Evaluations on New Drugs

Drugs 15: 169-197 (1978)

e ADIS Press 1978

Verapamil: A Review of its Pharmacological

Properties and Therapeutic Use 1
Bramah N. Singh, Gray Ellrodt and C. Thomas Peter
Department of Cardiology, Cedars-Sinai Medical Center , and the Department of Medicine, UCLA
School of Medicine, Los Angeles, California

TableofContents
Summary
I . Pharmacodynamic Studies
1.1 Effect on Cellular Mechanism s
1.2 Electrophy siological Effects: Mode of Antiarrhythmic Action
1.2.1 Experimental Stud ies
1.2.2 Clinical Studies
1.3 Effect on Coronary Circulation
1.4 Cardio vascular Haemod ynamic Effects
2. Pharm acokinetic Studies
2.1 Kinetics and Duration of Action
2.2 Pharmacokinetic Characteristics
3. Therapeutic Uses
3.1 Cardiac Arrhythmias
3.1.1 Experimental Arrhythmias
3.1.2 Clinical Arrhythmias
3.2 Myocard ial Ischaemia
3.2.1 Experimental Studies
3.2.2 Angina Pectoris
3.3 Hypertension
4. Side-Effects
5. Contraindications and Precautions
6. Dosage
References
" .....................................................................................................................

170
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178
178
179
179
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190
190
190
192
192
193
193
194

I Supported in part by the SCOR Grant No. HLl7651. National Institute of Health. Bethesda.
Maryland .

Verapamil:A Review

Summary

170

Synopsis: Verapamil' is a novel antiarrhythmic and antianginal agent which. although introduced in 1962. has only recently gained prominence not only as a significant agent in cardiovascular therapeutics but also as a powerful tool to examine the nature of some of the
biophysical phenomena at the membrane of cardiac and other excitable tissues. Verapamil is
the prototype ofthose agents which selectively inhibit membrane transport of calcium. an action
which accounts for the drug's peripheral and coronary vasodilator properties . its effect on excitation-contraction coupling and hence its negative inotropic propensity. as well as its depressail/ effects on the sinus node and atrioventricular conduction . Its pharmacological effects are
largely independent of the autonomic nervous system. The main therapeutic uses of the drug
are in the management of atrial tachyarrhythmias, angina. and possibly hypertension. The
overall experimental and clinical data suggest that verapamil will become an important and
safe addition to existing drug 'regimens . especially as an agent of choice for the short-term
treatment of most cases ofparoxysmal supraventricular tachycardias . The initial experience in
other arrhythmias. angina and hypertension. is also sufficiently encouraging tojustify further
detailed clinical/rials to define its potential role in cardiovascular therapeutics .
Pharmacodynamic Properties: Verapamil is a weak local anaesthetic; it does not depress
the upstroke velocity of the cardiac action potential . nor does it prolong the action potential
duration in heart muscle. It selectively depresses nodal tissues. presumably by an effect on the
calcium-mediated slow response. an action distinct from that of all other antiarrhythmic
agents .
Pharmacokinetics: Preliminary pharmacokinetic studies reveal major discrepancies between the duration of the electrophysiological and haemodynamic effects of verapamil and the
presence of unchanged drug in the plasma. raising the possibility of active metabolites .
Plasma protein binding of verapamil approaches approximately 90 % . Despite almost complete gastrointestinal absorption following oral administration. the overall bioavailability of
the drug is about 10 to 22 96 reflecting substantial first pass hepatic metabolism which may
account for the 8 to IO-fold greater oral compared with intravenous doses needed to produce
comparable pharmacodynamic effects.
Therapeutic Trials : The antiarrhythmic effects of verapamil are explained largely by its action on the atrioventricular node: intravenously administered verapamil (I Omg in adults. 3.5
to 5mg in children) produces prompt reversion to sinus rhythm of 80 to 100 96 of cases with
paroxysmal supraventricular tachycardias. especially those due to AV nodal re-entry. The
drug has little effect on the anomalous pathways in the Wolff-Parkinson-White syndrome so
that atrial fibrillation or flutter complicating this disorder are not affected by verapamil, in
contrast to other cases of atrial fibrillation or flutter in which the ventricular response is consistently reduced in most cases and sinus rhythm restored in a few. The role of oral verapamil
used alone or in combination with other agents in the prophylaxis of paroxysmal supraventricular tachycardias and in the maintenance of sinus rhythm following cardioversion of
atrial fibrillation remains to be defined. Verapamil is of little value in the control of ventricular arrhythmias.
Verapamil is also effective in angina pectoris in doses in excess of 120mg 3 times daily
orally. At this dose schedule. its efficacy is comparable with that of 80mg 3 times daily of
oral propranolol. although the latter produces a significant degree of bradycardia whereas
verapamil does not. The mode of antianginal action of verapamil is therefore not understood.
but unlike propranolol the drug has no effects on lung function . Experimental studies suggest
that verapamil might reduce myocardial infarct size and preliminary clinical studies raise the
possibility that the drug may be of value in the management of acute hypertensive crisis as
well as of treatment of essential hypertension.
2

lsoptin (Knoll AGJ: Cordilox (Abbott).

171

Verapamil: A Review

Side-effects: Orally administered verapamil is extremely well tolerated and few sideeffects have been encountered following intravenous administration of the drug. especially
when it is given slo wly. Transien t hypotension and prol ongat ion of A V conduction time or
even A V dissociation may occasionally be seen. Haemodynamic effects in patients with cardiac disease include short-lived decrease s in mean arterial pressure. first deri vative of the left
ventricular pressure. sys temic resistance and a rise in left ventricular filling pr essure . but with
little change in stroke volume. card iac index or heart rate . Rarely. severe hypoten sion. bradycard ia. or asystole have been reported. most cases occurring in patients previously treated
with ~ -ad renocep to r blocking drugs.

Precautions. Pr ior digitali sation is not a contraindication to the use of intr avenous or oral
veraparnil. except in the case of the sick sinus syndrome in which verapamil alone or in combination with other depressant drugs which influence automaticity or conduction may pro duce severe bradycardia or atrioventricular block. The drug is also co ntraindicated in unstable
atrioventricular block . heart failure (especially that complicating acute myocardial infarction).
cardiogenic shock or other hypotensive states . Side-effects resulting from vera pamil may be
rever sed . at least in part. by atropine. isoprenaline. intravenous calcium or glucagon. with
ventricular pacing being required occasionally.

Verapamil (iproveratril), a synthetic papaverine

derivative (fig. I). was first introduced as a smooth
muscle relaxant with potent peripheral as well as coronary vasodilator properties in animals (Haas and
-lartfelder, 1962; Melville et al., 1964; Melville and
Benfey, 1965; Nayler et al., 1968) as well as in man
(Mignault. 1966; Luebs et al., 1966). Therefore , initially it underwent evaluation as an antianginal agent
(Neumann and Luisada, 1966; Sandler et al., 1968)

Fig. 1. Structural formula of verapamil.

but subsequent studies have demonstrated that the

compound has significant antiarrhythmic properties
when tested in a variety of experimental arrhythmias
(Melville et al., 1965; Kaumann and Aramendia ,
1968; Schmid and Hanna , 1967; Rodriguez-Pereira
and Viana, 1968; Singh and Vaughan Williams ,
1972). At first. it was believed (Melville and Benfey,
1965; Bateman. 1967) that verapamil was a specific
~-adrenoceptor antagonist but this has not been subs-

172

Verapamil : A Review

tantiated by subsequent work (Ross and Jorgensen,

1967; Nayler et al., 1968; Kaumann and Aramendia,
1968).
Electrophysiological studies in different tissues
have subsequently revealed that verapamil has a unique cellular action in selectively inhibiting
transmembrane fluxes of calcium (Fleckenstein et al.,
1969; Kolhardt et al., 1972) in different excitable
tissues; a mechanism which undoubtedly accounts for
its antianginal, antiarrhythmic, coronary and peripheral vasodilator properties. Recently, the drug has
emerged as an agent of much value in the study of the
role of the_'slow response' (Cranefield, 1975) in the
genesis of different cardiac arrhythmias. Clinically,
the drug is proving of increasing significance in the
control of certain atrial tachyarrhythmias and also in
the management of angina pectoris. In this review,
the pharmacology of verapamil in relation to these
and other potential therapeutic applications of the
drug are discussed.

1. Pharmacodynamic Studies
I. I Effect on Cellular Mechanisms
Verapamil appears to exert its pharmacological
effects primarily through calcium antagonism at the
cell membrane of excitable tissues (fig. 2). It does not
modify calcium uptake, binding or exchange by cardiac microsomes, nor does it have an effect on
calcium activated ATP-ase (Nayler and Szeto, 1972;
Entman et al., 1972). Its fundamental action on heart
muscle is therefore distinct from that of ~-adrenocep
tor blocking drugs, (~-blockers), its main locus of action being the superficially-located membrane storage
sites for calcium (Nayler and Krikler, 1974). The interference with calcium transport at this level in the
heart is now thought to account for its antiarrhythmic and negative inotropic effects, while a similar action in the vascular smooth muscle cells leads to
peripheral as well as coronary vasodilatation. It is

Blocked by verapamil

Ca2

Ca2 storage

YJo"-H~ sites

Site of action of the /

cardiac glycosides
Myof ibr ils

Site of action of the thyroid

hormone and 3'S'-AMP

Fig . 2. Schematic representation of the sites at which certa in drugs and hormones act to alter the intracellular availability of

Ca2. in heart muscle cells. Verapamil acts primarily at the cell membrane. Reproduced with permission from Nayler and Dunnett
(1974) .

Verapamil: A Review

now recognised that verapamil not only blocks the inward current carried by calcium, but also the other
and presumably smaller component of the slow current carried by sodium. Thus , the primary mode of
action of the drug may have less specificity than previously believed, its effect being mediated through the
slow channel itself (Shigenobu et al., 1974) rather
than through the activity of a single ionic species.

1.2 Electrophysiological Effects: Mode of

Antiarrhythmic Action
1.2.1 Experimental Studies
Verapamil was initially considered to be a specific
~-adrenoceptor antagonist (Melville and Benfey,
1965; Bateman, 1967) and its mechanism of antiarrhythmic action akin to that of quinidine (Garvey,
1969). Subsequent investigation (Nayler et al., 1968;
Singh, 1971; Singh and Vaughan Williams, 1972)
has not borne out these early impressions.
Although verapamil has local anaesthetic potency
1.6 times that of procaine, in clinically relevant concentrations , it has a significant action neither on the
rate of depolarisation nor of repolarisation phases of
the cardiac action potential in atrial, ventricular or
Purkinje fibres. Since it is not a specific ~-blocker, it
does not therefore exhibit Class I, II or III antiarrhythmic actions (Singh, 1971; Singh and Vaughan
Williams , 1970, 1971). A separate category of action
with major emphasis on calcium antagonism was
therefore proposed (Singh and Vaughan Williams,
1972) and recent work (Wit and Cranefield, 1974;
Cranefield et al., 1974; Zipes and Fischer, 1974;
Rosen et al., 1976; Okada, 1976) appears to justify
the initial tentative conclusions.
It now appears that when the normal sodiummediated depolarisation (fast response') is inactivated, as may occur in myocardial ischaemia and
digitalis intoxication or other pathological conditions,
the so-called 'slow response' (Cranefield, 1975)
emerges. This may take 2 forms. The first type of
slow response is an action potential which is
qualitatively different from the normal action poten-

173

tial; such an action potential, carried largely by

calcium ions, is thought to be the basis of slow conduction through discrete segments of partially
depolarised fibres responsible for re-entrant arrhythmias (Cranefield, 1975). The second type of
slow response is mediated by action potentials with
pacemaker characteristics; under pathological conditions, they give rise to arrhythmias due to enhanced
automaticity. Such action potentials have been found
in Purkinje fibres exposed to stretch, hypoxia or other
adverse experimental conditions, or when they are
subjected to long depolarising electrical stimuli. Slow
response action potentials also occur under normal
conditions in the sinoatrial as well as atrioventricular
nodes (Zipes and Fischer, 1974; Aronson and
Cranefield, 1973; Okada, 1976) where they appear to
be responsible for the sinus rhythmicity and delayed
atrioventricular conduction respectively.
Thus , the depression of the slow response by selective calcium antagonists in pathological tissues may
abolish arrhythmias due to re-entry as well as automaticity. These agents, the prototype of which is
verapamil, will also reduce the spontaneous activity
of the sinoatrial node, and abolish re-entrant atrial
tachyarrhythmias that depend on nodal re-entry for
their mechanism (Goldreyer, 1972). It would thus appear that the overall antiarrhythmic activity of
verapamil results from its ability to depress the slow
response.
1.2.2 Clinical Studies
The results from various clinical studies are in
substantial agreement with the experimental data. For
example, in patients in sinus rhythm, intravenously
administered verapamil was found to have no effect
on the R-R, QRS and Q-Tc intervals of the electrocardiogram (Heng et al., 1975; Brichard and Zimmermann, 1970). The P-R interval, reflecting atrioventricular conduction however, increased after
verapamil in all patients in I study (table O. These
findings are thus consistent with the fact that the drug
has no significant effects on the depolarisation and
repolarisation phases of the intracellularly-recorded
action potential in isolated cardiac tissues, and that its

174

Verapamil: A Review

major action in conscious man is on atrioventricular

conduction through the depression of the slow
response fibres in this structure. The minimal effect
on heart rate is undoubtedly due to the fact that the
drug's depressant action on sinoatrial nodal frequency
is largely nullified by the reflex tachycardia that
results from hypotension due te peripheral
vasodilatation (Singh and Roche, 1977).
These findings are further supported by studies
using His bundle electrocardiography which has demonstrated that verapamil impedes AV conduction
proximal to the His bundle without having an effect
on intra-atrial or intraventricular conduction (Husaini et al,r 1973; Roy et al., 1974; Neuss, et al.,
1974). The site of maximal delay appears to be in the
atrioventricular node and is largely independent of
autonomic influences (Angus et al., I976). The blocking effect of verapamil on AV conduction is of clinical significance in that it represents the mechanism
through which the ventricular response in atrial flutter and fibrillation is controlled and nodal re-entrant
supraventricular tachycardia abolished (Heng et al.,
1975). However, programmed stimulation techniques have revealed that the drug has minimal effect
on anterograde and retrograde conduction or refractoriness in the anomalous pathway in the WolffParkinson-White syndrome (Spurrell et al., I974a).
It is, therefore, unlikely to be of value in the treatment of this syndrome complicated by atrial flutter or
fibrillation (Heng et al., 1975).

Table I . Effects of intravenous verapamil on the

electrocardiogram in patients with sinus rhythm (after Heng et

aI:, 1975)
Interval
(rn sec)

Before
verapamil

After
verapamil

No.
pts

Significance

R-R

743 38
186.1 6.2
65.54.1
457.89.9

73827
205.48.1
66.1 4.6
451.06.6

15
13
13
12

NS

P-R
QAS

Q-T c

p<O.OO1
NS
NS

crease coronary blood flow to a much greater extent

than does papaverine, while it reduced cardiac oxygen
uptake (Haas and Hartfelder, 1962). Nayler and Szeto
(1972) have demonstrated that like propranolol,
verapamil decreases myocardial demand for oxygen,
but whereas propranolol consistently increases coronary vascular resistance (Nayler et al., 1967),
verapamil has the opposite effect even during the hypotensive phase of the drug's action (Nayler et al.,
1968).
During selectivecoronary angiography, verapamil
has been reported to produce coronary vasodilatation
in patients with normal coronary arteries but not in
those with atherosclerotic disease(Mignault, 1966) so
that the mechanism Whereby the drug produces a
beneficialeffect in angina relates more to reduced cardiac work rather than to enhanced coronary perfusion. However, the effect of verapamil on myocardial
ischaemia induced by rapid atrial pacing in man has
not so far been reported.

1.3 Effect on Coronary Circulation

By inhibiting excitation-contraction coupling in
vascular smooth muscle (Golerhaufen and Lammel,
1972; Haeusler, 1972), verapamil has been shown to
cause marked vasodilatation in most peripheral
vascular beds including mesenteric, and canine hind
limb preparations (Ross and Jorgensen, 1967; Greenberg and Wilson, 1974). It is, also an extremely potent coronary vasodilator (Melville et al., 1964;
Schlepper and Witzel, 1962; Winbury et al., 1969).
For example, in animal studies it was found to in-

1.4 Cardiovascular Haemodynamic Effects

As might be expected, verapamil has a marked
negative inotropic effect on isolated cardiac muscle
(Singh, 1971; Singh and Vaughan Williams, 1972;
Fleckenstein, 1970) - this is in part reversed by
calcium, catecholamines or glucagon (Singh and
Vaughan Williams, 1972). In intact animals and in
man, the drug's depressant action on heart muscle is
not only dose-dependent but is greatly modified by ex-

Verapamil: A Review

tramyocardial factors. In anaesthetised dogs, Ross

and Jorgensen (I 967) reported a dose-related reduction in cardiac output and stroke volume but the hypotensive effect of the drug could be accounted for
almost entirely by peripheral vasodilatation in intravenous doses below 0.25mg/kg body weight.
More recent studies by Angus et aI. (I 976) are in
general agreement with these findings; in
anaesthetised dogs, they found that verapamil produced a dose-dependent peripheral vasodilatation
with a reflex increase in myocardial contractility and
heart rate. Propranolol pre-treatment blocked the
reflex cardiac stimulation but the vasodilatation was
unaffected, consistent with the fact that the vascular
effects of the drug were mediated through a mechanism independent of peripheral ~-adrenoceptor
stimulation . When doses of verapamil above the
range used c1inicalIy were administered, a direct
myocardial depressant action became apparent.
There is still a relative paucity of data on the
haemodynamic effects of intravenously administered
verapamil in man, but those available suggest that, as
in the experimental animal, the drug produces a complex interplay of simultaneous alterations in preload,
afterload, myocardial contractility and, in alI probability, coronary blood flow. Using right heart
catheterisation in 12 patients with cardiac disease,
Ryden and Saetre (1971) studied the haemodynamic
effects of 0.1mg/kg body weight of verapamil as an
intravenous injection folIowed immediately by continuous infusion of 0.005mg/kg/min for 30
minutes. In patients with sinus rhythm, the mean arterial pressure was reduced with a slight increase in
cardiac output but no significant reduction in stroke
volume was observed except in patients who were in
atrial fibrilIation. Very similar results for patients in
sinus rhythm have been reported by Seabra-Gomes et
aI. (I976) who studied the effects of 0.1mg/kg of
verapamil in 10 patients (7 with coronary artery disease). In healthy adults, a slight negative inotropic action of the drug was found but it could easily be
abolished by exercise (Attehog and Ekelund, 1975).
In another study (Lewis et al., 1976) in 6 patients (3
with valve disease) with normal ejection fractions,

175

120

C, 110
J:

'"3

100

' 1:

90

a;

~III
u

'E

80

:ll
::E

70 L...---L...

'"
I:
Control

L...-

Verapamil
5min

....J

Verapamil
10min

/--------------------1 3
2!l

Control
1-

p<O.OI

Verapamil
5 min

...J4

Fig. 3. Change in mean arterial pressure following intravenous verapam~ administration . Individual values (open circ1esl for 18 patients are shown as well as the mean (closed
squares) and standard errors of means (horizontal bars). There
was a significant decrease in mean arterial pressure at 5
minutes (p < 0.011 after drug administration.
Fig. 4. Changes in left ventricular eoo-diastolic pressure
following verapamil administration . A sil1'ificant increase (p <
0.01) in the left ventricular filting pressure occurred.

176

Verapamil: A Review

2600

E
u

.,u

2200

Vl

.,

*7

~o

Vl

>-

:E!
.,

1800

s
"iii
e
Vl

1400

1i:::l1
u

Vl

'"
>
u

Woo

"E

~~o

!~i

B
0

~I

Vl

en>-

0
0

600 Control

Verapamil
5min

80

Verapamil
10min

5
2400
o

IKO.05

2000

1600

Vl
<,

Cl

J: 1200

.5
x
'"
E

-6
.......

800

Q.

"tJ

400 L....".--l.---,.----,..,..-.J............,.,-"77"......J

Control

Verapamil
5min

Verapamil
10min

6
Fig. 5. Effect of verapamil administrat ion on system ic
vascular resistance. Individual values are shown by open circles
and closed squares represent means w ith standard errors of
means (horizontal bars). 5 minutes after verapamil a significant
decrease (p < 0.00 1) in vascular resistance occurred.
Fig. 6. left ventricular dp/ dt max before and after int ravenous verapamil in 11 patients. Details as in figure 2. Note
the mean decrease at 5 minutes (p < 0.05l.

10mg bolus injections of verapamil were found to

decrease left ventricular filling pressure. The effects
were similar in digitalised and non-digitalised patients.
Haemodynamic effects of intravenously administered verapamil (I Omg) during diagnostic cardiac catheterisation in 20 patients (13 males and 7
females) with coronary artery disease and rheumatic
valve lesions have recently been evaluated in detail by
Singh and Roche (1977) . The peak alterations in
various haemodynamic variables induced by the drug
occurred between 3 and 5 minutes after the completion of the injection with a relatively rapid dissipation
of the effects. so that by I0 minutes the mean changes
as compared with the control values were not
statistically significant. The overall haemodynamic
effects of the drug are summarised in figures 3
through 6 and records of the ventricular pressure
trace from a typical drug response in a patient is
shown in figure 7. Again, as in the study of Lewis et
al. (1976), no differences were noticed in the
responses to verapamil in digitalised or nondigitalised patients. The mean arterial pressure fell
from 97.8 3.4 to 85.9 2.7mm Hg (-12 % ; p <
0.0 I), accompanied by a significant decrease (-21 % ; p
< .00 I) in systemic vascular resistance (from
1435 80 to 1131 82 dynes/sec/em :") with an increase in left ventricular end-diastolic pressure (from
11.0 0.9to 15.0 l .Omm Hg, +36 %,p < 0.01)
and a reduction in LV dp/dt max from 1343 152 to
1007 102mm Hg (-25 %; p < 0.005). The changes
in heart rate (from 75.7 3.0 to 80.2 2.8
beats/min), cardiac index (from 3.17 0.15 to
3.61 0.17L1min/m 2), left ventricular minute
work, and mean pulmonary artery pressures were
not statistically significant.
These overall data (see fig. 8) therefore, indicate
that the negative inotropic action of verapamil is
substantially minimised by its effect on after load so
that cardiac index is not reduced by the drug in patients with cardiac disease. The data demonstrate that
the intravenous dose (I Omg) required for the antiarrhythmic action of verapamil in adult patients does
not usually produce severe depression on

177

Verapamil: A Review

,I I

\J II \) \) \,

Control

3 Minutes after
lOmg IV verapamil

Fig. 7. Effects of verapamil on left ventricular contractility in a patient with coronary artery disease. The left ventricular pressure was increased by high-fidelity catheter tip manometry during cardiac catheterisation and the f irst derivative of the pressure
(LV dp/dt max) was obtained by electronic differentiat ion. Verapamil diminished the peak systolic left ventricular pressure and
raised the left ventricular end -diastolic pressure; it produced only a small decrease in LV dp/dt. There was no change in the heart
rate.

HR

lbeatslmnl

90

NS

8O~

70
LVMW
Ilo3- m/m 2)

Mean AoP
(rrm Hgl

NS

'l ~
90
80

SVI
2)
Irrl/bllm

Sl
40

30oo~
SRI
!dynes sec 2000
em S)
LVEDP
( mmHg)

2l
10

LVtWdl 2000E
(rrm HgIsecllSoo
1000

NS

t-

haemodynamic variables; the effects on systemic arterial pressure , systemic vascular resistance, left
ventricular filling pressure and contractility being
mild to moderate in severity and relatively shortlived. However, caution should nevertheless be exercised in the use of verapamil in patients with severe
myocardial decompensation and in patients with
acute myocardial infarction with unstable clinical
state as very little data are available in these conditions, and the drug may well prove deleterious in patients with markedly compromised haemodynamics .

2. Pharmacokinetic Studies

p<OO1

~
II

Control

p<OOS
f
I

3-Smn

-----I
I

lOmn

Fig. 8. Summary of haemodynamic data with verapamil.

Although much is now known about the mechanism of cellular action of verapamil in terms of excitation-contraction coupling and competitive inhibition
of calcium effects in vitro. information regarding the
physiological disposition of the drug , either in
animals or in man, has been slow in becoming available. This has been due to the fact that , until very re-

178

Verapamil: A Review

cently (McAllister and Howell, 1976; Schomerus et

al., 1976), no accurate assay of the drug in biological
fluids and tissues had been developed. Early studies of
drug disposition therefore utilised C-14-labelled
verapamil (McHenney, 197 I) and indicated that the
compound was well absorbed, rapidly metabolised to
0- and N-dealkylated forms and eliminated largely in
faeces . Appel (J 962) reported that following intravenous verapamil in animals, less than 5 % of the
dose injected could be recovered in blood and free
verapamil could not be detected in the blood within
10 minutes after injection of even a large dose of
4mg/kg of body weight. A substantial protein binding of the lIrug was therefore postulated.

2.1 Kineticsand Duration

of Action
From these observations it might be inferred that
the effects of single intravenously administered doses
of verapamil are likely to be short-lived. Indeed, this
has been found to be so, with respect to the
haemodynamic effects of the drug in man; the peak
action occurring between 3 and 5 minutes following
bolus injections, with the virtual dissipation of the
effect between 10 to 20 minutes (Singh and Roche,
1977). A comparable duration of action of intravenous verapamil was also demonstrated in atrial
fibrillation in which the changes in ventricular
response could be related to the action of the drug
(Heng et al., 1975), These observations are in contrast
to the duration of action of intravenous verapamil on
the A-H interval of the His bundle electrocardiogram.
For example, Puech (J 972) found that following the
intravenous injection of the drug, the onset of action
was within I to 2 minutes, peak effectoccurring at I0
to 15 minutes , with the change in the A-H interval
still being detectable at 6 hours after the drug injection. These data suggest preferential uptake and binding of verapamil by the AV nodal tissues, since the
duration of the depressant effect on the AV node appeared to considerably outlast the duration of the
drug's haemodynamic actions.

Following single oral doses of verapamil,

measurable effects on the AV conduction time were
apparent in 30 minutes and lasted for 6 hours (Puech,
1972). These preliminary observations have now
been extended by the very elegant studies of Schlepper
et al. (J 975) on the pharmacodynamics of oral
verapamil in conventional and slow release forms, as
judged by the drug's negative dromotropic actions in
healthy volunteers. In this study, atrial stimulation
was undertaken at hourly intervals up to 14 to 16
hours and continued to the highest possible rate without the occurrence of second degree atrioventricular
block before and after the oral administration of
240mg of verapamil (ordinary formulation as well as
slow release tablets). The results demonstrated clearly
that both forms of verapamil were active when taken
orally. Verapamil acted at 2 hours after oral administration; the peak effect was at 5 hours at which time
AV block occurred at low atrial stimulation rates.
The effect of slow release verapamil was obvious only
after 6 hours but it was still apparent after 14 hours
and remained constant without an apparent peak
effectiveness.
The duration of these overall pharmacodynamic
effects ofverapamil with respect to its haemodynamic
and electrophysiological actions thus raise the
possibility that they may not be readily correlated
with the pharmacokinetic characteristics of the drug,
the knowledge of which is now becoming available
(Schomerus et al., 1976) and is likely to increase
rapidly in the future.

2.2 Pharmacokinetic Characteristics

For the present the only significant clinical study
is that of Schomerus et al. (J 976) who compared the
pharmacokinetic characteristics of verapamil after
single oral and intravenous doses of the drug. Both
after intravenous as well as oral administration of
verapamil, the disposition of the drug in plasma was
found to exhibit a bi-exponential decline with an initial rapid or distribution phase lasting from 18 to 35
minutes. The distribution phase (a-phase) was

179

Verapamil: A Review

followed by a much slower phase (elimination or ~

phase) with half-lives ranging from approximately 3
to 7 hours. Up to 70 % of an oral or intravenous dose
was found to be excreted by the kidneys and 16 %
was found in the faeces.
Despite almost complete gastrointestinal absorption after oral administration, the overall
bioavailability as of the order of 10 to 22 %, suggesting a substantial first pass metabolism in the liver, as
has been described for propranolol (Shand and Ragno, 1972). The degree of serum protein binding of
verapamil was found to be of the order of 90 % . The
extensive hepatic first pass metabolism effect of
verapamilrafter oral ingestion may account for the
marked observed differences between oral and intravenous doses required for similar pharmacodynamic effects. The data indicate that the oral
dose needs to be at least 8 to 10 times the intravenous
dose (I Omg) to produce comparable plasma levels of
unchanged verapamil.
The preliminary results of Schomerus et al. (I 976)
have also suggested that the plasma levels of the Ndimethylated metabolite and of the N-dealkylated
metabolites (formed by the loss of the 3-4-dimethyoxyphenyl ethyl moiety) of verapamil may be at
least twice as high as those of the parent drug
itself.
Therefore , the metabolites of the parent compound
may contribute to the overall pharmacological and
therapeutic actions of the drug. Details pertaining to
this possibility will, of course, be of interest.

3. Therapeutic Uses
3. I Cardiac Arrhythmias
3 . J.J Experimental Arrhythmias
A wide spectrum of antiarrhythmic actions have
been reported for verapamil in the setting of experimental arrhythmias. Melville et al (1964) found that
in cats, the drug had a marked protective action
against chloroform-adrenalin and ouabain-induced

ventricular fibriliation ; the drug also antagonised ST

and T wave changes in the electrocardiogram induced
by ouabain. Rodr igues-Pereira and Viana (I968) reported that established ventricular and atrial arrhythmias induced in the dog by cardiac glycosides
were all promptly reverted by intravenous verapamil.
Essentially similar results were obtained by Schmid
and Hanna (1967) who, in addition, found that
verapamil was effective in reverting ventricular arrhythmias following coronary artery ligation in the
dog. In this respect, the results of Kaumann and Aramendia (1968) are of particular interest. They found
that both the ~-blocking drug Mll999 or sotalol
(IOmj:Ukg) and verapamil (0.79mg/kg), given intravenously, provided virtually complete protection
against ventricular fibrillation resulting fromcoronary artery ligation, but whereas the dogs that received
sotalol died within 24 hours after ligation, the dogs
injected with verapamil remained in good health for
over 10 months . The authors suggested that coronary
vasodilatation induced by verapamil contributed to
the favourable haemodynamic recovery after coronary ligation.

3. J.2 Clinical Arrhythmias

In sharp contrast to the experimental data, clinical
experience to date has indicated a relatively narrow
antiarrhythmic spectrum of therapeutic use for
verapamil (Heng et al., 1975). Virtually all the experience with verapamil has been with the intravenous formulation. The drug appears to be of
most value in the control of atrial tachyarrhythmias.
with apparently negligible effects in those ofventricular origin (Heng et al., 1975; Gotsman et al., 1972)
although a systematic investigation relative to this
question is still limited. A summary of clinical data
from uncontrolled trials is presented in table II. An
analysis of the response of various arrhythmias to
verapamil as reported from 2 different centres is summarised in table III (Schamroth et al., 1972, Johannesberg, South Africa) and table IV (Heng et al.,
1975, Auckland , New Zealand). The role of the drug
in the control of different arrhythmias is examined in
some detail below.

Verapamil: A Review

180

Table II. Summary of antiarrhythmic effects of verapamil (after Singh, 1975)

Type of arrhythmia
Paroxysmal
supraventricular

Elective (intravenous)

Prophylactic (oral)

Sinus rhythm restored in 75-100% of cases

(especially effective in reciprocating tachycardias
including those complicating WPN syndrome).

May be of value but experience

limited

Mode of conversion characterised by:

a) Abrupt cessation of the arrhythmia
b) Restoration of sinus rhythm preceded by
alternating cycle length, or
c) Restoration of sinus rhythm preceded by the
occurrence of premature ventricular
extrasysto!es
d) Conversion preceded by atrial fibrillation
lIa

A trial fibrillation

Increase in AV block

3) Ventricular rate sometimes 'regularised'

4) Sinus rhythm rarely restored
5) Blood pressure usually reduced

Effect on relapse rate from sinus

rhythm to atrial fibrillation
after DC carc"oversion unknown
(when used .one or in
combination with other agents)

No effect

No effect

1) Increase in AV block

Effect on sustained atrial

flutter unknown

~1 )

2) Slowing of ventricular rate

lib

Atrial fibrillation
with WPN syndrome

III

Atrial flutter

2) Slowing of ventricular rate

3) No effect on flutter rate but fibrillation

sometimes precipitated
4) Sinus rhythm occasionally restored
5) Blood pressure usually reduced

II

Ventricular premature
contractions
Ventricular
tachycardia

Frequency reduced

Effect not known

Sinus rhythm rarely restored

(hypotension common)

Effect on recurrent ventricular

arrhythmias unknown

Atrial Fibrillation: 3 types of responses to intravenous verapamil in atrial fibrillation have been
described.
The first and the most common (see tables III and
IV) is the inhibition of atrioventricular conduction
with the subsequent slowing of the ventricular
response. A typical example of this is illustrated in
figure 9. Following intravenous administration of the
drug, the effect on atrioventricular conduction is
short-lived so that after 30 minutes the ventricular

response gradually accelerates. unless an infusion is

commenced after the completion of the injection.
However. since the onset of action of the drug is
prompt. a rapid control of the ventricular rate in
atrial fibrillation can be achieved with verapamil but
its usefulness and safety in different clinical situations
where this may be desirable has not been fully evaluated.
The second type of response with verapamil in
atrial fibrillation is what Schamroth (1971) has called

Verapamil: A Review

181

Table III . Response to verapamil in 181 patients w ith arrhythmias (after Schamroth et aI., 1972)

Arrhythmia

No. of cases

Response

Sinus tachycardia

Significant slowing in all

Idionodal tachycardia

Conversion to sinus rhythm in all

115

Ventricular slowing in 111

Ventricular regularisation in 71
Conversion to sinus rhythm in 1

Idioventricular tachycarcia
Atrial fibrillation

Atrial flutter

15

Conversion to sinus rhythm in 4

Decreased ventricular response in 11

Paroxysmal supraventricular
tachycardia

20

Conversion to sinus rhythm in all

Paroxysmal ventricular
tachycardia
Ventricular extrasystoles

No effect

23

Reduced or abolished in 11
No effect in 12

Table IV. Effects of intravenous verapamil in patients with various carciac arrhythmias (after Heng et aI., 1975)

Arrhythmia

No; of cases

Response

Atrial fibrillation

12

Ventricular slowing in 11
Conversion to sinus rhythm in 1

AtriaI flutter

11

Ventricular slowing in 6
Conversion to atrial fibrillation in 4
Conversion to sinus rhythm in 1

Paroxysmal supraventricular
tachycardia

17

Prompt conversion to sinus rhythm in 13

Late conversion to sinus rhythm in 2
Resistant to conversion in 2

Atrial fibr illation

complicating WPW

No effect

Ventricular tachycardia

Conversion to sinus rhythm in only 1 patient

182

Verapamil: A Review

9O/ff)

~ Control

_I....-..~

98100

Start of
injection

I
I
I
i
End of
~ i njec tio n

98l60~ l mi n
10016 5 ~ 5min

95170~ ' O min

110180 ~ 30 min

9
"00 /70

r, rr
r-J ~~r-J~(

AJ
"J '
..i:rJr-rJr,
!/'J

00100 ---.:

I ",J

00160

1 min

~,-Jr3min

rri r r
I

Control

4 min

Jrr~~/5min

10
Fig. 9. Serial electrocardiographic records ~Iustrating the
typical effect of verapamil in a patient with atrial fibrillation and
rapid ventricular rate (116/min); 10 minutes after verapamil
was given, the ventricular rate was reduced to 12/min, and at
30 minutes it was 78/min. Reproduced with permission from
Heng et al. (1975).
Fig. 10. Sequential electrocardiographic tracings demonstrating the 'regularising' effect of verapamil in a patient with
atrial fibrillation . Note the virtually regular slower ventricular
response 5 minutes after verapamil was given. Reproduced
with permission from Heng et al. (1975).

'regularisation' of the ventricular rate; an example of

this is shown in figure 10. This phenomenon was
noted in 3 out of our I 2 cases of atrial fibrillation
(Heng et al., 1975) but in very much larger number s
in Scharnroth's series of 181 patients. It was postulated that the regularisation of the ventr icular rate. explained by Schamroth as being due to a regulatory or
stabilising effect of verapamil on the A V nodal refractory period. may be of haemodynamic benefit. Th is
has not. however. been supported by detailed
haemodynamic stud ies (Ryden and Saetre, 1971;
Vohra et al., 1974c).
The third type of response of atrial fibrillation to
verapamil is reversion to regular sinus rhythm. This
is rare in the experience of most investigators
(Schamroth . 1971; Schamroth et al., 1972; Gotsman
et al., 1972; Heng et al., 1975). However. little information is available relative to the possible differences
in the response of patients with acute versus chronic
atrial fibrillation . especially in relation to the varying
degrees of left atrial enlargement. the major factor
determining success in the restoration and maintenance of sinus rhythm in the setting 'of atrial fibrillation. Nor is there much information regarding the use
of orally admini stered verapamil in maintaining controlled ventricular response in atrial fibrillation . with
the drug used alone or in combination with digoxin.
Similarly. it is not entirely certain whether verapamil
potentiates the effect of quinidine in maintaining
sinus rhythm in patients with atrial fibrillation converted to normal rhythm by cardioversion.
Atrial Flutter: The immediate effects of intravenous verapamil in atrial flutter is reasonably
consistent. most patients responding with an increase
in atr ioventricular block that slows the ventricular
response (fig. I I). rarely followed by a return to sinus
rhythm. In some. the response is characterised by the
development of atrial fibrillation with a controlled
ventricular response with the subsequent restoration
of sinus rhythm in an occasional patient (see fig. 12>Again. the clinical features of these patients who convert to sinus rhythm under the influence of the drug
as compared with those who do not remains uncertain . However . it must be emphasised that where ap-

183

Verapamil : A Review

100/80
6r::i~

90/50

I~~rY--'~M
.

Control

~y--I~~

lmin

I ,

:-:.... .....

---T'

.......
~...;..J~
.. ~-~ ~-~. ' . ~ . !
I

5 min

[ ',

72150

~~
I I I
.
-.

85/70

r.r~~r.

-t

10 min

30 min

in a few patients with supraventricular tachycardia

after verapamil administration (see below). The
mechanism of this action is obscure. Verapamil may
increase conduction velocity in isolated rabbit atria
(Singh, 1971; Singh and Vaughan Williams, 1972),
but this effect was not observed with c1inicalIy relevant concentrations of the drug . Furthermore, in the
studies of Heng et al. (1975), no increase in the flutter
rate after verapamil was found, including those in
whom conversion from atrial flutter to atrial fibrillation subsequently occurred.

Paroxysmal Supra ventricular Tachycardia: The

rapid and predictable reversion of 80 to 100 % of
cases with paroxysmal supraventricular tachycardia
by the intravenous adm inistration of 3 to 10mg of

Fig. 11. Effects of intravenous verapamil in a patient with

atrial flutter with 2:1 AV conduction, ventricular rate 140/min
(control tracing). After verapamil, there is increased AV block,
reduction in ventricular rate, and a fall in blood pressure. The
maximal AV block occurred between 5 and 10 minutes after
injection of 10mg of verapamil; the ventricular rate at 10
minutes was 83/min. By 30 minutes. the ventricular rate had
increased to about 120/min. Reproduced with permission from
Heng et al. (1975).

propriate facilities are available, the ideal method of

treatment of atrial flutter is cardioversion once the
decision has been made that reversion to normal
rhythm is desirable and that the probability of maintaining sinus rhythm folIowing conversion is high.
Nevertheless, a single intravenous dose of verapamil
has been found to be of diagnostic value in differentiating rapid atrial flutter from paroxysmal supraventricular tachycardia when these 2 arrhythmias are
not easily distinguished electrocardiographicalIy. If
the rhythm is atrial flutter, the atr ioventricular block
increases immediately after intravenous verapamil,
thus revealing the true nature of the arrhythmia
(Heng et al., 1975).
A feature of some interest is the observation that a
significant number of patients with atrial flutter
develop atrial fibrillation when given verapamil
(Heng et al.. 1975) . Atrial fibrilIation also develops

r-; 1"\/' J'\ " l" ~ r Control

r--J~~rN

End of
injection

80/60 ....

1 min

105lg0 ...J~r-Y"..J~[

30min

Fig. 12. An example of conversion of atrial flutter to sinus

rhythm by verapamil. Immediately after administration of
verapamil there was enhanced AV block, followed by transient
atrial fibrillation at 10 minutes after drug injection. Sinus
rhythm was restored at 30 minutes. Reproduced with permission from Heng et al. (1975).

Verapamil: A Review

184

Table V. Effects of intravenous verapamil in different

types of supraventricular tachycardia (Krikler, personal communicat ion)
Arrhythmia

No. of
cases

No. reverting
to sinus
rhythm
after
verapamil

No. with
AV delay
only following
verapamil

AV junctional
tachycardia (i.e.
int ranodal re-entry)

109

106

Circus movement
tachycardia due to
pre-excitation

90

89

Ectopic atrial
tachycardia

verapamil is the clinically most significant antiarrhythmic effect of the drug (Schamroth et al., 1972;
Gotsman et al., 1972; Heng et al., 1975). It undoubtedly constitutes a major recent advance in antiarrhythmic therapy (see table V). Although the overall
experience with verapamil in different types of supraventricular tachycardia is reviewed at length by
Krikler and Spurrell (1974), a number of observations of interest with respect to the drug's action in
this context need emphasis.
The onset of action is rapid, with reversion to
sinus rhythm occurring in most cases within 2 to 5
minutes of verapamil administration, the period of
time which is coincident with the peak depressant
effects of the drug on atrioventricular conduction
(Heng et al., 1975) and on cardiovascular
haemodynamics (Singh and Roche, 1977). In some
instances, reversion to sinus rhythm has been noted
to occur within 10 seconds after a bolus injection of

5 seconds

100

.,
80

Hfh ISO
I

'

!-fl. 125

"

tI ~ ~ ~ ~

40

,V Verqxlrril 5mg
injection <D'TlpIded

DJM 12673
Aged 9 ye:rs

Fig. 13. Effect of intravenous verapamil in a patient who developed SVT during cardiac catheterisation . Reversion to sinus
rhythm occurred 5 seconds after complet ion of injection of verapamil; the restoration of sinus rhythm was preceded by transient
asystole. Note the absence of effect on arterial pressure. Reproduced with permission from Heng et al. (1975).

185

Verapamil: A Review

lllI1l1l1l1l1l1lHI\1I\\III1IHI\\l\H\\IIIlHll1l\\1 t IIII\I' '"w"w"wr"TC.G

HR. 230

120

HR.136

80

40

'V \lerqxlmil 3~mg

E.P. 1&&73

njedicn~

Fig. 14. Effect of verapamil on arterial pressure during conversion by the aug of rapid SVT (230/min) to sinus rhythm
(136/min) during cardiac catheterisation . Note the prompt rasponse of the arrhythmia to verapamil, and the accompanying
improvement in blood pressure. Reproduced with permission from Heng et al. (1975).

the drug (fig. 13 and 14). The hypotensive actions of

the drug immediately following reversion of supraventricular tachycardia to sinus rhythm is usually
minimal or absent when the tachyarrhythmia is
relatively slow (fig. 13). Furthermore, when there is
existing depression of haemodynamic function with
an unusually rapid rate, the conversion to sinus
rhythm may be followed by an immediate improvement in cardiovascular dynamics with a rise in
systemic pressure (fig. 14). Under these circumstances, the favourable effect resulting from the
restoration of sinus rhythm clearly outweighs the hypotensive response to peripheral vasodilatation induced by verapamit.
A continuous monitoring of the rhythm has
revealed that the mode of conversion of supraventricular tachycardias to sinus rhythm by
verapamil is not always uniform. Perhaps the most
common occurrence is an abrupt termination of the
arrhythmia as might occur with carotid sinus pressure. In some cases, a slight reduction in the ventricu-

lar rate is caused by delayed atrioventricular conduction followed by a short pause before reversion to
sinus rhythm is noted. This is a common response to
~-adrenoceptor blocking drugs. In other instances,
frank atrioventricular dissociation followed by a junctional escape rhythm occurs before regular sinus
rhythm is established. In a few patients reversion to
sinus rhythm is preceded by transient atrial fibrillation (fig. 15), the mechanism of which is obscure.
Two other types of responses have been reported.
The first IS punctuated by the occurrence of premature ventricular extrasystoles (fig. 16) before the
reversion of supraventricular tachycardia (Vohra et
al., I974a). This phenomenon appears to be peculiar
to reciprocating tachycardia and in I series it occurred
in 6 out of 50 patients with supraventricular
tachycardia treated with verapamit. An explanation
for the occurrence of verapamil-induced premature
ventricular contractions in reciprocating tachycardia
is possibly related to the proximity of the ectopic
pacemaker to the alternate circuit, so that the dis-

186

Verapamil: A Review

charge from this focus can emerge in the relative

refractory period of the intraventricular conduction
(Vohra et al., I 974a). The final type of response of
I I
Control
supraventricular tachycardia to verapamil wh ich has
l.-\......
been reported (Vohra et al., 1974b) is the
phenomenon of alternating cycle length (fig. 17)
I
I I
, I I I I
I
I
l
:....-.A-J'-"'-'~.......-....,
I
I
"
min
"..,......,..-..~.....before conversion to sinus rhythm - in some cases.
alternation of cycle length being associated with
changing QRS morphology. Again. this phenomenon
appears to occur only in patients with reciprocating
tachycardia. presumably using dual AV nodal pathways. The alternating cycle lengths in response to
I.
verapamil are explained on the basis of a 2: I block in
.

.
.
-r- _.
.
.
5 min
the anterograde pathway unmasking a third pathway.
i
t.
"
. t - I,
ilv--\..r
~~ ~
thus providing 2 pathways with differing antegrade
conduction. Recent unpubli shed data (D . Krikler, per15
sonal communication) utilising programmed stimulation techniques have indicated that patients demonstrating alternating cycle length after verapamil had
Kent or atrial type bypass tracts.
Accumulated clinical experience at different
Before verapamil
centres. that of Krikler (see table V) being representative. perm its certain general isations about the efficacy
of verapamil in reverting supraventricular tachycardia to sinus rhythm. Virtually all cases of supraventricular tachycardia due to intranodal re-entry or
those related to circus movement type of tachycardia
in pre-excitation (see below) respond promptl y and
predictably to intravenous verapamiI. whereas only
about two-thirds of ectopic atrial tachycardias convert
, ----- ~ ----- >.,J'-J' \.r"'l.t--'l.r"vJ~vJ~
to sinus rhythm after adequate doses of the drug . It
TP (W PW)
After 8mg verapamillV
must. however. be emphasised that little in the way of
systematic studies have been done to compare the
16
overall efficacy of different therapeutic regimens in
Fig. 15. Serial records of the electrocardiogram in a patient
this setting. although Gibson and Sowton ( 1969) collwith SVT (167/min) given 10mg of verapamil intravenously.
ated the general experience and reported a success rate
Note the development of AV dissociation with slow ing of the
of about 56 % in the conversion of paroxysmal supraventricular rate at 1 minute after verapamil was given; atrial
ventricular tachycardia by the use of intravenously
fibrillation supervened at 2 minutes. and reversion to stable
administered ~ -blocking drugs .
sinus rhythm occurred at 5 minutes after the drug was administered. Reproduced w ith permission from Heng et at,
A recent study of verapamil and practolol in
(19751.
paroxysmal supraventricular tachycardia (Hartel and
Hartkainen, 1976) is therefore of interest. In this
Fig. 16. Supraventr icular tachycardia in a patient with
comparison.
40 patients with paroxysmal supraWPW lead II before and after verapam]. Reproduced with perventricular tachycardia were allocated to different
mission from Vohra et ai. (1974a).

'

187

Verapamil: A Review

VR
,

Before verapamil

' ''

''

, 11.

" ', 11.

, ,...

,,

'

After 3mg verapamil lV

-i.fu.~l/'"V'--.-.LJ\-.""""'I.J'\-.,I.J'\-.,~
After 6mg verapamil lV

Fig. 17. The first strip shows lead II during tachycardia

with a constant RR cycle length of 380m sec. After 3mg
verapamil. alternating RR cycle lengths measured 420 and 540
m sec. Reversion to sinus rhythm occurred after 6mg of the
drug. The P waves are seen embedded in the ST segment during tachycardia.

treatment groups according to their year of birth.

Those patients born on odd years were given 5mg of
practolol intravenously, those born on even years
received 5mg of verapamil, and if the tachycardia
continued, the same injection was repeated after 5
minutes. If practolol treatment failed, the patient was
given 5mg of verapamil half an hour later and vice
versa. Verapamil restored sinus rhythm in 19 out of
20 patients but practolol proved effective in only 8
out of 20 cases. In patients who switched over to the
other treatment, verapamil was effective in 9 out of
I I and practolol in the 1 patient who did not respond
to verapamil.
Thus, published data clearly indicate that intravenous verapamil is the most effective phar-

macological agent for the elective treatment of paroxysmal supraventricular tachycardia, especially of
the re-entrant type.

Verapamil and Pre-excitation: The effects of

verapamil in this context have been studied in detail
by Krikler and his associates (Krikler, 1974). The
drug has been found to induce a prompt reversion of
most cases of paroxysmal circus movement supraventricular tachycardia complicating pre-excitation
(Krikler and Spurrell, 1974). It is of interest that
these workers (Spurrell et al., I974a) found that in 5
of their 15 patients with AV junctional tachycardia,
who were converted to sinus rhythm by the drug,
there was evidence of an extranodal bypass as suggested by contrast ventriculoatrial conduction times
before the drug was given and while the influence of
verapamil was still present. This raises the interesting
possibility that in some cases of atrioventricular junctional tachycardia, a concealed bypass tract may be
present and may well account for the arrhythmia.
These cases, which appear to have intranodal
reciprocating tachycardia, may thus be related to occult pre-excitation.
From intracardiac recordings of electrical activity
during programmed electrical stimulation of the
heart, information has also become available on the
effects of verapamil on the electrophysiological properties of the anomalous pathway in overt cases of the
Wolff-Parkinson-White syndrome (Spurrell et al.,
1974a; Neuss and Schlepper, 1974). The drug has
minimal effect on both anterograde and retrograde
conduction times. For example, in the study of
Krikler and Spurrell (1974), in 8 patients the refractory period (anterograde) of the bypass tract was shortened in 3 cases, was unchanged in one, and
lengthened a little in four; the shortening was
minimal, being much less than that found with
digitalis (Wellens and Durrer, 1973). Verapamil had
little effect on the refractory period for retrograde
conduction. It was possible to initiate reciprocating
supraventricular tachycardia in 6 of the 8 patients, in
all of whom the resulting arrhythmia could be terminated promptly by intravenous verapamil.

Verapamil: A Review

The minimal effects of verapamil on the

electrophysiological properties of the bypass tract is
consistent with the observation that the drug, in contrast to the local anaesthetic-type of agents (Neuss and
Schlepper, 1974), is strikingly ineffective in atrial
fibrillation complicating the Wolff-Parkinson- White
syndrome (Heng et al., 1975) in which fibrillatory
impulses conduct predominantly through an
anomalous pathway (Spurrell et al., I974b).
However, Krikler and Spurrell (J 974) have reported
reversion to sinus rhythm in I case of atrial fibrillation complicating the Wolff-Parkinson-White syndrome . I~ their case, the conversion to sinus rhythm
was preceded by a slowing of the ventricular response
and the development of junctional rhythm . They
speculated that the initial decrease in ventricular rate
was due to a blocking action at atriobypass, with a
subsequent antifibrillatory effect on the atrium and
the restoration of sinus mechanism via a phase of
junctional rhythm.
Ventricular Arrhythmias: Published experience indicates that intravenous verapamil is not a very effective drug in the treatment of ventricular arrhythmias
although it has been shown to reduce the frequency of
premature ventricular contractions, especially in
acute myocardial infarction. In our own experience
(Heng et al., 1975) in 5 patients (see table VI) with
ventricular tachycardia, sinus rhythm was restored in
only one; the conversion was associated with tran sient hypotension. A reduction in blood pressure was
also found in 3 of the other patients in whom it was
recorded before and after the administration of
verapamil. Thus, unless further studies demonstrate
more encouraging results, verapamil is unlikely to
have a role in the management of ventricular arrhythmias and would appear to be contraindicated in
patients who have seriously compromised myocardial
function.
Oral Verapamil in the Treatment oj Arrhythmias:
The value of orally administered verapamil in the
elective as well as the prophylactic treatment of
different arrhythmias has not been clearly defined.

188

The recent availability of methods to measure the

levels of the drug in biological fluids (McAllister and
Howell, 1976), and the ability to assay pharmacodynamic effects of different antiarrhythmic
agents in man by using changes in atrioventricular
conduction (Schlepper et al., 1975; Neuss et al.,
1974), are likely to clarify the potential value of orally
administered verapamil in various cardiac arrhythmias . Early uncontrolled clinical experiencehas,
however, been summarised by Krikler (1974).
It appears that verapamil, alone or in combination
with quinidine, may be effective in preventing
relapses in the case of recurrent atrial arrhythmias
treated by electroversion. Very little data from controlled studies are available on the use of oral administration of verapamil in the prophylaxis of paroxysmal supraventricular tachycardia. If it can be
shown that prolonged oral administration of
verapamil does impede conduction and lengthen the
refractory period through the atrioventricular
transmission system, then it is likely that the drug,
alone or in combination with digitalis, will have a
role in reducing the frequency of recurrent supraventricular tachycardia of the re-entrant type.
A recent report (Storstein and Landmark, 1975)
about the use of oral verapamil in paroxysmal atrial
tachycardia with atrioventricular block is noteworthy. Paroxysmal atrial tachycardia with block is a
relatively uncommon arrhythmia, believed, in most
cases, to be due to digitalis intoxication. However, in
the experience of Storstein and Rasmussen (J 974)
and Storstein and Landmark (J 975), digitalis could
not be incriminated as a cause in many instances. Of
particular interest was the finding that verapamil
given orally in a dose of 40 to 80mg 3-hourly to 14
patients with paroxysmal atrial tachycardia with
block, led to reversion to sinus rhythm in 10 initially,
with subsequent relapse occurring in four. The best
effect was found in patients with . minimal cardiac
enlargement and in those with a short duration of the
arrhythmia.
Further experience is clearly needed to validate
these findings. It will also be of interest to evaluate
the efficacy of verapamil in controlling atrial ar-

Table VI. Effects of int ravenous verapamil on ventricular tachycardia (after Heng at al., 1975)

Patient
No.

Age
(yl

Diagnosis

Previous
t herapy

Before
verapamil

After
verapamil

HR/
min

BP
(mm Hg)

HR/
min

Dose
(mg)

Outcome

If
~

Ii

BP
Irnm Hgl

CIi'

62

IHD with acute MI

Procainamide

160

120/75

96

80/50

10

SR

55

IHD w ith acute MI

Propranolol

125

110/80

125

70/60

10

Unchanged

51

IHD with acute MI

Digoxin, procainamide

158

158

10

Unchanged

73

IHD, w ith acute MI

None

144

90/-

144

75/ -

10

Unchanged

55

IHD, LV aneurysm

Digoxin, procainamide

159

105/80

159

80/60

10

Unchanged

Abb reviations: IHD

ischaemic heart disease; MI

myocard ial infarcti on; HR

heart rate; BP = blood pressure; SR

sinus rhythm; LV

left ventricular .

ffl

Verapamil: A Review

rhythmias in clinical states such as thyrotoxicosis or

mitral stenosis. Since the possibility has been raised
that some of the arrhythmias complicating mitral
valve prolapse may originate on the basis of 'slowresponse' automatic fibres (Wit et al., 1973) demonstrated in the canine mitral valve apparatus, the
effects of verapamil as an antiarrhythmic agent -in this
context merits careful appraisal.
3.2 Myocardial Ischaemia

3 .2./ Experimental Studies

The potential role of verapamil in minimising the
severity of myocardial ischaemic injury following experimental coronary occlusion was initially suggested
by studies of Sodi-Pallares and his colleagues (1968).
They reported that the drug either prevented or
reversed the electrocardiographic manifestations of
myocardial ischaemia in the dog . Perhaps of greater
clinical significance was the report (see section 3.1.1)
by Kaumann and Aramendia (1968) who found that
dogs pretreated with intravenous verapamil before
coronary occlusion failed to develop ventricular
fibrillation and survived for many months, whereas
animals similarly treated with the ~-blocking drug,
sotalol , invariably died from ventricular fibrillation
within 24 hours of coronary occlusion. These results
thus raised the possibility that verapamil might act by
containing the extent of the initial ischaemic injury
(i.e, limiting 'infarct size') contributing to fewer arrhythmias and improved survival rate following coronary occlusion.
Various studies have since been undertaken to examine the effects of verapamil on experimental infarct
size but the results so far have not been entirely conclusive . For example, the drug has been found to im prove haemodynamics in experimental infarction
(Smith et al., 1975 ; Smith et al., 1977), reduce epicardial ST segment elevation following coronary occlusion (Smith et al., 1975 ; Singh et al ., 1975 ; Smith et
al., 1977), but without effect on metabolism, blood
flow or tissue enzyme levels ofthe ischaemic myocardium (Singh et al., 1975). However, in the recent
study of Reimer et al. (1977), beneficial effects of the

190

drug on the extent of tissue necrosis in the dog heart

was found . Pretreatment of dogs with verapamil
before the ligation of the circumflex coronary artery
resulted in significantly less necrosis (14 % treated
versus 35 % untreated) with minimal haemodynamic
consequences. In another study (Nayler et al ., 1976)
in the isolated perfused heart, verapamil was found to
reduce the extent of ultrastructural damage caused by
hypoxic perfusion.
These results hold promise but further work is
clearly needed to decide whether the drug does indeed
produce a salutary effect on infarct size in experimental animals and whether these findings are of clinical
relevance . In contrast, much more encouraging data
are now available on verapamil as an . antianginal
agent although published experience of a controlled
nature remains somewhat limited.

3.2 .2 Angina Pectoris

The prophylactic use of verapamil in angina pectoris stems from the original observations that the
drug had potent coronary vasodilator properties. Increasing evidence is now accumulating to confirm the
efficacy of verapamil in reducing the frequency and
severity of angina (Krikler, 1974 ; Singh, 1975 ;
Andreasen et al., 1975; Balasubramanian et al.,
1976) . However, the precise mode of action of the
drug in relieving angina is still poorly understood
(Andreasen et al ., 1975). Although the cardiocirculatory effects of intravenous verapamil in patients
with coronary artery disease is established (Singh and
Roche , 1977) little is known about the haemodynamic changes which might occur following longterm oral therapy with the drug. Thus, the results of
the various clinical studies using oral regimens in
angina cannot, .at present, be correlated with the
measured changes in myocardial oxygen supply and
demand ratios. Such clinical observations are
nevertheless of interest and do indicate the need for
stringent double-blind clinical trials to evaluate the
role of verapamil in the management of angina pectoris.
Neumann and Luisada (1966) in a double-blind
trial, studied the effects of oral verapamil (40mg 3

Verapamil: A Review

times daily) on the weekly consumption of glyceryl

trinitrate (nitroglycerin) in 30 geriatric patients with
stable angina. They found that over a 6-week period
of drug administration there was a significant
decrease in the number of glyceryl trinitrate tablets
required by anginal patients while on verapamil compared with the number of tablets consumed by the patients on placebo. Subsequently, in a controlled study
in 16 ang inal patients, Sandler et al. (1968) found that
the effects of I 20mg 3 times daily of verapamil were
comparable with those of 100mg 3 times daily of
propranolol in terms of a significant decrease in the
frequency of angina and improvement of exercise
tolerance . In these doses, both drugs had a beneficial
effect on the amount and duration of ischaemic ST
segment depression during exercise. When only
40mg 3 times daily of verapamil was used, there was
no objective benefit in the electrocardiographic appearances, despite appreciable subjective improvement. Unlike propranolol, verapamil had no effect on
resting heart rate or exercise tachycardia in this study,
but it produced a mild reduction in diastolic blood
pressure.
The study of Livesley et al. (1973) has also suggested no statistically significant difference between
the effects of verapamil I 20mg 3 times daily and
propranolol IOOmg 3 times daily in the treatment of
angina of effort: both regimens were more effective
than a placebo in reducing daily attacks of angina and
in prolonging exercise tests. Both verapamil and
propranolol reduced diastolic blood pressure as well
as the resting heart rate and exercise tachycardia. The
conflicting reports of Sandler et al. (1968) and that of
Livesley et al. (1973) on the effects of verapamil on
resting heart rate and exercise tachycardia are not
readily explained .
Two further clinical studies have recently been reported. In the multicentre trial in Denmark
(Andreasen et al., 1975), the effect of verapamil
80mg 3 times daily on angina pectoris as compared
with a placebo was studied in a double-blind crossover trial of two 4-week periods in 47 patients. The
frequency of anginal attacks and glyceryl trinitrate
consumption was 25 % lower during verapamil

191

therapy with a significant improvement in exercise

tolerance as judged by bicycle ergometry. However,
the exercise-induced tachycardia was not reduced by
verapamil, although the average resting heart rate on
verapamil was lower than that on the placebo. The
drug had no effect on the P-R interval of the
electrocardiograms. The study of Balasubramanian et
al. (1976) from India utilised a protocol in which the
efficacy ofverapamil in a dose of 120mg 3 times daily
was evaluated in 25 patients with ischaemic heart disease. The patients were subjected to serial measured
multistage treadmill exercise without any drugs, and
after propranolol 40mg 3 times daily for 3 days; the
tests were then repeated after 2, 4 and 8 weeks of
verapamil therapy. The evaluation was based on computerised ST segment alterations, anginal threshold
and electrocardiographic changes . Anginal threshold
was increased by verapamil in all patients, and 8 of
the 13 symptomatic patients became pain-free with a
significant improvement in the ischaemic ECG pattern in all cases. The resting and exercise heart rates
were reduced by verapamil but not to the same extent
as that by propranolol. No patient developed atrioventricular block , significant hypotension or heart
failure during the trial and side-effects from the drug
were limited to transient constipation in 4 patients .
Thus, the overall data suggest that verapamil may
be an effective antianginal drug which is extremely
well tolerated by the oral route . Since the drug does
not alter airways resistance (Hills, 1970) it may have
advantages over conventional ~-blocking drugs in
anginal patients who also have bronchial asthma.
There are indications that verapamil may also
prove of value in patients who have myocardial
ischaemia with angiographically normal coronary arteries. Recent evidence (see Carleton and Johnson,
1974) suggests that coronary arterial spasm may be
an important factor in producing myocardial
ischaemia in such patients , Because it exerts potent
coronary vasodilator properties (Mignault, 1966) in
vessels which are not atherosclerotic, verapamil
might be preferable in this setting to ~-blockers which
reduce coronary blood flow and may conceivably induce or aggravate coronary arterial spasm. It is also

192

Verapamil: A Review

possible that patients who have Prinzmetal type of

angina may benefit from prolonged therapy with
verapamil, although no clinical studies have so far
been reported with the drug in this condition .
Finally, work in animals has shown that pretreatment with verapamil not only reduces the incidence
of early ventricular arrhythmias but may also
prolong long-term survival following coronary occlusion (Kaurnann and Aramendia, 1968), an effect
which may be due to a reduction in infarct size. This
raises the intriguing possibility that anginal patients
on continuous therapy with verapamil may experience fewer lethal arrhythmias and sustain smaller
infarcts when they eventually develop coronary artery
occlusion. This possibility needs careful study.

patients with ischaemic heart disease (Tschirdewahn

and Klepzig, 1963; Hoffman, 1964; Livesley et al.,
1973). Again, no controlled studies have been
published relative to the efficacy of oral verapamil as
an ant ihypertensive agent, although Bender (1970)
has suggested that the drug is effective in lowering
blood pressure in oral doses of 80 to 160mg 3 times
daily.

4. Side-Effects

A recent review of the side-effects of verapamil in

8,072 patients reported to the Knoll Pharmaceutical
Company has indicated that the incidence adverse
effects of oral and intravenous verapamil was approximately 9 % , with severe reactions requiring discon3.3 Hypertension
tinuation of the drug occurring in 1% . This incidence
is thus lower than for most of the available antiarVerapamil has been shown to have hypotensive rhythmic drugs .
effects both after single dose intravenous injections as
Orally administered verapamil is extremely well
well as after repeated oral administration, but the tolerated with a very low incidence of gastric inoverall data remain inconclusive.
tolerance and constipation. Occasional cases of verIn 50 patients given 5 to 10mg of verapamil in- tigo, headaches, nervousness , pruritus and other nontravenously, satisfactory reduction of blood pressure descript symptoms have been reported . Imwas achieved within 5 minutes, without significant munologically-mediated side-effects of the type reside-effects of hypotension (Schmitt, 1967). Verapa- ported for procainamide or practolol have not so far
mil has therefore been suggested to be of value in the been encountered with veraparrul, although only
initial treatment of severe hypertensive crisis, limited data regarding the drug's potential toxicity
especially since it has been found to be safe in the pre- during long-term oral administration are available.
sence of renal insufficiency (Esser et al., 1969). In I
Following the intravenous administration of
study in 47 patients with renovascular hypertension, verapamil , the adverse effects found have been those
a single intravenous injection (Smg) caused a 21 to which might be expected to occur in relation to its
25 % fall in systolic and diastolic pressures within I pharmacological properties . The most common is a
minute of administration (Brittinger et al., 1970). transient and mild fall in arterial blood pressure. This
However, no clinical trials involving comparisons of has been our experience (Heng et al., 1975), and that
the efficacy of verapamil and other intravenous hy- of Schamroth (197 D, Schamroth et al. (J 972), and
potensive regimens (e.g. diazoxide, reserpine, sodium Donnelly and Scamps (1973). However, there have
nitroprusside) have so far been reported .
been reports of serious side-effects, including hyData pertinent to the hypotensive action of potension, bradycardia and, on rare occasions,
verapamil following long-term oral therapy are even ventricular asystole (Benaim, 1972; Boothby et al.,
fewer. Nevertheless, in several studies with the drug 1972; Sacks and Kennelly, 1972). In the majority of
in angina, blood pressure was found to be lowered by these cases, the patients had been on ~-adrenoceptor
verapamil when administered to mildly hypertensive . blocking drugs before verapamil was given, and since

193

Verapamil: A Review

the negative inotropic actions and depressant effects

on impulse generation of ~-antagonists and of
verapamil are likely to be additive. hypotension . bradycardia and asystole are predictable side-effects
when these drugs are administered in combination.
Side-effects that occur in this setting may be reversed
by intravenous atropine (may be partially effective).
isoprenaline or glucagon infusion. or intravenous
calcium (10 to 20ml of 10% solution) and. if necessary. temporary ventricular pacing may be instituted
(Krikler, 1974).

5. Contraindications and Precautions

The main contraindications to the use of
verapamil are the presence of advanced heart failure.
unstable atrioventricular block. disease of the sinus
node and cardiogenic shock. or other low blood pressure states. However. while there is no debate that the
drug should not be used in patients with manifest
heart failure. it should be emphasised that in situations in which the cardiac failure is directly related to
a persistent rapid atrial tachyarrhythmia, a prompt
reversion to sinus rhythm by verapamil may lead to
an improvement in the degree of cardiac decompensation. This is likely to occur particularly in patients
with paroxysmal supraventricular tachycardia. Of
particular importance is the necessity to avoid the
combined use ofverapamil and ~-adrenoceptor blocking drugs in patients with overt or marginal
haemodynamic dysfunction. For example. intravenously administered verapamil (0.1mg/kg) and
practolol (0.1mg/kg) produced minor haemodynamic
changes when given individually. but when the combination regimen of the 2 drugs was employed and
heart rate fixed by atrial pacing. a pronounced reduction in left ventricular contractility occurred independently of changes in preload and afterload (SeabraGomes et al., 1976). Thus. caution must be exercised
when the combined use of these drugs in patients
with impaired myocardial function is contemplated .
This consideration would also apply to patients with
the sick sinus syndrome and impaired atrioventricular conduction.

The influence of verapamil on sinus node function

in the sick sinus syndrome has been found to be
variable (Husaini et al., 1973; Grendahl et al., 1975;
Breithardt et al., 1976). there being minimal effects
on sinoatrial conduction and sinus node recovery
time after overdrive suppression in some studies
while markedly depressant effects have been apparent
in others . Further experience is clearly needed to
define the safety of verapamil for the conversion of
paroxysmal supraventricular tachycardias in the sick
sinus syndrome. For the present. it would appear unwise to combine either digoxin or ~-adrenoceptor
blocking drugs with verapamil in the prophylaxis of
tachyarrhythmias in this syndrome unless a demand
ventricular pacemaker is first inserted. However. it
must be pointed out that unless there is evidence of
impaired AV conduction . prior digitalisation is not a
contraindication to the use of intravenous verapamil,
since 6 I % of our patients with arrhythmias (Heng et
al., 1975) and 79 % of patients in Schamroth's series
(197\) were on digitalis at the time verapamil was
given. In neither series. was a significant untoward
reaction encountered. Furthermore. experimental
work has suggested that the positive inotropic effects
of cardiac glycosides (Singh and Vaughan Williams.
1972) is attenuated but not nullified. indicating that
digoxin may. at least in part . reverse the depressant
effects of verapamil in heart failure.
At present. no significant data are available
regarding the safety of verapamil in the clinical setting of acute myocardial infarction. and until this is
further clarified. theoretical and experimental considerations would suggest caution in the use of
calcium antagonists in the early phases of myocardial
infarction following coronary occlusion.

6. Dosage
For the reversion of atrial arrhythmias. the most
commonly used dose is a single bolus injection of
10mg (or 0.145mg/kg body weight) of verapamil
under electrocardiographic and blood pressure control. The dose may be administered over 10 to I5 sec-

Verapamil: A Review

onds if a rapid response is desired. However, most

clinicians prefer to give the drug over a 60 second
period. If there is no response with the first bolus injection, a further dose may be repeated with safety 30
minutes later. If the response is required to be maintained, the bolus injection may be followed by a continuous infusion of the drug at a rate of
0.005mg/kg/min. In patients with myocardial dysfunction, the dose should be reduced. In children, the
dose required to convert paroxysmal supraventricular
tachycardia is usually between 3.5 and Smg, again,
the dose may be repeated 30 minutes after the initial
bolus injection.
At present, 2 types of oral preparation are available: the ordinary formulation and slow release
verapamil tablets. The usual commencing dose of the
ordinary tablet formulation in angina pectoris is 40 to
80mg 8-hourly; the dose may then be increased
rapidly over 2 or 3 days to a probable maximum of
720mg daily in patients without known contraindications (see section 5). Verapamil slow release tablet is
at present under clinical investigation (Schlepper et
al., 1975).

Acknowledgement
We are much indebted to Mrs Maricathryn Evans and Mrs
Betty Garrigues for their secretarial help and to Mr Lance Laforteza for help with the illustrat ions and photography.

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Verapamil: A Review

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Author's address: Dr Bramah N. Sing". Department of Cardiology. Cedars-Sinai Medical Center . 8700 Beverly Boulevard.
Los Angeles. Califomia 90048 (USA).