Comparative Pharmacology of Calcium Antagonists: Nifedipine,

Verapamil and Diltiazem

PHILIP

D. HENRY,

MD,

FACC

St. Louis, Missouri

From the Cardiovascular Division, Department of

Medicine, Washington University, St. Louis, Missouri. This study was supported in part by Grant
HL 2 1187 from the National Institutesof Health and
HL 17848 from the Specialized Center of Research, Bethesda, Maryland, and from an Established Investigatorship, American Heart Association, Dalias, Texas. Manuscript received April 28,
1980, accepted July 3, 1980.
Address for reprints: Philip D. Henry, MD, Cardiovascular Division, Box 8088, Washington
University School of Medicine, 880 South Euclid
Avenue, St. Louis, Missouri 83110.

Calcium antagonists (slow, channel blocking agents) are a very heterogeneous group of agents with dissimilar structural, electrophysiologic and
pharmacologic properties. Nifedipine is a potent, long-acting vasodllator
that has proved highly eff lcacious In reiievlng anglnal symptoms caused
by coronary vasospasm. In vivo, it exerts no myocardial depressant effects
and has no antiarrhythmk properties. Treatment with nlfedipine can safely
be combined with administration of a beta receptor blocking agent.
Verapamil prolongs atrioventricular (A-V) conduction (A-H interval) in
a dose-dependent manner. It is the drug of choice for the treatment of
reentrant supraventricular arrhythmias, irrespective of whether reentry
occurs within the A-V node or through an accessory pathway (the
Wolff-Parkinson-White syndrome). Verapamil is only moderately effective
as an antianginai agent. Diitiazem is efficacious for the treatment of anglospastic angina, but its value as an antlarrhythmic agent remains to be
delineated.

In 1960 Lindneri observed that prenylamine, a newly developed coronary

dilator, depressed cardiac performance in canine heart-lung preparations. Shortly thereafter, Haas and Hartfelder2 noted that verapamil,
another phenylalkylamine
with coronary dilating properties, exerted
negative inotropic effects on isolated cat and rabbit myocardium. The
potent cardiodepressant
effects of these new agents appeared to distinguish them from classic vasodilators. Drugs such as nitroglycerin and
papaverine are potent smooth muscle relaxing agents, but depress cardiac muscle only at high concentrations, if at all. Because the inotropic
and chronotropic effects of prenylamine and verapamil were opposite
to those elicited by catecholamines, the new drugs were first thought to
be adrenergic blocking agents. 3,4 However, Fleckenstein et a1.5 were
among the first to recognize that the effects of prenylamine and verapamil differed from those of beta receptor blockers. They observed that
the drugs depressed cardiac contractility without altering the height and
contour of the monophasic action potential and concluded that the
agents acted as uncouplers of excitation-contraction
coupling. The action
of the drugs was attributed to an inhibition of the influx of calcium ions
(Ca++) into myocardial cells. Consequently, the agents were named
Later, Fleckenstein6 specified that Ca++ antagCa++-antagonists.5
onists acted by reversibly sealing specific Ca++ channels in the membrane of the mammalian myocardial cell.
In other studies, Grun and Fleckenstein7s applied the principle of
electromechanical
uncoupling to smooth muscle. In these reports, nitroglycerin was described as a Ca++- antagonistic agent with selectivity
for vascular smooth muscle.7y8 Thus, the term Ca++ antagonist was now
applied to drugs with little or no direct action on myocardium. Electrophysiologic data supporting the concept of electromechanical
uncoupling in vascular smooth muscle were not presented.
After the pioneering studies of Fleckenstein and associates numerous
drugs were included among the Ca++ antagonists. Some agents such as
and fendiline (demethyl-prenylamineJg
D 600 (methoxy-verapamil)4,6
were derivatives of the compounds originally studied by Lindner and

December 1990

The American Journal d CARDIOLOGY

Volume 46

1047

CALCIUM ANTAGONISTS-HENRY

Haas and Hlirtfelder.2 However, the majority of the

agents tentatively
listed as Ca++ antagonists were
structurally unrelated and appeared to differ in their
pharmacologic
properties.1~
Ca++ antagonistic
properties were attributed to drugs such as papaverine,12 diazoxide,13 perhexiline,ic lidofiazine,14 cinnarizine,j proadifen (SKF 525 A),16 diethylaminoethylhexestrol,14 bencyclane, 14,17RO ll-1781,s nifedipine,lg
diltiazem20 and molsidomine.21 Yet, comparative
studies1J1J4 defining the electrophysiologic effects of
these compounds were not performed, and consequently
it remained undecided whether their mode of action
depended predominantly
on the mechanism invoked
by Fleckenstein. In addition, some investigators22 began
to apply the term Ca++ antagonist to agents thought not
to block Ca++ influx, but to act intracellularly. These
authors23 further broadened the concept of Ca++ antagonism and included virtually every smooth muscle
relaxing agent among the Ca++ antagonists. Thus, local
anesthetics, drugs that block the inward movement of
sodium (Na+) rather than that of Ca++, and beta adrenergic agonists, drugs that tend to augment Ca++
influx into muscle cells, were paradoxically classified
among the Ca++ antagonists. As the precise mechanism
of action of most agents categorized as Ca++ antagonists
was not elucidated, the concept of Ca++ antagonism
remained somewhat vague, and a universally accepted
definition failed to emerge.14
Mechanism of Action of Ca++ Antagonists
Cardiac Muscle
To evaluate the question whether there are drugs that
act by selectively blocking specific calcium channels in
cardiac membranes, some electrophysiologic concepts
will briefly be reviewed (for more detail see Ref. 24 to
26). According to current views,24*25cardiac membranes
possess ionic channels or aqueous pores that permit ions
to move across the sarcolemma. These ionic movements
give rise to passive inward (depolarizing) and outward
(repolarizing) currents that appear to be responsible for
the electrical activity of the heart. The currents are
controlled by conformational changes in the channels
that determine an all-or-nothing opening of the pores.
These conformational changes are usually described as
gating. As the gating structures (macromolecules) bear
electric charges, conformational changes generate small,
nonionic currents referred to as gating currents. Gating
mechanisms are sensitive to the electrical field in the
membrane and to chemical agents such as neurotransmitters or drugs. Experiments with voltage clamps
have demonstrated that there are two distinct inward
currents that contribute to the depolarization of cardiac
membranes. A brief opening of fast sodium (Na+)
channels is responsible for the initial spike of the action
potential, and a subsequent opening of slow channels
contributes to the plateau of the action potential. The
current flowing through the slow channel is carried by
Ca++, but depending on the species and cell type Na+
may also contribute to this flow. In some normal cells
(sinus and A-V nodal cells) and in partly depolarized

1048

Docembef

1980

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Amorlcain Journal a4 CARDIOLOQY

contractile cells, a rapid spike is absent and depolarization appears to occur predominantly
through the
slow channel (slow response).
One classic mode124 for the description of the behavior of the depolarizing inward currents has been to
assume that the fast and slow channels are each controlled by two gating mechanisms located in series along
the channels (Hodgkin-Huxley
model). According to
this scheme, the outer and inner gates control the activation and inactivation of the currents, respectively. At
rest, the outer activation gate is closed, whereas the
inner inactivation gate is open. With depolarization, the
outer gate opens (activation),
leaving both gates
momentarily open and permitting ions to flow through
the channel. However, with some delay, the inner gate
closes, interrupting the flow of current (inactivation).
Thereafter, there is a period of recovery during which
the outer gate closes and the inner gate subsequently
reopens (recovery from inactivation, reactivation,
restoration). During this period of recovery, a repeat
depolarization
elicits only diminutive responses, a
phenomenon that may be explained by assuming that
not all of the inner gates have reopened yet.
At least four different repolarizing outward currents
have been distinguished in Purkinje fibers. 24*25These

late or delayed currents are carried predominantly by

potassium ions. Potassium (K+) channels are controlled
with activation gates, but in contrast to the fast and slow
channels do not appear to possess independent inactivation mechanisms.24 The effects of Ca++ antagonists
on K+ channels have not been analyzed in detail, and
outward currents will not be discussed here. However,
one mechanism influencing outward currents deserves
to be mentioned. There is evidence that the intracellular
Ca++ concentration ([Cali) regulates K+ conductance.27
Increasing [Cali causes an increase in the late outward
current of sheep Purkinje fibers.27 Therefore, an inhibited cellular Ca++ uptake leading to a decreased [Cali
may be anticipated to reduce the late outward current.
One major argument supporting the membrane pore
theory is the discovery that drugs may selectively in-

hibit specific currents.2s Thus, tetrodotoxin and local

anesthetic agents such as lidocaine exert inhibitory effects on the fast current without appreciably affecting
the slow current.24v26 However, the mechanism of action
of tetrodotoxin and of local anesthetics appear to differ
substantially. There is considerable evidence that tetrodotoxin
and related cationic compounds insert
themselves into the outer opening of the fast channels,
thereby physically blocking ion flow through the
channel. Tetrodotoxin
does not appear to affect the
deeper portions of the channel, and the gating machinery (gating currents) remains unaltered.26 However,
a local anesthetic such as lidocaine blocks the sodium
channels from the inner surface of the membrane.29 The
drug appears to immobilize gating charge movements
and to slow the kinetic parameters of the current.26
These effects are manifested by a decrease in the maximal rate of depolarization (activation) and in a delayed
recovery of the sodium conductance
(reactivation).

Volume 46

CALCIUM ANTAGONISTS-HENRY

lidocaine may have more than one site of action in canine Purkinje
fibers, and its effects may not
be limited to the fast Na+ channel.
In particular,
the
drug is known to increase the potassium
conductance
of Purkinje
fibers.2g Another interesting
feature is that
the action of local anesthetic
agents appears to depend
on the rate of stimulation
(that is, the blockade of the
Na+ channel may be small under quiescent conditions,
but may be markedly
enhanced
after a rapid train of
2s Because local anesthetic
agents do
depolarizations).
not act exclusively
on the fast Na+ channels,
and because tetrodotoxin
and local anesthetic
agents do not
act by a single electrophysiologic
mechanism,
little
would be gained by placing these drugs in a single category of Na+ antagonists.
The first agents shown to inhibit the slow inward
current without influencing the fast depolarization
were metallic ions such as manganese
(Mn++),30 nickel
(Ni++)24 and cobalt (CO++).~~ The mechanism
of action
of these divalent cations is complex and will not be reviewed here (for more detail see Ref. 24). However, one
important
mechanism
should be mentioned.
In cardiac
muscle, a coupled exchange mechanism
involving the
exchange of two Na ions for one Ca ion has been described.l
Thus, in contrast
to the electrogenic
slow
inward current described,
this exchange is electroneutral and cannot be detected
with electrophysiologic
techniques.
It has been suggested that Na+/Ca++
exchange may play an important
role in providing
activator Ca++ for the contractile
apparatus
of the myocardial ce11.32Thus, cardiodepressant
effects of metallic
cations may reflect not only a blockade of the slow inward current but also a displacement
of superficially
located
Ca++ participating
in the Na/Ca++
exchange.:j2
In the light of the electrophysiologic
concepts outlined, results of electrophysiologic
experiments
with
nifedipine,
verapamil
and D 600 (methoxy-verapamil)
will briefly be discussed.
Nifedipine:
Kaufmann14 Bayer et a1.33J4 and Ehara and
Kaufman35 have investigated the effects of nifedipine on the
membrane currents of cat papillary muscle under voltageclamp conditions. Nifedipine ( 10e7 to 10e5 M) did not influ-

However,

ence the fast Na+ inward current, but depressed

the slow inward current in a dose-dependent
manner. The drug had no
apparent effect on the kinetic parameters
of the slow current
(rate of activation
and inactivation),
and did not delay the
recovery from the inactivation
(refractoriness
after slow response). Nifedipine
consistently
increased
the delayed potassium outward current. Effects of nifedipine
were not influenced by rate changes between 6 and 60/min. In similar
experiments
with cat papillary
muscles,
Kohlhardt
and
Fleckenstein3
found nifedipine
not to affect the rate of inactivation
of the slow current or to prolong the period of recovery. These findings indicate that nifedipine
has no local
anesthetic
(Na+ channel blocking) properties and inhibits the
slow inward Ca++ current without altering the kinetic control
mechanisms
(gating mechanisms)
of the slow channels. The
action of nifedipine
on the slow channels resembles
that of
tetrodotoxin
on the fast channels. One may assume that nifedipine prevents the activation of some of the slow channels,
leaving the rest of the slow channels and their time-dependent
gating mechanisms
unaffected.
However, additional
experi-

December

ments are needed to determine

whether nifedipine obstructs
the outer pore of the slow channels.
Verapamil and D 600:
Experiments
with isolated cardiac
muscle have shown that the optical isomers of verapamil and
D 600exert disparate
electrophysiologic
effects.14,37-40 The
(R) (+)-enantiomers
(9 X 10e6 M) of the two drugs depress
appreciably
the maximal rate of rise of the monophasic action
potential at a frequency of 15/min, and this effect is markedly
enhanced
at a frequency
of 90/min. However, in equal concentration,
the (+)-isomers
appear to have modest effects on
the plateau phase and overall shape of the action potential.37
In contrast, the S( -)-enantiomers
(9 X lOpa M) depress the
plateau phase of the action potential in a frequency-dependent manner.37 These findings suggest that the (R+)-enantiomers have a substantial
fast channel blocking (local anesthetic) activity, whereas the (S)(-)-enantiomers
predominantly affect the plateau of the action potential,
a change
compatible
with a blockade of the slow current. This interpretation is supported by the observation that the (+)-isomers
mainly depress excitability,
whereas the (-)-isomers
are responsible
for the negative inotropic
effects of the racemic
mixtures.
Voltage-clamp experiments with cat papillary muscles
confirmed
that (-)-verapamil
in concentrations
ranging between 8 X 1O-7 and 2.2 X lo-: M suppresses
the slow inward
current in a frequency-dependent
manner.:j* Similarly, (f)-D
600 (10m7 to lop6 M) has been reported to inhibit the slow
inward current
in feline ventricular
myocardium41*42 and
bovine Purkinje fibers.43 Effects of verapamil and D 600 are
markedly enhanced by prolonged incubation.3sv41,43 Thus, the
inhibitory effects of these compounds strongly depend on the
rate of stimulation
and on the length of exposure to the drugs.
In contrast to nifedipine,
verapamil and D 600 alter the kinetics of the slow current. The agents slow down activation
and more prominently
the recovery from inactivation.14,38,42*44
The prolongation
of the recovery of the slow channel revealed
by voltage clamp experiments
appears to be an important
electrophysiologic
effect of verapamil,
as it provides a potential explanation
for the efficacy of the drug in terminating
reentrant
tachyarrhythmias.
( -)Verapamilas
and (f)D
60041,43 have also been noted to decrease the delayed potassium outward current(s).
As indicated,
a decreased
[Cali resulting from an inhibited
Ca++ influx might secondarily
reduce the delayed potassium
outward current.27 In some instances, (-)verapamil*
and (*)D 60041,4:3have been found
to reduce the outward currents, but this effect has been variable.38p43 In some instances, the outward current may increase
instead. Furthermore,
it does not appear that decreases in the
outward current result simply from the inhibition of the slow
inward current.43
Thus, the effects of (f)-uerapamil and (f)-D GOOappear
to be quite complex. First, the action of the drugs are a sum
effect of optical isomers possessing
different
electropharmacologic properties.
Second, the effects of the drugs are
markedly
frequency-dependent
and become fully manifest
only after prolonged incubation.
Third, in addition to inhibiting the slow inward current and altering its kinetic properties, the drugs affect the delayed outward current(s)
and (at
high concentrations)
the fast inward current. It is evident that
verapamil is not a selective blocker of the slow inward current.
In some respects, the action of verapamil on the slow channel
resembles
that of lidocaine on the fast channel. Both drugs
appear to affect the time-dependent
gating mechanisms
and
markedly retard channel recovery (reactivation).
In addition,
the drugs exhibit the phenomenon
of frequency dependence.
It would be interesting
to determine
whether verapamil, like
lidocaine, acts from the inside of the sarcolemma.

1980

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46

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CALCIUM

ANTA~NISTS-~NRY

The demonstration that nifedipine, verapamil and D 600

block the slow inward current supports, in part, Fleckensteins original hypothesis.6 However, current information

indicates that these drugs differ substantialIy in their mechanism of action. Nifedipine appears to be a more selective slow
channel blocker than are verapamil and D 600. Voltage clamp
experiments provide no information on the carrier-mediated,
electroneutral
Ca++/Na+ exchange which may play an important role in activating cardiac muscle.32 Little is known
about the nature of the coupled exchange mechanism, and
there is no information concerning the effects of Ca++ antagonists on this system. Thus, it would be premature to make
definitive conclusions regarding the dominant mechanism of
action of drugs with Ca++ antagonistic effects.
Diltiazem: Diltiazem (2.2 X 10m6M) lowers the plateau and
shortens the duration of the monophasic action potential of
canine Purkinje fibers. J5 In canine ventricular myocardium,
diltiazem (2.2 X low6 M) lowers the plateau and at the same
time depresses contractility. *s High concentrations (2.2 X 10-s
M) reduce the maximal rate of rise of the monophasic action
potential of canine Purkinje fibers,45 guinea pig atria46 and
guinea pig ventricular myocardium.47 These findings suggest
that diltiazem may block the slow current at low concentrations and exert fast channel inhibitory effects at high concentrations. Voltage clamp experiments with diltiazem have
not been reported.
Vascular Smooth Muscle
There is little detailed information regarding the mechanism of action of Ca++ antagonists on vascular smooth muscle.
Harder et a1.48studied the effects of (f)verapamil
on Ca+f
dependent action potentials in isolated large (more than 1
mm) and small (less than 0.5 mm) canine coronary arteries.
In these vessels, spontaneous action potentials or action potentials in response to electrical stimulation, are not observed.
However, electrical stimuli evoke Ca++-spikes
in the
presence of 10 mM tetraethyl ammonium ions (TEA), an intervention that acts by suppressing the K+ outward current
and reducing the rectifying properties of the membrane.
TEA-facilitated,
Ca++-dependent
action potentials were
blocked by lo-9 M (f)verapamil
in both large and small
vessels. Adenosine ( 10d5 M) blocked the spikes only in small
vessels, whereas nitroglycerin
( 10e5 M) was selective for large
_arterially perfused canine hearts,
vessels14s In ~brillating

NIFEDIPINE

verapamil and nifedipine were reported to relax only small

resistive arteries and arterioles, whereas nitroglycerin preferentially relaxed large ~conductance) coronary arteries.49
Thorens and Haeusle9 exposed isolated rabbit pulmonary
arteries to selected vasodilators in the presence of 50 mM of
potassium chloride (KCl) and 2.2 mM of calcium chloride
(45CaCls). After a subsequent 1 hour wash with 1 mM of lanthanum trichloride (LaCls), tissue-bound radioactivity was
measured as an index of Ca influx. (f)Verapamil,
RO ll1781 and papaverine produced dose-dependent
inhibitions
of 45Ca influx. Nitroglycerin, diazoxide and nitroprusside
exerted little or no inhibitory effects. Results were interpreted
to indicate that only verapamil, RO 11-1781 and papaverine
may cause vasorelaxation by interfering with Ca++ influx.18
Massinghams
and Nguyen Duong and Brecht51 demonstrated in isolated vessels that (f)verapamil,
(&)D 600 and
nifedipine relaxed KCl-induced contractures more effectively
than contractions evoked by norepinephrine.
The efficacy of
Ca++ antagonists in relieving KC1 contractures are thought
to reflect the fact that K+ evokes contractions indirectly by
promoting vascular Ca++ uptake.18~50~51
In agreement with this
concept is the observation that bovine coronary arteries
contracted by fluoride ions, a contracture thought to be independent of extracellular Ca++, are not effectively relaxed
with verapamil and prenylamine.s2 Interestingly, these contractures appear to be readily relaxed with nitroglycerin and
nitroprusside.52 Mikkelsen et a1.53reported that in isolated
human mesenteric arteries and veins, verapamil is equally
potent in relieving contractions induced by KC1 and norepinephrine, a finding that appears to be in conflict with the
studies mentioned.50,51
Studies with isolated arteries and oeins generally confirm
the view that the relaxing effects of verapamil and nifedipine
differ from those of classic vasodilators such as nitroglycerin
and nitroprusside. They strongly suggest that Ca++ antagonists act partly by blocking the inward movement of Ca++ into
smooth muscle cells. However, experiments demonstrating
the inhibition of Ca-spikes and 45Ca uptake were performed
in the presence of abnormal ionic conditions.
Structure

of Ca++ Antagonists

The subsequent discussion will focus on nifedipine, (3~)

verapamil and diltiazem, the agents currently receiving the
most clinical attention.

PAPAVERINE

~~~~CH*~~~~

PRENYLAMINE

ri-3

DIAZOXIDE

CH3
CH-CdH2-NH-:H-;n&)

VERAPAMIL

DlLTlAZEM

CH<

,CH3
Cti

HfCO

CH3

~-c~~-CH~-CH*-~-CH~-CH~

Ff#RE
1. Chemical structure of calcium entagonists
and other vasoactive drugs.

H3CO

1050

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1980

The American Journal of CARMOLOGY

Volume 48

CALCIUM ANTAGONISTS-HENRY

Nifedipine:
Nifedipine
(BAY a 1040; MW 343) is a dihydropyridine
derivative that bears no structural similarity with
other already known vasoactive
or cardioactive
drugs (Fig.
l).lg Nifedipine is not a nitrate, and its ortho NOs group is not
essential for its pharmacologic
activity.54 Multiple dihydropyridine derivatives
have been synthetized
and some (niludipine and nimodipine)
are receiving investigative
attention.
Verapamil: (f)-Verapamil
(D 365, Iproveratril, Isoptin and
MW 455) has some structural
features
in common
with
papaverine
(Fig. 1). Compared with verapamil, D 600 has one
more methoxy group attached to the benzene ring close to the
asymmetrical
C-atom.2~4*55
Diltiazem: Diltiazem
(CRD 401; MW 450) is a benzothiazepine derivative that is structurally
unrelated to diazoxide
(a benzothiadiazine
derivative)
(Fig. 1).20

Pharmacokinetics of Ca++ Antagonists

Nifedipine: The pharmacokinetics
of nifedipine in human
beings were studied with 14C-nifedipine
in conjunction
with
chromatographic
and mass spectrometric
analyses56s57 (Table
I). More than 90 percent of nifedipine
is absorbed after oral
administration.
Only approximately
20 to 30 percent of nifedipine is removed from portal blood by the liver, yielding
a systemic availability
(bioavailability)
of more than 65 percent. Bioavailability
is a measure of the fraction of the dose
reaching the systemic circulation,
and is defined as the ratio
of the area under the plasma concentration-time
curve after
oral administration
to that obtained
after intravenous
administration
of the same amount of drug. In the case of nifedipine, 15 pg/kg, intravenously,
produces approximately
the
same concentration-time
curve as 150 pg/kg orally or sublingually.56 The main metabolic pathway consists of an oxidation to a free acid, a small fraction of which is converted
to a lactone.s7 These metabolites
are pharmacologically
inactive. Intact nifedipine
is 90 percent bound to plasma proteins, whereas the free acid is only 54 percent bound.
The biexponential analysis of the disappearance of nifedipine in plasma yields an initial fast half-life (Tl/z cu) of
2.5 to 3 hours and a terminal slow half-life (Tl/z /3) of 5 hours.
Seventy to 80 percent of the radioactivity
administered
is

excreted in the urine, and approximately

90 percent of the
urinary excretion occurs during the first 24 hours. Only trace
amounts of intact nifedipine appear in the urine. Some 01 the
radioactivity
excreted in the bile is reabsorbed
(enterohepatic
circulation).
Only about 15 percent of the radioactivity
is recovered in the feces. There is no evidence that metabolites
accumulate
in the body during long-term administration
(for
more detail see Ref. 57).
Verapamil:
The pharmacokinetics
of ( f )-verapamil
in
human beings were studied with radioactive (14C-verapamil),
chromatographic
and mass spectrometric
technique@-60
(Table I). Absorption
after oral administration
varies from
88 to 92 percent. The low bioavailability
of verapamil
(10 to
22 percent) is due to extensive first pass metabolism
in the
liver. After oral administration
of i4C-verapamil, plasma levels
of radioactivity
and verapamil (assayed by gas chromatography/mass
spectrometry)
peak within 30 to 45 minutes.
Thereafter,
the levels decline biexponentially
with fast and
slow half-lives of 18 to 35 and 170 to 440 minutes, respectively.s8 Intact verapamil is 88 to 92 percent protein-bound.
The drug is extensively metabolized, and 1 to 2 hours after oral
administration
of 14C-verapamil only about 15 percent of the
plasma radioactivity
represents
intact verapamil.
A fluorometric assay of verapamil yields spuriously high drug levels,
probably because it measures metabolites
as welLfiOsl
The metabolism of verapamil is complex. Cleavage of the
C-N-C
bond by N-alkylation,
preferentially
at the C-atom
belonging to the shorter side chain, appears to be a major
metabolic
step. The pharmacologic
activity of the cleavage
products is only 5 to 10 percent that of verapamil. As cleavage
products are formed in large amounts and as their half-lives
are long (-24 hours), their plasma concentration
during
long-term
treatment
exceeds that of intact verapamil.8,5g
Therefore,
it is possible that metabolites
contribute
to the
action of verapamil. Between 67 and 71 percent of the radioactivity after oral i4C-verapamil is excreted in the urine within
5 days. Only 3 to 4 percent of the dose appears as unchanged
drug in the urine.5g
Diltiazem: There is surprisingly
little information
on the
pharmacokinetics
of diltiazem.
Data shown in Table I are
based on studies in dogs.62 Diltiazem is extensively
metabo-

TABLE I
Pharmacokinetics

of Calcium Antagonists
Nifedipine

Dosage
Oral (mg/8 h)
Intravenous @g/kg)
Absorption
Oral (%)
Bioavailability (%)
Onset of action
Sublinoual (min)
Oral (r&I)

Therapeutic plasma concentration

(ng/ml)

Protein binding (%)

Plasma half-time
Initial fast (a) (min)
Stow (P) (h)
Metabolism
Excretion
Renal (%)
Fecal

(%)

Diltiazem

(*) Verapamil

10-20
5-15

80-160
150

60-90
75-150

>90
65-70

>90

1o-22

.90
<20

<36
15-100
(3.2 X lo+-X 1O-7 M)

<3b
30-130
(7 x lo-*;;x
10-7 Af)

150-180
5
Extensively metabolized
to an inert free acid
and lactone

15-30
3-7
Extensive 1st pass
hepatic extraction
(70% of oral dose)

20
4
Extensively
deacetylated

70 1st day

50 1st day

3.5 (total)

<2:
25-100
(7 x lo-ii2
x 10-r M)

(8r?zat

December 1990

(70::b

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65

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1051

CALCIUM

ANTAGONISTS-HENRY

lized by deacetylation,
ation.
Cardiovascular

N-demethylation
Effects of Ca++

and O-demethylAntagonists

Nifedipine,7
( f )-verapami16
and diltiazem46
exert
potent negative inotropic
effects on isolated myocardium. In contrast, therapeutic
doses of these agents do
not appear to appreciably
depress the heart in the intact
organism.63-66
This seeming paradox
has often been
attributed
to reflex sympathetic
discharge masking the
direct negative inotropic action of the drug.63-66 However, negative
inotropic
threshold
concentrations
for
nifedipine,s4,67,68
( f)verapami137*55
and diltiazem46,47
in vitro are approximately
2 X 10m7 M, 5 X 10m7 M and
10-s M, respectively.
These concentrations
exceed by
a factor of 10 or more peak therapeutic
plasma levels of
free drug (drug not bound to protein) shown in Table
I. In addition,
nifedipine,
verapamil
and diltiazem
are
all quickly and extensively
metabolized,
and the full
effect of the drugs may develop slo~ly.~~,~~~~ Thus,
based on these quantitative
considerations,
there is no
strong reason why Ca++ antagonists
in usual therapeutic doses should exert potent negative inotropic effects. This is not to indicate that vasodilator-induced
arterial
hypotension
may not trigger a sympathetic
discharge. Although Ca++ antagonists
may inhibit Ca++
dependent
secretory
processes,gJ3
exocytosis
of norepinephrine
from sympathetic
nerve endings is not inhibited by clinically
relevant
concentrations
of verapamiF
and nifedipine. 7o As nifedipine,
verapamil
and
diltiazem exert disparate effects in vivo, their action will
be discussed separately.
Nifedipine
Vasodilator
effects:
Nifedipine
is a potent vasodilator that promptly relaxes isolated arteries contracted
by KCl, norepinephrine,
serotonin
and cardioactive
glycosides.7ya,51 It is in general about as potent as nitroglycerin,
but in contrast to nitrates the induced relaxations are sustained.
Concentrations
as low as lOA
M relax pig coronary arterial strips9 Isolated human
mesenteric
arteries and veins contracted
by KC1 and
norepinephrine
are relaxed by slightly higher concentrations.5s
In a study on conscious dogs, nifedipine,
0:43 mglkg
sublingually,
decreased
total peripheral
resistance
by
43 percent and mean coronary resistance by 38 percent,
but did not produce an appreciable
reduction
in aortic
mean pressure (-6 percent).71 Heart rate and cardiac
output increased by 62 percent, and the maximal first
derivative
of left ventricular
pressure
(dP/dt)
was
augmented
by 16 percent.71 In dogs anesthetized
with
pentobarbital,
hypotensive
doses of nifedipine
(150 to
1000 pglkg sublingually)
increased
coronary
flow,
whereas, equipotent
hypotensive
doses of nitroglycerin
decreased coronary flow. 72 Nifedipine-induced
increases
in coronary flow were associated
with increases in inferior caval flow (venous return)
and pulmonary
arterial flow (cardiac output).
In contrast,
nitroglycerin
tended to reduce venous return and cardiac output.71
In the isolated blood-perfused
canine heart, nifedipine

1052

December 1980

The American Journal of CARDIOLOGY

as a coronary
dilator was equipotent
compared
with
nitroglycerin,
but more potent than dipyramidol,
carbochromen,
verapamil,
prenylamine,
papaverine
and
khellin.71
Infused
into the renal artery,
nifedipine
abolished renal autoregulation.
Hemodynamic effects of nifedipine in human beings
resemble those observed in dogs (for more detail see
Ref. 64). In five healthy volunteers, nifedipine,
15 @g/kg
intravenously,
evoked increases
in heart rate (f27
percent), modest decreases in systolic and diastolic arterial pressure, decreases in peripheral
resistance
(-20
percent) and increases in cardiac index (+40 percent)?
In seven patients undergoing cardiac catheterization
for
coronary artery disease, nifedipine,
20 mg sublingually,
produced increases in heart rate (+21 percent), cardiac
output (+25 percent),
and maximal dP/dt (+13 percent). Total peripheral
resistance
declined
(-17 percent). Other measured variables including
mean aortic
pressure,
left ventricular
end-diastolic
volume index,
ejection fraction and mean circumferential
shortening
velocity did not change significantly.6:1,74
Myocardial
perfusion
assessed in 10 patients by a xenon perfusion
scanning
technique
revealed
increased
perfusion
of
normally
perfused and underperfused
segments after
intracoronary
injection of 100 lug of nifedipine.7
After
20 mg of nifedipine
sublingually,
improved
perfusion
of normal zones and of zones supplied by stenotic coronary arteries
was further
documented
by thallium
scintigraphy.74
These clinical observations
indicate that
nifedipine
augments
coronary flow in human beings.
Electrophysiologic
effects:
High concentrations
of nifedipine
(lo- M), in sharp contrast to (f)-verapamil, fail to reduce the excitability
of isolated guinea
pig atria.7 In conscious dogs, verapamil
prolongs the
P-R interval,7s,60,61 whereas nifedipine
in equally hypotensive
doses produces
moderate,
dose-dependent
P-R shortening.75
Injection
of large doses (up to 30 pg)
of nifedipine into the posterior septal artery of dogs (the
artery supplying
the upper A-V nodal area) evokes
dose-dependent
increases
in A-V conduction
time?
However, increases in blood flow through the posterior
septal artery requires only l/10 the dose necessary to
affect A-V conduction.
In contrast, with verapamil
increase in flow and prolongations
in A-V conduction
occur within the same dose range.7
In a study of 11 patients nifedipine,
7.5 pglkg intravenously,
did not affect the A-H and H-V intervals of
the His bundle
electrogram.
With a hypotensive
dosage of 0.15 mg/kg intravenously
(f)-verapamil
produced
in the same subjects
dose-dependent
prolongations of the A-H interval.77 The lack of a tendency
of nifedipine
to precipitate
A-V block is an essential
feature of this drug, as it permits its safe combination
with beta receptor blockers and digoxin7* and it may
be administered
to patients with potential
conduction
disturbances
(hradytachycardia
syndrome).l
The
electrophysiologic
properties
of nifedipine
explain in
part the lack of antiarrhythmic
activity of the drug.7g
Negative
inotropic
effects:
Nifedipine
in usual
clinical dosage has little tendency to depress the heart.

Volume 46

CALCIUM

On the contrary, the drug tends to increase left ventricular dP/dt and cardiac output, as indicated earlier.
Verapamil
Vasodilator
effects: (f )-Verapamil is a potent vasodilator, although its smooth muscle-relaxing effects
are weaker than those exerted by nitroglycerin and nifedipine.7ygv53 In open chest dogs administration
of
verapamil yielding plasma levels of less than 150 ng/ml
(fluorometric
assay) produced little hemodynamic
change. However, in large doses (bolus injections of 14
to 22 mg, plasm levels as high as 2,000 ng/ml) verapamil
induced marked decreases in arterial pressure, heart
rate, left ventricular dP/dt, peripheral resistance and
cardiac output.61 However such large doses are not used
clinically.
In seven healthy subjects, (f)-verapamil,
7.5 to 12.5
mg intravenously increased heart rate (+14 percent)
and cardiac index (+24 percent), and decreased peripheral resistance (-33 percent), mean aortic pressure
(-15 percent) and mean pulmonary
pressure (-11
percent).6s Changes in heart rate, cardiac index and
peripheral resistance were statistically significant. One
patient had 2 A-V block (Mobitz), and three others
exhibited prolongation of the P-R interval.65
Electrophysiologic
effects: In the aforementioned
study in open chest dogs,61 small dose verapamil
(plasma level less than 150 ng/ml) prolonged the P-P
interval from 397 to 442 ms, and the A-H interval (His
bundle electrogram) from 65 to 94 ms. At higher drug
levels (less than 400 ng/ml), the P-R and A-H intervals
increased to 554 and 136 ms, respectively. Fifty percent
of the animals had second or third degree A-V block.
The QRS duration, Q-T interval and H-V intervals were
not affected even at the highest plasma drug levels (400
to 2,000 ng/ml). Similar dose-dependent
prolongation
of the P-R interval in dogs have been reported by other
investigators.75
Therapeutic doses of (*) -verapamil (10 mg intravenously: 120 mg orally) evoke in patients plasma level
dependent prolongations of the P-R interval.60 Furthermore, 0.15 mg/kg verapamil intravenously prolongs
the A-H interval without altering the H-V interval.77
Because of its tendency to produce A-V block, verapamil should be used cautiously in patients in whom A-V
block is apt to develop (patients taking digitalis or those
with a possible bradytachycardia syndrome) and should
not be administered to patients treated with beta adrenergic blocking agents.l
Inotropic
effects:
Compared
with nifedipine,
verapamil has a greater propensity to exert direct
myocardial depressant effects. Nevertheless, in antiarrhythmic doses, precipitation
of cardiac failure is
unusua1.s

before and after 60 mg of diltiazem orally. The drug

produced small decreases in heart rate (-6.2 percent)
systolic aortic pressure (-9.1 percent), cardiac index
(-5.2 percent) and peripheral resistance (-4.1 percent).
In two patients undergoing cardiac catheterization for
angina1 symptoms,s1 an intravenous drip of diltiazem
(1 mg/min) evoked negligible hemodynamic changes.
Long-term treatment in 20 patients with diltiazem, 90
mg every 8 hourq81 was interpreted as having led to a
significant decrease in cardiac output.
Electrophysiologic
effects: Like verapamil, but
unlike nifedipine, diltiazem possesses antiarrhythmic
effects (for more detail see Ref. 45). This vasodilator has
the unusual property of producing no tachycardia or
minimal sinus bradycardia.66
Comparative Direct Cardiac Effects of Nifedipine,
Verapamil, Diltiazem and Other Vasodilators

Direct myocardial effects of vasodilators in vivo are

notoriously difficult to evaluate, because vasodilator
responses may affect major determinants
of cardiac
performance including heart rate, ventricular preload,
ventricular afterload and coronary flow. Therefore,
direct myocardial effects of these drugs are more easily
assessed in vitro.
Figure 2 depicts experiments with isolated right guinea
pig atria.82 The atria were mounted so as to contract iso-

metrically in a muscle bath containing oxygenated Krebs

buffer. Force (F) development and its first derivative, dF/dt,
were monitored before and during the cumulative addition
of drug to the buffer. Changes in spontaneous
rate and
changes in dF/dt during electrical pacing (2OO/min) served as
indexes of chronotropy and inotropy, respectively. Spontaneous frequency and dF/dt at fixed rate were expressed as
percent decrease of the control value (= 100 percent) before
addition of a drug.ss

Figure 2 shows the responses to selected vasodilators, all

administered to produce a drug concentration of lop6 M.

Each data point represents a mean f standard error of the

mean in five to six experiments. Verapamil, D 600, and to a
lesser extent prenylamine and perhexiline, were effective in
depressing both frequency and dF/dt. However, diltiazem
acted predominantly on frequency (chronoselectivity),
and
nifedipine predominantly on dF/dt (inoselectivity). In sharp
contrast, classic vasodilators (papaverine, nitroglycerin, nitroprusside and d&oxide) exerted no or negligible depressant
effects on chronotropic or inotropic properties at the 10-s M
level.
As indicated, the definition of the term Ca++ antagonist is
somewhat vague. I believe that if one wants to use the term
it should be applied only to those vasodilators that depress
the heart at low ( 10m6M or less) concentrations. This definition eliminates drugs such as diazoxide and nitroglycerin,
vasodilators that do not appear to inhibit Ca++ uptake by
vascular smooth muscle.18 Thus, Ca++ antagonists may be
thought of as drugs which act in vitro as potent cardiovasodepressants. Such a definition avoids making assumptions
about electrophysiologic mechanisms.

Diltiazem
Vasodilator

Therapeutic
effects:

In 20 patients undergoing
cardiac catheterization
for coronary disease or hypertensioqfi6 hemodynamic findings at rest were monitored

ANTAGONISTS-HENRY

Effects of Ca++

Antagonists

Although Ca++ antagonists have been used clinically

mainly as antianginal and antiarrhythmic agents, these
drugs may be of value for the treatment of other disease

December 1990

The American Journal of CARDIOLOGY

Volume 46

1053

CALCIUM

ANTAGONISTS-HENRY

DECREASE IN SPONTANEOUS
-60

-50

-40

-30

FREQUENCY

-20

-10

DILTIAZEM

PRAZOSlN

t
%

+5

A..$

z
Lu

PAPAVERINE
THEOPHYLLINE
HYDRALAZINE

NITROPRUSSIDE
NITROGLYCERIN

ii

-5

DIAZOXIDE

&e -151

NIFEDIPINE

-30

-20

-10

llO

CHANGE IN SPONTANEOUS

,
+20

,
+3o

-2

FREQUENCY

FIGURE 2. Responses of first derivative of force development(dF/dt) during electrical pacing and of spontaneous rate (frequency) of isolated guinea
DiQatrium to selected vasodllators all administered to produce a 6ug concentration of 10m6 hf. A, selected vasodilatws including calcium antagonists.
B.-classic vasodilators.

occurrence of coronary spasm was documented

by
modern angiographic techniques. Japanese workerssPss
were pioneers in studying the effects of newly developed
vasodilators on coronary vasospasm. A case collection
from 11 Japanese centerss7 revealed the extraordinary
efficacy of nifedipine and diltiazem for the relief of
coronary spasm. These agents were found to eliminate
chest pain in approximately 75 percent of the patients,
and improvement was noted in over 90 percent of the
patients (Table II). Interestingly, verapamil was strikingly less effective than nifedipine and diltiazem.
Subsequently, Yasue and collaboratorssss found that
coronary spasm triggered by exercise or alkalosis
(Tris-buffer
infusion; hyperventilation)gO
could be
prevented by nifedipine and diltiazem. Furthermore,
they observed89 that in some cases beta blockade with
propranolol was not only ineffective in suppressing the
attacks, but aggravated the disease in 8 of 13 patients.
In other reports,g1*g2 patients were described in whom
nifedipine abolished spasm producing life-threatening
ventricular arrhythmias. The efficacy of nifedipine in
the treatment of angiospastic angina has widely been
confirmed.ssvg3
Angina pectoris: Nifedipine appears to be less effective for the treatment of angina1 syndromes not attributable to coronary spasm.g3 In six controlled studies

states. Treatment with Ca++ antagonists have been

recommended
or proposed for the following conditions:
1. Angiospastic angina (Prinzmetals angina)
2. Angina pectoris, any type
3. Arrhythmias
4. Arterial hypertension
5. Left ventricular failure (vasodilator therapy)
6. Acute myocardial infarction
7. Cardiac preservation (cardiac surgery)
8. Cardiomyopathy
9. Cerebral vasospasm
10. Other vasospastic syndromes
The value of nifedipine, verapamil and diltiazem as
therapeutic agents is no longer in doubt. Nifedipine and
diltiazem are efficacious in relieving angiospastic angina, and verapamil is the drug of choice for the termination of supraventricular
reentrant tachycardias. In
the following I will focus on the main therapeutic applications of nifedipine, diltiazem and verapamil.
Angiospastic angina: Spontaneous angina with reversible infarct-like electrocardiograms (marked S-T
elevation and transient Q waves) was well described by
the classical electrocardiographers
who attributed the
episodes to coronary spasm.s3 However, this pathophysiologic mechanism remained speculative until the

TABLE
Effect

II
of Antianginal

Agents on Variant

Anglna

Total Cases (n)

Nifedipine
Diltiazem
Nifedipine + diltiazem
Verapamil

1054

December

1980

149
a7

:f

(11 Japanese

Institutiona)

Complete
Elimination of
Attacks

Decrease of
Attacks to
Less Than Half

No Effects

115
70
11
3

25
9

9
:

The American Journal of CARDIOLOGY

2:

Volume 46

% of Effective
Cases
94.0
90.8

100.0
85.7

CALCIUM ANTAGONISTS-HENRY

totaling 199 patients, nifedipine, 10 mg/8 hours orally,

decreased on average the frequency of angina1 attacks
by 60 percent. Current evidence indicates that therapy
with nifedipine plus beta receptor blockade yields better
results than either nifedipine or beta receptor blockade
alone?
Arrhythmias:
Nifedipine has no ant&rhythmic
activity.7g Verapamil, 0.15 mg/kg intravenously, is the
drug of choice for the treatment of reentrant supraventricular tachycardia, irrespective of whether reentry
is intranodal or occurs in association with an accessory
pathway.77~g4~gs
Verapamil probably acts by lengthening
the effective and functional refractory period of the A-V
node and prolonging the A-V nodal transmission time.
Reversion to sinus rhythm occurs in a very large percent
(more than 90 percent of the patienta.77pg4,g5Verapamil
may slow the ventricular rate in the presence of atria1
fibrillation or flutter.g6 Verapamil does not appear to
be a very effective drug for the treatment of ventricular
arrhythmias.g6
Of particular interest are ventricular arrhythmias
during acute myocardial ischemia. It has been postulated that during ischemia potassium accumulating
around the cells and other factors partly depolarize the
cells, inactivating the fast channels. The cells would
then depend on slow-channel action potentials (slow
response) that might be arrhythmogenic.
It is further
postulated that inhibition of such slow responses with
a Ca++ antagonist should exert an antiarrhythmic
effect. Ischemia impairs local conduction, and the inhibitory effects of a Ca++ antagonist should further
accentuate impaired conduction. In dogs with experimental ischemia it has been shown that verapamil improves conduction in ischemic zones.g7-gg The reason
for this paradoxical effect is not clear, but may be due
to the fact that verapamil, by augmenting collateral
flow, improves the electrophysiologic
performance of
the ischemic heart.
Arterial hypertension:
There is considerable evidence that Ca++ antagonists may have a place in the
treatment of arterial hypertension. Nifedipine has been
shown to lower promptly the arterial pressure in hypertensive criseslcc and in severe essential hypertension.Ol Other investigators, lo2 however, have concluded
that nifedipine, 10 mg orally every 8 hours has only a
modest hypotensive activity. Similarly, verapamil, 320
to 640 mg every 24 hours, has been found to produce
only small decreases in arterial pressure.lo3 It appears
likely that Ca++ antagonists will be useful for the

treatment of mild hypertension complicated by coronary disease or impaired left ventricular performance,
or both.64
Left ventricular
failure: Vasodilator therapy of left
ventricular failure with Ca++ antagonists has not been
extensively evaluated. In patients with coronary disease
and left ventricular failure, nifedipine has been found
to improve exercise tolerance and reduce pulmonary
occlusion pressure.64
Acute myocardial
infarction:
In conscious dogs
with coronary ligation, nifedipine administered intravenously has been shown lo4 to improve collateral flow
to ischemic zones, and to reduce ischemic injury assessed histologically and biochemically. In open chest
dogs, nifedipine has also been shownlo to improve regional shortening and increase local heat development
in the ischemic zones. On the other hand, verapamil
given to open chest dogs with coronary ligation has been
reportedise to selectively depress contractility in ischemit zones. Nevertheless, verapamil appears to reduce
infarct size in dogs subjected to coronary occlusion.lo7
There are no published data on the effects of Ca++ antagonists on myocardial infarct size in human beings.
Cardiac preservation:
In isolated rabbit hearts
perfused at low flow, nifedipine has been shownlo to
inhibit the development of myocardial contracture,
improve recovery after reperfusion and depress the
accumulation of Ca++ in the mitochondrial fraction of
ventricular myocardium. Similarly, verapamil has been
notedlog to inhibit hypoxic contracture in the isolated
perfused guinea pig heart. In dogs undergoing total
hypothermic cardiopulmonary
bypass for 2 hours, nifedipine has been shown 110to exert striking protective
effects on the heart.
Cardiomyopathy:
Jasmin et al. demonstrated that
verapamil prevents the development or reduces the
severity of heart lesions in the cardiomyopathic
hamster. Of considerable interest are reports112v113 indicating that long-term treatment with verapamil may
beneficially influence hypertrophic
obstructive cardiomyopathy in man.
In conclusion: Ca++ antagonists are a rather heterogeneous class of agents with dissimilar structural,
electrophysiologic and pharmacologic properties. There
are still some questions regarding the clinical utility of
the concept of Ca++ antagonism. However, the evidence
is overwhelming that some of these agents are of great
value for the treatment of specific cardiovascular disease
states.

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