Clinical applications of slow channel blocking compounds

Pharmac. Ther. Vol. 23, pp. 1 to 43, 1983 Printed in Great Britain. All rights reserved

0163-7258/83 S0.00 + 0.50 Copyright © 1983 Pergamon Press Ltd

,Specialist Subject Editor: I. CAVERO

CLINICAL APPLICATIONS OF SLOW CHANNEL BLOCKING COMPOUNDS A. GRAY ELLRODT* and BRAMAH N.

SINGH t

'~UCLA School of Medicine;

and Intensive Care Unit, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A. ~'UCLA School of Medicine; and Cardiovascular Research Laboratory, Wadsworth VA Hospital and Medical Center, Los Angeles, California, U.S.A.

1. INTRODUCTION Few classes of pharmacological agents have generated as much therapeutic interest as have lhe slow channel blockers during the last decade or so. A variety of terms have been used to descr'be this heterogeneous group of compounds including calcium antagonists, calcium influx blockers, and inhibitors of the slow calcium current. Since Fleckenstein's introduction of the term 'calcium antagonists' in 1969 (Fleckenstein et al., 1969) it has become apparent that, although these compounds have electrophysiologic properties which mimic calcium-free 'physiological' media, their actions on various tissues are not accountable in terms of the traditional receptor-antagonist concept (Zelis and Flaim, 1981). As a class, these compounds inhibit the slow calcium influx which occurs during the terminal phase of depolarization and the plateau phase of the action potential (Reuter, 1979). In addition, these drugs reduce the transcellular transfer of calcium in vascular smooth muscle (Fleckenstein et al., 1969; Fleckenstein, 1971). Recent experimental and clinical investigation has revealed that these compounds are not only structurally heterogeneous but also pharmacologically, electrophysiologically, hemodynamically, and therapeutically. This review deals with the properties of the three most extensively studied calcium channel blockers: nifedipine, verapamil and diltiazem (Fig. 1). The similarities and differences in their in vitro and in vivo pharmacological properties are emphasized relative to their expanding role in the control of a diversity of cardiocirculatory disorders.

2. ELECTROPHYSIOLOGICAL CONSIDERATIONS Cells in various parts of the myocardium differ significantly in their depolarization and repolarization characteristics in addition to the nature of their refractoriness to applied stimuli. In cardiac muscle the inward current has two distinct components. The first is the 'fast response' mediated predominantly by sodium which displays rapid activation and inactivation kinetics. It has a high conduction velocity, an activation threshold of - 6 0 to --70 mV and is selectively inhibited by tetrodotoxin and local anesthetic drugs. Inactivation of the fast response in these fibers reveals a slow inward current mediated essentially by calcium with a minor contribution from sodium. The slow channel is activated at - 3 5 to - 4 5 mV and displays sluggish activation and inactivation kinetics relative to the fast response. In myocardial cells with fast response characteristics the slow current has two functions. First, through mediation of the intracellular transfer of calcium ions during depolarization it is responsible for excitation-contraction coupling. Second, it contributes to the maintenance of the action potential plateau. The fast and slow currents are felt to flow through physiologically separate channels, but at present there has been no identification of distinct anatomic structures (Antman et JP'I" 2 3 / 1 ~

1

2

A . G . ELLRODT and B. N. SINGH

H3C~/CH3 CH CH t ] 3 CH30- - ~ C-CH2-CH2-CH2-N-CH2-CH2-~I- OCH3 CH30~J-,,~ C---N ~f-LOCH3 Veropomi[ H3CvCH3

CH CH3 CH 3 0 - ~ ¢-CH2-CH2-CH2-I~-CH~-CH2-~OCH3 CH30

Go[[opamil (D600)

CH30-r~ y "CH2-CH2-CHz-N-CH2-CH2-~'t-OCH3 CH30_L.. ~1 . q /~J-OCH3 Tiopo,rni[ (Ro li-1781) NO2 H3COOC-~ I~-COOCH3 H3C--~.N,,~I-CH3

~ v

.~OCH3 S ---~.-~CCOCH3 "-.INtO -Ell3 CH2-CH2-N<.cH3

Nifedipine

Diltiazem

FIG. 1. Structural characteristics of verapamil and its two congeners, gallapamil (D600) and tiapamil, plus nifedipine and diltiazem. Note that despite the structural heterogenecity, verapamil (and its congeners), nifedipine and diltiazem block the slow channel in the myocardium and calcium fluxes in smooth muscle. However, their relative potencies for these effects differ quantitatively.

al., 1980). The slow channels are thought to be specific protein macromolecular structures

which traverse the lipid bilayer (Diamond and Wright, 1969; Williams, 1970). In addition to its role in myocardial fibers displaying the fast response, the slow inward current plays a dominant role in several normal myocardial cells. For example, these 'slow response' fibers are particularly significant physiologically in the sino-atrial and atrioventricular nodes (Cranefield, 1975, 1977). They also occur in the mitral annulus and coronary sinus (Wit and Cranefield, 1976, 1977; Cranefield, 1977) where their functional role is ill-defined. In addition, the slow response can develop in partially depolarized fibers such as seen in myocardial ischemia. Table 1 and Fig. 2 summarize the essential differences between the fast and slow currents. Slow fibers demonstrate a slow upstroke, slow conduction velocity, low safety factor for impulse conduction with proneness for decremental conduction and block when compared to fast fibers. Slow channel depolarizations are augmented by low sodium, high calcium, high potassium concentrations and catecholamines; they are depressed by manganese, lanthanum and of course, calcium antagonists. Differences between fast response fibers and slow response fibers in terms of the effective refractory period deserve emphasis. In fast response fiber, the effective refractory period is voltage-dependent so that propagated action potential in response to an applied extrastimulus is elicitable before repolarization is complete, provided a crucial level of membrane potential is attained. In contrast, in slow response fibers, the effective refractory period outlasts the total duration of the action potential; this is an example of timedependent refractoriness. A number of factors are important in the interpretation of available data, particularly the relative blocking potencies of the compounds on the slow channel in cardiac muscle and of calcium transport in vascular smooth muscle. Interactions with the sympathetic and parasympathetic nervous systems, and possibly the marked chemical heterogeneity of the various slow channel blocking drugs, must be taken into consideration. Of particular note is the significant difference between in vitro and in vivo effects of certain compounds. For example, although nifedipine in vitro is undoubtedly the most potent calcium antagonist, in conscious animals or in man the drug's expected depressant effect on atrio-ventricular conduction is either nullified or reversed. Unlike verapamil and diltiazem, nifedipine does not exert nonspecific sympathetic

Clinical uses o f c a l c i u m antagonists

TABLE

1. A Comparison of the Properties of the Rapid and Slow Inward Currents in Cardiac Muscle

Electrophysiologic Properties and Other Associated Features 1. Activation and inactivation kinetics 2. Dependent on extracellular ion concentration of 3. Abolished by 4. T h r e s h o l d o f a c t i v a t i o n

5. Potential necessary for full availability 6. Conduction velocity 7. Overshoot potential 8. Maximal rate of depolarization 9. Action potential amplitude 10. Response to stimulus 11. Safety factor for conduction 12. T i m e course of refractoriness

13.

3

Relationship to nodal tissues

14. Relationship of catecholamines 15.

initiation

16.

Where found

Rapid Current (iNi; Fast Response)

Slow Current (isi; Slow Response)

Rapid

Slow

Sodium Tetrodotoxin ( T T x )

Calcium ( + Sodium) M n , C o , Ni, Verapamil and other Ca antagonists

- 6 0 to - 70 m V

-40

- 80 to - 9 0 m V

- 4 0 to - 6 0 m V 0.01 to 0.1 m/sec 0 to + l S m V

0.5 to 2 . 0 m / s e c + 2 0 to + 3 5 m V 100 to 800 V/sec 100 to 1 3 0 m V All or none High Usually ends with repolarization (voltage dependent) Probably little Have little effect on normal fibers Triggered by the slow pacemaker or normally conducted impulse Atria, ventricles His parkinje fibers

to - 50 m V

1 to 10 V/sec 35 to 75 m V

Affected by characteristics of stimulus Low More delayed, ends after full repolarization (time dependent) Mediates SA and AVnodal activity upstrokes Significant augmentation of is. by catecholamines Triggered by depolarization, acotinine, anox AV node, SA node, mitral and tricuspid valves, coronary sinus and under pathological conditions

antagonism; its overall effect therefore represents a balance between direct depressant action and reflex sympathetic responses to peripheral vasodilation (Henry, 1980). In normal tissues all calcium antagonists inhibit the slow current in a dose-dependent fashion. (Ehara and Daufman, 1978; Nawrath et al., 1977; Fleckenstein, 1977; Tritthart et al., 1973.) But significant differences have been found between verapamil and nifedipine with respect to their effects on the kinetic parameters of the slow inward current. Nifedipine does not affect the rate of activation and inactivation of the slow current, nor the recovery from inactivation. It inhibits the slow channel without altering the gating mechanism (Kohlhardt and Fleckenstein, 1977). In contrast, verapamil, especially its [,-isomer, blocks the slow current in a frequency-dependent manner and alters its kinetics (Ehara, 1978; Bayer et al., 1975; Baschack, 1976). Verapamil also produces a significant delay in the recovery from inactivation (Ehara, 1978). This effect may be particularly significant in the AV node where the resulting change in refractoriness may contribute to the drug's well known efficacy in supraventricular tachyarrhythmias (Stone et al., 1980; Singh et al., 1980). In isolated preparations, calcium antagonists slow sinus node frequency by depressing the slope of spontaneous diastolic depolarization (Singh, 1981; Refsum and Landmark, 1975). Similar effects are found in the AV node (Singh et al., 1982). In both the SA and AV nodes, impulse conduction becomes rate dependent with prolongation of the effective refractory period (Tritthart, 1980). Most in vit, o electrophysiologic data pertain to verapamil. In dogs, small doses of verapamil lengthened PR and AH intervals without affecting QRS duration, QT interval or HV interval (Mangiardi et al., 1978). Diltiazem is likely to be qualitatively but not quantitatively similar to verapamil but has not been studied as extensively (Singh et al., 1982; Mitchell et al., 1982). In contrast, nifedipine, when studied in animals with intact sympathetic nervous systems, produced a moderate, dose-dependent shortening of the PR intervals (Rashack, 1976b). However, when larger doses of the drug are injected directly into the posterior septal artery, a dose-dependent prolongation of AV conduction is found. Doses of nifedipine necessary to prolong AV conduction are approximately 10 times greater than those required for coronary vasodilation. In contrast, verapamil induces comparable increase in flow and decrement in AV conduction at the same dose range (Norimatsu and Taira, 1976).

4

A . G . ELLRODT and B. N. SINGH A FAST R[SFONS[

I

$ SLOW Iq[Sl~NS[

...

-90-

/

\

/'

"\

\,

~

~

)

0.5 - 5 ~/sec~-~ conduction velocity Na+

charge carrier during phase O

Fast c

activation and inactivation k i n e t i c s ~

Sluqgish

TTx and local anesthetics (

selective blocking agents

)

Mn, Co and calcium antagonists (veraDamil, diltiazem, nifedipine)

)

-40 to -50 mV

-60 to -70 mV<-----activation ootential a t r i a , ventricle, His Purkinje where found fibers (

)

0.01 - O.l mlsec Ca2+ (Na+)

AV and SA nodes, mitral and tricuspid valves and coronary sinus

FIG. 2. The configuration and the time course of the ionic currents in fast-response and slow-response dependent action potentials in cardiac muscle. The upper panels show examples of each type of action potentials; the slow response potentials developed when cardiac muscle was superfused with a high K + concentrationin the presence of catecholamines. The lower panels show the temporal sequence of the two types of currents (fast Na current indicated by solid lines; the slow inward current carried largely by calcium indicated by broken lines). The main electrophysiologicdifferences between the two types of currents are indicated. Calcium antagonists block only the slow inward current. Thus, experimental data would suggest that the observed differences between nifedipine and verapamil are largely related to their differing propensities to relax smooth muscle and to interact with the sympathetic nervous system. 2.1. CLINICAL ELECTROPHYSIOLOGIC EFFECTS

Table 2 summarizes the important electrophysiologic action of verapamil, nifedipine, and diltiazem. The excellent concordance between experimentally predicted and clinical observations is apparent. In particular, the minimal effects on the ventricular and atrial refractory periods should be emphasized. None of these compounds has an effect on the QRS duration. Q-Tc is unaffected since the acceleration of the plateau phase of the transmembrane action potential is not of sufficient magnitude to produce a measureable effect (Rosen et al., 1975). The effects of calcium antagonists on anomalous pathways is either minimal or absent in the anterograde or retrograde direction (Mitchell et al., 1982). In patients with normal sinus node function, neither verapamil nor other slow channel blocking agents significantly alter sinus node recovery time or sinoatrial conduction time (Mitchell et al., 1982). In patients with sinus node disease, however, both verapamil and diltiazem induce a marked prolongation of sinus node recovery time and sinus arrest (Carrasco et al., 1978; Breithardt et al., 1978; Sugimoto et al., 1980). Although less pronounced, nifedipine may also prolong the maximum corrected sinus node recovery time

Clinical uses o f calcium antagonists TABLE 2. Comparative Experimental and Clinical Electrophysiological effects of Verapamil, Nifedipine, and Dihiazem

1. Inhibitory Effect of Cardiac Slow-Channel (In vitro) 2. Relaxation of Smooth Muscle (In vitro) (In vivo) 3. Non-specific Sympathetic Antagonism 4. Effect on Heart Rate Isolated atria Intact organism and man 5. Effect on AV conduction In isolated heart In intact organism and man 6. Clinical Electrophysiologic Properties R - R Interval QRS Q Tc PR A-H H-V Atrial ERP AV Node ERP AV Node F R P Ventricular ERP HIS-Purkinje ERP Bypass Tract ERP Sinus Node Recovery Time Ventricular Automaticity

Verapamil

Nifedipine

Diltiazem

+ + +

+ + + +

+ + +

+ + + + + + +

+ + + + + + + + 0

+ + + + +

,L+ + + T~

.L+ + + + i'

J. + + + ~.

.l + + + ++ + + +

,L+ + + + 0 to T

.L + + + ++ + +

T~ 0 0 T T 0 0

TT T~" 0 0 _+ 0* 0

,. 0 0 0 0 0 0 + + 0 0 0 0 0

T$ 0 0 T 1" 0 0 T T 0 0 ? 0* 0

*Prolonged in Sick Sinus Syndrome. Abbreviations: .. - decrease, T - increase, T,L = variable effect ERP = effective refractory period F R P - functional refractory period

(Furanello et al., 1980). Clinically, in patients with sinus node disease a profound bradycardia may be precipitated, while in normal subjects with mild tachycardia, no change in heart rate generally occurs (Singh et al., 1982). The effects of calcium antagonists on AV nodal function have been extensively studied (Kawai et al., 1981). Verapamil and diltiazem prolong intranodal conduction time by 13-24~ during atrial and ventricular pacing and slow AV conduction in both anterograde and retrograde directions (Mitchell et al., 1982). Nifedipine, however, has no effect or may even facilitate AV conduction secondary to its potent hypotensive effects, reflex sympathetic stimulation, and probable lack of sympathetic antagonism. Verapamil and diltiazem, unlike nifedipine, lengthen the functional as well as the effective refractory periods (Fig. 3) of the AV node and prolong the AV node Wenkebach cycle length (Mitchell et al., 1982). Although there is little comparative quantitative data, it appears that despite equivalent depression of AV nodal conduction, verapamil prolongs AV nodal refractoriness to a greater degree than diltiazem (Mitchell et al., 1982). In contrast, nifedipine reduces the AV nodal effective refractory period and lengthens the Wenckebach cycle length (Mitchell et al., 1982; Kawai et al., 1981). Thus, the clinical electrophysiological effects of the calcium antagonists are predictable from their in vitro and in vivo activities. 3. CLINICAL APPLICATIONS IN CARDIAC DYSRHYTHMIAS The antiarrhythmic effects of slow channel blockers may be direct or indirect. Since the atrio-ventricular node is slow-channel dependent and may become the site of either deranged impulse formation or conduction, calcium antagonists may be antiarrhythmic by either decreasing automaticity or preventing reentry in this region. These actions may be considered the 'direct' antiarrhythmic properties of this class of drugs; they lead to the termination of acute episodes of paroxysmal supraventricular tachycardia (PSVT), the slowing of the ventricular response in atrial fibrillation and atrial flutter, and the prevention of recurrent PSVT. As discussed, calcium antagonists have little or no

6

A . G . ELLRODT and B. N. SINGH Veropamil

DiL'tiazem

N ifedipine

msec 500

ERP

nee

300 <

f

200

FRP

5oo 4oo

300

P<0.05

P<0.05 D

C

V

F C

P
FIG. 3. Effects of intravenous calcium antagonists on the effective refractory period (ERP) and the

functional refractory period (FRP) of the AV node in man. C= control, D =diltiazem, V = verapamil,and N = nifedipine.Note that the ERP and FRP are lengthenedby verapamiland diltiazem but shortened by nifedipine (From Kawai et al. Circulation 63:5. 1035 (1981) with permission of authors and Circulation).

significant electrophysiologic effect on ventricular muscle and are thus unlikely to be potent antiarrhythmic agents by 'direct' action. By influencing the course of myocardial ischemia in patients with coronary artery disease, however, the slow channel blockers may exert significant 'indirect' antiarrhythmic activity. Most of the clinical antiarrhythmic data on the calcium antagonists has been accumulated for verapamil and its congeners. Studies with diltiazem are also encouraging. Nifedipine in vivo appears to have no 'direct' antiarrhythmic properties but may have 'indirect' activity in the context of myocardial ischemic syndromes. 3.1. SUPRAVENTRICULARARRHYTHMIAS--ACUTETREATMENT

In most patients with paroxysmal supraventricular tachycardia (PSVT), the AV node constitutes the anterograde limb of the reentrant loop and the portion most susceptible to the depressant electrophysiologic action of calcium antagonists (verapamil and diltiazem). This probably accounts for the consistent observation that intravenous verapamil promptly and predictably reverts 80-100~o of cases at PSVT to sinus rhythm (Singh et al., 1980, 1978; Heng et al., 1965; Kuhn, 1981; Anderson and Neiser, 1981; Krikler, 1980; Dargie et al., 1981). The usual dose of verapamil is 3-5 mg in children or 10-15 mg in adults. Recent studies have concentrated on mechanisms by which the drug exerts its salutary effects (Sung et al., 1980; Rinkenberger et al., 1980). Intravenous verapamil now appears to be the drug of choice for the termination of PSVT due to reentry involving antegrade conduction through the AV node. Studies with diltiazem suggest that it may also be effective in the termination of narrow-QRS complex PSVT (Rozanski et al., 1982; Betriu et al., 1983). However, the number of patients thus far studied with this agent is small and direct comparisons with verapamil are not available. A knowledge of diltiazem's electrophysiological effects, however, would suggest that the drug might be less effective than verapamil in converting PSVT (Russell, 1981; Mitchell et al., 1982). In most cases of PSVT, verapamil induces reversion to sinus rhythm within two to three minutes although occasional cases convert within 10 min. The success rate can be further improved to nearly 100~ by concomitant carotid sinus massage or the addition of 5-10 mg of endrophonium in rapid succession. Similar data exist for the therapeutic efficacy of verapamil in children (Porter et al., 1981) and the elderly (Midtbo, 1981). Several modes of conversion to sinus rhythm in PSVT have been reported with verapamil. The most common observation is an

Clinical uses of calcium antagonists

7

abrupt termination. In addition, prolongation of the cycle length, transient AV dissociation, transient atrial fibrillation, occurrence of premature ventricular contractions, or development of alternating cycle length prior to conversion have all been reported (Heng et al., 1975; Singh et al., 1978, 1983). Limited information is available comparing 'standard' therapy to verapamil or other calcium antagonists in PSVT. In one study, verapamil appeared to be more efficacious than practolol (Hartel and Hartikainen, 1976). There is a paucity of data comparing the overall efficacy of slow channel blockers to that of vagal maneuvers, intravenous tensilon, alpha agonists or digoxin, alone or in combination. However, in certain instances verapamil offers distinct advantages. Where urgent termination is desirable, the delayed onset of action of digoxin (15-60 min or longer) may be unacceptable. Furthermore, with intravenous verapamil's short elimination half-life D.C. cardioversion can be attempted reasonably promptly. The ability of certain of the calcium antagonists (particularly verapamil) to impede conduction through the AV node and affect the SA node has led to their appqication in a variety of atrial tachyarrhythmias, in addition to paroxysmal supraventricular tachycardia. For example, the administration of intravenous verapamil may produce three different responses in patients with atrial fibrillation. The most common is temporary slowing of the ventricular response by the inhibition of AV conduction (Talano and Feerst, 1980; Aronow et al., 1979; Aronow and Ferlinz, 1980). However, unless an infusion is begun within 30 min, the ventricular response gradually accelerates almost immediately. In 25~ or more of patients with atrial fibrillation, verapamil by a yet unexplained mechanism may lead to 'regularization' of the ventricular response without conversion (Schamroth, 1981; Heng et al., 1975). Finally, an occasional patient may convert from atrial fibrillation to sinus rhythm (Singh et al., 1978; Rinkinberger et al., 1980). The administration of intravenous verapamil to already digitalized patients in atrial fibrillation can further decrease the ventricular response (Schwartz et al., 1982). Preliminary results with intravenous diltiazem in atrial fibrillation reveal an occasional case of conversion to sinus rhythm and slowing of ventricular response in the majority of patients (Rozanski et al., 1982; Betriu et al., 1983). In atrial flutter, verapamil has been most extensively studied and may be useful diagnostically and therapeutically. A single intravenous dose will generally increase the degree of AV block in atrial flutter with 2:1 block, without converting the arrhythmia, thus distinguishing it from PSVT (Heng et al., 1975; Singh et al., 1978). The slowing of ventricular response may obviously be therapeutically advantageous. Some patients develop atrial fibrillation for reasons that are not understood, before reversion to sinus rhythm, while an occasional person is restored directly (Heng et al., 1975). Consistent with the known electrophysiologic effects of verapamil, however, the overall conversion rate is low. Preliminary results with i.v. diltiazem are similar. In one study, ventricular response decreased to below 100 beats per minute in 50~o of patients; 25~o of patients experienced conversion to atrial fibrillation with controlled ventricular response, and 25~ had no response (Betriu et al., 1983). The effects of the calcium antagonists, particularly verapamil, on arrhythmias complicating pre-excitation syndromes are predictable from their basic electrophysiologic properties. Verapamil and diltiazem, but not nifedipine, depress AV nodal conduction in such patients. Verapamil generally appears to have minimal effect on the presumably fast channel dependent bypass tracts (Krikler and Spurrell, 1974; Gulamhusein et al., 1982). From the known electrophysiologic properties on the heart (Rozanski et al., 1982; Mitchell et al., 1982) one may infer that filtiazem will have similar quantitative effects, but systematic data are not yet available. Thus, verapamil has been found to be effective in terminating the acute paroxysms of the narrow QRS (orthodromic) supraventricular tachycardia complicating the W - P - W syndrome (Hamer el al., 1981). On the other hand, caution must be exercised in the use of calcium channel blockers in patients with preexcitation syndromes complicated by atrial fibrillation or atrial flutter. Agents which either shorten the effective refractory period of the bypass tracts (e.g. digitalis, or lengthen

/ /

,/

/

8

A.G. ELLRODTand B. N. SINGH

conduction over the AV node, digitalis, r-blockers, tensilon and calcium antagonists may augment the ventricular response rate and possibly precipitate ventricular fibrillation in such patients. In one electrophysiological study, verapamil decreased the shortest R-R interval between pre-excited ventricular complexes during atrial fibrillation and two patients demonstrated significant hemodynamic deterioration requiring cardioversion (Gulamhusein et al., 1982). Thus, verapamil and other calcium antagonists are contraindicated in patients in whom atrial fibrillation or flutter complicate the W-P-W syndrome. Although experience is limited, in a variety of acute supraventricular dysrhythmias other than those thus far discussed several potentially useful applications of verapamil have been studied. In one of two patients with sinus nodal tachycardias secondary to reentry within the SA node or its adjacent tissue, intravenous verapamil promptly terminated the tachycardia (Sung et al., 1980). There are increasing data to suggest that intravenous verapamil is less effective in converting ectopic atrial tachycardia than paroxysmal supraventricular tachycardia of the reentrant type (Rinkenberger et al., 1980). The efficacy of verapamil in patients with paroxysmal atrial tachycardia with block (not necessarily due to digitalis toxicity) has been evaluated. In 10 of 14 patients initial reversion of the arrhythmias to sinus rhythm was obtained but subsequent relapse occurred in four (Storstein and Landmark, 1975). One study of supraventricular tachyarrhythmias associated with chronic pulmonary disease, including multifocal atrial tachycardia, suggests that verapamil may be beneficial (Rabkin et al., 1980). More experience with this and other calcium antagonists in this area is needed, however. 3.2. SUPRAVENTRICULAR ARRHYTHMIAS--CHRONIC TREATMENT

The most extensive experience has been obtained with verapamil, but diltiazem and other calcium antagonists which prolong AV conduction and refractoriness have potential applications. Because of the extremely variable pattern of recurrences of PSVT among patients and in the same patient, prophylactic efficacy is difficult to determine. Nevertheless, in patients with PSVT who initially responded to intravenous verapamil, long term benefit has been observed (Gonzalez and Scheinman, 1981). In addition, in comparison with placebo the drug has been demonstrated to be both effective and well tolerated (Mauritson et al., 1982). It may be possible to predict long term efficacy in PSVT by response to intravenous verapamil studied by programmed electrical stimulation (Tonkin et al., 1980; Klein et al., 1982). Although promising, more experience is needed in this area. Chronic oral administration of verapamil has been shown to be effective alone or in combination with digitalis in reducing resting ventricular response in atrial fibrillation. Verapamil appears to be especially effective in attenuating the exercise induced increases in heart rate, whereas digoxin's major effect is on resting ventricular response (Schwartz et al., 1982; Morganroth et al., 1982; Klein et al., 1979, 1981, 1982; Lang et al., 1983). The potential summation of the effects of digoxin and verapamil in depressing AV node conduction, in addition to the significant interaction resulting in increased serum digoxin levels, should be emphasized in this setting (Schwartz et al., 1982). Verapamil's efficacy in maintaining sinus rhythm after conversion from atrial fibrillation is unclear, but on electrophysiological grounds the drug is likely to be ineffective in this regard. In one recent controlled trial, quinidine was significantly more effective in producing cardoversion and maintaining it at three months (Rasmussen et al., 1981). Limited data suggest that orally administered verapamil in combination with other antiarrhythmics may be of value in controlling the ventricular response in atrial flutter (Gonzalez and Scheinman, 1980). Other calcium antagonists with AV node inhibitory properties should also produce similar results. One study of oral verapamil in the chronic prophylaxis of PSVT in complicating the W-P-W syndrome revealed that electrophysiological studies aided in the prediction of long term responders and non-responders. Six of 14 patients remained symptom free during long term follow-up (Wu et al., 1983).

Clinical uses of calcium antagonists

9

3.3. VENTRICULAR ARRHYTHMIAS In the assessment of the role of calcium channel blocklade in ventricular tachycardia, it is important to emphasize the difference between antiarrhythmic and antifibrillatory properties. In addition, the distinction between experimental and clinical findings, and direct and indirect effects of these compounds are relevant considerations. Experimentally, interventions which promote intracellular calcium overload can precipitate ventricular fibrillation without ischemia. In the setting of ischemia, correction of calcium overload can prevent or slow the development of fibrillation (Clusin et al., 1983). Although the antifibrillatory properties of verapamil have long been recognized (Kaumann and Aramendia, 1968) these were originally believed secondary to improved coronary flow or reduced cardiac work. Recently, calcium channel blockers have been demonstrated to suppress ischemic ventricular fibrillation independently of improved coronary perfusion, reduction of cardiac work, or increase in myocardial high energy phosphates (Clusin et al., 1982; Thandroyen et al., 1982). Moreover, there is a reasonable theoretical role for the slow channel in the genesis of the arrhythmias of obstructive cardiomyopathies (Goodwin and Krikler, 1976), and those associated with mitral valve prolapse (Singh et al., 1980). Clinical experience to date however, especially with hypertrophic cardiomyopathy, has not confirmed their efficacy (McKenna et al., 1980). Although a few controlled studies have demonstrated reduction in number of PVC's complicating acute myocardial infarction (Filias, 1974; Fazzini et al., 1978), the very limited experience in ventricular tachycardia associated with myocardial infarction or that occurring in the setting of chronic cardiac disease has been disappointing (Heng et al., 1975; Wellens et al., 1977, 1980). Thus, preliminary clinical evidence fails to provide strong support for a major role for these compounds in ventricular tachyarrhythmias. In certain settings however, particularly in patients with variant angina, the indirect antiarrhythmic effects of the calcium channel blockers may be important (Elharar et al., ]977; Kimura et al., 1977). It must be emphasized however, that an occasional patient with recurrent ventricular arrhythmias resistant to the antiarrhythmic agents apparently responds to orally administered verapamil. The nature of such a beneficial response is unclear and detailed studies of the patients who respond in this manner may reveal the underlying mechanisms involved. Clinically, the antifibrillatory actions of the calcium channel blockers have not been adequately evaluated. The recent demonstration that fl-blocking drugs can significantly reduce the risk of sudden death after myocardial infarction (Norwegian Multicenter Study Group, 1981) and the presumption that this beneficial effect is due in part to decreased ischemia and perhaps a primary direct antifibrillatory effect, raises the possibility that the calcium antagonists may also be efficacious. Thus, there is a reasonable theoretical basis for the ongoing studies of the calcium antagonists in the prevention of sudden death due to ventricular fibrillation in the survivors of acute myocardial infarction. The further elucidation of 'direct' and 'indirect' antiarhythmic and antifibrillatory properties of these agents will clearly be of fundamental clinical importance. 4. EFFECTS OF SLOW CHANNEL BLOCKERS ON THE MYOCARDIUM The net myocardial effects of calcium channel blockers result from a complex interplay of direct action on excitation-contraction coupling, reflex autonomic stimulation and varying non-competitive sympathetic antagonism. In myocardial cells, actin and myosin make up the contractile apparatus and their interaction is an ATP-dependent process (Braunwald et al., 1976). Cellular depolarization raises myoplasmic Co 2+ concentration which releases tropnin's inhibition of the contractile apparatus, allowing muscular contraction (Katz, 1970; Langer, 1973; Fabiato and Fabiato, 1979). Thus, the action potential triggers the release of intracellular calcium stores through 'Co 2+-triggered Co 2÷ release' and contraction is initiated (Fabiato and Fabiato, 1979). The number of contractile sites activated appears to be related to the amount of calcium surrounding the myofibrils

10

A.G. ELLRODTand B. N. SINGH

which is dependent on the quantity of calcium entering the cell accompanying the action potential (Braunwald, 1982). The effects of calcium channel blocking drugs on myocardial contractility differ significantly in isolated preparations when compared to those in intact animals and man. In vitro experiments, in which reflex activity does not occur, demonstrate that all such agents exert a dose-dependent inhibition of myocardial contractility which is reversed by increasing extracellular calcium concentrations (Ono and Hashimoto, 1979; Fleckenstein et al., 1972; Mangiardi et al., 1978). In isolated atrial and ventricular muscle, there is good concordance between the negative inotropic effects of various calcium antagonists and their relative potency in inhibiting the myocardial slow inward current. In guinea pig atria and dog papillary muscle, the relative potency for depressing the maximal rate of force development is nifedipine > verapamil > diltiazem (Ono and Hashimoto, 1979). In addition, the positive inotropic effects of cardiac glycosides, glucagon, histamine and catecholamines are nonspecifically attenuated (but not abolished) by slow channel blockers (Singh and Vaughn Williams, 1972). Myocardial oxygen consumption also decreases in a dose-dependent fashion in association with the negative inotropic effect (Vater and Schlossman, 1976). In animals with intact sympathetic nervous systems, results differ significantly. Low doses of calcium antagonist drugs sufficient to cause peripheral arterial vasodilation may (Vater and Schlossman, 1976) or may not (Hinori et al., 1976) produce a negative inotropic effect. In clinically used doses this effect is probably insignificant. In higher doses resulting in greater peripheral vasodilation, the direct negative inotropic effect may be offset by baroreceptor-mediated reflex responses (Vater and Schlossman, 1976). Despite activation of reflex mechanisms, net myocardial oxygen demand remains reduced due to decreased afterload which exceeds the effects of reflex positive inotropic response and tachycardia (Vater and Schlossman, 1976). Diltiazem has been shown in intact dogs to have little effect on mean pulmonary capillary wedge pressure or stroke volume at doses which exert a significant electrophysiologic effect (Fujimoto et al., 1981). Intracoronary injection of nifedipine in the pig results in increased left ventricular end diastolic pressure (LVEDP) and decreased maximum LV d p / d t and peak velocity of circumferential fiber shortening. In contrast, drug infusion into the pulmonary artery results in a trivial negative inotropic effect (Verdouw et al., 1980). This study further emphasizes the importance of compensatory reflex mechanisms in attenuating the direct myocardial depressant effect of the calcium antagonists. 5. EFFECTS OF THE SLOW CHANNEL BLOCKER ON THE CORONARY AND SYSTEMIC VASCULATURES There are significant differences between myocardial muscle contraction and smooth muscle contraction in coronary and systemic arteries. In smooth muscle, excitationcontraction coupling is mediated through several mechanisms. First, there is calcium influx accompanying a change in membrane potential--termed electromechanical coupling. Second, there occurs receptor binding mediated calcium influx not associated with altered membrane potential--termed pharmacomechanical coupling (Casteels, 1980). In addition, a 'passive leak' accounting for calcium permeability in the resting state has been demonstrated (Van Breeman et al., 1982). It appears that the receptor-operated pharmacomechanical coupling is the primary mechanism mediating smooth muscle vascoconstriction (Zelis and Flain, 1981). Once calcium has crossed the cell membrane by one of these mechanisms, it can trigger stored calcium release from the sarcoplasmic reticulum and perhaps the sarcolemmal membrane. The modulator protein in vascular smooth muscle is calmodulin. The increased intraceilular calcium combines with calmodulin activating myosin light chain kinase. This kinase phosphorylates one of the light chains of myosin permitting actin and myosin to interact, resulting in contraction. It appears that the trigger mechanism, by its release of small amounts of calcium from intracellular pools, causes the rapid phasic contraction of vascular smooth muscle. Sustained tonic contraction

Clinical uses of calcium antagonists

11

results from more marked transarcolemmel influx of calcium through either channel. Relaxation occurs when a phosphatase-mediated dephosphorylation predominates over the myosin light chain kinase-mediated phosphorylation. When calcium is either taken up into the sarcoplasmic reticulum, or when calcium is extruded from the cell by a calcium activated pump or possibly through passive sodium-calcium exchange, myosin light chain kinase activity falls (Zellis and Flaim, 1981). Where the calcium influx blockers exert their fundamental action in this scheme is controversial. If, for example, coronary vasospasm is produced by potential dependent rhythmicity, these drugs may be efficacious by inhibiting a transmembrane 'calcium current' (Zelis and Flaim, 1981). Within this schema, differences in the action of various calcium antagonists may be elucidated. Whereas verapamil appears to inhibit calcium influx through receptor-operated channels, thereby inhibiting phasic vascular smooth muscle contraction, diltiazem stimulates the sodium-potassium pump with the reduced intracellular sodium possibly driving passive sodium-calcium exchange. Whether diltiazem stimulates energy-dependent calcium extrusion is unclear (Zelis and Flaim, 1981; van Breeman et al., 1982). In addition, diltiazem has been demonstrated to inhibit both membrane depolarization and receptor-operated calcium influx without the inhibition of intracellular calcium release (van Breeman et al., 1982). The precise clinical significance of these differences in the action of calcium antagonists remains uncertain. All slow channel blockers inhibit excitation-contraction coupling in coronary artery smooth muscle (Ginsburg et al., 1980; Haeusler, 1972; Golenhofen and Lammel, 1972; Ho, K_uriyama and Suzuki, 1978). By reducing smooth muscle tone, they reduce coronary vascular resistance and increase coronary blood flow (Fleckenstein, 1977). In an in vitro dog preparation with induced Co 2+-mediated action potentials, nitroglycerin preferentially blocked the Co 2+ current in large coronary arteries but verapamil blocked the Co 2+ dependent action potentials in both large and small vessels (Harder et al., 1979). In conscious dogs nifedipine has also been demonstrated to dilate both large coronary arteries and coronary resistance vessels. In vitro studies demonstrate the nifedipine is a more potent coronary vasodilator than are verapamil and diltiazem, which are equipotent (Fleckenstein e; al., 1976). Calcium antagonists have been shown to decrease the coronary vascular r~,'sponsiveness to a variety of stimuli. Verapamil decreases reactivity to ~-adrenergic, alagiotensin and cardiac glycoside-induced coronary vasoconstriction (Greenberg and Wilson, 1974). Thus, the relaxant effects of calcium channel blockers on coronary artery smooth muscle are due to Ca 2+ influx inhibition and are not receptor type dependent. The influence of calcium channel blockers on regional myocardial blood flow and coronary hemodynamics following acute and subacute experimental coronary occlusion are of clinical relevance. Administration of diltiazem, nifedipine or verapamil soon after coronary occlusion has been found to augment flow distal to the ligature (Nakamura et a/., 1979; Schmier et al., 1975; VanAckern et al., 1974; Henry et al., 1979; DaLuz et al., 1!)80). A drug induced decrease in coronary arteriolar resistance in vessels supplying collaterals to the ischemic zone, or a reduction in arteriolar resistance in vessels of the ischemic zone distal to the ligature are proposed as mechanisms of enhanced collateral flow (Henry et al., 1979). The calcium blocking agents are three to ten times more potent inhibitors of coronary artery smooth muscle than myocardial contractile cells (Fleckenstein, 1977; Hashimoto et al., 1972). This permits Ca 2+ channel blockers to dilate the coronary arteries in doses which do not decrease myocardial contractility (Ono and Hashimoto, 1979; Vater et al., 1972). In patients with and without ischemic heart disease there appears to be good concordance between experimental and clinical data. These agents appear to have qualitatively similar therapeutic effects in myocardial ischemic syndromes although quantitative differences may exist (Ellrodt et al., 1980; Stone et al., 1980). In patients with coronary artery disease nifedipine increases flow by 100~ in normal, as well as areas served by stenotic vessels, under resting and atrial paced conditions. The drug also reduced exercise-induced thallium detected perfusion defects (Lichtlen et al.,

12

A.G. ELLRODTand B. N. SINGH

1980, 1979a,b). Sublingual nifedipine increases myocardial blood flow, and decreases coronary arteriolar resistance without significantly reducing myocardial oxygen consumption (Simon and Nitter-Hauge, 1978). Verapamil reduces coronary arteriolar resistance without significantly affecting coronary sinus flow or oxygen consumption (Simonsen, 1978; Brown et al., 1981; Chew et al., 1983). In normal areas verapamil increases cross-sectional area in most large and small vessels. In mildly and severely stenosed segments verapamil increases cross-sectional areas and reduces estimated flow resistance (Brown et al., 1981). In addition, intravenous verapamil inhibits both sympathetic and ergonovine-induced coronary vasoconstriction in diseased human arteries (Brown et aL, 1981). Diltiazem dilates normal coronary arteries and induces a significant increase in coronary sinus flow with an insignificant decrease in myocardial oxygen consumption (Yamaguchi et al., 1979; Tubau et al., 1980). Thus, the calcium antagonists as a group appear to produce a small but significant dilatation of normal and stenosed coronary arteries with a reduction in estimated coronary vascular resistance. Additionally, these drugs appear to dilate both conductance and resistance components of the coronary circulation with variable effects on coronary sinus flow. The effects of calcium channel blockers on arteries of the peripheral circulation are similar to those on the coronary circulation. In animals they have been demonstrated to dilate pulmonary arteries (Haeusler, 1972), hepatic arteries (Ishikawa et al., 1978), femoral (Hashimoto et al., 1972; Ishikawa et al., 1978), superior mesenteric (Ross and Jorgensen, 1967; Ishikawa et al., 1978), and hindlimb arteries (Greenberg and Wilson, 1974). In the experimental animal, nifedipine dilated and abolished autoregularion in renal arteries (Hashimoto et al., 1972). Diltiazem has also been shown to dilate cerebral arteries in man (Lydtin et al., 1976). In dogs, calcium antagonists appear to increase blood flow most markedly in the femoral arterial bed followed closely by that in the coronary, renal and mesenteric circulations (Ono and Hashimoto, 1979; Hashimoto et al., 1972). Diltiazem appears to preferentially dilate the coronary vascular bed. At a dose that doubles coronary blood flow, the drug increases femoral flow by only 25~o, carotid by 37~ and renal by 10~ (Nagao et al., 1972). This widespread calcium antagonist induced vasodilation reduces systemic vascular resistance in both animals and humans (Stone et al., 1980).

6. NET HEMODYNAMIC EFFECTS IN MAN Most hemodynamic data in patients deal with the resting state and the response after a single intravenous dose of nifedipine, verapamil and diltiazem. Overall effects can in general be explained by the known direct inhibitory potencies of these compounds on the myocardium and peripheral vasculature (Ellrodt et al., 1980) combined with relative stimulation of sympathetic reflex mechanisms and intrinsic non-competitive sympathetic inhibitory effects present in some of the compounds. Patients with depressed ventricular function and myocardial infarction may, however, respond differently. The net effects of intravenous or sublingual nifedipine are consistent with profound peripheral vasodilatation and reflex increases in contractility in normal subjects and in those with underlying cardiac disease (Debraisieux et al., 1979; Lydtin et al., 1975; Ludbrook et al., 1980). In the latter, increments in heart rate, cardiac output, and LV d p / d l m a x have been observed with sublingual nifedipine (Lydtin et al., 1975). The drug induces increases in left ventricular ejection fraction and mean velocity of circumferential fiber shortening without significantly changing the LVEDP or end diastolic volume (Ludbrook et al., 1980). Occasionally, in patients with coronary artery disease, the LVEDP may fall (Kober et al., 1979). In patients with impaired left ventricular function, sublingual nifedipine reduces LV afterload and myocardial oxygen demand, enhances diastolic performance and improves systemic and pulmonary hemodynamics, left ventricular ejection function and cardiac output (Ludbrook et al., 1982).

Clinical uses of calcium antagonists

13

During bicycle exercise, orally administered nifedipine can reduce the mean pulmonary capillary wedge pressure and blunt the increases in systolic arterial pressure, while permitting a significant increase in workload (Grandjean and Valenti, 1979). In patients with coronary artery disease paced to anginal threshold, the drug also attenuates increases in LVEDP (Johnson et al., 1981). In such patients with normally or moderately impaired ventricular function, hemodynamic changes are relatively consistent. Nifedipine causes significant peripheral vasodilation provoking reflex increases in heart rate, contractility, ~.nd stroke volume indices (Jariwalla and Anderson, 1978). Coronary artery disease patients demonstrate regional increases in ejection fraction in ischemic areas in addition to improved global ventricular function (Pfisterer et al., 1983). Overall, however, without concomitant beta-adrenergic blockade, these global changes may not always be clinically beneficial (Jariwalla and Anderson, 1978). It must also be emphasized that if the reflex effects consequent upon peripheral vasodilatation are inhibited by fl-blockade, profound ~ypotension and cardiac failure may result in patients with severely impaired ventricular function. A significant body of literature exists with respect to the hemodynamic effects of verapamil in healthy individuals and patients with a variety of cardiac diseases. In healthy adults, a trivial negative inotropic action easily abolished with the increased sympathetic excitation of exercise is found (Atterhog and Ekelund, 1975). In patients with cardiac disease in sinus rhythm, mean arterial pressure is reduced slightly, cardiac output and increased slightly without a significant fall in stroke volume. In patients with atrial fibrillation, stroke volume has been reported to fall (Ryden and Saetre, 1971). Following intravenous verapamil in patients with coronary or rheumatic heart disease, peak hemodynamic effects are observed between three and five minutes with return to baseline by 10 min. A marked fall in systemic vascular resistance accompanied by a modest fall in LV dp/dtm, x has been observed (Singh and Roche, 1977; Ferlinz et al., 1979). The acute response to intravenous verapamil appears to be related to time, dose, and baseline ventricular reserve. In patients with ejection fractions (EF) greater than 35~ 0.1 mg/kg produces a transient decrease in EF with increased left ventricular volume and cardiac output equivalents. This is followed by an overshoot in EF with decreased systemic vascular resistance and LV volumes. In subjects with ejection fractions less than 35~o, similar but quantitatively milder effects are observed (Klein et al., 1983). Overall ejection fraction data is somewhat conflicting, with some investigators finding increases (Ferlinz et al., 1978), others decreases (Chew et al., 1981; Bonow et al., 1982). Patient selection, dose, and timing of study may explain their apparent disparate findings. In general, the expected myocardial depressant effects of verapamil are found to be offset by its vasodilator properties for most patients. In patients with left ventricular ejection fraction between 30-75~ despite slight increases in mean PCW, stroke volume and cardiac index generally remain unchanged or actually increase (Singh and Roche, 1977; Ferlinz et al., 1979, 1980; Singh et al., 1980; Ferlinz and Turbow, 1980; Vlieststra et al., 1981). Although diltiazem has been studied less extensively, its cardiocirculatory effects are similar to those of verapamil. Intravenous diltiazem (10 mg) administered to patients with essential hypertension significantly reduces mean arterial pressure and systemic vascular resistance while increasing cardiac index. There is no significant alteration in heart rate, pulmonary capillary wedge pressure, mean right atrial, or pulmonary artery systolic or diastolic pressure (Oyama, 1979). In patients with coronary artery disease continuous infusion of 1 mg/min of diltiazem does not alter left ventricular ejection fraction (Kusakawa et al., 1977). With various oral doses different effects have been noted. Doses of 60 mg significantly decrease systolic arterial pressure and stroke work index without corresponding alterations in cardiac index, stroke volume index, heart rate or systemic vascular resistance. These alterations are abolished by exercise (Kinoshita et al., 1979). Higher doses (90 mg p.o.t.i.d.) administered chronically to coronary artery disease patients significantly reduce cardiac output, stroke volume and stroke work index (Kusukawa et al., 1977).

14

A.G. ELLRODTand B. N. S~NGI4 7. SLOW CHANNEL BLOCKERS IN ISCHEMIC MYOCARDIAL SYNDROMES

The net hemodynamic properties of the calcium antagonists make them potentially useful in a variety of clinical syndromes resulting from altered myocardial supply and demand relationship. The efficacy of nifedipine, diltiazem and verapamil has been well established in Pinzmetal's variant angina, and chronic stable (exertional) angina. In addition, there are a number of studies supporting the efficacy of these agents in unstable angina and in myocardial infarction as well as in the preservation ofischemic myocardium. Differences between the drugs exist in these settings. Pari passu with the development of calcium antagonists, there has been a reappraisal of our thinking of the pathogenesis of ischemic myocardial syndromes. Myocardial ischemia is now thought to develop as a result of a variable contribution of coronary artery stenosis due to atherosclerotic disease and of coronary artery vasomobility. At one end of the spectrum, coronary spasm may occur in patients without fixed coronary lesions, while at the other ischemia is due largely to severe stenoses which become critical because of increased myocardial oxygen demand. A large number of patients fall between these extremes with a combination of pathophysiological mechanisms producing varied and quantifiable manifestations (Maseri et al., 1978; Figueras et al., 1979). 7.1. VASOSPASTICANGINA Coronary vasospasm has been confirmed as the pathogenetic mechanism in Prinzmetal's variant angina by angiographic and scintigraphic techniques (Maseri et aL, 1976, 1977; Oliva et al., 1973). Pain and evidence of ischemia precede increases in the major determinants of myocardial oxygen demand (Maseri et al., 1979; Figueras et aL, 1979). Verapamil, nifedipine and diltiazem have all been shown to be effective in controlling frequent attacks of variant angina resistant to fl-blockers with or without nitrates. Initial reports indicated that 40-80 mg of nifedipine daily dramatically reduced symptoms in such patients (Hosada and Kimura, 1976; Endo et al., 1975; Muller and Gunther, 1978). Experience with 127 patients, most of whom had previously failed conventional antianginal therapy, with or without underlying fixed obstructive coronary lesions, demonstrated that nifedipine in doses of 40-160 mg per day completely eliminates spontaneous pain episodes in 63% of patients, and in 87% of patients decreased the frequency of attack by at least 50%. Side effects were severe enough to require discontinuation of the drug in 5% (Antman et aL, 1980b). In a multicenter, randomized double-blind withdrawal study comparing nifedipine to placebo, the former was again demonstrated to be significantly more efficacious (Schick et aL, 1982). Nifedipine also effectively blocks ergonovine-induced coronary spasm in patients with variants angina (Theroux et al., 1979). Furthermore, the drug has been found to prevent malignant ventricular arrhythmias and conduction disturbances associated with variant angina attacks (Antman et al., 1980b; Heupler and Proudfit, 1979; Goldberg et al., 1979). The efficacy of verapamil in variant angina has also been demonstrated (Fig. 4). For example, the drug has been found to reduce the anginal frequency, NTG consumption, number of hospitalizations and number of episodes of ST deviations on 24 hr ambulatory ECG recordings when compared to the effects of placebo (Johnson et al., 1981a). 59% of patients became entirely asymptomatic and an additional 29% had a reduction in pain episodes to less than two per month in one long-term study of verapamil (Freedman et al., 1979). In another long-term follow-up study of verapamil with or without nitrates, in 138 patients with spontaneous angina associated with ST segment elevation, results were also encouraging. By one year, 20% and by four years, 50~o of patients were asymptomatic, with remission occurring more frequently in those with less severe underlying coronary artery disease (Severi et al., 1979). At present, experience with diltiazem is less extensive but promising. In a small double-blind crossover study, 240 mg daily of this drug significantly reduced the number of episodes of pain and the amount of NTG consumption while 120 rag/day was without effect (Rosenthal et al., 1980). A study of short- and long-term efficacy of diltiazem

Clinical uses o f calcium antagonists

15

20

15

I

IO

m

<

o

m

@;

z~ "~ 48

.o_

-

36-

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I--

(.0

0--

Placebo Verapamil I

I

m

Placebo VerapamiL IZ

IT

FIG. 4. Effects of orally administered verapamil in vasospastic angina: double blind placebo controlled evaluation. Each period indicated represents data from months of study with weekly observations. Note that verapamil reduces anginal episodes, ST segment d on 24 hr ambulatory ECG recordings and the amount of nitroglycerin consumed per week. (With permission from Johnson et al. (1981a) and the American Heart Association).

revealed that the short-term response was generally predictive of the long-term outcome (Feldman et al., 1982). Finally, in a multicenter, randomized controlled crossover study, 120 mg of diltiazem daily was less effective than 240 mg daily (Schroeder et al., 1982). Limited information is available on the relative efficacy of the various calcium antagonists in variant angina. In one small direct comparison of verapamil, nifedipine and p~acebo, verapamil and nifedipine demonstrated similar effectiveness but nifedipine was associated with more frequent side effects (Johnson et al., 1982b). In a large Japanese multicenter survey, both nifedipine and diltiazem completely eliminated evidence of ischemic syndromes in about 75~ of patients, with clinical improvement in more than 90~o, whereas verapamil eliminated variant anginal attack in only 11~ of cases but was effective in 86~o (Kimura et al., 1981). In a comparison of efficacy in preventing ergonovine-induced coronary vasospasm, although nifedipine, diltiazem and verapamil all increased the spasm threshold, nifedipine was the most potent agent (Waters et al., 1979). Although no systematic data are available, calcium antagonists may be used in combination in resistant cases of Prinzmetal's angina since their mechanism of action in relaxing smooth muscle in the coronary circulation may differ. The combination of long-acting nitrates and calcium channel blockers may be more effective than either agent alone (Muller and Gunther, 1978; Raizner et al., 1980). In patients with variant angina, withdrawal of nitrate preparations or calcium channel blockers is potentially dangerous and should therefore be done with caution (Muller and Gunther, 1978; Schick et al., 1982). Thus, the overall data suggest that as a class of therapeutic agents, calcium antagonists represent a significant advance in the control of vasospastic angina in which they can be used as single agents or in combination with one another or with long acting preparations of nitrates. Since they are also effective in chronic stable angina (see below), their overall

16

A . G . ELLRODT and B. N. SINGH

clinical utility in coronary artery disease is clearly evident in the largest numbers of patients with ischemic myocardial syndromes. 7.2. CHRONIC STABLE ANGINA Nifedipine, verapamil and diltiazem are found efficacious in classic exertional angina. They have been studied using various endpoints, alone and in combination with other antianginal drugs and occasionally compared to each other. They all decrease anginal episodes, increase exercise duration on treadmill, reduce nitroglycerin consumption while diminishing the number of episodes of ischemia on 24 hr ECG recordings. However, the mechanism of their beneficial effects has not been completely elucidated and may indeed vary from patient to patient. The observed salutary response may be mediated through a number of properties. By reducing peripheral vascular resistance, and therefore afterload, and by reducing myocardial contractility they may decrease myocardial oxygen demand. The drugs' inherent non-competitive fl-antagonistic property or lack of it may further complicate the interpretation of net effects of some of the agents since reflex adrenergic mechanisms may be activated. In addition, calcium channel blockers may oppose the tendency to inappropriate coronary vasomobility which may play a role in the pathogenesis of ischemic episodes in some patients with classic angina pectoris (Mudge et al., 1976; Gunther et al., 1979). 7.2.1. Nifedipine Studies with nifedipine have demonstrated consistent efficacy over short- and long-term observations. A single sublingual dose of 10 or 20 mg has been found to reduce anginal frequency and to increase exercise tolerance as judged by graded stress-testing against the background of placebo control (Ebner and Dunschede, 1976; Ekelund and Atterhog, 1975; McIlwraith, 1975). Four double-blind controlled studies using a single dose of nifedipine have demonstrated an average reduction in exercise-induced ischemic ST depression of 32~ (Stone et al., 1980). Improvement noted acutely appears to persist long-term. Beneficial results have been reported in over 4,000 patients treated from two weeks to three years (Ebner and Dunschede, 1976). Although the doses used in many of the earlier studies ranged from 10-60 mg daily, the improvement in angina may be dose-dependent, and therefore 120 mg or more per day may be required for optimal therapy in some patients (Stone et al., 1980). Nifedipine's antianginal effect appears due to the diminution in the rate-pressure product at any given workload (Prempree and Tabatznik, 1976; Stein, 1976). Maximum systolic blood pressure is decreased and the double-product as the onset of angina or exercise termination is similar compared with that for control. These data suggest that the improved exercise capacity observed with nifedipine is related primarily to its ability to decrease afterload rather than to increase myocardial oxygen supply (Corbalan et al., 1981; Moskowitz et al., 1979). It is also noteworthy that nifedipine (20 mg s.1.) can reverse the hemodynamic evidence of left ventricular dysfunction in patients with exercise or pacing induced ischemia (Majid and DeJong, 1982). In patients with recent myocardial infarction, nifedipine reduces left ventricular end-diastolic pressure and volume, and increased ejection fraction. In patients with moderate left ventricular dysfunction, nifedipine appears safe and efficacious (Majid and DeJong, 1982). In addition to nifedipine's peripheral vasodilator properties, there is evidence that the drug may also block abnormal coronary vasoconstriction in patients with exertional angina. In such patients abnormal coronary vasoconstriction induced by the cold pressor test could be blocked in all subjects with this abnormality (Gunther et al., 1981). In general, the reflex increases in heart rate observed after nifedipine do not nullify the overall decreases in M V O 2 resulting from changes in the determinants of myocardial oxygen demand. However, in patients with chronic stable angina treated only with nifedipine, symptoms of ischemia have been found to be exacerbated in up to 11~o (Stone et al., 1980). It is unclear whether this deleterious effect is due to increased heart rate,

Clinical uses of calcium antagonists

17

augmented contractility, coronary steal phenomena, or to a combination of these potential mechanisms. Propranolol administered concomitantly with nifedipine not only abolishes the increases in resting heart rate but lowers heart rate, blood pressure, and hence the double-product at a given workload (Itoh et al., 1975). Clinically, the combination of nifedipine (10 mg l.i.d.) with propranolol (40 mg t.i.d.) or metoprolol, leads to a greater decrease in anginal frequency and nitroglycerin consumption than during the administration of either drug alone (Kenmore and Scruton, 1979; Ekelund and Ono, 1979; Fox et al., 1981). Thus, nifedipine alone, or especially in combination with//-blockade, is an effective and relatively safe drug for the treatment of patients with classical angina pectoris. 7.2.2. Verapamil A number of controlled double-blind clinical trials have demonstrated a significant reduction in the frequency of anginal episodes and nitroglycerin consumption while improving exercise tolerance when verapamil is given at varying doses (Atterhog and Porje, 1966; Neumann and Luisada, 1966; Livesley et al., 1973; Andreasen et al., 1975; Balasubramanian, 1980). However, the mechanism by which the drug exerts its beneficial effect in chronic stable angina is not entirely certain and may be multifactorial. The drug causes a 10~ reduction in rate-pressure product at rest and a 12~ reduction in rate-pressure product at sub-maximal exercise compared to over 30~ by//-blockers (Josephson et al., 1982). In addition, at peak exercise and at a pressure-rate product similar to that obtained on placebo, there appears to be less marked ST-segment depression, suggesting a favorable redistribution of coronary blood flow to ischemic zones (Brodsky et al., 1982). However, in a study of pacing-induced angina, oral verapamil did not appear to increase coronary flow as measured by coronary sinus blood flow by thermodilution. Decreased myocardial oxygen demand resulting from lower arterial pressure at each rate seemed most important (Rouleau et al., 1983). Verapamil's dose-response relationship is of particular significance in patients with classical angina. Higher dose regimens of verapamil (e.g., 120mg, t.i.d.) significantly decrease anginal frequency and prolong exercise tolerance. Neither 40 mg (t.i.d.) nor 80 mg (t.i.d.) are significantly better than placebo, however (Livesley et al., 1973; Sandler et al., 1968). In addition, in one dose titration study, patients who failed to respond to 360 mg per day derived a significant benefit from 480 mg of verapamil per day. However, the incidence of side effects increased markedly at the higher dose (Pine et al., 1982). In appropriately selected patients with good ventricular function, the combination of ,~erapamil with a//-blocker may be significantly more efficacious than either agent alone (Balasubramanian, 1982). Such combination therapy, however, may prove hazardous in patients with a significant impairment of ventricular function. 7.2.3. Diltiazem Two recent multicenter, double-blind placebo controlled trials have demonstrated that the drug significantly decreases anginal frequency and nitroglycerin consumption, while increasing total exercise duration and the time to onset of angina (Hossack et al., 1982; Strauss et al., 1982). In this setting the drug appears safe with no effect on PR or QRS intervals on the surface ECG. Side effects necessitating discontinuation of diltiazem have been very rare (Strauss et al., 1982). As with verapamil, the dose of diltiazem is an important determinant of the therapeutic response. In early study with the drug utilizing 30-60 mg t.i.d., signs and symptoms of myocardial ischemia were improved in about 55~ of patients but in 26~o of patients placebo was more effective than diltiazem (Ono, 1972; Mizuno et al., 1973). More recent studies have demonstrated that 240 mg of diltiazem daily is more potent than 180 mg daily, a dose more effective than 120 mg daily, emphasizing the dose-dependence of the beneficial effects (Hossack et al., 1982). It is possible that the JPT 23/1

B

18

A.G. ELLRODTand B. N. SINGH

major mechanisms mediating the prolongation of duration of exercise by diltiazem in chronic stable angina is a reduction in the rate-pressure product (Hossack et al., 1982), although as in the case of all three calcium antagonists, augmented perfusion as a subsidiary effect is not excluded. The hemodynamic effects of diltiazem vary with the underlying hemodynamic status. For example, in one study patients were classified into two groups on the basis of pulmonary capillary wedge pressure: those with a PCW less than 16 mmHg (Group 1), and those pressures greater than 16 mmHg (Group 2). One hour following the administration of 120 mg of diltiazem, both groups experienced decreases in the frequency of anginal attacks, mean systolic blood pressure, systemic vascular resistance and in the rate-pressure product. However, those patients with a pulmonary capillary wedge pressure greater than 16 had a significant increase in cardiac output and a reduction in mean pulmonary artery pressure, mean PCW and pulmonary vascular resistance at peak exercise, compared to placebo (Hossack et al., 1982). Thus, although experience is still limited, diltiazem appears efficacious and safe in chronic stable angina when used at an appropriate dose and has therapeutically desirable effects in patients with disturbed left ventricular function, especially if the latter is due essentially to ischemia. 7.2.4. Calcium Channel Blockers and Other Antianginal Agents--Comparative Effects Since the antianginal efficacy of calcium channel blockers and other antianginal compounds are dose-dependent, direct comparisons are difficult. Using the degree of ST segment depression during an exercise tolerance test as test criteria, single doses of several agents have been compared. Nifedipine (20 mg sublingually), propranolol (80 mg orally), pindolol (2.5 mg orally), and nitroglycerin (0.8 mg sublingually) appear equally efficacious. Verapamil (5 mg intravenously) in this setting is somewhat less effective, and isosorbide dinitrate (10 mg orally) or pentaerythrityl tetranitrate (150 mg orally) are least effective (Kaltenbach, 1975). For the primary therapy of exertional angina nifedipine appears equal to isosorbide dinitrate in efficacy (Kimura, et al., 1975). Nifedipine (10 mg t.i.d.) is approximately equipotent to propranolol (20 mg t.i.d.) but less effective when compared to higher fl-blocking doses (40 or 80 mg t.i.d.) in reducing the frequency of anginal attacks (Kimura, Mabuchi and Kukuchi, 1975; Kenmure and Scruton, 1979). Nifedipine (10 mg) appears more effective than propranolol (20mg) in reducing exercise-induced ST segment depression, and more effective than metoprolol in enabling patients to tolerate greater workloads (Itoh et al., 1975; Ekelund and Ono, 1979). Verapamil (120mg t.i.d.) is equieffective to propranolol (100mg t.i.d.) in reducing anginal frequency, nitroglycerin consumption, and exercise induced ST depression and in prolonging the duration of exercise (Sandier and Clayton, 1968; Livesley et al., 1973). Propranolol (80 rag, q.i.d.) and verapamil (80 mg q.i.d.), improved exercise performance as judged by the prolongation of time to ST segment depression and comparable improvement in the ischemia-induced changes in ventricular ejection fractions. Neither drug at these doses reduces resting ejection fraction patients with good baseline ventricular performance (Sadick et al., 1982). Oral verapamil (480 mg per day) and oral propranolol (320 mg per day) are comparable in reducing the ischemic consequences of exercise. A comparison of two propranolol doses (40 mg q.6.h, and 80 mg q.6.h.) to two verapamil dosages (80 mg q.6.h, and 120 mg q.6.h.) has demonstrated that both propranolol and high-dose verapamil significantly reduce the need for nitroglycerin, and decrease ST segment deviations on ambulatory EKG recordings. Although neither drug has a deleterious effect on left ventricular volumes or left ventricular ejection fraction, propranolol may worsen forced vital capacity and forced expiratory volume (Johnson et al., 1981c). Finally, in a comparison of increasing doses of propranolol and verapamil, the latter produced greater improvement in exercise duration and in ischemic ST depression at the end of exercise. Of note was the observation that two patients experienced propranolol

Clinical uses of calcium antagonists

19

rebound while none had an exacerbation of angina during verapamil withdrawal (Frishman et al., 1982). Little information is available comparing different calcium antagonists with one ,'mother. In one double-blind randomized trial of verapamil (120 mg t.i.d.) and nifedipine (20 mg t.i.d.), both drugs increased maximum work capacity, decreased anginal frequency, consumption of glyceryl trinitrate, and systolic blood pressure at rest and with exercise. Overall efficacy was felt to be equal but side effects were more commonly encountered with nifedipine (Dawson et al., 1981). Thus, nifedipine, verapamil, and diltiazem all appear efficacious in the treatment of chronic stable angina, although their precise mechanism of action is not fully clarified. 7.3. UNSTABLE ANGINA PECTORIS Preliminary studies suggesting that the calcium channel blockers might be efficacious in unstable angina pectoris are currently being substantiated. Early results with nifedipine suggested that the addition of the drug (30-120 mg daily) to propranolol and long-acting nitrates could abolish rest pain in about 85~o of patients acutely, an effect that was maintained during a six-month follow-up (Moses et al., 1980; Previtali et aL, 1980). A large, double-blind randomized trial confirmed these preliminary observations. The efficacy of adding nifedipine to propranolol and nitrates using failure of medical treatment ~defined as sudden death, myocardial infarction or bypass surgery within four months) as an endpoint was assessed. Nifedipine was significantly more effective than placebo in the entire group. In the subset of patients with ST-segment elevation during attacks, nifedipine was particularly beneficial (Gerstenblith et al., 1982). Verapamil has also been effective in patients with unstable angina. A majority of patients will experience reduction in ischemic ¢,'pisodes without significant side effects (Parodi et al., 1979; Mehta et al., 1981). Thus, although experience is somewhat limited, nifedipine and verapamil are both efficacious in unstable angina, particularly in the group of patients in which coronary artery spasm may play a pathogenetic role. It is likely that diltiazem and other calcium antagonists will exert comparable beneficial effects. 7.4. MYOCARDIALINFARCTION Animal studies have demonstrated potential efficacy of the calcium channel blockers in preserving myocardium and perhaps attenuating the consequences of severe ischemia. Extrapolating the known hemodynamic effects of these drugs from the available data, it is reasonable to assume that these compounds are likely to be of therapeutic value in man with acute infarction. If coronary artery spasm is involved in the production of ischemic necrosis, calcium channel blockers may clearly be advantageous. In the context of fixed arterial obstruction; the dilatation of collateral vessels may enhance myocardial oxygen supply. Myocardial oxygen demand may be decreased through diminished contractility and decreased afterload induced by calcium antagonists. An additional potential mechanism by which these compounds may limit myocardial cell necrosis is through their effects on cellular calcium ion flux. After a period of myocardial ischemia and subsequent reperfusion, excess Ca 2+ has been observed to accumulate intracellularly, localized as dense bodies within the mitochondria (Shen and Jennings, 1972). A destructive chain of events ensues with a reduction of high-energy phosphate compounds, impairment of intra-cellular ion transport and contribution to myocardial cell death (Fleckenstein, 1971; Katz and Reuter, 1979). A direct relation between the amount of C a 2 + accumulated within the mitochondria and a degree of ventricular stiffness after ischemia has been observed (Henry, 1979). Thus, in myocardial infarction calcium channel blockers may be beneficial in limiting necrosis by their hemodynamic actions as well as by a direct effect at a subcellular level. In dogs with coronary occlusion nifedipine augments collateral flow to ischemic myocardium, improves subepicardial blood flow, decreases anatomic infarct size, preserves ventricular function, and improves contraction of the ischemic ventricular wall (Schmier et al., 1976; Perez et al., 1979; Clark et al., 1979; Henry, 1979). The dose of nifedipine

20

A.G. ELLRODTand B. N. SINGH

appears important. 'Low doses' appear protective but 'high doses' (13 mg/kg body wt) produce excessive hypotension, reflex tachycardia and increased infarct size (Selwyn et al., 1979). The effect of verapamil on myocardial necrosis is also in part dose-dependent. Low doses (0.005/~g/kg per minute do not improve coronary flow or metabolic indices of myocardial ischemia (Karlsberg et al., Jennings, 1977; Singh et al., 1975). Moderate doses (0.8 mg/kg) reduce the amount of myocardial necrosis without significantly affecting heart rate, LVEDP, or left ventricular dp/dt. Larger doses (3.5 mg/kg) produce a greater reduction in myocardial necrosis but depress myocardial contractility and cause AV block (Reimer et al., Jennings, 1977; DeBoer et al., 1980). DaLuz et al., 1980). Unlike nifedipine, verapamil appears to selectively depress the contractility of the acutely ischemic myocardium in doses at which the contractility of normal myocardium is unaffected (Smith et al., 1976). Whether this effect is protective or detrimental is at present unclear. Diltiazem has also been shown to increase subepicardial blood flow in iscnemic zones after coronary occlusion in animal models. Despite the reduction in epicardial ST-segment elevation, no decrease in infarct size or protection of mitochondrial function has been seen when the drug is administered post-coronary ligation (Nakamura et al., 1979; Weishaar et al., 1979). However, pretreatment of animals has demonstrated preservation of mitochondrial and ventricular function during reperfusion (Nagao et al., 1980). In summary, experimental data suggest a promising role in the preservation of myocardium in acute ischemic syndromes, and provide the basis for controlled clinical trials and evaluation in man. However, for the present, the clinical use of calcium antagonists for myocardial preservation or 'cardioprotection' during open heart surgery (see below) must be considered investigational. 7.4.1. Cardiopulmonary Bypass Experimental work and early clinical studies suggest the efficacy of calcium antagonists in protecting myocardium during open-heart surgery. In isolated rabbit hearts the addition of nifedipine has been shown to prevent ischemic contracture. In addition, C a 2+ accumulation in mitochondria is inhibited and ventricular function preserved (Henry et al., 1979). Prophylactic treatment of rabbit hearts with verapamil, nifedipine, or propranolol prevents ischemic and reperfusion induced decline in ATP-generating and oxygen utilizing capacity of the mitochondria (Naylor et al., 1980). In dogs undergoing cardiopulmonary bypass, nifedipine preserves ventricular function. This occurs under hypothermic as well as normothermic conditions (Henry, 1979; Clark et al., 1979). Administration of nifedipine during either the ischemic or reperfusion period improves stroke-work index and left ventricular dp/dt, and reduces the volume of myocardial injury. Myocardial function and structure are further improved by the administration of the drug during both the ischemic and reperfusion periods (Clark et al., 1979b). It has been proposed that K + added to cardioplegic solutions to preserve myocardial function may serve as a physiologic Ca 2+ channel blocker (Stone et al., 1980). Comparisons of nifedipine or diltiazem and potassium in cardioplegic solutions have been performed in animals. In one study of canine hearts, nifedipine arrest offered no significant advantage over potassium arrest (Johnson et al., 1982). In another comparison of two concentrations of nifedipine (10 and 100 #g/dl) during hypothermic cardiac arrest, the low dose was not protective and high dose was as efficacious as K + in preserving left ventricular functional capacity (Vorhe et al., 1982). In a comparison of diltiazem and K + as cardioplegics in dogs, the calcium antgonist provided better overall myocardial protection even when coronary flow was impaired by a critical stenosis (Vorhe et al., 1982). Early results suggest that in the addition of nifedipine (275 #g/i) to standard cardioplegic solution improves hemodyamic function immediately following cardiopulmonary bypass, and decreases myocardial enzyme release (Clark et al., 1981). These preliminary experimental data on the use of various calcium antagonists suggests a potential utility in minimizing the severity of ischemic damage during open-heart surgery.

Clinical uses of calcium antagonists

21

However, the relative potency of individual agents in this context is uncertain. It is unclear whether as a class of agents they are superior to other cardioplegic regimens. It must nevertheless be emphasized that a great deal of the safety of these compounds may depend on reflex actions induced by peripheral dilatation. If these are blocked by concomitant lherapy with/3-antagonists, while ischemic injury might be reduced, severe hemodynamic depression may result. This possibility merits further detailed investigation. The clinical significance of these promising overall experimental observations need therapeutic validalion. 8. SLOW CHANNEL BLOCKERS IN HYPERTROPHIC CARDIOMYOPATHY Patients with hypertrophic cardiomyopathy have systolic and diastolic abnormalities of ventricular function (Lorell et al., 1982). The degree of 'dynamic obstruction' to left ventricular ejection is directly related to the inotropic state. For this reason, fl-blockers have long been utilized in this context (Harrison et al., 1964), with variable success. However, propranolol neither reduces the incidence of serious ventricular arrhythmias nor lhe risk of sudden death (Harderson et al., 1976; Goodwin and Krikler, 1976; McKenna et al., 1980). The calcium channel blockers by their negative inotropic activity might be expected to exert a salutary effect on systolic performance in hypertrophic cardiomyopathy. Early studies with verapamil (480 mg daily) demonstrated significant improvement in comparison with /~-blockers. Uncontrolled clinical studies found reduction in electrocardiographic signs of left ventricular hypertrophy and heart size assessed radiographically with the calcium antagonist (Kaltenbach et al., 1976). A decline in the resting outflow tract obstruction in 50~o of patients with decrease in left ventricular mass in 70~ of patients has also been demonstrated (Kaltenbach et al., 1979). Improvement in basal and provoked left ventricular outflow gradients is significant in most patients and is dose dependent. Cardiac output remains unchanged or increases slightly, without significant increases in left ventricular end-diastolic pressure (Rosing et al., 1979). A direct but uncontrolled comparison of verapamil and propranolol at varying doses has shown that both produce an increase in exercise tolerance of about 20-25~ acutely. However, with long-term therapy, exercise capacity deteriorates more frequently with propranolol and may actually increase with verapamil (120 mg q.i.d.). Patients symptomatically prefer verapamil. However, a large number of patients develop significant side effects with long-term verapamil use including sino-atrial and atrioventricular node dysfunction, and occasionally severe myocardial dysfunction and heart failure (Rosing et al., 1979b). In children with hypertrophic cardiomyopathy intravenous verapamil increases cardiac output, decreases LVEDP and diminishes the intraventricular 'pressure gradient' at rest. With exercise, total workload at maximal cardiac output are increased while max LVEDP and maximum systolic outflow gradient are reduced (Spicer et al., 1983). Diastolic dysfunction in patients with hypertrophic cardiomyopathy may also be improved with calcium antagonists. Verapamil has been shown to shorten the abnormally prolonged isovolumic relaxation time in such patients (Hanrath et al., 1980). Nifedipine has also been demonstrated to favorably modify abnormal left ventricular relaxation and diastolic filling rates. This effect does not appear to be related to depression of left ventricular systolic function (Lorell et al., 1982). Administration of nifedipine alone could be deleterious through its potent abilities to stimulate reflex sympathetic discharge. The combined administration of nifedipine and propranolol has been demonstrated to be superior to the use of the calcium channel blocker alone (Landmark et al., 1982). The combination reduced left ventricular peak systolic pressure, total peripheral resistance and resting left ventricular outflow gradient without altering cardiac index, pulmonary capillary wedge pressure, or inducing conduction defects (Landmark et al., 1982). A study of diltiazem in hypertrophic cardiomyopathy has demonstrated attenuation in exercise-

22

A.G. ELLRODTand B. N. SINGH

induced elevation of pulmonary artery diastolic pressure, suggesting an improvement in left ventricular diastolic function (Nagao et al., 1981). Thus, the calcium antagonists, alone or in combination with fl-blockers, appear to improve both systolic and diastolic function in hypertrophic cardiomyopathy. Long-term follow-up studies and comparative efficacy of the various calcium antagonists and combination regimens will be of interest. Of special importance will be the effect of these drugs on the mortality secondary to sudden death. 9. ACUTE AND CHRONIC SYSTEMIC HYPERTENSION Sound theoretical considerations and the available experimental data suggest an important role for the calcium channel blockers, in the treatment of hypertension. Their clinical utility in this setting has not, however, been fully elucidated. Increased intracellular sodium with increased intracellular calcium in vascular smooth muscle may be a pathogenetic mechanism in systemic hypertension (Wei et al., 1976; Zsoter et al., 1977; Blaustein, 1977). A reassuring clinical observation is that nifedipine and verapamil appear to lower blood pressure to a degree directly related to pretreatment levels. In normotensive patients with preserved ventricular function there is usually little or no reduction in blood pressure following 10 mg of nifedipine orally or 5 mg of verapamil intravenously (Aoki et al., 1978; Brittinger et al., 1970). In contrast, in patients with elevated blood pressures the magnitude of. reduction is related directly to the basal levels of arterial pressure and systemic vascular resistance (Brittinger et al., 1970; Bartorelli and Guazzi, 1979). Thus, with 10 mg of nifedipine (orally or sublingually) or 5 mg of intravenous verapamil, the blood pressure reduction in severely hypertensive patients may be highly significant (Brittinger et al., 1970; Aoki et al., 1978). In the canine renovascular hypertension model nifedipine decreases systemic vascular resistance, lowers systolic and diastolic arterial pressure, induces tachycardia and increases cardiac output. The drug reduces coronary vascular resistance and decreases myocardial oxygen consumption thereby improving the myocardial supply demand relationship (Hiwatari et al., 1979). Studies of the calcium antagonists have thus far examined the acute and chronic treatment of hypertension in uncontrolled pilot studies only. Preliminary information is available regarding the combination of calcium antagonists with other antihypertensive medication, but such combinations need further controlled studies. 9.1. ACUTE ANTIHYPERTENSIVE EFFECTS OF CALCIUM CHANNEL BLOCKERS Several reports demonstrating the efficacy of nifedipine in patients with hypertensive emergencies have been published (Kuwajiami et al., 1978; Veda et al., 1979; Guazzi et al., 1977). In a study of nifedipine in the emergency room setting, nifedipine was also efficacious. In patients whose initial blood pressures were less than 100 mmHg diastolic, 10ms of nifedipine administered sublingually decreased the average systolic pressure between 172-140mmHg, and the average diastolic pressure between 109-88 mmHg. In that group of patients with more severe hypertension (diastolic pressure greater than 110 mmHg), the administration of 20 mg of nifedipine sublingually produced a decrease in average systolic pressure from 203 mmHg to 160 mmHg and average diastolic pressure from 128 mmHg to 97 mmHg. The onset of action was seen within one to five minutes and minimal adverse reactions were observed; these included facial flushing in three patients and symptomatic orthostatic hypotension in one (Beer et al., 1981; Ueda et al., 1979). 9.2. CHRONIC ANTIHYPERTENSION EFFECTS OF CALCIUM CHANNEL BLOCKERS Limited data concerning the utility of the calcium antagonists as single agents in chronic hypertension are available (Lederballe, 1978; Ueda et al., 1979). The efficacy of nifedipine appears to be dose-related with 10 mg three or four times daily, producing a moderate decrease in arterial pressure (Ueda et al., 1979, Murakawi et al., 1972) and 30 mg orally, producing more dramatic reductions in pressure (Aoko et al., 1976). The duration of

Clinical uses of calcium antagonists

23

antihypertensive action is also dose-related. At about 90 min after a 10 mg sublingual dose, blood pressure begin to return toward baseline, but the hypertensive effect of a 20 mg dose is still present at six to eight hours (Lederballe and Mikkelsen, 1978). During chronic oral therapy, 10 mg of nifedipine has an anti-hypertensive effect which lasts 8-12 hr. Administration every 6 hr significantly reduces blood pressure throughout the day without postural hypotension, development of drug resistance, sodium retention, plasma volume expansion, renin release or production of angina pectoris. The average blood pressure in one study fell from 198/122 mmHg to 165/97 mmHg. These preliminary results suggest that nifedipine may be useful as a single agent in the control of hypertension. The combination of nifedipine with either propranolol or methyl-DOPA produces an additive hypotensive effect. Whereas 30 mg of nifedipine administered sublingually decreases systolic pressure by 27~ and diastolic pressure by 28~, the addition of oral propranolol (0.2mg/kg) further decreases systolic pressure and diastolic pressure. In addition, the reflex increase in heart rate and plasma renin activity seen after a single dose of nifedipine is abolished, and its duration of antihypertensive action prolonged by propranolol (Aoki et al., 1978). The addition of methyldopa to nifedipine produces a significant additive reduction in arterial pressure. This combination demonstrates sustained efficacy over a 12-month follow-up (Guazzi et al., 1980). Experience with verapamil during prolonged trials has yielded conflicting results. The drug's hypotensive effect was not sustained in one trial of 320°640 mg daily over a seven-week period (Lederballe, 1978). However, using a continuous intra-arterial pressure monitoring system before and after six weeks or oral verapamil therapy (1200160 mg t.i.d.), the drug was demonstrated to produce a consistent reduction in arterial pressure (Gould et al., 1982). Preliminary studies with diltiazem (60-90mg daily) demonstrated acute lowering of arterial pressure but gradual return to control values after several weeks of therapy (Sakuri et al., 1972). More information regarding the long-term efficacy of verapamil and diltiazem is needed before their role as single chronic antihypertensive agents is established. The delineation of dose-response characteristics and utility in hypertension of various etiologies is needed. In addition, the utility and safety of verapamil and diltiazem in combination with other antihypertensive needs to be examined. Although experience remains limited, nifedipine, with its potent vasodilator properties, appears most promising in the acute and chronic treatment of hypertension. The combination of nifedipine and a fl-blocker may prove of particular value in patients with combined hypertensive and coronary disease. Future controlled studies should address not only the issue of comparative efficacy of these compounds as single agents and in combination regimens, but also the mechanisms that might be involved in mediating their observed beneficial responses. The data will be of particular interest in patients with systemic hypertension and angina. 10. P U L M O N A R Y HYPERTENSION AND SLOW CHANNEL BLOCKERS Caclium channel blockers are promising from the theoretical as well as the experimental standpoint in pulmonary hypertensive disorders arising from increased pulmonary arterial vasomotor tone. However, as with most pharmacological interventions in this context, lhere is little controlled data confirming the clinical efficacy of these agents. The effects of intravenous verapamil (mean dose 9.6 mg) have been studied in patients with pulmonary hypertension (Landmark et al., 1978). In a group of patients with a mean pulmonary arterial pressure of 57 mmHg secondary to pulmonary fibrosis, congenital heart disease or primary pulmonary hypertension, the drug caused a slight decrease in mean pulmonary artery pressure and right ventricular performance in several patients. In others it had a marked negative inotropic effect with an increase in pulmonary arteriolar resistance. Overall, right atrial pressure, right ventricular end-diastolic pressure, pulmonary arteriolar resistance, and cardiac index were unchanged. Perhaps because of

24

A.G. ELLRODTand B. N. SINGH

nifedipine's less inherent negative inotropic properties in man, very preliminary studies have suggested that it may be effective in selected patients. In one case of primary pulmonary hypertension, nifedipine produced a 54~o decrease in pulmonary vascular resistance, a 49~o decrease in systemic vascular resistance and a 90~o increase in cardiac output. This improvement was maintained over a three-month period (Camerini et al., 1980). In another study of patients with acute respiratory failure and chronic airflow obstruction, nifedipine dilated pulmonary vessels constricted by hypoxemia. No further vasodilatory effect was demonstrated, however, when hypoxemia was corrected. No adverse effects on arterial oxygenation were noted (Simonneau et al., 1981). Experience with diltiazem is also limited. A case report demonstrating the drug's effectiveness in primary pulmonary hypertension has been published (Kambara et al., 1981). In one study of five patients with pre-capillary pulmonary hypertension, hemodynamic improvement occurred in four patients. The decline in pulmonary artery pressure and total pulmonary resistance at rest and during exercise was modest, however. No worsening of gas exchange or ventilation-perfusion distribution was noted (Crevey et al., 1982). Although available data concerning calcium antagonists in pulmonary hypertensive states are somewhat encouraging, they are preliminary and essentially anecdotal. In addition, adverse effects have been noted probably due to inherent myocardial depressant properties and possibly due to differential vasodilation of the pulmonary and systemic vascular beds. It is premature to conclude that available calcium antagonists will make a major impact on the chronic prophylactic therapy of pulmonary hypertension. However, as more selective calcium channel blockers become available, specific vasodilation of the pulmonary arterial bed might be possible with improved clinical results. Nevertheless, it appears inherently unlikely that calcium antagonists as a class of therapeutic agents will constitute a major advance in the management of pulmonary hypertension. 11. SLOW CHANNEL BLOCKERS IN ACUTE AND CHRONIC CONGESTIVE HEART FAILURE Since calcium antagonists are potent vasodilators, they may function as agents to improve myocardial function in patients with heart failure by impedance reduction. As a class, however, these compounds are unlikely to become the first-line therapy in this regard. Their greatest value may prove to be in the patient who has myocardial ischemia in the setting of cardiac decompensation and/or systemic hypertension. Available data suggest that nifedipine may be an effective preload and afterload reducing agent in the setting of acute pulmonary edema. The adminstration of 10 mg of nifedipine sublingually appears to rapidly improve congestive heart failure secondary to hypertensive, rheumatic or primary heart disease. The drug induces a sustained decrease in preload and afterload and appears to enhance contractility (Polese et al., 1979). Compared to nitrates, nifedipine has a greater tendency to increase cardiac output, without inducing venous pooling (Henry et al., 1979). In patients with advanced chronic congestive heart failure, the acute administration of nifedipine (2 mg sublingual) increases cardiac index and stroke work index, while significantly decreasing preload. These changes appear to be due to decreased systemic vascular resistance. Sustained hemodynamic improvement has been noted in less than 50~o of patients, however, suggesting tolerance or possible sodium retension (Matsui et al., 1979). The role of the other calcium antagonists in this setting is essentially unexplored. 12. SLOW CHANNEL BLOCKERS IN CEREBRAL AND PERIPHERAL VASOSPASTIC DISORDERS Early experimental observations with nifedipine demonstrated reversal of acute cerebral arterial spasm induced by injection of blood into the subarachnoid space (Allen and Bahr, 1979). In vitro nifedipine appeared to exert a relatively selective activity, preventing spasm-induced in basilar artery segments more so than in femoral arteries (Allen and Bahr, 1979). Nimodipine, a substituted 1,4 dihydropyridine, is an analog of nifedipine. This drug

Clinical uses of calcium antagonists

25

appeared particularly promising in experimental studies for the treatment of cerebral vasospasm complicating subarachnoid hemorrhage in humans. The drug is lipid soluble and therefore should cross the blood-brain barrier to reach the cerebral artery smoothmuscle cells (Allen et al., 1983, Cohen and Allen, 1980). Nimodipine, like nifedipine, appears to be a more potent vasodilator of cerebral arteries than those of other regional circulatory such as the femurals. However, animal studies demonstrated that nimodipine was a more potent cerebral vasodilator than nifedipine and was therefore chosen for a prospective, randomized, double-blind, placebo controlled trial in preventing or modifying ischemic neurologic deficits in humans with subarachnoid hemorrhage secondary to aneurysm (Allen et al., 1983). This multicenter trial demonstrated a significant reduction in the occurrence of severe neurologic deficits due to cerebral vasospasm in patients who were essentially neurologically normal at entry into the study. During the three week period of drug administration, no increase in the rate of rebleeding or surgical complications was noted. In addition, no significant medical side effects were noted. Finally, significant levels of the drug were found in the cerebrospinal fluid of subjects suggesting that the drug crossed the blood-brain barrier and explaining, in part, its efficacy (Allen et al., 1983). The authors of this study appropriately point out that these results should not be extrapolated to other slow channel blockers and that studies attempting to delineate the optimal dose of ninodipine are needed. Nevertheless, this study appears to be a significant advance in the prevention of cerebral vasospasms complicating subarachnoid hemorrhage. Moreover, it demonstrates that in the future, slow channel blockers will be targeted for specific areas of the cardiovascular system. Another vasospastic disorder that has been particularly vexing for physicians has been the peripheral vascular disorder precipitated by cold or emotional stress. These attacks have been characterized by sequential white pallor, cyanotic blue and deep red color changes of the digits. This has been referred to as Raynaud's Disease in its primary or idiopathic form, and Raynaud's phenomenon or syndrome when such attacks are secondary to occlusive vascular disease or connective tissue disease (Jobe et al., 1982). Several trials and case reports addressing the role of slow channel blockers in Raynaud's disease and phenomenon have recently been reported. An open-label study of oral verapamil in patients with Raynaud's phenomenon associated with progressive systemic sclerosis demonstrated that 80~o of patients had pronounced symptomatic improvement as judged by frequency and severity of attacks. In addition, there appeared to be a good correlation between symptomatic benefit and reappearance of digital pulse volume recordings after cold water immersion, and increased digital pulse pressures (Kinney et al., 1980). A preliminary study of nifedipine demonstrated efficacy in 14 of 16 patients. Response to therapy was considered excellent in seven patients (four with Raynaud's phenomenon) and good in seven (Kahan et al., 1981). In a double-blind crossover study of 17 patients with moderate to severe Raynaud's phenomenon, nifedipine significantly reduced the frequency and severity of attacks in 12 patients although skin temperature recovery time was not affected (Smith and McKendry, 1982). Preliminary reports suggest that diltiazem may also be efficacious in Raynaud's disease and phenomenon. The drug has been found useful in the long-term management of Raynaud's disease in a study of 26 patients (Vayssairat et al., 1981). Diltiazem has also been reported to be efficacious in the long-term treatment of patients with occupational Raynaud's phenomena (vibration disease) (Matoba et al., 1982). Thus, preliminary data support the further investigation of verapamil, nifedipine, and diltiazem in Raynaud's disease and syndrome. 13. ANTIPLATELET PROPERTIES OF SLOW CHANNEL BLOCKERS Three independent biochemical pathways appear responsible for platelet activation. Cellular release of adenosine diphosphate, the prostaglandin cyclic endoperoxides and

26

A.G.

ELLRODT a n d B. N. SINGH

thromboxane A2, and the platelet aggregating factor pathway have been well described. All result in decreased cyclic adenosinel-monophosphate, an increase in cytoplasmic calcium (Pumphrey et al., 1983). Reduction of the calcium flux might, therefore, alter platelet response regardless of the primary stimulus. Therefore, the possibility must be considered that slow channel blockers may exert clinically significant rate as inhibitors and platelet aggregatability. In vitro, verapamil appears to reduce or prevent epinephrine-induced thromboxane f12 release, platelet aggregation, and serotonin release and uptake. This has been observed in animals and healthy human volunteers (Addonizio et al., 1980; Chierchia et al., 1981; Ribeiro et al., 1980). In dogs verapamil, nifedipine and dipyridamole have been compared in the prevention of indium-Ill labeled autologous platelet deposition and thrombus development in polytetrafluoethylene grafts. In this model, the three drugs were equally effective in the prevention of thrombus formation (Pumphrey et al., 1983). The administration of verapamil to patients with coronary artery disease results in a rapid decrease in circulating platelet aggregates (Chierchia et al., 1981). In the same clinical setting, nifedipine reduces the mean maximal rate of primary platelet aggregation (a process dependent upon extracellular calcium). The mean bleeding time is also slightly prolonged (Dale, Landmark and Muhre, 1983). Thus, nifedipine and verapamil appear to have moderate effects on calcium dependent platelet function. Although their clinical utility in this area requires further definition, an understanding of the net cardiovascular effects of the slow-channel blockers requires an understanding of their 'direct' and 'indirect' actions. 14. CLINICAL PHARMACOLOGY OF SLOW CHANNEL BLOCKERS The optimum therapy of any patient obviously requires an understanding of the pathophysiology of their disease process and the pharmacodynamics and pharmacokinetics of drugs used in treatment. Although nifedipine, verapamil and diltiazem have been available in the United States for a relatively brief time, significant pharmacologic data have been obtained, particularly with verapamil. Table 3 summarizes the pharmacokinetic observations with these three agents. 14.1. NIFEDIPINE Ninety per cent of orally or buccally administered nifedipine is absorbed (Horster et al., 1972; Horster, 1975). The drug first appears in the plasma approximately 3 min after buccal TABLE 3. Clinical Pharmacokinetic Parameters of Three Calcium Antagonists Verapamil

Absorption Bioavailability Onset of action Peak action Elimination half-life

Protein Binding Metabolism First pass Metabolites Activity Accumulation Excretion Gastrointestinal Renal Dose

Nifedipine

Diltiazem

> 79% 10-20% 1 2 hr (oral) ~1 min (i.v.) 3-4 hr (oral) 2-5 min (i.v.) 3 7 hr (up to 26 hr in hepatic cirrhosis) 90% Liver 85%

> 90% 65-75% 15 min (oral) 2-3 min (s.L.) 1 2 hr (oral) 20 min (s.L) 4 hr

4hr

90% Liver 20-30%

90~ Liver 50%

20-35% (nor-verapamil) 100%

None

4(~50% (desacetyldiltiazem) 10-30%

25 75 i.v.: 0.075~.15 mg/kg

15 85 s.L.: 10-40 mg tid or lid oral: 10-40 mg tid or qid

None

> 90~ 45% 15 min (oral) 2-3 min (i.v.) 30 min

15 85 i.v. 0.25 mg/kg oral: 30-90 mg tid or bid

Clinical uses of calcium antagonists

27

administration and 20 min following oral administration. Peak blood concentrations are reached 1-2 hr after an oral dose. First-pass extraction by the liver is low and systemic bioavailability is about 65~o. Nifedipine is more than 90~ bound, and is completely metabolized to inactive polar forms. Approximately 80~o of a given dose is excreted in the urine and 15~o eliminated via the gastrointestinal tract (Horster, 1975). No accumulation of the drug or its metabolites has been reported during chronic therapy. The plasma half-life 4-5 hr (Horster, 1975). Since difficulties exist in interpretation of results with present assay methods, data correlating nifedipine plasma concentrations with clinical drug effects are rare (McAllister, 1982). A dose dependent aspect of drug administration within a relatively narrow acute and chronic therapeutic range is, however, well described (McAllister, 1982). The usual starting dose of nifedipine is 10 mg three times per day. The dose should be increased until relief of symptoms occurs, side effects develop, or the generally recommended maximal close of 120 mg daily is reached. Adjustment of the dosing interval to every four hours may be necessary if symptoms recur before the next scheduled dose (Stone et al., 1980). Blood pressure should be monitored carefully as a guide to drug effect (McAllister, 1982). 14.2. VERAPAMIL Verapamil is well absorbed orally with measurable electrophysiologic effects appearing at two hours. Peak action is at five hours following a single dose (Schlepper et al., 1975; Singh et al., 1980). A disparity exists between verapamil's hemodynamic and electrophysiologic effects. Following intravenous administration, the hypotensive effect of the drug is shortlived with a peak effect at five minutes and dissipation by 10o20 min (Singh and Roche, 1977). The negative dromotropic effect is seen within one to 2min, peaks at 10015min, but may still be observed after 6hr. Preferential uptake and binding of verapamil by the atrioventricular node has been postulated to explain this observation (Singh et al., 1980). Verapamil is about 90~ protein bound without significant clinical differences between normals and patients with renal disease (Keele et al., 198 l). After either oral or intravenous administration, the drug exhibits biexponential decay. An initial distribution phase of about 18-35 min is followed by an elimination phase of 3-7 hr. Although verapamil is 90~o absorbed by the oral route, a substantial first-pass effect in the liver reduces the overall bioavailability to about 10-20~o (Schomerus et aL, 1976). Verapamil has been observed to accumulate to a greater extent than predicted by its half-life due to decreased hepatic clearance. Its active metabolite nor-verapamil accumulates 2.5 fold during attainment of steady state after oral dosing (Shand et al., 1981). Variations in verapamil plasma concentrations may be explained by differences in hepatic blood flow (Woodcock et al., 1981). As is the case with nifedipine, the clinical usefulness of following serum concentrations of verapamil is controversial. Different patients demonstrate wide variations in serum levels on similar doses. Although plasma levels increased with increasing dose in patients with paroxysmal atrial tachycardia, they were not helpful in planning therapy in one study (Pritchett et al., 1981). In another study, during chronic oral therapy for recurrent supraventricular tachycardia or vasospastic angina, heart rate and PR interval did not significantly change, but plasma levels correlated with relief of symptoms (Reddy et al., 1981). In patients with hypertrophic cardiomyopathy, plasma levels have been found to be of limited utility because of marked interpatient variation, and the finding of similar serum levels in patients who responded to therapy and those who experienced serious side effects (Leon et al., 1981). Although an initial dose of 5 mg administered intravenously over 60 sec has been recommended for the termination of atrial arrhythmias, the most common dose is l0 mg (0.1 mg/kg body wt). This should be given with electrocardiographic and blood pressure monitoring (Singh et al., 1980). If the arrhythmia is not terminated by the initial injection, l0 mg may be administered within 30 min following the initial injection. If a continuous effect is desired, an infusion of 0.005 mg/kg per minute may be administered. The dose of verapamil should be reduced in the presence of myocardial dysfunction. The usual initial

28

A . G . ELLRODT and B. N. SINGH

oral dose is approximately 10 times the intravenous dose due to the extensive first-pass hepatic effect. A starting dose of 40-80 mg every 8 hr is recommended. This may be rapidly increased over the next several days to the usual 240-360 mg per day. In patients without known contraindications, doses as high as 720 mg daily have been suggested (Singh, Collett and Chew, 1980) and may be tolerated in a few patients. 14.3. DILTIAZEM Although no studies examining the relationship between plasma blood level and effect have yet been reported, some pharmacokinetic data are available. Diltiazem is rapidly and almost completely (90~o) absorbed following oral administration. The drug first appears in plasma at 15 min with peak concentrations occurring after 30 min. The plasma half-life is about 4-5 hr. A 50~ first-pass effect has been observed with hepatic conversion to the active metabolite desacetyldiltiazem. Approximately 60~o of the drug is hepatically metabolized with the remainder excreted by the kidneys. Diltiazem is about 80~o protein bound (Piepho et al., 1982 Zelis and Kinney, 1982; Kohno et al., 1977; Meshi et al., 1971). The usual oral dose of the drug is 30-60 mg every 8 hr, but doses up to 120 mg every 8 hr are well tolerated. 15. SIDE EFFECTS, CONTRAINDICATIONS, AND PRECAUTIONS The major side effects of verapamil, nifedipine, and diltiazem are generally predictable from their inherent vasodilatory and relative negative inotropic and dromotropic properties (See Table 4). Side effects may also vary in relation to the route of administration. 15.1. NIFEDIPINE The safety and incidence of side effects with nifedipine has been reasonably studied. A recent review of the records of over 3,000 patients treated with the drug provides useful information (Terry, 1982). In this report, patients with various anginal syndromes, some complicated by CHF, and many studied for longer than six months, about 60~o experienced no adverse side effects. Dizziness and lightheadedness were reported in 21.1~o of the total population and were more frequent in patients with congestive heart failure and in those on long-term therapy. Edema, swelling and fluid retention occurred in 7.7~o of the population and was also more common in patients with congestive failure and on long-term therapy. Disturbances of upper gastrointestinal tract function and headache occurred in about 7~o of patients, while flushing or burning, and a general or specific feeling of weakness were reported in 7.4~o and 5.9~o of cases, respectively. Less common side effects included hypotension, precipitation of angina, precinfarction angina or myocardial infarction, and congestive heart failure in less than 4~o of patients. The total percentage of patients in whom therapy was discontinued due to an adverse experience was 5~ (Terry, 1982). The overall incidence of side effects may, however, be considerably higher and has been estimated to be about 17~o. 15.2. VERAPAMIL Following intravenous verapamil, the adverse effects reported have been predictable from the drug's known pharmacological properties. Perhaps the most common is a TABLE4. Adverse Effects of Calcium Channel Blockers Nifedipine Verapamil (17~o)* (9~o)* Ankle edema Constipation Headache Headache Dizziness Dizziness Tinnitus Nausea Flushing Galactorrhea Hypotension Hepatotoxicity Aggravation of angina (occasionally) AV block Nasal congestion Congestive Heart Failure *Estimated overall incidence of side effects in therapeutic doses.

Diltiazem (4~o)* Dizziness Headache Fatigue Blurred vision Flushing AV block

Clinical uses of calcium antagonists

29

transient fall in blood pressure (Heng et al., 1975; Schamroth, 1971). More serious side effects, including hypotension, bradycardia and rarely ventricular asystole have been observed, however (Benaim, 1972; Boothbey et al., 1972). In general, these latter patients were receiving concomitant fl-blocking drugs. Suicidal overdose with verapamil, manifested by unconsciousness, hypotension, anuria and AV block has been reported (Immonen et al., 1981). These severe side effects of verapamil can be successfully treated with intravenous atropine (partially effective), catecholamines (particularly Isuprel), and intravenous calcium gluconate. Occasionally, temporary transvenous ventricular pacing may be necessary (McGoon et al., 1982). Oral verapamil is well tolerated. The most common side effects include constipation, dizziness, nausea, headache and ankle edeman. In general, these symptoms are relatively mild and can be managed symptomatically (McGoon et al., 1982). Unusual side effects include galactorrhea (Gluski et al., 1981) and reversible hepatic toxicity (Brodsky et al., 1981). Prolongation of first degree AV block occurs in a proportion of patients given chronic oral verapamil therapy, but in the absence of antecedent conduction system disease, more advanced grades of heart block are unusual. In patients with normal ventricular function, the precipitation of clinically evident cardiac failure is very uncommon. The overall incidence of side effects following oral verapamil therapy is about 9%. Verapamil should be used with great caution in the presence of advanced heart failure, unstable AV block, diseases of the conduction system including the sick sinus syndrome and hypotensive states, particularly cardiogenic shock. In situations in which heart failure is related to persistence of a rapid atrial tachyarrhythmia, however, prompt reversion to sinus rhythm by verapamil may lead to improvement in the clinical status. As already emphasized, verapamil is contraindicated in cases of atrial flutter or atrial fibrillation complicating the Wolff-Parkinson-White syndrome (Rinkenberger et al., 1980; Gulamhusein et al., 1982). 15.3. DILTIAZEM Experience with diltiazem is more limited in terms of side effects and data are derived from studies in angina. Dizziness, headache, fatigue, blurred vision, flushing and minor degrees of AV block have been reported when the drug is administered in daily doses of 240-360 mg. Overall, however, diltiazem appears to have the lowest incidence of side effects with estimates of about 4%. Diltiazem, like verapamil, is contraindicated in patients with atrial flutter or fibrillation complicating the Wolff-Parkinson-White syndrome (Gulamhusein et al., 1982). In all, nifedipine, verapamil and diltiazem produce predictable side effects. However, there appear to be significant differences in frequency of side effects and propensity to produce specific reactions. In addition, the underlying disease process may significantly influence the frequency and severity of adverse reactions, and the selection of a slow channel blocker. 16. SLOW CHANNEL BLOCKERS--INTERACTIONS BETWEEN DIGITALIS GLYCOSIDES AND fl-BLOCKERS Since a significant number of patients in whom calcium channel blockers may be receiving concomitant digitalis or fl-blocker therapy, an understanding of potentially beneficial and adverse interactions is important. Such interactions may have pharmacokinetic, hemodynamic and/or electrophysiologic repercussions. The two most important precautions in combining digitalis preparations and calcium channel blockers are the potential additive electrophysiological effects and the tendency for certain calcium antagonists to increase serum digoxin levels. However, unless there is evidence of impaired AV conduction, prior digitalization is not a contraindication to the use of intravenous verapamil. In two studies of intravenous verapamil, 61% and 79% of patients were receiving maintenance oral digitalis at the time of administration of verapamil. In neither case could a significant untoward reaction be attributed to the

30

A.G. ELLRODTand B. N. S~NGH

combination (Heng et al., 1975; Schamroth, 1971). The combination of intravenous diltiazem and digoxin in patients with underlying SA or AV node disease appears to have an additive depressant effect with significant adverse effects (Mitchell et al., 1982). Verapamil has been shown to decrease the renal clearance of digoxin and increase its plasma concentration (Belz et al., 1981). This effect appears dependent upon the dose of verapamil used. It develops gradually over the first few days after the addition of the calcium antagonist to a stable oral digoxin dose (Klein et al., 1982). In one study, the mean digoxin levels rose from 0.76 to 1.31 with 7 of 49 subjects developing signs and symptoms suggesting digitalis toxicity (Klein et al., 1982). In another study, in patients with chronic atrial fibrillation, the mean serum digoxin levels rose from 1.6 to 2.7 mg/ml during the addition of verapamil, but no patients developed evidence of digitalis intoxication (Schwartz et al., 1982). Thus, caution and careful surveillance are advised in the concomitant administration of verapamil or diltiazem with digitalis preparations. Increases in serum levels of digoxin during nifedipine therapy have also been reported (Belz et al., 1982). The combination of a calcium antagonist and fl-blocker is advantageous in a number of clinical settings. Care must be taken, however, in selecting patients to avoid untoward side effects. The potentially deleterious effect of combining verapamil and fl-blockers has received the most attention. Persistent hypotension, bradycardia, high-grade AV block and ventricular asystole have all been observed, particularly following the intravenous administration of verapamil (Waxman et al., 1981; Singh et al., 1979; Benaim, 1972; Boothby et al., 1972; Krikler and Spurrell, 1974). One must avoid the combined use of verapamil and fl-blockers in patients with overt or marginal hemodynamic dysfunction. For example, the administration of verapamil or practolol individually produces minor hemodynamic changes. The combined regimen, however, produces a pronounced reduction in left ventricular contractility (Seabra-Gomes et al., 1976). Caution must also be taken, of course, in any patient with sick sinus syndrome and/or impaired AV conduction where the additive effects of verapamil and fl-blockers may be disastrous. The combination of nifedipine with a fl-blocker theoretically poses less risk since nifedipine has little effect on AV nodal function compared to verapamil (Rowland et al., 1979), and its net hemodynamic effects appear to cause less myocardial depression. In properly selected patients, minimal side effects can be expected from the combination of fl-blockers and nifedipine. In a review of over 1,400 patients receiving this combination, the incidence of congestive heart failure and, indeed, all side effects, was no greater with combined therapy than with nifedipine alone (Terry, 1982). This observation has been confirmed in a second study (Krikler et al., 1982). Nevertheless, it must be emphasized that a major component of nifedipine's net hemodynamic effect is mediated through reflex adrenergic mechanisms and when these are not present, the drug may exert significant negative inotropic effect. Hemodynamic studies of the acute effects of nifedipine on left ventricular function in patients on fl-blockers reveal that the addition of the calcium channel blockers significantly depresses left ventricular d p / d t and systolic blood pressure. The increase in cardiac output results from vasodilation compensating for the negative inotropic effect (Joshi et al., 1981). Several anecdotal reports of heart failure associated with combined nifedipine and propranolol administration have already been published (Nakamoto, 1975; Anastassiados, 1980). In addition, several reports of potentiation of nifedipine's hypotensive effects by fl-blockers have appeared (Opie and White, 1980; Aoki et al., 1978). Finally, unpublished data suggest that the combination of nifedipine and fl-blockers in patients with coronary disease may increase the difficulty of discontinuing heart-lung bypass following open heart surgery. This may be further complicated by the hypocalcemia induced during the surgical procedure. This observation obviously requires further study. Although diltiazem appears to have minimal intrinsic negative intropic activity, its electrophysiologic properties would suggest similarity of action to that of verapamil during combined therapy with fl-blockers. Thus, it appears that in selected patients with relatively normal ventricular function and intact impulse generation and conducting systems, the combination of a calcium antago-

Clinical uses of calcium antagonists

31

nist and a fl-blocker is potentially advantageous. However, in patients with impaired hemodynamic performance or abnormalities of the SA or AV node, considerable care must be exercised to obviate potentially life-threatening side effects during combination therapy. 17. SELECTING A SLOW CHANNEL BLOCKER The overall spectrum of therapeutic activity of calcium antagonists rivals that of fl-adrenoceptor blocking drugs. Unlike the case of fl-antagonists, however, calcium channel blockers often significantly differ in their electrophysiological, pharmacological and hemodynamic actions. They also have individual side effect profiles and pharmacokinetic characteristics. These overall considerations, therefore, govern the choice of a particular calcium antagonist for a specific clinical indication. At this time, studies directly comparing slow channel blockers to one another in experimental and clinical settings are limited. Significant quantitative differences between nifedipine, verapamil and diltiazem have, however, been demonstrated. In isolated tissue preparations the addition of equimolar doses of the three drugs demonstrates that nifedipine is clearly the most potent calcium-channel blocker when assessed by its vasodilator activity and negative chronotropic, dromotropic and inotropic effects (Ono and Hashimoto, 1979; Henry, 1979). Diltiazem is the least potent and verapamil is of intermediate potency. However, if the drugs are evaluated in isolated preparations at equieffective vasodilator doses, all exhibit negative inotropic effects which are dose dependent; verapamil is then more potent than nifedipine, which is in turn more potent than diltiazem (Millard et al., 1982). In conscious dogs, nifedipine exerts a positive inotropic effect, verapamil a negative intropic effect, and diltiazem no significant effect. Atrioventricular conduction is unchanged with nifedipine but decreased with diltiazem and verapamil. Heart rate is increased by all three drugs, most by nifedipine, less by verapamil and least by diltiazem (Millard et al., 1982) (see Table 2). Since nifedipine is an extremely potent vasodilator, it elicits a marked fl-adrenergic response which counteracts its intrinsic negative inotropic, chronotropic and dromotropic actions (Rowland et al., 1979; Vater and Schlossman, 1976; Amlie and Landmark, 1978). Nifedipine may also exhibit a vagolytic action which appears to be less prominent with verapami! and diltiazem. This may also contribute to the observed differences in overall properties of the three compounds in intact animals (Millard et al., 1982). Finally, nifedipine may be devoid of the non-specific sympathetic antagonist activity of the type present in verapamil and diltiazem (Ellrodt et al., 1980; Singh et al., 1978). Doses of verapamil producing the same degree of vasodilatation as nifedipine produce a much greater negative dromotropic effect (Rowland et al., 1979). Administration of equipotent coronary vasodilatory doses of verapamil and diltiazem cause prolongation of AV nodal functional refractoriness and conduction time, whereas nifedipine is without significant effect (Taira et al., 1976). Comparison of clinically equimolar doses ofverapamil and diltiazem in conscious dogs reveals potentially significant differences. Although heart rate and arterial pressure change equally, verapamil depresses left ventricular function but diltiazem does not (Taira et al., 1975). The precise clinical significance of these differences, however, needs to be further evaluated in patients with varying spectra of myocardial performance in relation to the integrity of the autonomic nervous system. The available data suggest that the overall electrophysiologic and hemodynamic actions of different calcium antagonists are determined not only by their intrinsic potency with respect to their effects on cardiac and smooth muscle but also by the reflex changes that occur by the level of function in the ventricular muscle and the conduction system, as well as by the presence or absence of myocardial ischemia. These factors are significant in interpreting the actions of calcium channel blockers in various cardiovascular disorders in which these agents are now being used, and selecting the appropriate agent. As predicted by comparative experimental studies, nifedipine is without effect in supraventricular tachyarrhythmias. The most effective agent--both intravenously and orally--is verapamil. Its congeners may also be effective in this regard. Diltiazem appears

32

A. G. ELLRODT a n d B. N. SINGH TABLE 5. Slow-Channel lnhibitors in Cardiovascular Therapeutics

Condition Cardiac arrhythmias PSVT (elective) PSVT (prophylactic) Control of ventricular rate in atrial flutter and fibrillation Ventricular arrhythmias Myocardial Ischemia Vasospastic angina* Angina, any type* Infarct size reduction Cardiac preservation during open heart surgery Other indications Arterial hypertension (acute as well as chronic treatment) Pulmonary hypertension Hypertrophic cardiomyopathy Cardiac failure (afterload reduction) Cerebral Vasospasm Raynaud's Disease

Verapamil

Nifedipine

Diltiazem

i.v. drug of choice Of value Of value acutely as well as chronically

Of no value Of no value Of no value

Likely to be of value Likely to be of value Likely to be of value

Limited efficacy except by indirect effects (e.g. vasospasm)

Limited efficacy except by direct effects (e.g. vasospasm)

Limited efficacy except by indirect effects

Agent of choice Effective Experimental data encouraging Appears beneficial

Agent of choice Effective Experimental data encouraging Appears beneficial

Agent of choice Effective Experimental data encouraging No significant data

Encouraging

Encouraging

Likely to be of value

Probably of limited value clinically May reduce gradient and improve exercise tolerance Not recommended

Probably of limited value clinically Potentially useful

Probably of limited value clinically No data

May possibly be used as an afterload reducing agent Under study Promising

Not recommended

? Promising

? Promising

*All slow-channel inhibitors appear to be effective in these conditions, particularly in vasospastic angina. Their comparative efficacy against one another as well as against long acting nitrates needs further evaluation by controlled studies. Abbreviations: PSVT = paroxysmal supraventricular tachycardia.

quite promising in the treatment of supraventricular tachyarrhythmias. In the case of ventricular arrhythmias complicating coronary artery spasm, all calcium antagonists are likely to be effective and the choice of an agent will be dictated by other clinical considerations. Similarly, for the control of nearly all myocardial ischemic syndromes (Prinzmetal's angina, unstable angina, chronic stable angina), verapamil, nifedipine and diltiazem in appropriate dosage regimens are probably equi-effective. Which of the three agents the clinician might use will be dependent on one's familiarity with the agents and the presence of associated clinical features. For example, co-existing sick sinus disease, AV conduction will make nifedipine preferable to diltiazem or verapamil. For other cases of ischemic syndromes, one's choice will be dictated essentially by the frequency and severity of side effects. The rational choice of various agents in other conditions (obstructive cardiomyopathies, myocardial preservation, hypertension, pulmonary hypertension, Raynaud's phenomenon and other vasospastic syndromes) is at present limited by paucity of data relative to efficacy and side effects and must await further clinical evaluation. Table 5 summarizes the current status of the slow channel blockers in various cardiovascular diseases. 18. SUMMARY The slow-channel blockers constitute a structurally diverse group of drugs with varying mechanisms of action, propensities for site of greatest cardiovascular activity, and clinical efficacy. They share however the property of blocking the slow inward channel in heart muscle and of inhibiting calcium fluxes in smooth muscle. Their in vivo and in vitro actions must be distinguished. The overall actions represent a balance of direct and autonomicallymediated reflex actions interacting with the compounds' varying degrees of intrinsic non-competitive sympathetic antagonism. A knowledge of the pharmacodynamic differences between these drugs allows the physician to select the most appropriate agent for a given clinical situation. The central role of calcium in the cellular processes in the heart and the vascular system forms the basis for the utility of this class of drugs in a wide variety of cardiovascular disorders.

Clinical uses of calcium antagonists

33

C u r r e n t intensive e x p e r i m e n t a l a n d clinical investigations are likely to further define the roles o f nifedipine, verapamil a n d diltiazem a n d their congeners in cardiovascular therapeutics. The prospect o f d e v e l o p m e n t o f newer c o m p o u n d s with greater selectivity o f action is real. As p o i n t e d o u t by B r a u n w a l d (1982 a,b), with further clarification o f the m e c h a n i s m s of actions o f these c o m p o u n d s a n d elucidation o f the role of calcium fluxes t h r o u g h o u t the body, more specific a n d p o t e n t agents m a y be developed. The a p p a r e n t efficacy of the nifedipine c o n g e n e r n i m o d i p i n e , in the t r e a t m e n t of cerebral v a s o s p a s m associated with s u b a r a c h n o i d h e m o r r h a g e (Allen e t al., 1983) m a y simply be the first o f a large n u m b e r of 'specific' or targeted slow c h a n n e l blockers. The d e v e l o p m e n t o f such c o m p o u n d s m a y offer further therapeutic possibilities in the c o n t r o l of a variety o f cardiocirculatory diseases.

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