comparative clinical electrophysiologic effects of diltiazem, verapamil and nifedipine: a review

Comparative Clinical Electrophysiologic Effects of Diltiazem, Verapamil and Nifedipine: A Review

L. BRENTMITCHELL, MD JOHN S. SCHROEDER, MD, FACC JAY W. MASON, MD, FACC

Stanford, Cafifornia

The slow channel blocking agentsDdiltiazem, verapamil and nifedi- pineDhave generated clinical interest for the treatment of a variety of cardiovascular disorders. These agents, despite a similar basic mechanism of action, produce disparate clinical cardiac electrophysiologic effects in human beings. In usual doses, the acute administration of dilUazem slows heart rate. Verapamil and nifedipine, however, increase heart rate. Although diitiazem and verapamil produce equivalent slowing of atrioventricular (A-V) nodal conduction, verapamil prolongs A-V nodalre- fractoriness to a greater degree. In contrast, nifedipine facilitates A-V nodal conduction and shortens A-V nodal refractoriness. Knowledge o~ these differences may aid in the appropriate selection of specific slow channel blocking agents in specific clinical situations.

From the Cardiac Arrhythmia Study Unit, Car- diology Division, Stanford University Medical Center, Stanford, California 94305. Dr. Mitchell was supported by the Canadian Heart Foundation, Ottawa, Ontario, Canada. Dr. Mason was supported by a scholarship from the Brotman Foun- dation, Los Angeles, California.

Address for reprints: Jay W. Mason, MD, Car- diology Division, Stanford University Medical Center, Stanford, California 94305.

The slow channel blocking agents (diltiazem, verapamil and nifedipine) are a group of compounds with diverse structures (Fig. 1) and net electrophysiologic effects in human beings. Although these agents share a basic mechanism of action--inhibition of transmembrane ion flux (predominantly calcium) through the slow channel during the action potentiall,2--their net effects are dissimilar because of differences in kinetic characteristics of slow channel blockade, effects on other transmembrane ion fluxes, potencies of action on various cardiac and vascular tissues and interactions with autonomic nervous system reflexes. 2-6 This review compares and contrasts the clinical electrophysiologic effects of diltiazem, verapamil and nifedipine.

Slow Channel Versus Fast Channel Cardiac Tissues

At the risk of oversimplification, we can separate normal cardiac tissues into two groups based on their action potential characteristics. 7 Slow channel-dependent tissues, such as the sinoatrial (S-A) and atrioventricular (A-V) nodes, have low diastolic potentials, sl0w rates of phase zero depolarization (slow conduction velocities), spontaneous phase 4 depolarization (automaticity) and delayed recovery of excitability outlasting the action potential duration (long refractory periods), s In fast channel tissues, such as the His-Purkinje system and atrial and ventricular muscle, electrical excitability results primarily from transmembrane sodium flux. These tissues have high diastolic potentials, rapid rates of phase zero depolarization (fast conduction velocities) and recover excitability coincident with repolarization (short refractory periods). 2

The slow channel does, however, contribute to the action potential of fast channel tissue. It is primarily responsible for maintenance of the plateau phase s and provides the route for calcium influx that initiates contraction. 1° Furthermore, some investigators 11 postulate that the slow channel may be the predominant transmembrane flux in certain disease states that inactivate the fast channel. The effects of slow channel blocking agents would therefore be most evident in the S-A node, A-V node and diseased fast channel tissues. No effect on, or only subtle changes in, the clinical electrophysiologic characteristics of normal fast channel tissues would be expected.

February 18, 1982 The American Journal of CARDIOLOGY Volume 49 829

DILTIAZEM, VERAPAMIL AND NIFEDIPINE ELECTROPHYSIOLOGY--MITCHELL ET AL.

I DILTIAZEM I

~ OCH 3

OCOCH 3

r 3 CH2-CH2-N \ • HCI

CH 3

I VERAPAMIL I H3C CH3 \cd I ~ H3

H 3CO , . . ~ ' ~ ~-C H2-C H2-C H2-N-C H2-CH 2 ~ OCH 3

H3CO ~ . . , ~ C=-N ~ L ~ OCH3

[ ~ N O 2 [ NIFEDIPINE I H3COOC ~ C O O C H 3

H3 C~ ~N r -CH 3 I H

FIGURE 1, Chemical structures of dilt iazem (a benzothiazepine derivative), verapamil (a papaverine derivative) and nifedipine (a dihy- dropyridine derivative).

Short-Term Drug Administration

Sinus Nodal Function (Table I)

Sinus nodal function is commonly assessed by the spontaneous heart rate, maximal corrected sinus nodal recovery time after overdrive suppression by atrial pacing 12 and conduction characteristics of perinodal tissues as measured by the sinoatrial conduction time. 13 The changes in these measures predicted by slow channel blockade are reversed to varying degrees by autonomic nervous system reflexes accompanying their hypotensive effects, especially after short-term administration.

H e a r t rate: After short-term administration of diltiazem, either no cl~ange or a slight decrease in heart rate has been reported. 14-19 However, those investigations showing no significant change used small doses or assessed the effect of diltiazem shortly after administration. Bourassa et al. 17 noted a tendency for heart rate to decrease further after the end of their 15 minute study. In our experience, 19 the acute administration of diltiazem reduces heart rate significantly after 10 minutes, and the peak reduction occurs at an average

TABLE I

Effects of Shor t -Term Administrat ion of S low Channe l Blocking Agents on the Sinus Node

Drug and Investigator Patients Diag- Dose Time" (first author) (n) nosis (mg) (min) AHR ACSRT ASACT

Diltiazem Oyama 14 9 IHD 10 IV 10 NS NS NS Kinoshita is 24 Misc 60 PO 90 --6 % - - - - Sugimoto ~s 9 Normal 1/min IV 10-20 NS NS - -

8 SSS 1/min IV 10-20 - 2 4 % NS T - - 9 A-V Dis 1/min IV 10-20 ( - -3%)NS NS - -

Bourassa 17 8 IHD 30 ~g / 15 (-- 3 % )NS - - - - kg/min IV

17 IHD 120 PO 180 -- 11% - - - - Kawai ~8 10 Misc 10-20 IV ? NS NS - - Mitchell ~9 15 Misc 0.26/kg IV~ 5-30 - - 7 % NS NS

Verapamil Rizzon 2° 21 Misc 0.15/kg IV 15-30 + 14 % NS NS Wellens 21 10 EHD 10 IV 10 - - - - - - Carrasco 22 7 SSS 0.15/kg IV 5-30 (-- 14 %)NS 418 % - -

14 Misc 0.15/kg IV 5-30 ,1,11% + 9 6 % - - 9 Misc 0.20/kg IV 5-30 + 18 % ,1,73 % - -

Breithardt 23 18 Misc 0.10/kg IV 10-15 ,1,6 % NS NS 7 SSS(a) 0.10/kg IV 10-15 NS NS NS

11 SSS(b) 0.10/kg IV 10-15 - -10% Inc ~; NS Rowland 24 10 EHD 0.15/kg IV 5 ,1,10% - - - - Tonkin 25 13 EHD 0.15/kg iV 10 NS NS - - Kawai is 13 Misc 10 iV ? (-I-9 %)NS NS - -

Nifedipine Padaletti 2e 10 Misc 20 SL 20 ,1,14 % NS NS Furlanello 27 20 Misc 20 SL 15-30 Inc NS - - Rowland 24 i I EHD 7.5 #g /kg IV 5 + 16 % - - - - Kawai 18 8 Misc 1 IV ? ,1,26% - -25% - -

" interval between drug administration and electrophysiologic reassessment. T Includes at least one patient with sinus node arrest. ~ Mean total dose of two dosing groups.

A-V dis = A-V nodal dysfunction ACSRT = percent change in maximal corrected sinus nodal recovery t ime; AHR -- percent change in heart rate; ASACT = percent change in sinoatrial conduction t ime; EHD -- electr ical heart disease exclusive of A-V nodal dysfunct on or sinus node disease; IHD = ischemic heart disease; Inc = increased but percent change not reported; IV = intravenous; Misc = patients from several diagnostic categories; NS = not significant (where the percent change was more than trivial but not significant, it is presented in parentheses); PO = orally; SL = sublingually; SSS = sinus node disease; SSS(a) = sinus node disease without prolongation of corrected sinus nodal recovery t ime; SSS(b) = sinus node disease with prolongation of corrected sinus nodal recovery time; ? = not stated; - - -- not measured.

630 February 18, 1982 The American Journal of CARDIOLOGY Volume 49


of 17 minutes. Diltiazem produces even greater reduc- tions in heart rate in patients with sinus node disease than in patients with normal sinus nodal function. 16

The other slow channel blocking agents, that is, ni- [edipine and, to a lesser extent, verapamil, produce heart rate acceleration. 18,2°,22,27 Verapamil, like diltiazem, slows the heart rate in patients with sinus node disease, particularly in the subgroup with an abnormal control maximal corrected sinus nodal recovery time. 23

Sinus nodal recovery and conduction times: Neither diltiazem 14,16,1s,19 nor the other slow channel blocking agents 18,20,22,23,25-27 produce clinically significant changes in the maximal corrected sinus nodal recovery time or sinoatrial conduction time in patients with normal sinus nodal function. However, in patients with sinus node disease, diltiazem or verapamil may produce marked prolongation of the maximal corrected sinus nodal recovery time, including sinus arrest. 16,22,23 Although nifedipine may also prolong the maximal corrected sinus nodal recovery time in some patients with sinus node disease, 27 the changes are less pronounced.

Atrioventricular Nodal Function (Table II)

Clinical electrophysiologic measures of atrioventricular (A-V) nodal function include A-V nodal conduction time and refractoriness characteristics. The former is measured by the A-H interval during antero- grade conduction and is estimated by the V-A interval during retrograde conduction. Atrioventricular nodal refractoriness is estimated by the functional and effective refractory periods 2s and the shortest cycle length

of atrial pacing conducted with Wenckebach periodicity (Wenckebach cycle length). 29 Changes in the A-H interval during constant rate atrial paced rhythm should be used to compare the A-V nodal effects of interven- tions that also alter heart rate. a°

A-V and V-A conduction time: In c0nstant-rate paced rhythm, diltiazem prolongs A-H cOnduction time by 13 to 24 percent.14.! 6,18,19 The effects of diltiazem on retrograde (V-A) conduction have not been previously reported. In our experience, retrograde conduction time was prolonged during right ventricular pacing in eight of nine patients, with third degree V-A block occurring in half of these. 25 This was presumably a result of A-V nodal rather than His-Purkinje depression. Like diltiazem, verapamil slows A-V conduction in both antero- grade and retrograde directions, ls,2°-25 Wellens et al.21 demonstrated that verapamil, in usual doses, prolongs the A-H interval by 24 percent during constant rate atrial paced rhythm--an effect Similar in magnitude to that of diltiazem. In contrast, nifedipine either has no effect or facilitates A-V nodal conduction. 18,24,26,27 Padaletti et al.26 demonstrated that nifedipine shortens the A-H interval by 14 percent in constant rate atrial paced rhythm. This effect is explained in part by re- versal of the expected direct A-V nodal effects of nifedipine by autonomic nervous system reflexes accompanying its potent hypotensive actions. 18

These direct effects are modified by concomitant heart rate changes during sinus rhythm. Verapamil and nifedipine, by increasing heart rate, tend to slow A-H conduction, thereby accentuating the direct effect of verapamil and partially masking the effect of nifedipine. The decrease in heart rate after diltiazem partially masks its slowing of A-H conduction.

TABLE II Effects of Short-Term Administration of Slow Channel Blocking Agents on the A-V Node

Drug and A-H INT Investigator (first author) Type Sinus Paced V-A INT A-V FRP A-V ERP A-V WCL

Diltiazem Oyama TM IHD + 1 6 % + 2 4 % - - + 1 8 % + 2 5 % - - Sugimoto is Normal + 1 4 % + 1 3 % - - (+7%)NS (+10%)NS (+20%)NS

SSS (47 %)NS (,1,11%)NS - - NS NS (410%)NS AV Dis (416%)NS (47 %)NS - - (46%)NS (410%)NS (410%)NS

Kawai 18 Misc ,1,21% - - - - + 1 0 % + 2 2 % + 1 2 % Mitchell 19 Misc -t- 12 % 4 22 % Delay 4 6 % ,1,16 % ,1,13 %

Verapamil Rizzon 2° Misc ,1,31% - - - - + 1 2 % ,1,21% ,1,24% Wellens 21 EHD - - ,1, 24 % Delay ,1,12 % ,1,32 % - - Rowland 24 EHD ,1,25 % . . . . . Tonkin 25 EHD ,1, 25 % - - Delay ,1,15 % ,1, 23 % .1.19 % Kawai is Misc ,1,26% - - - - ,1,12% ,1,35% ,1,17%

Nifedipine Padaletti26 Misc NS (-- 14 % )NS - - (-- 11% )NS (-- 13 % )NS - - Furlanello 27 Misc NS - - - - Short Short Short Rowland 24 EHD NS . . . . . Kawai 18 Misc - -4% - - - - - -13% - -17% - -7%

Reports summarized are the same as those in Table I. A-V ERP = percent change in A-V nodal effective refractory period; A-V F.RP = change in A-V nodal function refractory period; A-H INT = percent

change in A-H conduction time determined in spontaneous sinus rhythm (Sinus) and in constant rate atrial paced rhythm (Paced); A-V WCL = percent change in A-V nodal Wenckebach cycle length; Delay = conduction time delay; Short = refractory period shortening; V-A INT = percent change in V-A conduction time determined during ventricular pacing. Other abbi'eviaUons as in Table I.


DILTIAZEM,,VERAPAMIL AND NIFEDIPINE El FCTROPHYSIOLOGY--MITCHELL ET AL.

TABLE III

Effects of Short-Term Administration of Slow Channel Blocking Agents on Fast Channel Tissues

Drug and Investigator Diag- (first author) nosis

HRA-LSRA H-V INT

Sinus Paced Sinus Paced A-FRP A-ERP

Diltiazem Oyama 14 IHD NS NS NS NS NS NS Sugimoto is Normal . . . . NS NS

S S S . . . . N S N S

AV Dis . . . . NS NS Kawai 18 Misc - - - - NS - - - - - -

Mitchell 19 Misc NS NS NS NS - - 3 % NS Verapamil Rizzon 2° Misc NS - - NS - - NS NS Tont~ in 25 EHD NS - - NS - - - - NS Kawai 18 Misc - - - - NS - - - - - -

Nifedipine Padaletti 2s Misc NS NS NS NS -I-1 1% NS Furlanello 27 Misc - - - - NS - - NS NS Rowland 24 EHD - - - - NS - - - - - -

Kawai 18 Misc - - - - NS - - - - - -

Reports summarized are the same as those in Table I and II. A-ERP = right atrial effective refractory period; A-FRP = right atrial functional refractory period; HRA-LSRA = high right atrial to low septal right

atrial conduction time (intra-atrial conduction time); HV-INT = His-Purkinje system conduction time. Other abbreviations as in Table I.

A-V nodal refractoriness: Slow channel blocking agents also affect A-V nodal refractoriness. Diltiazem prolongs the A-V nodal functional refractory period by 6 to 18 percent, the A-V nodal effective refractory period by 10 to 25 percent and the A-V nodal Wenckebach cycle length by 10 to 20 percent. 14.16,1s We observed changes in A-V nodal functional and effective refractory periods of 6 and 16 percent, respectivelyJ 9 Although these changes are comparable with findings of previous investigations, they are only half as great as those observed in similar groups of patients given verapamil. 18,20,21.25

It appears that, despite equivalent depression of A-V nodal conduction, verapamil affects A-V nodal refractoriness to a greater degree than does diltiazem. This may explain the greater incidence of spontaneous sec- ond and third degree A-V block after verapamil than observed after diltiazem in the doses currently used. The importance of this apparent difference in the use of these two drugs as antiarrhythmic agents remains to be established.

The effects of nifedipine on A -V nodal refractori- uess, as with AV nodal conduction, are opposite to those of diltiazem and verapamilJ 8,2~,27 Nifedipine reduces the A-V nodal functional refractory period by 11 to 13 percent, the A-V nodal effective refractory period by 13 to 17 percent and the A-V nodal Wenckebach cycle length by approximately 7 percent. Patients with A-V node disease do not appear to be more sensitive than patients with normal A-V nodal function to these three slow channel blocking agents. 16

Other Cardiac Tissues (Table lU) Action potential duration: Slow channel blocking

agents generally do not cause measurable changes in conduction or refractoriness of normal fast channel tissues in human beings. 14JeJS-2°,24-27 The upstroke velocity of phase zero of the action potential of such tissues is not changed by the application of clinically

relevant concentrations of slow channel blocking agents in tissue models. 31-33 Therefore, no direct change in conduction times should occur in human beings. Al- though each of these agents shortens the plateau phase of the action potential, this change is not reflected in clinical measures of cardiac electrophysiology. The overall action potential duration, which determines refractoriness of fast channel tissues, is not simply a function of the plateau phase duration and is altered slightly, and differently, by the various slow channel blocking agents. 5,31,33,34

Diltiazem shortens the overall action potential duration slightly in some tissue models, and therefore might reduce refractoriness in fast channel tissues in human beings. 5,:~3 We observed a slight but significant reduction in right atrial functional refractory period (3 percent) in our series of 15 patients. A similar degree of reduction of right atrial effective refractory period was noted, but statistical significance was not achieved. However, we did not observe a change in the refractory periods of other fast channel tissues after administration of diltiazemJ 9

Diseased fast channel tissues: Study of the clinical electrophysiologic effects of slow channel blocking agents on diseased fast channel tissues in human beings is limited by available techniques. As previously dis- cussed, experimental evidence suggests that the effects of slow channel blocking agents on such tissues are probably more pronounced than on normal fast channel tissues. However, the clinical expressions of these effects have not yet been characterized.

Long-Term Drug Administration S-A node: The clinical electrophysiologic effects of

chronic administration of slow channel blocking agents in human beings have not been adequately studied. In general, observations have been limited to the effects of these agents on heart rate (Table IV). 35-46 The dif- fering reflex autonomic effects produced by these agents

632 February 18, 1982 The American Journal of CARDIOLOGY Volume 49


TABLE IV

Effect of Long-Term Administration of Slow Channel Blocking Agents on Heart Rate

Drug and Investigator Dose (first author) n Type (mg) Time Heart Rate

Diltiazem Kusukawa 35 18 IHD 30 PO tid 4-8 weeks NS Naka~ama 3e 19 IHD 30 PO tid 8 weeks -- 10 % Pool ~1 15 IHD 60 PO qid 1 week N$ Hossack 38 6 IHD 240-360/day 8 months --9 %

Verapamil Sandier 39 16 IHD 120 PO tid 4 weeks (--5 % )NS Livesly 4° 32 IHD 120 PO tid 4 weeks NS Andreasen 41 47 IHD 80 PO tid 4 weeks --4 % Bala Subramanian 42 25 IHD 120 PO tid 8 weeks NS

Nifedipine Braasch 43 118 IHD 10 PO tid 13 weeks NS McArthur 44 5 IHD 30 PO tid 1 week NS Moskowitz 4s 10 IHD 20 PO tid 2 weeks NS Kenmure 48 21 IHD 10 PO tid 2 weeks NS

Abbreviations as in Table I.

diminish with time, and the similar direct effects be- come more evident. Diltiazem and verapamil produce either no significant change or a slight reduction in heart rate, with the negative chronotropic effects of diltiazem being more pronounced. In general, the administration of nifedipine on a long-term basis does not affect heart rate.

By serial electrophysiologic testing, Wellens et al. 2~ demonstrated that the depressant effects of verapamil on A-V nodal conduction and refractoriness are main- tained in the short term, that is, 2 to 3 weeks. The per- sistence of effects of diltiazem or nifedipine on A-V nodal function has not been studied.

Conclusions

Clinical Significance The differences in net electrophysiologic effects of

diltiazem, verapamil and nifedipine appear sufficient to warrant preferential use of specific agents in specific clinical situations, especially when short-term administration is necessary. Other differences, including relative therapeutic efficacy and frequency of adverse hemodynamic effects, must also be considered.

When therapeutic aims include a reduction in heart rate, as in symptomatic ischemic heart disease, diltiazem may be preferred. Nifedipine would be beneficial when an increase in heart rate is desirable. Although the presence of sinus node disease is a relative contraindi- cation to the use of diltiazem or verapamil, clinically significant adverse effects have not been noted with nifedipine. In patients with depressed A-V nodal function, nifedipine might be preferable to verapamil or diltiazem.

In antiarrhythmic therapy, the slow channel blocking agents are used because of their electrophysiologic effects rather than in spite of them. The antiarrhythmic efficacy of verapamil is well established, particularly where the arrhythmia requires the partic- ipation of slow channel t i s sues -49 The antiarrhythmic potential of diltiazem has not been fully established but

appears to be significant. 14 Nifedipine, as expected, has not proved to be an effective antiarrhythmic agent.

Electrophysiologic Effects The comparative net acute electrophysiologic effects

of these slow channel blocking agents are shown in Figure 2. Although data obtained by different investigators in different patients may not be validly compared, the only "comparative" study using these agents to date 18 has serious drawbacks including the use of small study groups and different groups for each agent, comparison of conduction times without correction for changes in sinus rate and the measurement of only se- lected electrophysiologic characteristics. Nevertheless,

MEAN BP HEART RATE

I I AH-SINUS AH-PACED

OLTAZEM--22 +27% VERAPAMIL ~ + 2 4 %

-14% ~ NIFEDIPINE I

AV-FRP AV-ERP

DILTIAZEM ~%+ DILTIAZEM ~+16% VERAPAMIL 13% VERAPAMIL ~ +28%

-12% ~ NIFEDIP'NE - 1 5 % ~ NIFEDIPINE I I

FIGURE 2. Summary of percent changes in mean arterial pressure (BP), heart rate, A-H interval (in sinus and constant-rate atrial paced rhythms), and A-V nodal functional (FRP) and effective (ERP) refractory periods after short-term administration of diltiazem, verapamil or nifedipine. (Diltiazem data from Ref 19; verapamil data from Ref 18 and 20-25; nifedipine data from Ref 18, 24, 26, 27 and 50-52.)



the observations made during that study are generally comparable with those illustrated.

In summary, the net cardiac electrophysiologic effects of slow channel blocking agents in human beings are a function of the particular agent used. The short- term administration of diltiazem usually slows heart rate whereas administration of nifedipine and verapamil increase heart rate. None of these agents affect other measures of sinus nodal function to a clinically relevant degree in the absence of sinus nodal dysfunction. However, in patients with sinus node disease, diltiazem or verapamil may seriously reduce sinus rate and may produce sinus arrest. The extent of depression of A-V nodal conduction by diltiazem and verapamil is similar;

however, prolongation of A-V nodal refractoriness is more pronounced with verapamil. Unlike these two agents, nifedipine facilitates A-V nodal conduction and shortens A-V nodal refractoriness. With long-term administration the differences among these agents are reduced, but information in this area is limited.

Further investigations regarding the effects of slow channel blocking agents on normal and diseased fast channel tissues are necessary before firm conclusions can be drawn regarding the effects of these agents on such tissues in human beings. Where other consider- ations are equal, these electrophysiologic differences allow the rational selection of specific slow channel blocking agents in specific clinical situations.

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comparative clinical electrophysiologic effects of diltiazem, verapamil and nifedipine: a review

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