Clinical pharmacology of slow channel blocking agents

Progress

in

Cardiovascular VOL. XXV,

Clinical

Diseases SEPTEMBER/OCTOBER

NO. 2

Pharmacology

of Slow Channel R. G. McAllister,

R

ATIONAL and effective pharmacotherapy requires an understanding of the patient’s diseaseprocessas well as an appreciation of both the pharmacodynamics and the pharmacokinetics of the drug(s) selected for use. Although the slow channel antagonist drugs have been widely used outside the United States for the past decade, the body of data contributing to our understanding of the clinical pharmacology of these agents is only now beginning to expand. Clinical studies that have shown the dramatic effectiveness of the slow channel blockers in control of supraventricular tachyarrhythmiasif2 and in relief of symptoms associatedwith vasospastic coronary artery disease3-’ have been largely empiric, and therefore, have demonstrated the potential usefulness of these new drugs largely in qualitative fashion. Further elaboration of the clinical value of the slow channel antagonist compounds will depend heavily on data from which rational dosing schedulescan be derived, on which appropriate dosing intervals may be based, and with which predictable drug toxicity may be avoided. The purpose of this article is to examine the information currently available pertaining to the clinical pharmacology of the three slow channel antagonists undergoing advanced clinical evaluation in this country-verapamil, nifedipine, and diltiazem-and which have received preliminary FDA approval for marketing. Other compounds with similar effects on transmembrane calcium flux, such as perhexilene and lidoflazine, have not been studied in this country to the extent the former group has and are not so far along in the lengthy processleading to clinical availability.

Progress

in Cardiovascular

Diseases,

Vol. XXV,

No. 2 (September/October),

Blocking

1982

Agents

Jr. VERAPAMIL

Actions

Verapamil was originally thought to be an adrenergic blocking agent because its myocardial effects (negative inotropic and chronotropic action) were opposite to those resulting from catecholamine action.6 Fleckenstein, however, showed that the drug reversibly blocked transmembrane ionic flow through calcium channels’,* and Haeusler pointed out that this action could inhibit excitation-contraction coupling in smooth muscle without specific adrenergic blockade.’ The demonstration of a specific pharmacologic probe for characterization of calciumdependent slow channel phenomenastimulated a great outpouring of in vitro and ultimately in vivo electrophysiologic investigation. Studies with isolated cardiac muscle sought to characterize both the slow calcium channel as well as the actions of verapamil and its optical isomers.‘G’3 Extension of these observations to the intact heartI indicated that verapamil should act rather specifically to affect slow-channeldependent activity in (1) sinusand atrioventricular (AV) nodal tissues’5.‘6and (2) in partially

From the Research Service, Veterans Administration Medical Center, and the Departments of Medicine and Pharmacology, University of Kentucky College of Medicine, Lexington, Ky. Reprint requests should be addressed to R. G. McAllister, Jr., MD., I5l-CDD, Veterans Administration Medical Center, Lexington, Ky. 40511. 0 I982 by Grune & Stratton, Inc. 00334620/82/2502-0001%02.00/0

1982

83

84

depolarized ventricular myocardium in which slow-channel-dependent automatic depolarization might occur.‘7-‘9 Subsequent clinical studies indicate, in fact, a major role for this drug in control of supraventricular tachyarrhythmias by virtue of its effects on calcium-sensitive AV nodal conduction (see recent review by Singh et al.‘), but while the efficacy of verapamil in suppression of “slow response” activity in ischemic myocardial tissue has been demonstrated,” the drug has not been consistently active against ventricular arrhythmias.20,2’ In addition to electrophysiologic activity, verapamil has negative inotropic effects on myocardium” and is a potent dilator of coronary and peripheral vessels,23 both actions presumably related to its ability to interrupt excitationcontraction coupling.’ The drug-induced reduction in peripheral vascular resistance and resultant hypotension may reflexively increase heart rate and contractility so that impairment of ventricular function is not apparent.‘324 However, hemodynamic depression by verapamil can be demonstrated after pretreatment with autonomic blocking drugs24 and was a prominent presenting feature in two young patients who survived massive overdoses of verapami1.25326The negative inotropic effects of the drug have been utilized to reduce symptoms27328 and ventricular outflow tract obstruction29”0 in patients with hypertrophic cardiomyopathy. The latter effect may be due to verapamil’s action in reducing calcium availability to myocardial cells, thereby preventing mitochondrial calcium overload under conditions of reduced relative coronary arterial flo~,.~’ The vasodilator properties of the drug have been shown to be similar to those produced by nitroprusside, diazoxide, and hydralazine in the anesthesized rat,32 and the demonstrated hypotensive effects are additive to those of clonidine and prazosin.33 Two recent clinical studies have shown verapamil to be a promising therapeutic agent in patients with established essential hypertension.34’35 Verapamil-related reductions in contractility and associated decreases in myocardial oxygen demand may account for the reported efficacy of the drug in the treatment of exertional angina pectoris.36337 Unstable angina, now commonly believed to be associated with coronary spasm, has also been responsive to verapamil, either

R. G. MC ALLISTER,

JR.

alone3,38 or combined with nitrates.38a Verapamil pretreatment reduced the extent of ischemic injury in dogs subjected to coronary occlusion,39 but no patient studies are currently available to help define the role of this drug in acute myocardial infarction. Since calcium is essential to the process of excitation-secretion coupling,40 a role for calcium-channel antagonists in control of hormonal secretion has been suggested, but only tentatively explored. In high concentrations, verapamil and its analogs can block insulin secretion by isolated pancreatic islet cells4’ and by the perfused rat pancreas preparation.“’ Intravenous verapamil infusions decrease significantly, but do not wholly block, the insulin response to a glucose stimulus in conscious dogs.43 In addition, verapamil can inhibit release of adrenocorticotropic hormone and growth hormone,44 as well as glucagon.45 It is apparent that broad therapeutic potential must be assumed for a drug such as verapamil that can interfere, in moderately selective fashion, with a basic cellular process. The concern must be, however, whether or not verapamil and other calcium channel antagonists can produce effects that are clearly therapeutic without simultaneously evoking significant toxicity. Pharmacokinetics

Verapamil is a papaverine derivative (Fig. 1) that undergoes extensive hepatic biotransformation in animals46 and in man.47 Metabolism with isolated rat hepatic microsomes conformed to Michaelis-Menten kinetics, and the NADPrequiring enzyme systems involved were not saturated under the experimental conditions employed.48 The only metabolite that appears to possess significant pharmacologic activity is the N-demethylated form (nor-verapamil), with about 20% of the activity of the parent compound as a coronary vasodilator in dogs.” After intraperitoneal administration in rats, Verapamil

H3C,

CH

943 $H3

+cH2-cH2 Fig. 1.

Structure

of verapamil.

CLINICAL

PHARMACOLOGY

OF Ca++

85

BLOCKERS

mass fragmentography method” that was used to evaluate the pharmacokinetics of verapamil in three elderly subjects” and the metabolic disposition of the drug in four.47 A simple spectrophotofluorimetric methods3 has been used to characterize the drug’s pharmacokinetic and pharmacodynamic properties in dogs5”s6 and in man.57 Although dismissed as yielding “spuriously high drug levels,“58 this assay procedure is apparently quite satisfactory for studies after single intravenous doses of verapamil, where fluorescent metabolites are present in concentrations too low for assay detection.59 Fluorescent methods are clearly inadequate for plasma level measurement during oral drug therapy, such as attempted by Koike et a1.57High-pressure liquid chromatography (HPLC) can be used to quantitate both verapami16’ and nor-verapamil.6’962 Gas chromatographic procedures originally suffered from a lack of sensitivity,59 but use of a nitrogen-specific

verapamil is distributed throughout the body in rough proportion to organ blood flow, except in the brain (where low concentrations are found) and the liver (where the drug is highly concentrated).49a After oral administration, absorption is rapid and virtually complete.50 Verapamil given orally is subject to extensive first-pass hepatic extraction,47350 resulting in a bioavailability of only lo%-20%. Most of the drug is excreted in the urine as conjugated metabolites with less than 5% eliminated in (70%), unchanged form.47 During long-term oral verapamil therapy, no cumulation of either parent drug or nor-verapamil occurred in patients with hypertrophic cardiomyopathy.51 A major problem in the interpretation of pharmacologic studies with verapamil has derived from the varying approaches to analysis of drug and metabolite plasma concentrations. Spiegelhalder et al. developed a sensitive and specific Table

1. Verapamil

Pharmacokinetics

S”bj@X Data Source A.

lnbavenous

”

admlnistratlon-“normal

1.

Schamer”s

2.

Koihe

et aLso

3.

Eichelbaum

et al.”

DoselTlme

Tf,z

hnl

v,

olr)

ClCdW”Ce

fLltwSl

Bioavailabllity

Liter/mid

I%)

subwzts

(19761

I19791 et aIL’8a

T/2

Age 3

59-69

10 mg/45

6

21-68

10 m9/3-5

8

21-27

10 mgl5

(1961)

min min

23.9

*

3.9

5.32

*

1.10

380.3

+ 42.0

6.68

5 1.26

13.8

*

3.6

4.21

t 75.0

162.4

i- 2.3

0.50

+ 0.07

min

-

3.69

402

1.26

(ApproximateI 4.

W00dcoch

et al.66

,198ll

4

37.5

5 mgJ5

ml”

22.9

+ 15.2

2.83

t

1.2

3.51

*

1.09

1.84

+ 0.16

r

5.1

t

296

zk 67

1.57

r 0.40

178.0

t 9.2

1.06

i

2.4

338.0

+ 40.2

* 0.20

360.3

+ 55.9

(Mead 5.

Dominic

et al.”

(1981)

8

24-26

0.2

mglhgl <5

8.

McAkter

and

Kirsd’”

20

21-34

0.09

min

,omg/5min

4.9

4.8

0.664

* 0.36

(19821 8.

Oral

administration

(smgle

1.

schomer”s

et aLso

11976)

2.

Eichelbaum

ef aI.78a

(198

3.

Woodcock

4.

McAllister

et al.and

dosek-normal

(198

Kirsten””

11982)

subyxts

1) 1)

3

51-64

80mg

6

21-27

80mg

-

3.51

80mg

-

-

2

?

20

21-34

22.6

{ 80mg 160

mg

+ 3.7

3.06

-

4.5

-

4.9 Verapaml

i

1.39

2 0.30

10-22 22

-

1.33

0.54

401.5

k 68.6

+ 0.85

394.2

i

Pharmacokinetncs

Patientsl

71.8

0.997 1.01

19.25

r 0.08

18.0

f 2.3

2 0.11

20.4

+ 2.7

Subjects Dam C.

source

” Disorder

Dose/Tjme

CleFTa”Ce CLlter/min)

v, (Liters)

Bioavailability

Tn;iP (mm)

% (hr)

-

15.7

445.2

0.391

38.2

-

15.3

468.7

0.384

81.5

(%I

Patienfs 1.

Eichelbaum

et ~1.~’

II 960)

1 Cirrhosis

10 mgl5 40

(A)

WwdcochetaLee,198T)

shunt

After me*OCa”al

2.

+

Before me*ccaYal

(8)

min mg p.0.

5 Liver

shunt 6 mg/5

disease

+

21.3

f 2.19

13.6

5 4.3

481

_t 70.5

5 mg/5 min + 80 mg pm.

4.54

A 3.26

1.57

f 0.50

330

t 92.6

2.84

f 44.4

1.077

80

min mg

0.545

+ 0.090

23.8

k

13.6

p.0.

(ctrrhosis) 5Trauma(l). sepsis and 3.

Katsseta1.~7~11981~

( 1 j,

+ 0.27

13.4

(2 pts)

arrlvdmma

12 Chronic atrial fibrillation

15mg/15min 120

+ mg

p-0.

-

6.3

t

1.15

348.3

t

0.18

35

+ 3.5

86

detector5’,63*64has provided both sensitivity and a capacity for simultaneous measurement of verapamil and its N-demethylated metabolite5’ equal to that found with HPLC methods.64 Pharmacokinetic data after single intravenous bolus doses of verapamil to normal subjects are summarized in Table 1. The drug disappears from plasma according to first-order kinetics and has been adequately analyzed with a twocompartment open model. Beyond this statement, agreement among studies ceases, with a 16-fold variation in reported clearance rates and a threefold variation in observed elimination half-life. Further work clearly must be carried out to resolve the apparent differences among the reported studies. An additional complicating factor may involve variations in hepatic drug clearance dependent on concomitant drug plasma level. Bourne et a1.65 reported that verapamil kinetics observed during multiple intravenous infusions in normal subjects failed to conform to a computer-generated kinetic model when plasma drug levels exceeded about 60 rig/ml, and suggested that higher drug concentrations might affect liver blood flow in such a fashion as to result in diminishing clearance values. These observations have not yet been confirmed by further work. Studies by Woodcock et a1.66,66aand Eichelbaum et a1.67have emphasized the importance of intact hepatic function in the elimination of verapamil. In patients with biopsy-proven liver disease (cirrhosis and acute fatty liver), clearance of verapamil after an intravenous bolus dose was only 30% of that observed in control subjects, the elimination half-life was prolonged by 476% (to 13.6 hr), and the distribution volume increased by 40%. In these studies, routinely available indices of hepatic function were of no real value in predicting the extent of abnormality observed in drug disposition. On the basis of these limited observations, it would appear that verapamil elimination is quite sensitive to changes in liver function; drug dosage should, therefore, be appropriately reduced in such patients. Even fewer pharmacokinetic data are available after oral verapamil administration (Table 1B). Three elderly subjects were studied by Schomerus et al.” using the mass fragmentography technique for drug level assay; verapamil elimination half-life was about 3 hr, considera-

R. G. MC ALLISTER,

JR.

bly less than the half-life observed by these investigators after intravenous drug administration. The data reported by Koike et a1.57should be viewed with caution, since these investigators used a spectrophotofluorimetric assay method that will detect the fluorescent metabolites promptly generated after oral drug administration.5g A recent study involving 20 normal subjects analyzed verapamil kinetics after single 80 and 160 mg oral doses, as well as single 10 mg intravenous doses.67a The pharmacokinetics of verapamil were similar after both dosing routes (see Table l), with a bioavailability of 18%20% that was not dose-dependent. A few recent studies66*67,67b have evaluated the pharmacokinetic profile of verapamil in patient subjects (see Table 1C). Kates et a1.67bstudied disposition of the drug in 12 patients with chronic atria1 fibrillation, finding kinetic parameters similar to those earlier reported in normal subjects (Table l), but a higher bioavailability (35%). Since verapamil is likely to be used in a variety of patients, including those with ischemic heart disease, cardiomyopathy, and hypertension, further work must be done in these specific types of disorders to determine whether significant differences exist between such patients’ handling of the drug and those patterns established in normal individuals. Krikler6’ observed that antiarrhythmic effects from verapamil required oral doses lo-20 times greater than the amount of drug needed for similar activity when used intravenously; Schlepper et a1.69found a similar oral:intravenous ratio when evaluating verapamil effects on AV conduction. Since verapamil is well absorbed after oral administration,46 the striking difference between intravenous and oral doses required for similar effects must be due to a pronounced first-pass extraction of the drug from the portal circulation. Other cardioactive drugs subject to metabolic elimination on their initial pass through the liver after oral administration include lidocaine” and propranolol.” Drugs subject to first-pass elimination may have complex pharmacokinetic profiles and require multicompartmental analysis for thorough evaluation.‘* To further complicate analysis, drugs whose clearance is dependent on hepatic blood flow may, themselves, affect blood flow to the liver by induced hemodynamic changesy3 and such drug-related effects may result in altered

CLINICAL

PHARMACOLOGY

OF Ca++

elimination of the original compound or simultaneously administered drugs also subject to hepatic clearance.74 Since verapamil has potential for pronounced hemodynamic effects, one might predict that such types of drug interactions will occur, particularly during chronic oral verapamil administration. Schomerus et a15’ studied verapamil binding to plasma proteins in 3 elderly subjects, finding a range of 88.7%-92.0% over a wide concentration range. These observations were confirmed by Keefe et a1.,7s who found similar binding in normal subjects, in patients with renal disease, and in patients undergoing coronary artery surgery. Heparinization for cardiac catheterization reduced verapamil binding to 83.3%. Yong et a1.75adetermined that several drugs, including propranolol, disopyramide, diazepam, and lidoCaine, displaced verapamil from protein binding sites in vitro. The clinical importance of this observation is not yet clear. A recent report by Strigl et a1.76indicates that verapamil rapidly passes the placenta; intravenous drug given to women during labor resulted in fetal verapamil plasma concentrations at delivery that were 50% of the simultaneously measured maternal drug levels. No adverse effects on the newborn infants were reported, but the mean drug levels were well below those associated with detectable drug activity. Plasma

Level-Effect

87

BLOCKERS

Correlations

In Vitro Studies Several in vitro studies have indicated the concentration-dependent aspects of verapamil’s activity. In an evaluation of the electrophysiologic effects of verapamil on canine Purkinje fiber bundles, Rosen et al.” varied drug concentrations from 10m5M to 2 x lo-’ M (i.e., 4546-91 rig/ml). At concentrations below 2 x 10m6M (909 rig/ml), the drug had no effect on the Purkinje fiber action potential but suppressedautomaticity induced by low potassium perfusates or ouabain. Hadof et al.” found that verapamil concentrations of 100-l 000 rig/ml depressedonly the plateau of the action potential in normal human right atria1 tissue, with lower concentrations markedly depressing action potentials in fibers from dilated atria; slow response automaticity was suppressedeven at the lowest drug concentrations studied. Imanishi et a1.13useddepolarized ventricular myocardium

from guinea pigs pretreated with verapamil to characterize the effect of the drug on slowchannel-dependent automatic depolarizations resulting from inactivation of the fast sodium current; plasma verapamil levels ranged from 100 to 1850 rig/ml at the time of sacrifice, and the apparent depressanteffects on both rate and overshoot of the spontaneous depolarizations were directly related to the corresponding plasma drug concentrations. In Vivo Studies-Animals In vivo studies in animals have, in general, confirmed extrapolations from in vitro investigations regarding the range of concentrations in which verapamil’s effects become manifest. In healthy but anesthetized dogs, Reiner et a1.39 gave verapamil intravenously up to a dose of about 3.5 mg/kg before the onset of electrophsiologic toxicity (second or third degree heart block), but plasma levels were not reported. In consciousdogs, the effects of verapamil on AV conduction as reflected in the surface electrocardiogram were linearly related to the log of the corresponding verapamil concentrations in plasma.54 Furthermore, the P-R interval change versus log verapamil concentration relationship was identical regardlessof whether drug plasma levels were rapidly rising or falling. Using anesthetized open-chest dogs, Mangiardi et aLs5gave verapamil intravenously in a protocol designedto produce and maintain stable drug plasma concentrations at different levels over a 20-min period, with evaluation of both electrophysiologic and hemodynamic drug effects. Verapamil slowed the sinoatrial pacemaker only at levels above 1.52rig/ml and sinus arrest occurred only at levels exceeding 400 rig/ml; even at drug concentrations reaching 2000 rig/ml, significant prolongation of corrected sinus recovery time did not occur. A direct relationship between the log of the plasma verapamil levels and A-H interval prolongation was found, with higher degrees of heart block seenonly when drug levels exceeded about 400 rig/ml; when atria1 pacing was used, heart block appeared at lower drug concentrations, indicating the rate-related aspectsof verapamil’s apparent effects on AV nodal conduction. Significant impairment of ventricular function was not detected at drug levels below 152 rig/ml, but progressively increasedas plasma concentrations

88

_

R. G. MC

125

-

-

2 F g

‘; I 100

-

-

r = 0.775

100

g

2 Y ,”

75

-

-

75

:

% 3 P Y

JR.

125

_1. 2

ALLISTER.

50

-

25

-

Y = 33.6

50

-

25

-

0

log x-60.7

se 0’

1 20

40

60 PLASMA

100

200 VERAPAMIL

400

600

(NG/ML)

rose. Figure 2 shows a summary from these studies, indicating that substantial depression of AV nodal impulse transmission can be achieved at drug levels associated with insignificant degrees of impairment of ventricular pump function in the experimental model used. The same group of investigators also studied the ability of intravenous CaCl, to reverse the electrophysiologic and hemodynamic changes induced by verapamil in the open-chest dog.‘6 Across a wide range of plasma verapamil concentrations (70-2042 rig/ml), relatively small amounts of calcium (15 mg/kg over 5 min) were required to reverse the drug’s negative inotropic effects and raise cardiac output and left ventricular dp/dt above the levels present in the control period; the peripheral vasodilator activity of verapamil, as reflected in a drugrelated fall in peripheral vascular resistance, was unaffected by CaCl,. In addition, doses of CaCl,, which reversed the ventricular depressant activity of verapamil, had no significant effects on verapamil-dependent prolongation of A-H interval or slowing of sinus rate. These studies, therefore, revealed dramatic differences in the susceptibility of verapamil’s activity on ventricular, vascular, and conducting tissue to reversal by CaCl,. The efficacy of the doses of CaCl, given was not related to corresponding verapamil concentrations in plasma. The plasma levels of verapamil required to affect insulin release were evaluated in conscious dogs by Dominic et a1.43 Plasma glucose and immunoreactive insulin were measured serially after an intravenous glucose load, both during

1000

3 z ; 9 2 z a s

Fig. 2. Correlation of plasma verapamil levels with corresponding effects on A-H interval (solid line) and LV dpldt (broken line). The data are derived from studies by Mangiardi et aI.% in dogs. The appearance of heart block (at approximately 400 rig/ml) is indicated by a vertical bar. These data suggest that pronounced electrophysiologic effects can be achieved at drug concentrations producing minimal depression of left ventricular function.

control periods and during verapamil administration. The drug was given systemically by protocols designed to result in stable plasma concentrations in low (84 k 9 rig/ml), medium (191 t 30 rig/ml), and high (367 5 51 ngfml) ranges. Insulin release was blunted, and peak glucose levels higher, in dogs with drug levels in both the medium and high ranges, but the degree of suppression of insulin release was not increased at higher verapamil plasma concentrations. These data showed that slow channel blockade by verapamil could interfere with hormonal release at drug levels associated with both electrophysiologic and hemodynamic effects. Similar studies in patients have not yet been reported. In Vivo Studies-Human (See Table 2)

Subjects

Koike et a1.57gave verapamil, 10 mg intravenously, to 6 normal Japanese subjects as a bolus dose, subsequently measuring plasma drug concentrations at intervals and evaluating simultaneous electrocardiographic changes. All subjects were in sinus rhythm, and P-R interval prolongation was reported to be linearly related to the log of the verapamil levels over a range of 10-250 rig/ml, with a maximum change in P-R intervals of about 200 msec. One subject developed Wenckebach type AV block at a verapamil level of 127 rig/ml, resolving promptly as the drug levels fell. No changes in QRS or Q-T intervals were observed. Dominic et aL7* carried out a similar study in 8 healthy young men, each of whom was given 0.2 mg/kg verapamil intrave-

CLINICAL

PHARMACOLOGY

OF Ca++

Table

2.

2.

et al. (1 97915’

Eichelbaum

Verapamil

Plasma

Level-Effect

et al.

Correlations

Dose (mg) and Route

Subjects

Data Source 1. Koike

89

BLOCKERS

6 (Normals)

10 mg 1i.v.)

6 (Normals)

10 mg (i.v.) and

160

Results P-R prolongation between = 30-250 rig/ml [fl correlated closely with

mg

P-R both

(p.0.)

(1 980jTeb

[V]

interval changes with i.v. and p.o. dosing;

higher [V] required after p.o. doses than with i.v. for 3.

Dominic

et al. (198

4.

McAllister

1 17’

equivalent effects P-R prolongation between

8 (Normals)

0.2 mg/kg

(i.v.)

20 (Normals)

10 mg (i.v.1; 80,120,160

[q and Kirsten

mg

(p.0.)

(1 982J7*’

P-R

= 30-300 prolongation

doses higher

requires [V] 3-4-fold than needed after

i.v. doses fect 5.

Dominic

et al. (1 979)79

15 (Atrial

flutter

or fibrillation)

0.075-o.

15 mg/kg

(i.v.1

rig/ml after p.o.

for equivalent

Ventricular rate slowing: ( 1) Responders-60 beats/min at [Vj (2)

ef-

=

52 + 7 rig/ml Nonrespondersbeats/min at [V] = 95 + 16 rig/ml

6. Sung

et al. (1980ja4

0.075-O.

19 WI-r)

15 mg/kg

(i.v.1

Conversion 17/19 mean

7.

McAllister

and Reddy

(198 1) (unpublished servations)

4 (Atrial

flutter

or fibrillation)

ob-

nously over 3-5 min. In each subject, the P-R interval increased after drug was given, with the maximum interval change for the group (52 + 19 msec) corresponding to the peak plasma level of verapamil (270 * 21 rig/ml). In this study group, log plasma verapamil concentrations were closely related to P-R prolongation for each individual subject, but considerable scatter was seen when between-subject analyses were attempted. As in the earlier study by Koike et al., one subject developed transient Wenckebach block (plasma verapamil 162 rig/ml). Drug levels below 30 rig/ml had no effect on the P-R interval. Neither QRS or QT intervals were affected, but a mean decrease in T-wave amplitude of 35% f 11% was observed at peak verapamil concentrations. Small increases in heart rate (mean 13.5 + 3.0 beats/min) and declines in systolic arterial pressure (mean 10.4 * 4.4 mm Hg) occurred just after the drug was given, with a return to control values within 30-60 min. The authors suggested that P-R interval prolongation should serve as a useful guide to verapamil effect in individual patients with sinus rhythm. Eichelbaum et a1.78aanalyzed the relationships

200-640

mg/day

(p.0.)

to sinus rhythm in at [Vl> 72 rig/ml; effective

[q

=

123 c 40 rig/ml Effective [V] for chronic rate control appears to be 300400

rig/ml

between P-R interval prolongation in normal subjects given intravenous and oral doses of verapamil and the simultaneously obtained plasma drug concentration. There was a linear relationship between plasma levels and observed effect with both dosing routes, but the slope of the oral plasma concentration-response curve was significantly less than that of the i.v. plasma-level-response curve. Furthermore, verapamil plasma levels 2-3-fold higher were required after oral drug administration to produce the same increase in P-R interval as after intravenous drug. The same observations were recently made in another study.67” The explanation given for the different slopes of the plasma-level-response curves after oral and i.v. drug administration suggested stereoselective presystemic elimination, with the more active l-isomer preferentially metabolized during passage through the liver, allowing relative cumulation of the less active d-form.78b Between-subject variation in the effects of verapamil on AV conduction was also reported in a study of the efficacy of the drug in reducing ventricular response in patients with atria1 fibrillation and atria1 flutter.79 Patients who were

90

clinically stable responded to intravenous verapamil (mean dose 0.066 f 0.099 mg/kg) with a mean fall in ventricular rate of 60 beats/min; the corresponding mean plasma drug level was 52 r 7 rig/ml. However, patients with similar dysrhythmias accompanied by clinical evidence of cardiac failure required a higher dose (0.189 + 0.028 mg/kg) and a higher drug concentration (95 t 16 rig/ml) to produce a decrease in ventricular rate only half as great (28 k 11 beats/min). The considerable difference in response to verapamil was attributed to increased endogenous sympathetic tone in the patients with congestive heart failure; in such patients, increased plasma levels of norepinephrine” would be likely to antagonize the actions of verapamil on the AV node.15 The importance of sympathetic activity as a factor modifying the effects of verapamil was recently emphasized by a report from Urthaler and James,*’ who showed that well tolerated concentrations of verapamil produced high degrees of AV block after elimination of sympathetic tone by pretreatment with propranolol or reserpine. This study provides an explanation for anecdotal reports of toxicity developing unexpectedly with usual clinical doses of verapamil in patients previously given antiadrenergic drUgs.68,82.83 As yet unpublished studies in patients given beta adrenoceptor blocking agents together with verapamil have involved subjects with supraventricular tachycardias but no apparent compromise of vertricular function (Packer ME, personal communication); in these patients, verapamil toxicity has not been evident. However, the degree of variability in endogenous sympathetic tone in different individuals, healthy or ill, would imply that a similar degree of variability may be inherent in the responses to verapamil in different subjects at the same plasma drug concentrations. Sung et a1.84gave verapamil intravenously to 19 patients with supraventricular tachycardias (SVT) refractory to control with digitalis or propranolol; each patient was regarded as clinically stable, and the investigators were able to induce sustained SVT in each using programmed intracardiac stimulation techniques. These studies confirmed earlier workJ5 indicating a pronounced effect by verapamil on the AV node, with no apparent drug effect on accessory AV nodal bypass tracts. Giving 0.075 mgfkg verapamil as an intravenous bolus dose during induced SVT, the investigators found that all 9

R. G. MC ALLISTER.

JR.

patients with plasma drug levels above 72 rig/ml converted to sinus rhythm; those who did not respond had levels ranging from 0 to 62 rig/ml. After another bolus dose (0.15 mg/kg), 6 additional patients converted to sinus rhythm, with plasma drug levels at the time of conversion ranging from 98 to 1320 rig/ml. Two additional patients with plasma verapamil concentrations above 100 rig/ml failed to respond to the drug. The authors concluded that drug levels above 75 rig/ml were associated with therapeutic effects of verapamil in patients with SVT. Similar efficacy in patients with SVT was observed by Rinkenberger et a1.,86 who used somewhat smaller doses of verapamil. However, when the drug was given orally (180-480 mg/ day) to patients who had previously responded to intravenous drug administration, 10 of 19 patients discontinued therapy within a month because of “side effects or ineffectiveness.” No plasma drug levels were measured, a major weakness in such a study, since considerable variation can be anticipated in plasma concentrations found with similar oral dosing regimens in different individuals in any drug subject to significant first-pass effects. The extent of such variability was demonstrated in a recent report from Kaltenbach’s group,” in which plasma verapamil and norverapamil levels were measured with gas chromatography in patients with hypertrophic obstructive cardiomyopathy. On a fixed dose of 480 mg daily, patients had plasma verapamil concentrations at the end of a dose interval that ranged from barely detectable to over 300 rig/ml (mean 91 f 76 rig/ml), approximately a 25-fold difference among patients on the same dose. No cumulation of the drug or its active metabolite was observed during chronic treatment. This demonstration of large interpatient variation in plasma drug levels indicates that oral therapy with verapamil must be guided by (1) measurement of drug plasma concentrations or (2) an objective assessment of drug action before concluding that treatment with verapamil is ineffective. We have (McAllister RG, Reddy CP, Cottril CM: unpublished observations) used oral verapamil to control heart rate response in patients ranging in age from 7 to 69 yr with chronic supraventricular tachyarrhythmias. Although there is in vitro evidence that myocardial sensitivity to verapamil may vary with age:’ our data indicate that optimum drug effects, as mani-

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fested by ventricular rate control in atria1 flutter or fibrillation, occurs at plasma drug levels in the 300400 rig/ml range, regardless of age or concomitant glycoside administration. However, more data are clearly needed to define the therapeutic window for the various effects of verapamil (Table 2). As an additional complication, we** have recently observed that the P-R interval prolongation resulting from initial doses of verapamil producing plasma levels in the therapeutic range tends to disappear with chronic dosing, even though the drug’s plasma levels remain satisfactory and the clinical efficacy of the drug is unimpaired. A possible explanation may lie in altered parasympathetic-sympathetic balance on the AV node produced by chronic antagonism of calcium-dependent mechanisms, but this is unproved. The observation does, however, imply that P-R interval prolongation cannot be used as a guide to the presence of therapeutic plasma drug concentrations when the drug is given chronically, as for therapy of angina pectoris. No data are currently available on plasma level ranges associated with various hemodynamic effects of verapamil except for the observations67a,78indicating that the slight fall in arterial pressure seen in normal subjects after single intravenous bolus doses of (0.2 mg/kg) drug occurred at peak drug plasma concentrations and resolved promptly. Side Effects,

Toxicity,

and Drug Interactions

Intravenous administration of verapamil, both as bolus and infusion, appears well tolerated by normal subjects, patients with arrhythmia, and patients with acute myocardial infarction.‘,78*79,s9 Side effects occurring with parenteral administration in patients untreated with other drugs appear to derive from the drug’s pharmacologic activity on the myocardial conducting system, on ventricular pump function, and on peripheral vascular tissue. A slight fall in arterial pressure occurs commonly with therapeutic dosesof the drug, but troublesome hypotension is distinctly uncommon. Clinical observation2 and extrapolation from animal studies55suggest that, in the presence of adequate ventricular function, electrophysiologic toxicity (i.e., sinusor atrioventricuiar nodal suppression)will occur before significant degrees of myocardial depressionare seen. Excessive degrees of AV nodal block may be treated with intravenous atropine or isoproterenol,‘j* although transvenous ventricular pacing

91

may be used if needed. Patients with the sick sinus syndrome may be particularly sensitive to verapamil,90~9’with appearance of atria1 arrest and asystole unresponsive to anticholinergic drugs, and require ventricular pacing until drug effects disappear. Side effects during chronic oral verapamil administration are either directly attributable to predictable pharmacologic activity or are nonspecific and infrequent.2 Even patients with cardiomyopathy appear to tolerate the drug we11.27-30 Vague symptoms such as dizziness, headache, constipation, and nausea may disappear with continuance of therapy. Massive overdoses with oral verapami125326 responded to a combination of intravenous calcium gluconate and temporary transvenous pacing, with no residual drug-related disability. No disturbances of the immune system attributable to verapamil have been reported. Verapamil appears well tolerated by patients with chronic pulmonary disease9’and may be particularly useful for treatment of supraventricular tachyarrhythmias in such patients. The combination of verapamil with beta-adrenoceptor blocking agents may be hazardous, and Krikler68 has suggestedthat most of the serious adverse experiencesreported with the drug could be attributed to inappropriate administration of verapamil to patients already given beta-blockers. The animal studies reported by Urthaler and James” imply an augmented effect by verapamil on sinus and AV nodal tissue after administration of antiadrenergic drugs, and exaggerated myocardial depressanteffects with this combination93 would indicate a need for particular caution. On the other hand, verapamil and digitalis glycosides may be an advantageous combination in the control of ventricular responsein patients with atria1 fibrillation.94995Patients previously given digoxin for a variety of other arrhythmias have tolerated the addition of verapamil acutely without adverse effect.2,96During chronic drug administration, however, verapamil therapy appears to decrease renal digoxin clearance by 50%, resulting in a dose-dependent increase in digoxin plasma levels.97 Whether this is associated with enhanced glycoside effects, therapeutic or toxic, is not clear at this time. Verapamil has been recently shown to inhibit platelet aggregation both in vitro and in vivo98 and to have been implicated in increased anticoagulant effect in two patients receiving

92

R. G. MC ALLISTER,

warfarin sodium (Guerrero J: personal communication). The implications of these observations for clinical use of verapamil have not yet been established. Dosing

Recommendations

Intravenous verapamil used for treatment of supraventricular tachyarrhythmias is commonly given in dosesof 0.075-0.20 mg/kg (i.e., approximately 5-15 mg); this may be given as a rapid bolus, but prudence indicates that it may be better given over 1-2 min. Singh et a1.2recommended use of a continuous infusion of 0.005 mg/kg/min, following initial bolus doses, to maintain arrhythmia control; based on the drug’s kinetics after intravenous use, however, this level is likely to result in cumulation, and lower doses may be more appropriate. The effects of the drug on the surface electrocardiogram-P-R interval if the patient is in sinus rhythm and ventricular response if supraventricular tachyarrhythmia is present-should be frequently evaluated as a guide to drug effect, with appropriate alterations of doseas indicated. Measurement of drug plasma levels is not likely to become available as a routine clinical tool until new and lesslaborious assayprocedures are developed. Initial dosing of verapamil must be titrated to a specific endpoint (such as P-R interval prolongation or control of original symptoms), since the enormous variability in plasma drug levels resulting from similar dosesin different individuals5’makes a fixed-dose regimen irrational. Contraindications to verapamil administration include advanced atrioventricular block and clinical conditions associated with pronounced depression of ventricular function. Caution is required in any patient suspected of having the sick sinus syndrome or who has recently been given antiadrenergic drugs.99)‘00Patients with impaired hepatic function appear to have reduced drug clearance, and reduction in dose will likely be necessary to avoid overdosage and drug toxicity. NIFEDIPINE Actions

The pharmacology of nifedipine was first detailed by Vater et al. in 1972.“’ Fleckenstein and his associates subsequently demonstrated that the drug was a potent inhibitor of trans-

JR.

membrane calcium flux in myocardium and vascular smooth muscle,102~‘03 suggesting that nifedipine might be the most potent of the calcium-flux inhibitor compounds when compared to others on a molecular basis.lo4That it had no effect on the rapid sodium current that generates the action potential was ingeniously demonstrated in experiments with isolated cat papillary muscle; in an effect similar to that of verapamil, nifedipine strikingly decreased the calciumdependent contractile responsewithout effect on such action potential parameters as the upstroke velocity and the height of the overshoot.‘04 Further studies from Fleckenstein’s laboratory demonstrated that nifedipine was not only a potent antagonist of contraction in coronary arterial tissue, but also that the drug could inhibit the enhanced sensitivity to calcium induced in coronary vasculature by exposure to cardiac glycosides.‘05The therapeutic value of nifedipine in coronary disease was predicted from the following actions: (1) reduction in myocardial oxygen requirements by restriction of cardiac metabolism; (2) decrease in cardiac oxygen demand indirectly by reduction in afterload as a consequenceof decreasedarterial pressure from peripheral vasodilation; and (3) improvement in myocardial oxygen supply due to potent coronary vasodilator effects.lo4 Each postulate has been subsequently confirmed with in vivo studies. The electrophysiologic effects of nifedipine are much less prominent than those of verapamil. The injection of large dosesof nifedipine into the arterial supply of the AV node in dogs results in dose-dependent increases in AV conduction time.‘06 However, when compared with verapamil in consciousdogs, nifedipine given in doses producing similar decreasesin arterial pressure did not result in widening of the P-R interval.‘07 In a study in patients comparing the two drugs, Rowland et al. showed that nifedipine had no effect on A-H and H-V intervals at a doseof 7.5 hg/kg given intravenously, while verapamil (0.15 mg/kg) produced the expected prolongation in A-H intervals.“* The dosesof nifedipine required to impair AV nodal conduction appear to be about tenfold those needed to augment coronary Aow.‘06 This lack of affinity for AV nodal tissue explains the absenceof therapeutic activity, in tolerable doses, in patients with supraventricular tachyarrhythmia.“’ Although nifedipine has prominent negative

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inotropic effects on isolated ventricular myocardium, ‘02,‘04it does not appear to depress cardiac pump function in vivo. Two explanations have been proposed for this observation:58 (1) the drug concentration required for negative inotropism exceeds by a considerable margin the plasma levels of free drug likely to be achieved with therapeutically useful doses; and (2) peripheral vasodilatation produced by the drug results in a fall in arterial pressure with a reflex sympathetic enhancement of cardiac performance.“’ The net hemodynamic result of nifedipine administration in vivo, therefore, includes reduction in peripheral and coronary vascular resistance, increase in coronary flow, and a slight increase in left ventricular dp/dt.“’ Nonetheless, the hemodynamically inapparent direct myocardial activity of nifedipine may have important clinical implications. Henry et al. showed that nifedipine inhibited calcium accumulation and ischemic injury in rabbit hearts perfused at low flow,“’ and postulated a similar direct, flow-independent drug effect when nifedipine was found to reduce myocardial injury in conscious dogs with acute coronary occlusion.“* The ability of slow channel antagonists to limit the accumulation of calcium has been proposed as the basis for the therapeutic efficacy of verapamil in patients with hypertrophic cardiomyopathy.27X28 Nifedipine has recently been shown to improve diastolic relaxation in such a patient, lowering left ventricular end-diastolic pressure notwithstanding a significant fall in peripheral vascular resistance and systolic arterial pressure.‘i3 The potential role of nifedipine in myocardial preservation in conditions associated with mitochondrial calcium overload3’ must be regarded as promising.“““6 Since nifedipine has no important myocardial depressant actions or electrophysiologic effects in therapeutic doses, the drug has found primary clinical application in disorders associated with abnormal or inappropriate vasoconstriction. Several clinical studies have shown that it is an effective antihypertensive agent.“7-‘24 The reduction in elevated arterial pressure is due to reduced peripheral vascular resistance and accompanied by an increase in cardiac output;“’ for similar doses, the fall in arterial pressure is greater in hypertensive than normotensive subjects, implying an abnormality of calcium handling in chronic hypertensive disorders. “9*‘2’~‘24 Nifedipine may be combined safely

93

or with clonidine or propranwith methyldopa”’ with apparent synergistic effects. Its 0101,‘** rapid onset of action with sublingual administration (l-5 min) has been demonstrated in patients with hypertensive emergencies.“s,123 As with other drugs having predominant vasodilating effects, acute increases in plasma catecholamines and plasma renin activity occur, but tend to return to control levels with chronic drug administration.125 The effect of nifedipine in patients with pulmonary hypertension has not yet been explored. The peripheral vasodilating effects of nifedipine have also been explored in the therapy of cardiac failure.‘26-‘28 Polese et al.‘*’ found that a single 10 mg sublingual dose relieved acute pulmonary edema from a variety of causes, producing a sustained reduction in both preload and afterload. Clinically insignificant increases in heart rate occur when nifedipine is used as an unloading agent in cardiac failure, but cardiac index improves consistently.‘27~‘28 Perhaps the most dramatic clinical responses to nifedipine therapy are seen in patients with vasospastic angina,5.‘29m133even when refractory to conventional treatment with beta-adrenoceptor blockers and nitrates.‘34 The effect of nifedipine in patients with coronary spasm is rapidly apparent, dose-dependent, and prolonged over several months. In the multicenter study reported by Antman et a1.,13’ angina1 attacks were abolished in 63% of 127 patients, with at least a 50% reduction in the frequency of angina in 87% of the subjects. In a patient with variant angina associated with multivessel coronary artery spasm, ventricular tachycardia and fibrillation associated with ischemic episodes were abolished, together with chest pain, by nifedipine administration; the authors attributed this effect to relief of ischemia rather than to an antiarrhythmic action of the drug.135 Furthermore, ergonovine-induced coronary arterial spasm can be prevented by nifedipine treatment.‘36s’37 Rich et al. noted that while effective against focal spasm in larger coronary arterial segments, nifedipine did not abolish the rather diffuse vasoconstriction following ergonovine administration, which was reversed by nitroglycerin; these authors suggested that nifedipine and nitrates should be used together in the chronic therapy of vasospastic, or variant, angina.13’ Although less dramatically effective, nifedipine also appears to be useful in treatment of

94

angina1 syndromes not clearly related to coronary spasm. In a review of data from several study centers (199 patients), Ebner and Dunschede”’ reported that, even in rather low doses (10 mg, 3 times daily), nifedipine decreased the frequency of attacks in patients with chronic exertional angina by 60%. Recent reports have confirmed an improvement in exercise capacity’38 and left ventricular performance during exercise13’ in angina1 patients given nifedipine. These effects have been attributed to afterload reduction and subsequent decrease in myocardial oxygen demand as well as the drug’s direct myocardial effects. However, the peripheral vasodilator effects of nifedipine may result in sufficiently large decreases in arterial pressure to cause reflex tachycardia associated with aggravation of ischemic cardiac symptoms.‘40 For this reason, nifedipine in combination with beta-adrenoceptor blocking agents appears to be more effective than either drug alone.“’ Other potential applications for nifedipine relate primarily to its vascular effects and have not yet been confirmed. There appear to be significant differences in the mechanisms of action of nifedipine, verapamil and its analogs, and nitroprusside on the inhibition of the excitation-contraction process in vascular smooth muscle. 14’ More precise elaboration of the actions of nifedipine in specific tissues may expand its therapeutic usefulness. Pharmacokinetics

Nifedipine is a dihydropyridine derivative (Fig. 3) unlike other known cardioactive drugs.“’ Analogs have, however, recently been synthesized and are being studied.s8Preliminary studies reported that the drug was rapidly and almost completely absorbed after oral or sublingual administration, appearing in plasma within 2-3 min.14’ First-pass extraction by the liver is not high, and systemic bioavailability is approximately 65%. Nifedipine is metabolized to inactive polar forms; about 80% of a given dose will be excreted in the urine, with 15% eliminated by the gastrointestinal tract.‘42,‘43No cumulation of the drug or its metabolites occurs during chronic therapy. Nifedipine is 90% bound to plasma proteins.‘43 Pharmacokinetic studies initially involved use of 14C-labeled drug,‘42 but both fluorimetric144 and gas chromatographic’45 assay techniques have been subsequently reported. Jakobsen et al.

R. G. MC ALLISTER,

JR.

Nifedipine

H3CAN2-CH3

A Fig. 3.

Structure

of nifedipine.

reported that nifedipine was sensitive to light, with rapid appearance of photo-oxidation products complicating analytical approaches;14’ blood samplescollected for plasma drug concentration measurement must be stored in brown tubes and care taken to avoid exposure of samplesto light throughout the assay procedure. This observation must obscure interpretation of data obtained with the fluorescent assay method. ‘24X’25*‘44,‘46 Using a specific gas chromatographic procedure, for instance, Jakobsen and colleagues found considerable variability in the rate of absorption of nifedipine in normal subjects after sublingual drug administration (10 mg); a fast absorption pattern resulted in peak drug concentrations of 70-100 rig/ml within 30-60 mitt, and slower absorption produced peak levels of 20-40 rig/ml at 90-120 min.14’ These findings have not been confirmed by other investigators.‘47 In view of these difficulties with assay methodology, present descriptions of nifedipine’s pharmacokinetic characteristics must be regarded as subject to revision.58,‘42*‘48 Currently available data suggestan elimination half-life of about 5 hr14’ and a large volume of distribution (extrapolation from data presented in reference 145). Plasma

Level-Effect

Correlations

Perhaps becauseof the difficulties involved in interpretation of results with presently used assay methods, data correlating nifedipine plasma concentrations with simultaneous drug effects are uncommon. Vater and Schlossman

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reported that the effective cardioactive concentrations of nifedipine were l-10 rig/ml, whether from in vitro or in vivo experiments, and observed that a 20-mg sublingual dose in man resulted in plasma drug levels well above this range, even at 6 hr after dosing.‘49 In studies with patients, using the fluorimetric method for analysis of nifedipine plasma concentration,‘44 peak plasma levels occurred within 1 hr of buccal administration of 10 and 20 mg doses, but no difference in drug plasma concentrations after the two different doses was found in normotensive subjects; nifedipine levels were higher (c. 100 rig/ml) after the larger dose in hypertensive patients than with the smaller (c. 50 ng/m1).‘24 A general relationship between plasma drug levels and reduction in calculated vascular resistance was found in the hypertensive group.‘24 A subsequent study from the same laboratory failed to show any correlation between the decrease in blood pressure observed in hypertensive patients given chronic treatment with nifedipine (lo-20 mg, 3 times daily), either alone or combined with a beta-adrenoceptor blocking drug, and plasma drug levels measured over the course of one dosing interval.‘46 The absence of an obvious relationship between plasma drug level and effect was explained by the complex hemodynamics resulting from administration of vasodilator drugs to hypertensive subjects and the variation in intensity of compensatory hormonal responses.125,146 Although plasma level-effect correlations have not been reported in other clinical disorders in which nifedipine has been successfully used, a dose-dependent aspect to the drug’s action has been

frequently

observed,"0,"9,'23.'26,'3','33,'46

al-

beit within a narrow range (lo-20 mg acutely, 30-80 mg daily). Further information should be available in these areas when assay techniques are better evaluated and established. Side Effects,

Toxicity,

and Drug Interactions

A review of world-wide clinical experience with nifedipine in 1975”’ found the drug to be remarkably well tolerated and safe. The most common side effect (and most frequent reason for discontinuation of the drug) was headache, reported in 5.9% of over 5000 patients; other side effects were primarily due to the drug’s vasodilator actions and included feelings of warmth, flushing, dizziness, palpitation, and hypotension. Nausea and vomiting occurred in 3.6% of the

patients reviewed. Nifedipine treatment was discontinued due to adverse effects in only 4.8% of patients, although total patient-reported side effects occurred in 17%. No abnormalities in laboratory studies of the renal, hepatic, hematopoietic, or immune systemswere detected. In a multicenter trial in this country in which the efficacy of nifedipine was evaluated in 127 patients with coronary spasm,13’side effects were noted in 39% of the patients but were sufficiently severe to necessitatehalting the drug in only 5%. The most common adverse effect was dizziness (13%); headache occurred in only 3% but was the symptom most commonly resulting in alteration of therapy. In 7% of the patients, the drug was regarded as ineffective. In Pedersen’shypertensive patients’46 5 of 18 receiving chronic therapy discontinued the drug due to side effects, including headache, palpitations, and sensationsof heat in the face. Urthaler and James found that high concentrations of nifedipine selectively perfused into the AV nodal artery in dogs produced highgrade heart block and asystole after pretreatment with propranolol.‘50 Electrophysiologic toxicity has not, however, been observed in patients given clinically tolerable dosesof the drug, even in the presence of beta-receptor blockade. No clinically significant interactions with other drugs have been reported, including digitalis glycosides, beta-adrenoceptor blocking agents, nitrates, diuretics, and anticoagulants.“’ Dosing

Recommendations

Nifedipine should be given in lo-mg dosesto initiate therapy and is usually given 3 times daily.15’ The dosemay be increased in amount or frequency, depending on clinical response.The blood pressureshould be carefully monitored as a guide to drug effect. Plasma drug concentration measurementsare unlikely to be useful in general clinical useof this drug. DILTIAZEM Actions

Diltiazem is an antagonist of the slow calcium channel,’ originally described in 1971.152In electrophysiologic studies by Saikawa et al., the compound was found to lower the action potential plateau and depress contractility in canine ventricular myocardium; in high concentrations, however, it reduced the rate of rise of the mono-

96

phasic action potential in Purkinje fibers, suggesting an additional effect on the fast channel carrying the rapid inward sodium current.ls3 Diltiazem appears to have negative chronotropic effects;rs4 during exercise in patient subjects, heart rate is reduced both at rest and during submaximal exercise.ls5 Oyama et a1.‘56 reported that the drug depressed both sinoatrial and atrioventricular nodal function in normal subjects. Diltiazem also has some negative inotropic effects,1529’57 but has been reported to have less myocardial depressant activity than verapami1.15’ Single oral doses of 120 mg in 11 patients after myocardial infarction produced no significant changes in cardiac index, or in systemic resistance or arterial pressure, but heart rate fell 13% from control levels;‘59 nifedipine, in contrast, given in a single 20-mg oral dose, lowered peripheral resistance and blood pressure and resulted in increased levels of heart rate and cardiac index. In another clinical study where diltiazem was given as a single dose (60 mg), a slight drop in systolic blood pressure occurred, but no change in heart rate or cardiac output at rest was seen.16’ Walsh et al. compared the effects of verapamil and diltiazem on left ventricular function in conscious dogs and found that while the former drug had detectable negative inotropic activity, no changes were observed The limited data available with diltiazem.‘6’ suggest that diltiazem does not have clinically important ventricular depressant effects when given alone in doses between 60 and 120 mg in adult patients. A possible explanation for this observation may be inherent in a report by Kondo et a1.‘62 These investigators studied the effects of verapamil, nifedipine, and diltiazem on the constrictor responses to potassium and norepinephrine in isolated arterial segments from rats. They found that all three drugs blocked vascular responses to potassium chloride, but only verapamil inhibited norepinephrine-induced contraction in a calcium-free medium. Since potassium-related vascular contraction is due to increased movement of calcium across the depolarized cell membrane, all three drugs were confirmed as inhibitors of calcium flux. Vascular contraction with norepinephrine in the calcium-free medium, however, is presumably due to drug-related release of calcium from intracellular stores. The absence of effect on this latter preparation by diltiazem and nifedipine suggests that they

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selectively block calcium movement across the cell membrane but do not affect intracellular calcium. Verapamil, on the contrary, abolished norepinephrine-induced responses, indicating that it may have more profound effects on intracellular calcium shifts and its results (such as contractile events) than diltiazem or nifedipine. The direct myocardial effects of diltiazem have been observed, however, in several studies concerned with myocardial preservation during ischemia. Weishaar et a1.‘63 found that diltiazem administered as an intravenous bolus dose (0.2 mg/kg) to dogs 10 min after coronary artery ligation reduced the extent of ischemic myocardium compared to that found in control animals, but did not prevent resultant decreases in mitochondrial oxygen consumption. These results were extended in a recent report by Nagao et a1.,‘64 who pretreated anesthetized, open-chest dogs with intravenous diltiazem (0.02 mg/kg/ min for 35 min) prior to coronary artery occlusion. In these experiments, diltiazem prevented the fall in developed tension seen in the ischemic area of myocardium in control animals; in addition, the depression of mitochondrial respiration in ischemic cardiac tissue was not observed in animals given diltiazem. Both these studies suggest a potential clinical application for diltiazem in patients with acute myocardial infarction. Primary clinical interest has been placed on the therapeutic action of diltiazem in patients with symptomatic ischemic heart disease. In an experimental model with dogs designed to simulate unstable angina pectoris, Franklin et a1.‘65 found that diltiazem significantly increased coronary collateral blood flow in ischemic myocardium. Regional myocardial dysfunction, however, did not improve. The vasodilator activity of the drug was further demonstrated in a series of reports from Yasue and colleagues in which diltiazem was shown to be effective in preventing coronary arterial spasm associated with alkalosis166 or exercise.167,‘68 A larger experience from Japan confirmed the efficacy of diltiazem (and of nifedipine) in the treatment of angina1 symptoms due to coronary spasm,‘69 and recent studies from investigators in this country have reported similar findings.‘70,‘7’ The drug also appears to be effective in treatment of patients with stable angina on exertion, producing a decrease in pressure-rate product at submaximal exercisels5 and improving exercise

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duration during standard treadmill protocols. 172,173 Clinical experience with diltiazem in patients with hypertension or cardiomyopathy has not yet been reported. The drug has not been as extensively studied as verapamil or nifedipine and appears, at this time, to occupy an intermediate position between the two in terms of clinical activity.14*

Diltiazem

/rl

,--OCH3

Pharmacokinetics

Diltiazem (Fig. 4) is a benzothiazepine derivative.‘52 Considering the extent of clinical investigation done to date, the lack of pharmacokinetic data available is surprising. Kohno et a1.174 studied the drug in dogs, finding rapid and almost complete absorption with a prominent first-pass effect. The drug appeared in plasma within 15 min and the half-life was estimated at 4 hr. Almost 80% of the drug was bound to plasma proteins. Hepatic metabolism involves primarily deacetylation, but a significant fraction of the compound may be excreted unchanged. A sensitive gas chromatographic assay method for measurement of diltiazem concentrations in plasma has been reported.175 The bioavailability of oral diltiazem in normal subjects was found to be 13% for several different formulations;‘76 with 60-mg doses,peak plasma drug levels varied from about 50 rig/ml following slow-releaseformulations to 68 rig/ml with a fast-dissolving tablet. Further studies on human pharmacokinetics are needed to guide clinical drug administration protocols. Plasma

Level-Effect

Correlations

No studies involving drug plasma level-effect relationships in human subjects have been reported to this time. Rosenthal et a1.17’ measured diltiazem levels in plasma in patients with exertional angina given the drug chronically but did not report the values. In this study, plasma drug concentrations were apparently similar in patients with a good therapeutic

Fig. 4.

Structure

of diltiazem.

response to the drug and in those who were unresponsive. Side Effects,

Toxicity,

and Drug Interactions

The reported clinical experience with diltia-

zem is yet inadequate

for establishing

conclu-

sions regarding toxicity, especially during chronic oral administration. It has been well tolerated in limited series,‘55,‘60,166-173 without reported side effects or abnormalities in routine laboratory screening procedures. In doses between 120 and 240 mg daily, no changes on the resting electrocardiogram were observed.17’ No data are available regarding potential or observed drug interactions. Dosing

Recommendations

The oral drug dosesused in clinical studies with diltiazem have varied from 120 to 240 mg/day, with the drug given every 6 or 8 hr. Clinical experience is presently inadequate for definitive recommendations. Note. Two recent studies’77*178 found that chronic oral administration of verapamil resulted in cumulation of the drug and its active metabolite, possibly due to a reduction in hepatic clearance.

REFERENCES 1. Singh BN, Ellrodt G, Peter CT: Verapamil: of its pharmacological properties and therapeutic 15:169-197,197s 2. Singh BN, Collett JT, Chew CYC: the pharmacologic therapy of cardiac Cardiovasc Dis 42:243-301, 1980 3. Hansen

JF,

Sandoe

E: Treatment

A review use. Drugs

New perspectives in arrhythmias. Prog of Prinzmetal’s

angina due to coronary artery spasm using verapamil: A report of 3 cases. Eur J Cardiol 7:327-335, 1978 4. Yasue H, Omote S, Takizawa A, et al: Pathogenesis and treatment of angina pectoris at rest as seen from its response to various drugs. Jpn Circ J 42:1-S, 1978 5. Muller JE, Gunther SH: Nifedipine therapy for Prinzmetal’s angina. Circulation 52:237-242, 1978 6. Mel&e KI, Benfey BC: Coronary vasodilatory and

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cardiac adrenergic blocking effects of iproveratril. Can J Physiol Pharmacol43:339-342,196s 7. Fleckenstein A: Die Zugelung des Myocardstoffwechsels durch Verapamil: Angriffspunkte und Anwendungsmoglichkeiten. Arzneim Forsch 20:1317-1322, 1970 8. Fleckenstein A: Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Annu Rev Pharmacol Toxic01 17:149-166, 1977 9. Haeusler G: Differential effect of verapamil on excitationcontraction coupling in smooth muscle and on excitation-secretion coupling in adrenergic nerve terminals. J Pharmacol Exp Ther 189:672-682,1972 10. Bayer K, Kaufmann R, Manhold R: Jnotropic and electrophysiologic actions of verapamil and D600 in mammalian myocardium. II. Pattern of inotropic effects of the optical isomers. Naunyn Schmiedeberg Arch Pharmacol 290:69-80,1975 11. Grant AO, Katzung BG: The effects of quinidine and verapamil on electrically induced automaticity in the ventricular myocardium of guinea pig. J Pharmacol Exp Ther 196:407-419,1976 12. Raschack M: Relationship of antiarrhythmic to inotropic activity and antiarrhythmic qualities of the optical isomers of verapamil. Naunyn Schmiedeberg Arch Pharmaco1 294:285-291,1976 13. Imanishi S, McAllister RG, Surawicz B: The effects of verapamil and lidocaine on the automatic depolarizations in guinea pig ventricular myocardium. J Pharmacol Exp Ther 207:29&303,1978 14. Zipes DP, Besch HR, Watanabe AM: The role of the slow current in cardiac electrophysiology. Circulation 51:761-766,1975 15. Zipes DP, Fischer JC: Effects of agents which inhibit the slow channel on sinus node automaticity and atrioventricular conduction in the dog. Circ Res 34: 184-l 92, 1974 16. Rosen MR, Ilvento JP, Merker C: The electrophysiologic basis for the suppression of cardiac arrhythmias by verapamil. Am J Cardiol 33:166, 1974 (abstr) 17. Rosen MR, Ilvento JP, Gelbank H, et al: Effects of verapamil on electrophysiologic properties of canine cardia Purkinje fibers. J Pharmacol Exp Ther 189:414-422, 1974 18. Surawicz B: Calcium responses (“calcium spikes”). Am J Cardiol 33:689-690, 1974 19. Spear JF, Horowitz LN, Moore EN, et al: Verapamilsensitive “slow response” activity in infarcted human ventricular myocardium. Circulation 54(Suppl II):75 1976 20. Elharrar V, Gaum WE, Zipes DP: Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs. Am J Cardiol 39:544-549,1977 21. Heng MK, Singh BN, Roche AHG, et al: Effects of intravenous verapamil on cardiac arrhythmias and on the electrocardiogram. Am Heart J 90:487-498, 1975 22. Haas H, Hartfelder G: or-Isopropyl-o-(N-methylhomoveratryl)-(cr-aminopropyl)-3,4-dimethoxy-phenylacetonitol, eine Substanz mit coronargefisserweiternden Eigenschaften. Arzneim Forsch 12:549-558, 1962 23. Fleckenstein A, Nakayama K, Fleckenstein-Grtin G, et al: Interactions of H ions, Ca-antagonistic drugs and cardiac glycosides with excitation-contraction coupling of vascular smooth muscle, in Berlin BE (ed): Ionic Actions on Vascular Smooth Muscle. Berlin, Springer-Verlag, 1976, pp 117-126

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