Professional Documents
Culture Documents
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
172
172
173
173
173
174
174
177
178
178
179
179
179
179
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
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.
172
Verapamil : A Review
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
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.
173
174
Verapamil: A Review
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
Verapamil: A Review
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.
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
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
179
Verapamil: A Review
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
Verapamil: A Review
180
Type of arrhythmia
Paroxysmal
supraventricular
Elective (intravenous)
Prophylactic (oral)
A trial fibrillation
Increase in AV block
No effect
No effect
1) Increase in AV block
~1 )
lib
Atrial fibrillation
with WPN syndrome
III
Atrial flutter
II
Ventricular premature
contractions
Ventricular
tachycardia
Frequency reduced
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
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
Idionodal tachycardia
115
Idioventricular tachycarcia
Atrial fibrillation
Atrial flutter
15
Paroxysmal supraventricular
tachycardia
20
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
No effect
Ventricular tachycardia
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
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).
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
r--J~~rN
End of
injection
80/60 ....
1 min
105lg0 ...J~r-Y"..J~[
30min
Verapamil: A Review
184
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
120
HR.136
80
40
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).
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
.
.
-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.
, ,...
,,
'
-i.fu.~l/'"V'--.-.LJ\-.""""'I.J'\-.,I.J'\-.,~
After 6mg verapamil lV
macological agent for the elective treatment of paroxysmal supraventricular tachycardia, especially of
the re-entrant type.
Verapamil: A Review
188
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
Procainamide
160
120/75
96
80/50
10
SR
55
Propranolol
125
110/80
125
70/60
10
Unchanged
51
Digoxin, procainamide
158
158
10
Unchanged
73
None
144
90/-
144
75/ -
10
Unchanged
55
IHD, LV aneurysm
Digoxin, procainamide
159
105/80
159
80/60
10
Unchanged
sinus rhythm; LV
left ventricular .
ffl
Verapamil: A Review
190
Verapamil: A Review
191
192
Verapamil: A Review
4. Side-Effects
193
Verapamil: A Review
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
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.
References
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Arzneimittel-Forschung. 12: 562-566 (1962) .
194
Verapamil: A Review
195
196
Verapamil: A Review
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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).