mg of nifedipine was administered sublingually; the average systolic BP reduction was 32 mm Hg, while diastolic BP fell 21 mm Hg. Forty-two of the 43 patients responded favorably to a single sublingual dose. While an insignificant rise in heart rate occurred with a lo-mg sublingual dose,

SySldiC 220 2otla0 160 t

* p < 0.001 -

FIG 3.

ll=26

140 thstok

! $;

1: in 120

.p
I

lOOr-

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0

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Effect of oral placebo and nifedipine (20 mg) on blood pressure (BP) and heart rate in patients with severe hypertension (diastolic BP > 110 mm Hg). Compared with placebo, a significant reduction in both systolic and diastolic BPS was seen 30 minutes after ~ nifedipine therapy. There was a significant Increase in heart rate (From Beer N, Gallegos I, Cohen A, et al: Efficacy of sublrngual nifedipine in the acute treatment of systemrc hypertension. Eur J C/in Pharmacol 1978; 14:375-381. Used by permission.)

301

the heart rate rose an average of 13 beats per minute in response to the ZO-mg dose. Guazzi et al4 treated 26 patients with severe essential hypertension with 10 mg of nifedipine, administered either orally or sublingually. Maximum mean arterial pressure reduction was 36 mm Hg 30 minutes after drug administration, and the extent of blood pressure reduction in individual patients was associated with pretreatment blood pressure levels. Mean arterial pressure was 19.5% less than control 120 minutes after nifedipine was given. Side effects occurred in several patients; headache, palpitations with dysrhythmia, and burning leg and facial paresthesias were most common Pedersen and Mikkelsen63 also demonstrated an immediate reduction in BP with nifedipine administered buccally. The onset of action was within ten minutes, peak effect was seen approximately 35 minutes after drug dosage, and average decrement in systolic and diastolic BP observed was 21 and 16 mm Hg, respectively. In ten patients given nifedipine (mean dose, 58 mm Hg) for six weeks, a mean reduction in systolic and diastolic BP of 24/21 mm Hg was seen. A significant increase in pulse rate was also seen. In a subsequent clinical trial,64 Pedersen et al. treated 18 patients with control diastolic BP values of 105 mm Hg or more for a one month period. The mean daily nifedipine dose was 44 mg and the mean reduction in systolic and diastolic BP was 21 and 17 mm Hg, respectively. Heart rate also significantly rose in patients in this trial. Moreover, there was a high occurrence of side effects. Five of the 18 patients dropped from the study due to flushing, palpitations, and headache. Recently, Ben-Ishay et al. demonstrated the safety and efficacy of oral nifedipine use in elderly patients.65 It appears that when nifedipine is administered with food, the peak plasma levels obtained with the drug are attenuated, and this may reduce vasodilatorinduced side effects. In a double-blind, crossover study, the antihypertensive effects of nifedipine (20 mg slow-release twice daily) were compared with verapamil (160 mg three times daily).66 Although more side effects were reported with nifedipine, both agents provided antihypertensive efficacy. In a similar study, nifedipine and diltiazem used as antihypertensive agents were both shown to be effective in lowering BP.67 Twenty-four hour ambulatory BP monitoring has confirmed that nifedipine was effective consistently in ambulatory patients, and that with long-term follow up of these patients, the drug action was sustained.68 Combination

Therapy

Because reflex activation of the sympathetic nervous system is responsible for many of the drug’s adverse effects, conventional nifed302

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ipine has been used together with antihypertensive drugs that attenuate adrenergic responses.6g Guazzi et ala administered nifedipine alone (10 mg orally, four times daily) and then together with methyldopa (250 mg orally four times daily) to 23 patients with essential hypertension whose diastolic BPS exceeded 120 mm Hg. Blood pressure decreased from 210/ 126 to 170/101 mm Hg with nifedipine alone, and to 145/87 mm Hg with nifedipine plus methyldopa. During combined therapy, systemic vascular resistance and heart rate were significantly reduced; cardiac index rose modestly, while pulmonary artery and pulmonary capillary wedge pressures declined. Of 23 patients who entered the study, 18 continued on combined treatment for one year. Although clinical data were not reported, titration of the doses of both drugs were able to maintain diastolic BPS between 84 and 100 mm Hg. Aoki et a17’ reported the first study, which evaluated nifedipine combined with propranolol. In 24 patients with an average BP of 176/109 mm Hg, propranolol potentiated the hypotensive effects of sublingual nifedipine, while suppressing nifedipine-induced tachycardia and abolishing nifedipine-related side effects. Similar findings were observed by other investigators who combined nifedipine with P-blockers.71-74 Nifedipine has been combined with many other types of antihypertensive drugs as we11.75’76 In a study of 14 patients with severe systemic hypertension, nifedipine was combined with the angiotensin-converting, enzyme-inhibitor captopril.76 The antihypertensive response of the combination was additive, so that BP was controlled. A “stepped care” approach was reported by Brennan and Blake,77 who added nifedipine to a regimen consisting of a P-blocker and a thiazide diuretic in 21 hypertensive patients. After a six month follow-up period, 18 patients had a significant reduction in BP, and 17 of the 21 patients achieved BPS less than 140/100 mm Hg. Side effects were mild and well tolerated. Dean and Kendal17’ used nifedipine (30-60 mgday) as an alternate third-line antihypertensive drug in 20 patients who had unsatisfactory BP control, despite a regimen of P-blockers, diuretics, and vasodilators (hydralazine or prazosin). Seventeen patients approached normotension when nifedipine was substituted for the vasodilator. These and other studies7s-8Z have shown nifedipine to be effective when other third-line agents, such as hydralazine, captopril, and minoxidil, have proven ineffective or produced troublesome side effects. Vasodilators are generally relegated to the “third line” of antihypertensive therapy to be given in combination with diuretics and sympatholytic agents. When used alone, vasodilators induce reflex stimulation of the sympathetic and renin-angiotensin system, resultCurr

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303

ing in frequent side effects and limited antihypertensive efficacy. Although not agreed on by all investigators, nifedipine monotherapy with the conventional short-acting preparation would seem to have a similar profile of adverse r&ktions, with a significant number of patients developing side effykts necessitating discontinuation of the mechanisms drug use.70’ 71 However, thg activation of homeostatic does seem to decline as tir‘ne passes?’ b GA. BELLER: Although the acute administration of nifedipine (e.g., sublingual) produces a reflex tachycardia and an increase in plasma norepinephrine and plasma renin activity, chronic oral use of this drug does not appear to result in a sustained increase in heart rate or elevated catecholamine levels.

Sustained-Release Nifedipine (The Push-Pull Osmotic Pump) Recently, a new sustained-release drug delivery system was developed by Alza Corporation that allows nifedipine to be used once daily in the treatment of hypertension and angina pectoris.83,84 This drug delivery system is a push-pull osmotic pump Wig 4) that allows nifedipine to be r&eased over 18 to 36 hours without severe plasma

FIG 4. A push-pull osmotic pump. The sdid drug, whether alone or in combination with an osmotic driving agent, is surrounded by a semipermeable membrane having one delivery orifice. During pump operation, water from the environment is continuously imbibed across the semipermeable membrane by osmosis to produce the fluid drug formulation. The membrane’s structure does not allow expansion of the tablet’s volume; thus, fluid must leave the interior of the tablet at the same rate that water enters by osmosis. As the system moves through the gastrointestinal tract, fluid (i.e., drug in solution) flows out through the single, small orifice at a constant rate until the last of the solid drug in the core has dissolved. Then the osmotic driving force begins to decline, and drug release-rate ceases to be constant, but declines predictably. The membrane is excreted intact. (From Eckenhoff B, Theeuwes Fr, Urquart J: Osmotically actuated dosage forms for rate controlled drug delivery. fharmaceut Tech 1981; 53544. Used by permission.) 304

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peaks of drug, usually associated with the adverse reactions of the studies would suggest that this new preparadrug? 84 Preliminary tion, Nifedipine GITS, is effective in reducing elevated BP.85 At the same time, adverse reactions from Nifedipine GITS, even at high doses, are minimal to absents5 Hypertensive

CrtXs

The effectiveness of nifedipine in the acute treatment of hypertensive crisis has been demonstrated in several studies and previously reviewed by us (Table 3).4,50,86-g8Takekoshi et algl administered nifedipine to ten patients in hypertensive crisis with a BP exceeding 200/120 mm Hg associated with either encephalopathy, intracranial hemorrhage, acute left ventricular failure, or acute aortic dissection. Three patients received nifedipine, 5 or 10 mg orally, four received 10 mg sublingually, and four received enemas containing 5 to 20 mg. The clinical response was highly satisfactory in all cases; the initial BP (227/126) fell by 65134 mm Hg. The time to maximum hypotensive effect varied with the route of drug administration: five to 15 minutes sublingually, 30 minutes by enema, 60 minutes orally. The authors suggested that patients with malignant hypertension may be particularly responsive to nifedipine. Similar beneficial results from nifedipine therapy were reported in six geriatric patients with hypertensive encephalopathy by Kuwajima et al.” Guazzi et al. evaluated the hemodynamic effects of nifedipine in three patients with hypertensive encephalopathy and acute left ventricular failure. After the initial IO-mg sublingual dose the pretreatment arterial BP (3071164 mm Hg) declined to 237/115 mm Hg after I5 minutes, to 248012 mm Hg after 60 minutes, and to 203/99 mm Hg after a second lo-mg dose. Pulmonary artery pressure decreased from 91/55 mm Hg initially to 68/35 and to 56/27 mm Hg after the first and second doses of nifedipine, respectively. As expected, systemic vascular resistance was greatly reduced, and cardiac index was substantially increased. Polese et al.= treated seven patients for hypertensive heart disease complicated by pulmonary edema with 10 mg of sublingual nifedipine. Patients had initial BP values of 2211 120 mm Hg and initial pulmonary artery and wedge pressure levels of 59/29 and 28 mm Hg, respectively. After treatment, the average BP was 177/94 mm Hg, the pulmonary artery pressure was 45/22 mm Hg, and the wedge pressure was 18 mm Hg. In another study,g7 patients with moderate-to-severe hypertension were categorized according to their response to nifedipine. Group A represented patients who responded promptly to lo-mg doses of nifedipine. With one dose, BP came down and leveled off at an appropriate level. Twenty patients in this group did not respond well to 10 mg and were placed in group B to be titrated up. Between the two groups, 61 of 63 patients responded to nifedipine. The mean Cur-r Pmbl

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TABLE

3.

Effects

of Nifediaine

in Patients NO.

STUDY

OF

PATIENTS

Conen” BefieF PolesesB Huysmar#

With SW M/F

Hvuertensive AVER. AGE

18

9/9

64

25 7 10

6/l

49

BASELINE OOSAGE

SF,

2OmgPO

313 9/7

69%

MagometshniggYZ Etielg3

17 30

1017 4/26

58 66

Lacche% DilmenYs

40 21

18122 S/13

11:3

58

70

MAX HG

DROP,

BP MM

150/86 152/89 177&l 172/107

10 mg PO/GT 10 Ing PO, SL, enema

2361109 23M24

15of73 158/90

20mgW 20 mg SL

260/160 235023

170/91

20 Ing SL 0.25-0.50

2321122 181/136

168/87 132/98

10 mg SL lo-2omg

10

MM

220/122 221/126 221/120 221/134

10-zomgw

Kuwajin# Takekoshi”

6

Crisis*

SL

178/100

Cuazzi4

3

mgkg SL 10 mg SL

307/164

248/112

Bwtorellig6

5

10 mg SL

298/162

2331117

10 mg SL

206/123 212/128 224/125

165/94 177/97

Haft et al.”

22

10 Ellmdt

et aI.%

30

21/43 10/20 16/14

59 56 65

20 mg SL 10-20 mg SL

HG

157/89

‘Two upward zumws indicate sign&ant increase in heart rate; two sideward armws, increase baseline prior to cessation of antihypertensive effect; one downward arrow, decrease in heart wte; accident.

time to endpoint was 30 minutess7; our experience was 30 minutes with one dose.62 Group B patients received two doses and, consequently, the mean time to effect increased. Despite concomitant therapy with diuretics and other treatments, no hypotension developed during nifedipine use. The study concluded that in patients receiving a single lo-mg dose of nifedipine, BP decreased within 30 minutes and the decrease was sustained as long as 100 minutes. We found the effect to be sustained for three hours in our study!’ In the group B patients, a single lo-mg dose produced some reduction, but not the reduction expected. At 22 minutes, an additional lo-mg dose was administered with prompt reduction of BP. Ellrodt and associatess8 assessed the effects of 10 and 20 mg of sublingual nifedipine in 30 patients with hypertensive emergencies. Before treatment, mean and diastolic BP was 224/125. Administration 306

Curr

Probl

Cardiol,

May

'87

45 hr X30 min >I hr

74-85

>I

83-98

hr

3 hr 2-4 hr

t

78+34t 88-96~

t

Flushing Flushing ND

t t

t

(2) (3)

Flushing (21 Palpitations 11) ND Dryness of mouth

fs ND

(3) Burning

sensation

(3) 15 5

30-45 20

>SO min >2 hr

7-T 95-83

5 ND

30-45 30

X50 min 6 hr

99-86 J 108-117 t

<15

60

ND

110-113 f)

ND

After 2nd lo-mg dose, BP decreased 176/89

ND

ND

ND

After

ND

t 4

t

ND Flushing Urticaria

(21 II)

ND Flushing

(41

2nd lo-mg

dose, BP decreased 178/89
12 hr


<2 hr
but not statistically significant; PO, ord; SL, sublingual; ma&

++ e-3

ND ND

ND

Flushing (11, CVA (1)

one upward mw, significant increase in he& rate, which returned to maximum; HR, heart rate; ND, not discussed; and CVA, cerebbrovascolar

of nifedipine initiated a smooth and predictable decline in BP values within five minutes, and produced a peak effect between 30 and 60 minutes. By 60 minutes, nifedipine had decreased the diastolic BP to less than 120 mm Hg in 97% of patients, to less than 110 mm Hg in 93%, and to less than 100 mm Hg in 67 percent. Twenty milligrams of nifedipine was more effective than 10 mg. These investigators concluded that nifedipine sublingual is a safe and effective means for treating patients with hypertensive emergencies. Nifedipine seems especially suited for use in the management of hypertensive crisis for the following reasons.86’ ” 1. Oral nifedipine is rapidly absorbed. However, the rapid absorption of nifedipine can produce a rapid fall in BP, which at times may be undesirable.100 The initial dose of nifedipine is 10 to 20 mg, repeated at 30 minutes if necessary. Sublingual administration of niCur-r

Probl

Cardiol,

May

‘87

307

fedipine may not enhance the rapidity of nifedipine absorption when compared with bite-swallow capsules or oral absorption. The drug may not be absorbed by the buccal mucosa.lol 2. A one- to three-hour duration of action allows the clinician time to institute therapy for stable long-term BP control. 3. Blood pressure is lowered in direct relation to the magnitude of the pretreatment BP. Profound hypotensive responses are rarely observed and invasive BP monitoring is not mandatory. 4. Cardiac output is maintained or increased. A fall in cardiac output may produce neurologic defects or oliguria. 5. Reflex cardiac stimulation precipitating angina or myocardial infarction is rarely seen because of the concomitant coronary vasodilator action of the drug. Conversely, nifedipine can be effective in the treatment of patients presenting with both angina and severe hypertension. 6. Left ventricular afterload is reduced, which is of critical importance in cases of hypertensive crisis complicated by congestive heart failure. Hypertensive

Patients

With

Angina

Pectoris

Nifedipine monotherapy has been used successfully in patients with hypertension and concomitant angina pectoris.‘02’ lo3 In a recent double-blind, crossover trial in ten patients with angina and hypertension,1”“ nifedipine was shown to be as effective as diltiazem in relieving anginal symptoms and reducing nitroglycerin consumption. The drugs also caused increases in exercise tolerance while reducing elevated systemic BP. VERAPAMZL Hemodynamic

Eficts

Like nifedipine, verapamil produces significant decreases in arterial BP because of its ability to reduce systemic vascular resistance. The expected activation of the sympathetic nervous system occurs, but its effects on the myocardium and sinus node are attenuated by verapamil’s direct negative inotropic and chronotropic effects. The observed hemodynamic effects of verapamil are the net result of these two opposing forces; hence, it is not surprising that the drug’s effects on cardiac output and heart rate have been reported to vary ~dely.2,32,8Z,103,105 After verapamil, heart rate may increase, not change, or decline; similarly, cardiac output may increase, remain the same, or decrease. Nevertheless, most investigators agree that verapamil must be used cautiously in patients with hem fa~ure.2'82.103,105.108 The vasodilating capacity of the drug cannot always be relied on to overcome its negative inotropic effects. 30s

Curr

Probl

Cardiol,

May

‘87

Monotherapy A number of studies have investigated the acute and long-term hypotensive effects of verapamil in hypertensive patients. The drug has recently been approved by the Food and Drug Administration for clinical use in hypertension. Muiesan et allo evaluated the antihypertensive effects of verapamil in 28 patients with mild-to-moderate hypertension. Verapamil (160 mg orally) reduced BP within one hour with a peak effect at 1.5 to 2.0 hours, and a duration of action of four hours; heart rate and plasma renin activity were unaltered. Twelve patients received verapamil 80 mg three times daily for eight days; the mean reduction in supine systolic and diastolic pressures was 23 and 15 mm Hg, respectively; heart rate, plasma renin activity, plasma and urinary catecholamines, plasma and urinary aldosterone, and plasma volumes were not signiilcantly affected. Six hypertensive patients who received 80 mg of verapamil three times daily for two to three months experienced a sustained reduction in mean supine BP without signihcant changes in heart rate, plasma renin activity, or plasma catecholamines. Gould et allo evaluated the BP response in 16 hypertensive patients analyzed by intraarterial ambulatory BP monitoring after at least six weeks of receiving 120 to 160 mg of verapamil three times daily. The drug produced a consistent reduction of BP over 24 hours. Mean daytime intraarterial ambulatory BP was reduced from 180/95 to 158/79 mm Hg; at night, mean intra-arterial supine BP fell from 173188 to 146/71 mm Hg. Verapamil also caused an overall reduction in BP with dynamic and isometric exercise. Side effects included mild constipation and epigastric pain. Twelve hospitalized patients with mild-to-moderate hypertension were given 80 to 160 mg of verapamil in three divided doses over ten days .los Supine systolic pressure decreased from 177 to 150 mm Hg, and diastolic pressure decreased from 111 to 96 mm Hg. The antihypertensive effect was dose-dependent and remained constant throughout the day. Heart rate did not change significantly. In addition, plasma renin activity did not increase, there was no retention of salt and water, and creatinine clearance was unchanged. Side effects consisted of facial flushing in two patients, and Mobitz 1 atrioventricular block in one patient. Frishman et al.l1’ found verapamil (320 mg/dayl giverrin two divided doses also to be safe and effective in the treatment of essential hypertension (Fig 5). A trough verapamil plasma level of more than 80 rig/ml was associated with a good hypotensive response (Fig 61, as patients with plasma levels above this value had mean sitting BP reductions from 1531104 to 137/88 mm Hg. Compared to Other Antihypertensive Agents Lewis et al.‘ll investigated the hypotensive effects of oral verapamil in 48 patients with hypertension; 26 had previously received no therCurr

Probl

Cardiol,

May

‘87

309

160 + P

PC01

140

E e‘

N=2l 120

! I

100

~3

PC01

f SO, OC

FIG 5. Effects of maximum dose of verapamil hydrochloride (mean, 154 f 19.2 mg) on sitting blood pressure and heart rate in all study patients with hypertension. Values are shown as mean 2 SEM. (From Frishman W, Charlap S, Kimmel B, et al: Twice-daily oral verapamil in essential hypertension. Arch Intern Med 1986; 146:561-565. Used by permission.)

apy and 22 had been treated with @blockers or methyldopa, the use of which was discontinued just prior to the trial; thiazide diuretic use was continued in the 25 patients who were receiving this medication. Verapamil was administered in doses of 80 to 240 mg three times daily. In the 26 patients on no previous BP therapy, verapamil reduced supine systolic pressure by an average of 37 mm Hg and reduced supine diastolic pressure by an average of 27 mm Hg. There was no significant change in heart rate. The patients who previously received P-blockers and methyldopa were better controlled when verapamil was substituted for the original drug. Side effects with verapamil included constipation and mild flushing. In another study, verapamil administered at a dose of 120 mg three times daily for three weeks and then 160 mg three times daily for three more weeks was compared with propranolol given at a dose of 60 mg three times daily for three weeks and then 80 mg three times daily for three more weeks.112 Verapamil decreased mean supine BP from 179/104 to 148/&t mm Hg without significantly affecting heart rate; this response was superior to propranolol in the 310

Cur-r Pmbl

Cardiol,

May

‘87

200

r

n=7 P-c.01

PC.ol

FIG 6. Effects of verapamil hydrochloride on sitting blood pressure in seven patients with trough verapamil levels greater than 80 ng/mL at visit 9. Closed circles represent individual patient measurements; open circles, mean values 5 SEM. (From Frishman WH, Charlap S, Kimmel 6, et al: Twice-daily oral verapamil in essential hypertension. Arch Intern Med 1986; 146561-565. Used by permission.)

doses used. In addition, verapamil was well tolerated with minimal side effects. after longIn a more recent study,‘13 the levels of BP reductions term therapy with propranolol (40-240 mg twice daily) and verapamil (120-240 mg twice daily) were compared. Both drugs were shown to produce a uniform and comparable reduction in BP throughout the whole day, together with a reduction in heart rate that was greater with propranolol. Both drugs were equally well tolerated without patient withdrawals being observed. The antihypertensive efficacy of verapamil was evaluated in 43 patients with essential hypertension in a study that also examined relationships between age and pretreatment renin level and BP, and comparing intraindividually the responses with those obtained using P-blockers (n = 29) and diuretic therapy (n = 18).lX4 Verapamil produced a decrease in mean BP that was directly related to the patient’s age and pretreatment BP, but inversely to pretreatment renin level. Although there was no difference ‘in overall pressure response between verapamil, P-blocker, and diuretic therapy, the pressure reCurr

Probl

Cardiol,

May

'87

311

sponses with diuretics and those obtained with verapamil were similar, whereas in the elderly and in patients with low renin activity, the responses with P-blockers correlated inversely with patient age and directly with pretreatment renin. The authors proposed the use of verapamil as the first choice for older patients and those patients with low plasma renin levels, and P-blockers as first-line therapy for younger patients and those with high plasma renin levels. In a large, double-blind trial, verapamil (80, 120, and 160 mg three times daily) was compared with propranolol (40, 80, and 120 mg three times daily). Verapamil lowered BP more effectively than propranolol in black and white patients.*15’“6 Verapamil was equally effective in black and white patients, whereas propranolol was most effective in white patients.115,116

Combination

Therapy

Lewis et al.‘17 evaluated 75 patients who were treated for hypertension with verapamil over one year. Most of these patients were also receiving a thiazide diuretic, and some were receiving methyldopa or clonidine. Fourteen patients stopped taking the drug because of side effects (most commonly constipation), poor control of BP, or noncompliance. The addition of verapamil caused a 25 to 30 mm Hg decline in diastolic BP. The decrease in BP after one month remained at the same level for 12 months. Another gro~p”~ studied 17 hypertensive patients in a randomized double-blind, crossover trial. The antihypertensive effects of verapamil (120 mg three times daily) and a thiazide diuretic were compared with pindolol (7.5 mg twice daily) and thiazide diuretic combination. Blood pressure fell about 14/1x mm Hg with both treatment regimens compared with placebo over six weeks. The verapamil-thiazide combination did not affect plasma renin concentration, body weight, or heart rate. Two patients complained of mild constipation with verapamil. Combination verapamil-P-blocker therapy for the treatment of hypertension has generally been avoided because of the common negative inotropic and chronotropic actions of these drugs, and the availability of other antihypertensive agents. Studies evaluating combination verapamil-propranolol therapy in patients with angina pectoris have found the two drugs used together to have potent hypotensive effects.*lg The concomitant use of these two drugs for BP control requires further clarification.

Sustained-Release

Verapamil

A new sustained-release formulation of verapamil Usoptin SR, Calan SR) for the treatment of hypertension is now available, having recently been approved for clinical use. Midtbo et al.“’ evaluated 24 patients with mild-to-moderate systemic hypertension using sustained-release verapamil (240-mg tablet). They compared sustained312

Cum

Probl

Cardiol,

May

‘87

release verapamil twice daily to instant-release verapamil (160 mg twice daily). Both formulations were effective in reducing BP. Zachariah et al.,“’ using ambulatory BP monitoring, demonstrated that sustained-release verapamil is effective once daily. The usual dose of sustained-release verapamil in clinical trials in which we participated was 240 mg given once daily by mouth in the morning with food. Initial doses of 120 mg (one-half tablet) may be necessary in patients who have an increased response to verapamil. Upward titration should be based on therapeutic efficacy, and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of sustained-release verapamil are usually evident during the first week of therapy. If an adequate antihypertensive response is not obtained with 240 mg, the dose can be increased to 240 mg in the morning, plus 120 mg (one-half tablet) in the evening, and then to 240 mg in the morning and evening. When switching from verapamil to sustained-release verapamil, the total daily dose in milligrams usually remains the same. Hypertensive

Crisis

Several hundred patients have been treated with IV verapamil for hypertensive emergencies, with most of the experience being reported &om Europe and Brazil.S6J12z-131We previously reviewed this subject (Table 4) .@ In one study of 47 patients with renovascular hypertension, 5 mg of verapamil administered IV caused a 20% to 25% fall in systolic and diastolic pressures within one minute.lz3 In another study, 20 children with severe hypertension accompanying renovascular disease or chronic renal failure were treated with verapamil.12s A single IV injection of 0.1 mg/kg was followed by a 25% decrease in systolic BP; maximal effects were observed at 30 minutes. A continuous IV infusion was used successfully for prolonged hypertensive crisis. Hypotension has been reported rarely (eight patients of approximately 4OOY; these few were in cases in which a large dose (up to 50 mg) of verapamil had been infused over several hours. The effect was quickly reversed by halting the infusion. Hypertensive

Patients

With

Angina

Pectoris

Frishman et al.13’ compared oral propranolol and verapamil in patients with hypertension and angina pectoris in a placebo-controlled, double-blind, randomized, crossover trial involving 12 patients with stable angina pectoris and mild-to-moderate hypertension. Doses of propranolol were titrated from 60 to 320 mgday and doses of verapamil were titrated from 240 to 480 mgday. No significant differences in effects on angina or on total exercise work were found between the two drugs (Fig 7). Similarly, both drugs reduced supine and standing systolic and diastolic BPS at rest (Fig 8) Curr

Pmbl

Cardiol,

May

‘87

313

TABLE

4.

Effects

of Verapatnil

in Patients

With

Severe

Hypertension

and

Hypertensive

Crisis*

Brittinger’2z Brittinger’23

Bender’” Gushi”’

Schart+Ze

*

Nicita-Maurn”’ dehlelo’”

Martins’z5

ND

ND

36114 14116

ND 24-60

1317

8 Ino-

5 mg IV BFBI .07-1.5 mg amin 5-10 mg N 25 mg in 15 min

yr

187/98

190/114 197/128

146/86 148/100

0.1 mg/kg BFBI .05-.73 mg/kg/hr

215/156

161/120

10 129

ND 71/58

ND 54

5 mg in 5 min 50 mg N in 3 hr

24W128 226/139

180/98 165/101

14

1014

58

25 mg N in 20

195030

148/98

239/139

179/108

226/141

161/100

min Antonio’30

24

ND

ND

CarvaIho’31

45

ND

ND

signiticant

increase

*Two

upward

arrows indicate prior to cessation contmction.

to baseline

mature

of antihypertensive

25 mg N in 60 min .37 mg/kg/hr up to 50 mglhr in heart

effect;

rate; two sideward armws, increase one downwzd arrow, decrease in

and with exercise. Verapamil, however, caused a significantly greater fall in standing diastolic pressure compared with propranolol. Five patients were maintained on verapamil480 mg/day for one year with sustained antianginal and antihypertensive effects.” DILTMZEM Hemodynamic Ejgects In 20 patients with coronary artery disease or hypertension who underwent cardiac catheterization, diltiazem (60 mg orally) decreased systolic BP, heart rate, cardiac index, and peripheral resistance.133 Similar results were seen in a long-term study using 90 mg of the drug orally three times daily.l= In an experimental study, the effects of diltiazem on renal blood flow and renal function were observed in anesthetized dogs.135 Infusion of diltiazem into the renal artery increased renal blood flow. In addition, diltiazem induced natriuresis, which persisted even when renal blood flow was held constant. The clinical implications of this finding in hypertensive patients is not known. 314

Cur-r

Probl

Cardio!,

May

‘87

2.

2min

>30 min

1

1 min

>30 min

1 min IO-15 min

ND 230 min

5

30 min

>60 min

5 2

5 min 2 hr

>30 min 3 hr

5

10 min

2 hr

CJ

lo heart block II), 2” heart block (11, 3' heart block II) None reported vertigo 131,WCS (21, nausea or vomiting (3) lo heart block (41, 2” heart block (11, 3’ heart block (2), drowsiness None reported 3’ heart block (21, vomiting W, hypotension (6) Nausea (2)

ND

ND

2 hr

u

None reported

2

2 hr

3 hr

1 5-10

100-80 1

but not statistically significant; one upward heart rate; BFBI, bolus followed by infusion;

I

t)

91-80 1

92-83 1

None reported

3” heart block hypotension

All with renal hypertension All with renal hypertension

All with renal hypertension

Hypotension contmlled by reducing infusion rate

121, 12)

armw, signiticant incwase in heart rate, which returned ND, not discussed; HR, heart rate; VF’C, ventricular pre-

Clinical Studies Maeda et al.136 studied the hypotensive effect of diltiazem in 28 patients with mild, moderate, and severe essential hypertension. Two treatment protocols were used; one group received only diltiazem, 180 mg/day orally, and a second group received diltiazem in combination with a thiazide diuretic. Diltiazem alone reduced systolic and diastolic pressures in 89% and 67% of the patients, respectively. This effect was seen after the first week of therapy and became more pronounced after six to eight weeks of treatment. The combination of diltiazem and diuretic was effective in all patients, including those who did not respond to diltiazem alone. The maximum hypotensive effect of diltiazem after a single oral dose occurred at three to four hours. There was a gradual rise in BP after this period, though the duration of effect was not determined. Only two patients experienced side effects; one had dizziness, and the other “gastric fullness.” In another study,13’ 14 patients with mild or moderate hypertension were treated with diltiazem, 180 to 360 mgday, in divided doses for two months. The drug reduced sitting systolic BP by a mean of 18 mm Hg and diastolic BP by 16 mm Hg. All but one Cur-r

Probl

Cardioi,

May

‘37

316

* p405 l *p~o.ol

Pllctlo MsflHt

Zl[lIs IKOWK

3 WEEKS llttl IzonK POSI-b

iizio WElKE

TEFik 3zom

PROPRANOLOL

ix-is Kam

3Ei Posl-h

VCRAPAMIL

FIG 7. Standing blood pressure and heart rate at rest before, during, and after treatment with increasing doses of oral propranolol and verapamil in hypertensive patients with angina. Comparisons are made with placebo baseline. Data are shown as mean f SEM. Rx indicates treatment. (From Frishman WH, Klein NA, Klein P, et al: A comparison of oral propranolol and verapamil in patients with hypertension and angina pectoris. A placebocontrolled double-blind randomized crossover trial. Am J Cardiol 1982; 50:1164-l 172. Used by permission.)

patient had at least a lo-mm Hg reduction in diastolic pressure, to a value less than 90 mm Hg. In these patients, the BP reduction with diltiazem was similar to that with diuretics. Although plasma norepinephrine was higher after two months, heart rate was unaffected. There was a low incidence of side effects. Sustained-Release Diltiazem The safety and efficacy of sustained-release diltiazem (X20-, MOmg tablets) used twice daily were compared with that of hydrochlorothiazide (25-, 50-mg tablets) administered twice daily in 207 patients with mild-to-moderate hypertension in a placebo run-in, randomized, double-blind, parallel titration study.13’ Patients whose conditions were not well controlled on either drug alone received combination therapy. Diltiazem and hydrochlorothiazide were both effective in lowering both systolic and diastolic BPS for up to six 316

Cum

Probl

Cardiol,

May

‘87

.* P
pc0.05

I lEEI

IWEEK PROPRANOLOL

VERAPAMIL

FIG 8. Treadmill exercise duration before, during, and after treatment with increasing doses of oral propranolol and verapamil in hypertensive patients with angina. Comparisons are made with placebo baseline. Values are shown as mean k SEM. (From Frishman WH, Klein NA, Klein P, et al: A comparison of oral propranolol and verapamil in patients with hypertension and angina pectoris: A placebo-controlled double-blind randomized crossover trial. Am J Cardiol 1982; 50: 1164-l 172. Used by permission.)

months (Fig 9), and were also equally effective in black patients and the elderly. The combination of diltiazem and hydrochlorothiazide was found to be more effective than either drug alone (Fig 10). Side effects were minimal with both drugs; however, more patients developed hypokalemia with hydrochlorothiazide and combination therapy than with diltiazem alone. Moser et al.13’ studied a subpopulation of 20 black patients with hypertension as part of the study described above, and demonstrated that sustained-release diltiazem was as effective as hydrochlorothiazide in controlling BP. Combination therapy was more effective than either drug alone. Preliminary results from a study where sustained-release diltiazem (60 to 120 to 180 mg) used twice daily was compared with propran0101 (80 to 160 to 240 mg) used twice daily demonstrated comparable BP lowering efficacy in patients with mild-to-moderate hypertension.lW In this placebo run-in, randomized, double-blind, titration, parallel design study, propranolol was shown to cause a greater heart rate reduction and more side effects than diltiazem. The addition of hydrochlorothiazide to either propranolol or diltiazem caused a greater BP lowering effect. than either drug alone. In a recent study evaluating exercise tolerance in hypertensive patients Cur-r

Probl

Cardiol,

May

‘87

317

100 YP
rp
-I-

T

DILT

Hclz

SBP (mmHg1

DBP (mmHg)

k

BASELINE +

‘p < 0.0005 “p

DILT

HCli!

OIL1

+WK14+

ncz?

+WK26---(

< 0.01 baseline

A comparison of sustained-release diltiazem to hydrochlorothiazide in patients (n = 207) with mild-to-moderate hypertension. Both diltiazem and hydrochlorothiazide reduced systolic and diastolic blood pressures (BP) compared with placebo baseline. In this study, high-dose hydrochlorothiazide was associated with a greater effect on systolic BP than diltiazem. The antihypertensive effects of both drugs were maintained for over 20 weeks. (From Frishman WH, Zawada ET, Smith LH, et al: Comparison of hydrochlorothiazide and sustained-release diltiazem for mild to moderate hypertension. Am J Cardiol 1987; 59:615-623. Used by permission.)

treated with propranolol or diltiazem, exercise time more than propranolol.21s Hypertensive

diltiazem

therapy

preserved

Crisis

There is very limited experience with diltiazem in the treatment of severe hypertension and hypertensive crisis.86 In one study141 involving only five patients, a moderate response was demonstrated. Intravenously administered diltiazem caused a reduction of BP from 318

Curr

Probl

Cardiol,

May

‘87

DIP (mmHg1

m

BASELINE

WK 41 (End Mono TheraW)

H

H

‘P * : 0005. “P < 0.05 VI baseline “‘NO s plflcont dittctences mm obsemd P b-2 -es rePreSent pooled COmPOriS~S

due to the order 01 odministrotlon b&ueen week 14 and 26.

L

FIG 10. A comparison of diltiazem, hydrochlorothiazide, and their combination in patients with mild to moderate hypertension. Both diltiazem and hydrochlorothiazide monotherapies are effective in lowering systolic and diastolic blood pressures compared with placebo baseline. The combination of diltiazem and hydrochlorothiazide was more effective than either drug alone. (From Frishman WH, Zawada ET, Smith LH, et al: Comparison of hydrochlorothiazide and sustained-release diltiazem for mild to moderate hypertension. Am d Cardiol 1987; 59:615-623. Used by permission.)

mm Hg to approximately 175/100 mm Hg in 35 to 40 minutes. In this study, patients were treated with an escalating dose schedule starting at 5 mg, increasing to 10 mg at 30 minutes, and further increasing to 20 mg at 40 minutes. The hypotensive effect persisted for approximately three hours. There were no major effects on heart rate and no side effects reported. .

225/125

Curr

Probl

Cardiol,

May

‘87

319

Hypertensive

Patients

With

Angina

Pectoris

As mentioned earlier, Frishman et all@’ compared oral nifedipine to diltiazem in patients with concomitant systemic hypertension and angina pectoris. In this placebo run-in, double-blind, randomized, crossover study, the two drugs were equally effective in reducing angina attacks, improving exercise tolerance, and reducing BP (Figs 11-14). Diltiazem, however, was associated with fewer adverse reactions. b GA. BELLER: From available data in the literature (Moser M: Am J Cardiol 1987; 59:115A-12lA), it appears that diltiazem and propranolol show equivalent efficacy as monotherapy for mild to moderately severe hypertension. The addition of hydrochlorothiazide to either propranolol or diltiazem produces a greater decrease ifi blood pressure. Drug-related adverse reactions increase when combination therapy is used. Side effects of diltiazem include edema, dizziness, fatigue, headache, and impotence. Side effects of propranolol include hyperlipidemia, fatigue, insomnia, depression, and impotence. Side effects of thiazide diuretics include hypokalemia, hyperlipidemia, glucose intolerance, and hyperuricemia. It is obvious that, although one can achieve better blood pressure control with combination therapy, the frequency of disturbing side effects may sigrrificantl~y increase.

NZTZWNDZPZNE

Nitrendipine is a new calcium-channel blocker belonging to the dihydropyridine subgroup (Fig 15). It is now under consideration by the Food and Drug Administration for approved use in patients with systemic hypertension. Nitrendipine differs from nifedipine in having a long plasma half-life, allowing once or twice daily dosage. Hemodynamic

and

Metabolic

Eficts

The effect of nitrendipine in relaxing vascular smooth muscle, when compared with nifedipine, differs in its duration of action. After administration of nitrendipine to strips of aorta, nitrendipine continued to inhibit contraction for eight hours even after repeated washings. Nifedipine, however, did not inhibit the aortic strip after one washing, and had a half-life of 3.3 hours compared with nitrendipine’s half-life of 5.4 hours.14’ Nitrendipine effectively reduces BP in both the supine and erect positions in patients with hypertension. Diastolic BP reduction is detected 60 minutes after administration of nitrendipine; systolic pressure is reduced in 30 minutes.‘43 The maximum effect occurs one to two hours after an oral dose. In two studies by Hansson et al. and Burris et al., BP reduction was maintained for six to eight hours :@, ‘4~ Blood pressure is maximally reduced for four hours and remains below pretreatment levels for six to eight hours. Hansson et al.14 observed a BP reduction for eight hours, although the author thought that the long rest period contributed to the depressed BP. 3za Curr Probl Cardiol, May ‘87

A N NIFEDIPINE

A N 0lLnAzEY

FIG il. Weekly frequency of angina pectoris attacks (A) and nitroglycerin consumption (N) during placebo, nifedipine, and diltiazem therapy in hypertensive patients with angina. Comparisons are made with placebo baseline. NTG indicates nitroglycerin. (From Frishman WH, Charlap S, Goldberger J, et al: Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension. Am J Cardiol 1985; 56:41 H46H. Used by permission)

The reduction of BP with nitrendipine in hypertensive patients is associated with a reflex tachycardia that varies in severity among individuals. Hansson et al.lM and Andren et al.‘& observed an increased incidence of tachycardia with a 40-mg dose of nitrendipine. The increased heart rate produced an increase in cardiac output since stroke volume was unchanged by nitrendipine. The tachycar-

FIG 12. Treadmill exercise duration during placebo, nifedipine, and diltiazem therapy in hypertensive patients with angina. Comparisons are made with placebo baseline. (From Frishman WH, Charlap S, Goldberger J, et al: Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension. Am J Cardiol 1985; 56:41 H-46H. Used by permission.)

Corr

Probl

Cardiol,

May

‘87

321

FIG 13. Standing blood pressure and heart rate at rest during placebo, nifedipine, and diltiazem therapy in hypertensive patients with angina. Comparisons are made with placebo baseline. (From Frishman WH, Charlap S, Goldberger J, et aI, Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension. Am J Cardiol 1985; 56:41 H46H. Used by permission.)

G 95r

6SL

T

_

,

I PLACEBO BASELINE

I

NIFEDIPINE

DILTIAZEM

dia diminished and cardiac output returned to baseline with longterm nitrendipine therapy. Nitrendipine has various renal and humoral effects in humans. In several studies, 10 to 40 mg of nitrendipine was given either once or twice-daily and plasma renin and aldosterone levels were measured in a group of patients. The response of renin to nitrendipine therapy varied. Studies report no change in renin levels or variation among the study subjects.147-14s In other studies, nitrendipine increased

FIG 14. Supine blood pressure and hearl rate at rest during placebo, nifedipine, and diltiazem therapy in hypertensive patients with angina. Comparisons are made with placebo baseline. (From Frishman WH, Charlap S, Goldberger J, et al: Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension. Am J Cardiol 1985; 56:41 H46H. Used by permission.)

L *2

la0 160

l

Pam

** PamP

SYStOllC

i-140

.

+20

l

g,,

Y h 2

a0 60

w,

zl

;g as

;

$a

65

60 55 1,

I

DiIlSlOlk

I

l

. .

i

f

i 1 PlACEBO BASELINE

Curr

l

NIPEOIPINE

Probl

Cardiol,

DlLTlAZEM

May

‘87

FIG 15. Molecular structure of the long-acting dihydropyridine nitrendipine.

H

renin activity.lsO’ x51 A consistent finding in all studies, however, is that plasma aldosterone levels do not rise during nitrendipine treatment. A similar observation has been made with nifedipine. There are also conflicting reports on the effect of nitrendipine in urinary Naf and K+ excretion. In one clinical trial,‘52 ten hypertensive patients were fed a 100 mEq Na+ and 80 mEq K+ diet and treated with 10 to 20 mg nitrendipine twice daily. After one week of treatment the patients had increased Na+ excretion during the second and third day and increased K+ excretion during the first week. These patients also had increased free water clearance after three weeks. However, in two other studies in which patients consumed a regular diet, urine Na+ and K+ were unchanged.15” *53 Renal blood flow and glomerular filtration rate were unchanged by nitrendinitrendipine produces no change in Pine.l=’ 152 Similar to nifedipine, serum electrolytes or creatinine. Monotherapy.-Nitrendipine monotherapy was shown to lower BP in several clinical trials. In a study by Esper et al.,l” 29 of 37 patients reached a diastolic BP of less than 90 mm Hg with 10 or 20 mg of nitrendipine administered once daily. The remaining eight patients required 20 to 30 mg twice daily to reach the goal diastolic BP. Andren et al.‘& found that a 20 mg once-daily dose of nitrendipine continued to reduce BP over a three-week period. In contrast, a 40mg dose did not cause a further reduction in BP and increased the incidence of side effects. Hansson et al. had similar observations with 20- and 40-mg doses.‘44 However, Ruddel et al.15’ observed, in a group of patients receiving 20 to 40 mg of nitrendipine once-daily, a continuous reduction in BP during the three-month treatment period. Toukantonis et al. also reported a significant reduction in BP with a once-daily regimen ranging from 10 to 60 mg.156 In this study, the authors also observed a decrease in the incidence of side effects with a 20-mg dose. Muller et al.157 reported a signiticant decrease in BP in a group of 16 hypertensive patients receiving 20 to 40 mg once daily. Two patients discontinued the drug use because of severe headache in one patient and ankle edema in the other patient. The Cur-r

Probl

Cardiol,

May

‘87

323

dosage these patients received was not reported. Ferrara et al.:58 using a 20-mg once-daily regimen, also found that a majority of patients had a reduction in BP when compared with placebo. In this study, four patients suffered from headache, ankle edema, and dryness of the mouth, which improved when the dose was reduced to 10 mg for one week. Ventura et aLla also used 20 mg/day of nitrendipine in a group of 12 patients; seven patients responded to the drug. The authors did not compare the characteristics between the responders and nonresponders because of the small number of patients . In a large study by Moser et al.‘5s of 135 patients, 5 to 20 mg of nitrendipine twice daily was administered and compared with a control group r&eiving placebo. In the nitrendipine group, 38% reached goal BP during the maintenance period compared with 12% in the placebo group. One patient was withdrawn from the study because m&aria developed with nitrendipine therapy. Fouad et a.l.15’ studied 12 patients (ten patients receiving 20 mg nitrendipine twice daily and two receiving 40 mg nitrendipine twice daily). In this group, nine patients achieved BP control, while the remaining three required a diuretic. In this study a hyperkinetic circulation was observed with nitrendipine in half of the patients, manifested by tachycardia and chest tightness. The authors concluded that the addition of a diuretic or B-blocker may be needed in some patients receiving nitrendipine therapy.15’ Burris et al?45 studied ten patients who received nitrendipine three times daily. Eighty percent of these patients had controlled BP. Half of the patients complained of headaches, and electrocardiographic changes were noted in one patient who received the maximum dose without BP control. These changes were not associated with elevated cardiac enzymes and resolved once the drug was withdrawn. In clinical trials with nitrendipine, several parameters were observed that correlated with the greatest reduction in mean arterial pressure. Patients with high pretreatment BPS had greater reductions in BP with nitrendipine when compared with patients with lower pretreatment BPS. Blood pressure reduction with nitrendipine also correlated directly with age, and the drug was very effective in patients older than 60 years. Nitrendipine was also effective in patients with low pretreatment renin levels.‘4”‘50J 151J160t 16’ One study reported a greater reduction in diastolic BP among patients less than 50 years old.161 Comparisons to Other Antihypertensive Drugs.-The antihypertensive efficacy of nitrendipine has been compared with other calcium-channel blockers, B-blockers, and vasodilators. Nitrendipine is as effective in reducing BP as diltiazem, verapamil, and nifedipine. The dihydropyridine subgroup of calcium blockers, however, do a24

Curr

t’robl

Cardiol,

May

‘87

have a greater propensity for inducing mild side effects than diltiazem or verapamil.162 Fritschka et al.*63 observed nitrendipine and propranolol to be equally efficacious in reducing BP. In contrast, the results of a multiclinic trial found nitrendipine better tolerated; two patients receiving nitrendipine discontinued the study because of adverse effects, while seven patients treated with pmpranolol withdrew from the study? Monotherapy with nitrendipine or atenolol was equally effective in a hypertensive population, although the majority of patients require combination therapy to achieve normotension?65 Franz et alT6’ compared acebutolol with nitrendipine and found both drugs reduced systolic and diastolic BPS during rest and exercise. Acebutolol, however, caused a greater depression of systolic BP during exercise than either nitrendipine or nifedipine. When compared with hydralazine, nitrendipine was shown to be a better tolerated drug.lz6 In this study, BP was reduced during the first week of nitrendipine treatment, without any pressure variability between dosing intervals. In contrast, hydralazine did not affect BP in the first week and pmduced varying BP levels between doses.16‘j’ Lopez et al.‘67 observed a greater reduction in systolic and diastolic BPS with 5 mg of nitrendipine as compared with 25 mg of hydralazine.

Combination Studies.-Nitrendipine is also effective in combination therapy. Schoenberger et al.16’ studied a regimen combining twice-daily nitrendipine with 25 mg of hydrochlomthiazide. This combination reduced BP by 16 mm Hg, and 25 of 39 patients reached their goal BP. Massie et al. also observed a decrease in BP in a group of patients receiving both nitrendipine 10 mg twice daily and hydmchlomthiazide 50 mg daily.16’ Bmuwer et al.‘7o demonstrated that the combination of captopril and nitrendipine decreased diastolic BP to less than 95 mm Hg in 15 of 16 patients with hypertension. This treatment combination was as effective as captopril and a diuretic. We are now conducting a double-blind study looking at the safety and efficacy of a nitrendipine-enalapril combination regimen compared with nitrendipine monotherapy. Nitrendipine is ideally suited for use with P-blockers that can inhibit the adrenergic activity induced by vasodilatation. DeDivitus et all= studied atenolol and nitrendipine in combination given once daily and observed a reduced BP and pulse rate in 14 of 20 patients. In another study, Nannan et al.17’ found nitrendipine and atenolol in combination effective in reducing BP and heart rate during rest and exercise. In a multicenter trial combining nitrendipine twice daily with pmpranolol, McMahon et al. reported 59% of the patients reached a diastolic BP of less than 95 mm Hg on this regimen.lw The Curr

Probl

Cardiol,

May

‘87

325

combination of nitrendipine and p-blockers might also be useful in hypertensive patients with coronary artery disease, but no study to confirm this is yet available. b G. A. BEL.LER: Since the 1,4 dihydropyridines are relatively selective for vascular smooth muscle, nitrendipine has excellent potential as an antihypertensive agent while avoiding cardiodepression. Its prolonged duration of action and its tendency to decrease, rather than increase, plasma renin activity, makes it an attractive alternative to other vasodilators for blood pressure lowering.

NKARDZPZNE

Nicardipine ‘(Fig 16) is another new dihydropyridine calcium blocker172 that is under consideration by the Food and Drug Administration for use in patients with hypertension and patients with angina pectoris. Hemdynamic [email protected] exerts its principal effect on the cardiovascular system through its peripheral vasodilator actions. The decrease in BP and systemic vascular resistance observed with the drug are not associated with signiticant changes in left or right ventricular filling press~res,~” 174indicating that nicardipine dilated arterioles with minimal effects on the venous bedTnJ 175 In addition, Hulthen has shown that nicardipine exerts a greater vasodilatory effect in patients with essential hypertension than those who are normotensive.lm Silke et al.‘77 compared the hemodynamic effects of IV nicardipine and verapamil in 30 patients with coronary artery disease. At rest, the administration of 7.5 mg of nicardipine and 16 mg of verapamil decreased arterial pressure, systemic vascular resistance, and afterload, and increased stroke volume. During exercise, neither drug was shown to improve stroke volume index. Nicardipine was shown to increase heart rate at rest, whereas verapamil lowered the rate while it increased pulmonary capillary wedge pressure. The investigators concluded that verapamil had more negative chronotropic and inotropic effects than nicardipine. In experimental studies, nicardipine, in a dose-dependent manner, has been shown to reduce coronary vascular resistance while

02

FIG 16. Molecular

structure

of nicardipine.

’

Ii j coot kc

P

W

COOCH2CH2

N(, CH2

N H

CH3

Con-

Probl

Cardiol,

May

‘87

increasing coronary blood flow, and seems to be equipotent to nifedis ten times more potent than ipine in this regat~.L~‘~~~* Nicardipine verapamil in reducing coronary vascular resistance,170 and compared with nifedipine has one tenth the myocardial depressant activity.‘82 Nicardipine has been shown to cause cerebral vasodilation accompanied by reductions in cerebral vascular resistance in animal models*‘83, 184 Nicardipine has also been shown to have favorable effects on renal perksion and may increase the glomerular filtration rate in 25% of hypertensive patients.*= Abe and associates showed that infusion of nicardipine could cause an increase in urinary sodium and potassium excretion and urine blood flo~.‘~ They attributed this action to an increase in glomerular filtration rate, a decrease in the fractional reabsorption of sodium in the proximal tubules, and alterations in intrarenal hemodynamics.1s6 Open Studies.-In a number of open studies using doses ranging from 20 to 40 mg administered three times daily, nicardipine has been shown to reduce both systolic and diastolic BPS in patients with mild-to-moderate hypertension by as much as 25% .18’-ls2 In addition, investigators have shown that in patients whose conditions are poorly controlled on other antihypertensive drugs, nicardipine can cause a further BP lowering effect to normalize BP.lso Studies have been done showing that nicardipine’s BP lowering effect is sustained for at least a year.‘87J1s1 The drug also appears to be effective in patients with renal failure either on dialysis or conservative treatment.ls3 Although nicardipine seems to be effective when used twice daily in doses of 20 to 40 mg, the majority of studies have demonstrated the drug to be most effective and best tolerated with a three-timesdaily dosing regimen. Our group recently demonstrated that 20,40, and 60 mg twice-daily dosing regimens were effective (Fig 171, but associated with increased adverse reactions, especially at higher doses.lH Placebo-controlled Trials.-A number of placebo-controlled trials have shown that nicardipine, 30 to 90 mg in three divided doses, produces significantly greater falls in BP than placebo in hypertensimilar results in 16 elsive patients.‘s5-‘s8 Forette et al.ls7 reported derly patients (mean age, 64.4 years, range, 57 to 95) who were treated with daily doses of nicardipine 30 to 90 mg daily, with minimal side effects observed. Taylor et al.“’ showed similar results in 30 of 31 patients who achieved BP control with doses of 30 mg or less of nicardipine three times daily. Combination Studies.-Kolloch et al?” assessed the efficacy of adding either placebo or nicardipine in increasing doses to patients receiving 100 mg/day of atenolol. They showed that nicardipine inCorr

Probl

Cardioi,

May

‘87

3a7

180 l .

N=l7

140

160 loo/ /

3 A

.*. 80 0

L

FIG 17. Effects of nicardipine 30 mg twice daily on supine blood pressure and heart rate at one hour and 12 hours after dosing in patients with hypertension. The drug is more effective at one hour than at 1,2 hours. Values are shown as mean -c SEM. Asterisk indicates P i .05 compared with placebo; double asterisks, P < .Oi compared with placebo; triple asterisks, P < ,001 compared with placebo; A = P < ,001 compared with one hour. (From Charlap S, Kimmel 6, Laifer L, et al: Twice daily nicardipine in the treatment of essential hypertension. J C/in Hyperfen 1986; 3:271-277. Used by permission.)

duced further significant reductions in supine and standing BPS, as opposed to placebo. They then concluded that the combined use of nicardipine and atenolol may be a rational combination for patients with essential hypertension and good cardiac function; atenolol may prevent the tachycardia produced by nicardipine, and nicardipine may block the peripheral vasoconstriction induced by p-blockers. Bellet et al.*% evaluated the combination of pindolol (15 mg/dab) and nicardipine (90 mg/day) in patients whose BP was not controlled on nicardipine alone. They noted an additive antihypertensive effect 328

Curr

Probl

Cardiol,

May

‘87

when the two drugs were combined, suggesting that these two drugs can be used simultaneously when one drug is not sufficient. More recently, Douglas-Jones and Coxhead”’ compared the efficacy of 30 mg of nicardipine three times daily combined with 50 mg of chlorthalidone to 100 mg of atenolol combined with chlorthalidone. They showed that both combination regimens were equally efficacious; however, the atenolol combination produced more side effects. The nicardipine-diuretic regimen caused an increase in heart rate, whereas the atenolol-diuretic regimen caused a decrease. Sustained-Release Formulation .-A sustained-release formulation of nicardipine has been tested, but because of poor bioavailability from this formulation, a search for a more effective sustained-release system is in progress.2o2 Hypertensive Patients With Angina.-Nicardipine is an effective drug for long-term treatment of angina pectoris, when used alone203-205 or in combination with other antianginal medications. A population of patients with angina with concomitant hypertension has not been systematically studied, but one would predict that the drug would be clinically beneficial. CLINICAL USE OF CALCIUM WITH HYPERTENSION

BLOCKERS

IN PATIENTS

CLINICAL PHARMA COLOGY The different calcium-channel blockers and their sustained-release preparations have different pharmacokinetic properties (Table 5J7 that influence the way they are used in clinical situations (Table 6).7 Since the calcium-channel blockers are mainly metabolized in the liver, their daily dosages have to be reduced in patients with concomitant hepatic diseases. Dosage adjustment may also have to be made in elderly patients who may be hypersensitive to the drugs or may metabolize them more slowly. In patients with renal disease, little dose modification is necessary. There are drug-drug interactions that are of clinical importance when using calcium-channel blockers in hypertension. Long-term verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this may result in digitalis intoxication.z06 Maintenance digoxin doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over or underdigitalization. This digoxin interaction has not been shown with diltiazem or nifedipine. There are limited data available with other anti-

Cut-r

Probl

Cardiol,

May

‘87

329

*Extraction

ratio.

GITS

SR

Verapamil

Nifedipine Nifedipine Nicardipine Nitrendipine

Cardizem

SR

Diltiazem Diltiazem Verapamil

Cardene Baypress

C&II Isoptin Calan SR, Isoptin SR Prucardia

SYNONYMS

>90 >90 >90 >80

>90

>90 >90 >90

ABSORFIlON, 96

of the Calcium-Channel

AGENT

TABLE 5. Pharmacokinetics and

6.5 85 =30 -20

10-20

35-60 35-60 10-20

90 >95 >90 98

90

78 78 90

PROTEIN BINDING, w

Sustained-Release

BIOAVAILABlW,‘,* w

Blockers

1.32 1.32 0.66 5.4

4.3

5.0 5.0 4.3

VOLUME OF DlSTRIBUTION WKGI

Preparations

=2 N 27

-5

6f4IV 8+6 PO

4.1-5.6

T’h p (HR)

500-600 500-600 14 88

13-c7

15 15 13’7

CLEARANCE (MLJMINIKG)

‘SL

indicates

Nitrendipine

Nicardipine

Nifedipine

2040 mg (once or twice daily)

30-180 mg 424 hr lo-20 mg TID

Blockers

DOSAGE

240480 mg ql2 or 24 hr 1040 mg q6-8 hr

SO-120 mg q6-12 hr

30-90 mg q6-8 hr

sublingual.

GITS

SR

Verapamil

Nifedipine

SR

Diltiazem Verapamil

Clinical

ORAL

6.

Use of Calcium-Channel

TABLE

@kg

1.15 mg/ hour

5-15

150 I%% (10-20 mgl

75-150 pgkg (10-20 mg)

Iv

<20

<20

<30

<30

<30

min

min

min

min

min

ORAL

<5 min

(3 min

sl)

min

Iv

<5 min


ONSET OF ACTION*

28-50

25-100

>50

>50

50-200

rig/ml

rig/ml

rig/ml

rig/ml

rig/ml

THER‘4PEuTK PIASMA CONCENTRATION

Major hepatic pass effect

first-

A hydruxycarboxylic acid and a lactone with no known activity major hepatic first-pass effect

N-dealkylation N-demethylation major hepatic first-pass effect

Deacetylation N-demethylation 0-demethylation major hepatic first-pass effect

SITE OF METABOLISM

No

No

No

No

Yes

Yes

No No

ACTIVE METABOLWES

35% fecal, 60% renal 70% renal, 8% fecal

15% fecal 70% renal 2040% fecal 50-80% renal

15% fecal 70% renal

ExcaEnON

arrhythmic agents, although it is recommended that disopyramide be avoided when verapamil is used because of additive negative inotropic actions, and that quinidine be used with extreme caution with verapamil because of additive hypotensive effects.44 Diltiazem and verapamil need to be used with some caution in elderly patients receiving P-blockers in whom heart block or heart failure may be precipitated. Cimetidine may reduce verapamil clearance and increase its elimination half-life.207 Verapamil may result in a lowering of serum lithium levels in patients receiving long-term oral lithium therapy. Verapamil may also increase carbamazepine concentrations during combined therapy. Rifampin therapy may markedly reduce oral verapamil bioavailability. Possible interaction between diltiazem and the benzodiazepam agents have also been reported.207 Finally, there are clinical data that suggest that verapamil may potentiate the activity of neuromuscular blocking agents and inhalation anesthetics. Treatment of calcium blocker overdosage should be supportive.2o8 Intravenous calcium should first be administered. Beta-adrenergic stimulation with IV isoproterenol or dobutamine may increase calcium ion flux across the slow channel and have been used successfully clinically after calcium administration. Significantly hypotensive reactions or high-degree AV block should be treated with vasopressor agents or cardiac pacing, respectively.z08 ADVERSE

REACTIONS

The calcium-channel blockers are remarkably safe agents in the treatment of hypertension.7”03 They are contraindicated in patients with serious cardiac conduction abnormalities, and relatively contraindicated in patients with overt congestive heart failure.“1o3 The less severe side effects are more numerous and their relative frequencies are listed in Table 7.7 There seem to be no effects of calcium-channel blockers in therapeutic doses on glucoregulatory hormones,2” parathormone,210’211 plasma lipids and lipoptoteins,2121213 uric acid, and serum electrolytes. SPECZAL

CLINICAL

SZTUATZONS

As mentioned earlier, many calcium-channel blockers have been shown to be effective in patients who are young and old, and black and white. The drugs have also been used in patients with hypertension and concomitant angina pectoris, asthma, hyperlipidemia, diabetes, anhythmia, peripheral vascular disease, and renal dysfunction (Table 81.214,2’S 332

Cut-r Probl

Cardiol,

May

‘87

Nicardipine Nitrendipine

GITS

=8 -20 =lO

SR

Verapantil Vet-apamll Nifedipine Nifedipine

5 a

120 20

=5

SR

Diltiazem Diltiazem

of Calcium-Channel

Adverse

9

7.

Effects

TABLE

cl 5 g 0 & .-6’ z 4

+

+

3+ 2+

3+ + 3+

3+ + 2+

0 3+ + 3+

0

3+ 3+ + + +

+ +

FL”SHlNG

+ +

+ + + +

CL

+ + + +

Blockers*

t?4RESTHESlA

0

3+ 0 0 0

3+ 3+ 3+

C”NDLlCTlON

+

2+ + + 0

+ + 2+

CHP

TABLE

8.

Calcium-Channel Hypertension

Blockers

in the Treatment

of Systemic

Advantages No detrimental effects on lipid profile and glucomgulatory hormones No kaluretic actions Safe in patients with bronchospasm, peripheral vascular disease, and renal dysfunction Low incidence of depression and sexual dysfunction. Effective in treating coexisting angina pectoris and/or arrhythmias Effective in black and white patients Effective in young and old patients Disadvantages Can exacerbate congestive heart failure (less with diiydmpyridines) Can adversely affect atrioventricular and sinus node function (less with dihydrop.yridines)

Finally, the calcium-channel blockers from the various subclasses have all been shown to cause regression of left ventricular hypertrophy in hypertensive patients. This subject will be reviewed in greater detail by our group in a future issue of Current Problems in CardioZogy? GA. BELLER: There is no doubt that calcium blockers are effective antihypertensive agents. It should be emphasized that they appear to be almost as effective in black as in white patients. This is in contrast to beta-adrenergic blockers or converting enzyme inhibitors, which may be less effective in black patients. Another major advantage of calcium blockers over beta blockers and thiazide diuretics is the lack of significant metabolic changes. The advent of sustainedrelease preparations of the various calcium blockers and the availability of longer-acting calcium blockers, like nitrendipine, should increase patient compliance. At present, one major drawback to the use of calcium antagonists as monotherapy for hypertension is relatively high cost compared to the existing first-line drugs. b

OTHER

DRUGS

Other calcium-entry blockers undergoing testing in hypertension include oral amlodipine (a long-acting dihydropyridine compound), nivaldipine (a dihydropyridine compound), and isradipine (a dihydropyridine derivative). Intravenous diltiazem and nicardipine are under development for parenteral treatment of hypertension.

334

Cum

Probl

Cardiol,

May

‘87

CONCLUSION

Scientific rationale and clinical investigation have suggested a potentially important role for calcium-channel blockers in the treatment of systemic hypertension (see Table 8).‘17 The true place of these drugs in the stepped-care approach to hypertension will ultimately be defined through further clinical research and by their use in clinical practice. b R.C. SCHLANT: This is a very thorough, scholarly, and appropriately critical review of a new major advance in cardiovascular therapeutics, Both currently available and new calcium-channel blockers will almost certainly prove to be extremely useful in the therapy of selected patients with hypertension and will assist in the even greater control of systemic hypertension, this great syndrome, which, in all likelihood, has many still-hidden subsets and causes. With the addition of calcium-channel blockers to the armamentarium of the physician for the management of arterial hypertension the physician will be able to select the optimal therapy on the basis of individual patient characteristics (such as age, sex, race, body habitus, level of blood pressure, pulse rate, ventricular anatomy and function, occupation, desired level of physical activity, cardiac rhythm and conduction, presence or absence of coronary artery disease, diabetes, bronchospastic disease, etc.). It is probably time to abandon the well-publicized “stepped-care” therapy of systemic hypertension in favor of individualized therapy for different subsets of patients, including the use of calcium-channel blocking agents, whose current status is so well reviewed by Dr. Frishman and his colleagues.

REFERENCES 1. Fleckenstein A, Tritthart H, Fleckenstein B, et al: A new group of compatible Ca++ antagonists (iproveratril, D600, prenylamine) with highly potent inhibitory effects on excitation-contraction coupling in mammalian myocai’dium. Fluegers Arch 1969; 307:25-32. 2. Stone PH, Antman EM, Mueller JE, et al: Calcium channel blocking agents in the treatment of cardiovascular disorders: II: Hemodynamic effects and clinical applications. Ann Intern Med 1980; 93:886-904. 3. Krikler DM, Rowland E: Critical value of calcium antagonists in tmatnient of cardiovascular disorders. J Am Co11 Cardiol 1983; 1:355-364. 4. Guazzi M, Oliveri MT, Polese A, et al: Nifedipine, a new antillyper,telrsi\tr with rapid action. Clin Pharmacol Ther 1977; 22:528-531. 5. McCall D, Walsh RA, Frohlich ED, et al: Calcium entry blocking drugs: Mechanisms of action, experimental studies and clinical use. Curr Proh Cardiol 1985; lO:l-80. 6. Frishman WH, Charlap S, Michelson EL: Calcium-channel blockers in s.vstemic hypertension. Am J Cardiol 1986; 58:157-160. 7. Keefe D, Frishman WH: Clinical pharmacology of the calcium-channel blocking drugs, in Packer M, Frishman WH (eds): Calcium Channel Antagonists in Cardiovascular Disease. East Norwalk, Conn, Appleton-Centurycrofts, 1984, p 3. 8. Braunwald E: Mechanism of action of calcium-channel blocking agents. i\’ Engl J Med 1983; 307:1618. 9. Bayer R, Rodenkirchen R, Kautinan R, et al: The effects of nifedipine on

Cur-r Probl Cardiol, May '87

335

10. 11. 12.

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23. 24. 25. 26. 27. 28. 29. 336

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