Cocaine can induce lethal cardiovascular events, in- cluding myocardial infarction and ventricular fibrilla- tion. The mechanisms responsiblefor these cardiotoxic.
Mechanisms
for the cardiotoxic
effects
of cocaine GEORGE
E. BILLMAN
Department
of Physiology,
The Ohio State University,
Columbus,
gency
Cocaine can induce lethal cardiovascular events, including myocardial infarction and ventricular fibrillation. The mechanisms responsible for these cardiotoxic effects of cocaine remain largely to be determined. Co-
has both sympathomimetic of norepinephrine)
and
(inhibition of neuronal local anesthetic (Na
channel blockade) properties. Neurotransmitters released from cardiac sympathetic nerves bind to both aand /3-adrenergic receptors eliciting a cascade of intracellular responses. Stimulation of f3-adrenergic receptors activates adenylate cyclase, increasing cyclic AMP levels, whereas a-adrenergic receptor stimulation activates phospholipase C, increasing inositol trisphosphate. These second messengers, in turn, elicit increases in cystolic calcium. Elevations in cystolic calcium can provoke oscillatory depolarizations of the cardiac membrane, triggering sustained action potentialgeneration and extrasystoles.Cocaine also acts as a local anesthetic by inhibiting sodium influx into cardiac cells, which impairs impulse conduction and creates an ideal substrate for reentrant circuits. Thus,
the adrenergic and anesthetic properties of cocaine could act synergisticallyto elicitand maintain ventricular fibrillation. Adrenergic receptor activation would trigger the event whereas sodium channel blockade would create the reentrant substrate malignant arrhythmias. BILLMAN, nisms responsible for the cardiotoxic 4:
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2469-2475;
Key Words: cocaine cium sympathomimetic
THE
ESCALATING
USE
drugs
OF
to perpetuate the G. E. Mechaeffects of cocaine.
1990.
ventricular .
ing
with
increase
increased
in the
fibrillation
.
cytosolic cal-
local anesthetics
as a recreational
COCAINE
cocaine
number
visits,
drug
use has been
of cocaine-related
0892-6638/90/0004-2469/$01 .50.© FASEB
an alarm-
emer-
hospital
admissions,
and
deaths.
continues to mount, documenting provoke lethal cardiovascular events,
(2, 3), myocardial infarction (3, 4), rhythm disorders such as ventricular In addition, chronic cocaine abuse may result in dilated cardiomyopathy (9-10). Yet in spite of the enormity of this problem, the mechanism precipitating these life-threatening cardiovascular events remains to be determined. This article summaincluding and lethal fibrillation
stroke cardiac (4-8).
rizes
what
is known
heart
and
about the actions of cocaine on the a possible mechanism responsible cardiac rhythm disorders.
proposes
for cocaine-induced HISTORY
Cocaine is an alkaloid extracted from the leaves of the Erythroxylon coca plant. Archaeological evidence suggests that the indians of the Andes region of South America have used cocaine (coca leaves) for perhaps as long as
5000 years
(11-13).
The
coca plant
was considered
to be
of divine origin by the Inca indians. According to one myth, the coca plant was created by the sun god, Inti, as a giftto the Incas to alleviate their hunger and thirst.
The
Incas controlled the cultivationand use of coca.
The chewing of coca was reserved and the ruling class. Coca leaves rifice to the gods, were chewed
ceremonies, to ensure
Casual was
has reached epidemic proportions as graphically manifested by the tragic deaths of young, otherwise healthy adults, including prominent sports figures. It has been estimated that 30 million Americans (or more than 10% of the U.S. population) have used cocaine at least once; as many as 5 million people use it daily (1). Concomitant
room
USA
Clinical evidence that cocaine can
ABSTRACT
caine uptake
Ohio 43210,
and were placed a
chewing punished
favorable
largely for priests offered in sacas part of religious
were
in the mouths
journey
into
of coca was considered accordingly.
With
the
of the dead next
world.
sacrilegious the
decline
and of
the
Incan empire, coca use began to lose much of its religious significance. By the time of the Spanish conquest, coca chewing was widespread among all classes. The first reports of coca use reached Europe with the discovery and conquest of the New World. Reference to coca leaf chewing can be found in the letters of Amerigo Vespucci and the chronicles of Garcilasso de
‘To whom correspondence should be addressed,at Department of Physiology,The Ohio State University, 4196 Graves Hall, 333 W. 10th Ave.,Columbus, OH 43210, USA. Abbreviations: G,, stimulatory 0 protein;AC; adenylate cyclase; SR, sarcoplasmic reticulum; DAG, diacylglycerol; IP3, inositoltrisphosphate; LVP, leftventricularpressure;HR, heart rate;NE, norepinephrine;PKC, proteinkinaseC.
2469
la Vega (11, 12). The Spanish authorities first banned coca use, then enthusiastically exploited the drug when reports that chewing coca leaves increased the endurance work with
and
alleviated the hunger of the force. The Indians were often paid coca
opposed tion,
leaves. The
coca
and
The
use
Catholic
as sinful,
maintained
use
coca
of coca
church,
began
which
systematic
plantations
leaves
in
captive Indian for their labors
for this
Europe,
originally
cultivapurpose.
however,
was
sporadic until the 19th century, partly because of the difficulty of growing the coca plant and its loss in potency during transport. After 1859, when Albert Neiman isolated and identified cocaine as the active ingredient in coca leaves, the alkaloid became more widely
available
for clinical
and
experimental
use (11, 12). In
1880, Vassili von Anrep described the potent cardiac acceleratory effects of cocaine in dogs and also noted the loss of sensation when applied to the surface of his tongue (11, 12). In 1884, Freud began a series of studies on the central neural stimulatory effects of this drug and played a central role in popularizing itsuse in the treatment of patients. He advocated cocaine’s use as a stimulant, an aphrodisiac, and in the treatment of asthma, wasting diseases, digestive disorders, and morphine addiction. For example, Freud used cocaine to wean
phine.
a friend
and
This
resulted
colleague,
in one
von
Fleischl,
of the
first
from mordocumented
cases of cocaine addiction, including such sequelae as paranoid delusions and hallucinations (of bugs crawling underneath the skin). During the same period, Carl Koller, a colleague of
Freud’s, was among the first to appreciate the practical importance of the anesthetic properties of cocaine and introduced its use during ophthalmic procedures (11, 12). By 1884, Hall had introduced local anesthesia into dentistry and Halsted had demonstrated that cocaine
could As was
stop the
signal
transmission
in nerve
custom
of the time, Halsted on himself, and as a result,
fibers
the
literature.
By
1887,
Erlenmeyer
(11) forcefully
attacked Freud’s enthusiastic praise for cocaine, calling Freud the father of the third scourge of mankind (behind opium and alcohol). In the United States, the adverse abuse
publicity and growing concern led to the passage of the Harrison
about cocaine Narcotic Act
of 1914, which banned the use of cocaine in proprietary medicines (13). According to Kleber (13), the term dope fiend was coined about this time to describe cocaine addicts. With respect to cardiovascular actions, Hammond reported that a large dose of cocaine (selfadministered) provoked a rapid irregular heartbeat, and speculated that a toxic dose of cocaine probably causes death due to actions on the heart (11). By 1911, Price and Leakey (8) reported that cocaine, when used as a local anesthetic during dental procedures, could induce severe myocardial damage leading to death. In 1947, Young and Glauber (7) presented the first electro2470
Vol. 4
May 1990
evidence provoked
of severe by cocaine
intractable during
ventricular routine nasal
surgery. With its wider use as a recreational drug, the number of cardiac events related to self-administration of cocaine has increased. Benchimol et al. (5) in 1978 presented the first case reports of the deleterious effects of cocaine on cardiac rhythm. Each year the number of case
reports
grow, 3),
confirming
with
evidence
myocardial
these
that
infarction
arrhythmias
(4-8)
cardiovascular ing association
risk
individuals
factors
(4,
continues to stroke (2, lethal ventricular
can induce
(3, 4),
in
between the mechanism
events,
findings
cocaine
and
otherwise
14).
In spite
free
of the
of
grow-
cocaine abuse and lethal cardiac by which cocaine precipitates
these cardiovascular effects, particularly malignant arrhythmias, remains largely unknown. In fact, there have been only a few experimental studies in which cocaine was reported to induce cardiac arrhythmias. Ruben and Norris (15) demonstrated that
cocaine could induce ventricular tized dogs during epinephrine co-workers (16,
17) found
that
fibrillation infusions. a lethal
in anestheTrouve and
concentration
of
cocaine (60 mg/kg) elicited ventricular arrhythmias in rats. Inoue et al. (18) found that cocaine potentiated the effects of norepinephrine, significantly increasing heart rate and reducing the refractory period, factors known to enhance arrhythmia formation (19, 20). In fact, arrhythmias could be more readily induced in dogs with
healed
myocardial
cocaine.
More
found caine
that (1.0
infarctions recently,
after pretreatment
Billman
after pretreatment with mg/kg), the combination
and
with
Hoskins
(21)
a low dose of exercise
of coand
acute ischemia consistently evoked ventricular fibrillation. The exercise plus ischemia test failed to provoke arrhythmias unless cocaine was given first.
(11, 12).
experimented became depen-
extensively dent on cocaine (13). As cocaine became more widely used clinically, concern about addiction began to mount and a number of adverse cardiovascular reactions to the drug appeared in
cardiographic arrhythmias
MECHANISM Cocaine
has potent
as a powerful vous system
potentiate
OF
ACTION local anesthetic
sympathomimetic stimulant effects
the effects
in cardiac and other take of catecholamines
of sympathetic tissues
properties
and acts
agent with central ner(12). It has been shown to by the
nerve inhibition
stimulation of the
up-
by nerve terminals (12). Since is the major means of termi-
catecholamine reuptake nating sympathetic neural transmission, the adrenergic response is potentiated by cocaine. Thus, cocaine has been shown to elicit a dose-dependent positive inotropic and chronotropic response both in humans and animals In
(22, 23). a similar
manner, cocaine has been shown to block sodium (fast) channel and thereby to inhibit action potential generation in both nerve and cardiac tissue (12). Weideman (24) demonstrated that cocaine decreased Purkinje cell automaticity and depressed phase 0 of the cardiac action potential (the rapid upstroke due to sodium influx). Recently Pryzwara and Dambach (25) confirmed these findings and further demonstrated that cocaine also blocks the potassium effiux channel but has no effect on calcium channels.
The FASEB Journal
BILLMAN
These adrenergic and alone or in combination
anesthetic effects of cocaine could contribute significantly
to the development
of ventricular
fibrillation.
CATECHOLAMINES ARRHYTHMIAS:
AND CARDIAC MECHANISM OF
ACTION
Alterations in autonomic activity have been shown to alter the electrical stability of the heart, particularly during ischemia (26). Several lines of experimental evidence suggest that any intervention that elicits an increase of cardiac sympathetic nerve activity enhances the development of lethal cardiac arrhythmias. For example, direct electrical stimulation of cardiac sympathetic nerves, exercise, or psychological stress decrease ventricular fibrillation (VF) threshold (the current necessary to induce VF) and increase arrhythmogenesis (26). As it is well established that cocaine inhibits the reuptake of norepinephrine by nerve terminals, the resulting potentiation of the catecholamine effects probably contributes significantly to the development of malignant cardiac arrhythmias. This potentiation occurs not only at cardiac or vascular smooth muscle neuromuscular junctions, but also within the central nervous system and peripheral sympathetic ganglia (12, 22). The net effect is an increased sympathetic efferent outflow to the heart and vasculature. Thus, cocaine elicits an increased sympathetic efferent activity, which cular junction.
in turn
is accentuated
at the
neuromus-
The mechanism by which the catecholamines trigger the ventricular arrhythmias is yet to be defined. Ultimately, these transmitter substances must bind with membrane receptors on the target tissue, which would evoke a cascade of intracellular responses. These intracellular events could prove to be the cellular mechanisms The
that cause cardiac arrhythmias. release of catecholamines by sympathetic
nerves
is known to stimulate a-adrenergic and i3-adrenergic receptors located in the myocardium and vascular smooth muscle (26). Enhanced a-adrenergic receptor activation of coronary vascular smooth muscle could elicit a powerful vasoconstriction, reducing oxygen delivery to the heart. Ventricular arrhythmias could therefore be evoked secondarily from the resulting myocardial ischemia. Indeed, the angiographic finding of normal coronary vessels subsequent to documented cocaine-related ischemic episodes suggests that cocaine may induce a coronary vasospasm (4, 14). A number of recent reports further demonstrate that cocaine can adversely affect coronary perfusion. For example, it has been shown to elicit contractions of isolated porcine coronary artery strips, contractions that were prevented by the a-adrenergic agonist prazosin (27). In a similar manner, Lange and co-workers (28) found that intranasal cocaine even in low doses (topical anesthesia) produced large reductions in coronary vessel diameter and large increases in coronary vascular resistance in patients with and without preexisting atherosclerotic lesions. These vascular effects of cocaine occurred despite marked increases in myocardial oxygen demand (due COCAINE
AND
VENTRICULAR
FIBRILLATION
to increased heart rate, inotropic state, and arterial blood pressure) and could be prevented by a-adrenergic receptor antagonists (28). Cocaine therefore could create an imbalance between oxygen supply and demand, increasing the probability for ischemic events, and thereby
cardiac
arrhythmias.
In addition to indirect influences can directly affect the myocardium.
on the heart, Stimulation
cocaine of my-
ocardial 13-adrenergic receptors activates adenylate clase and thereby elevates cellular cyclic AMP
cylevels
(29). Cyclic AMP activates a cyclic AMP-dependent protein kinase (PKA) that phosphorylates a variety of regulatory proteins, including calcium channels and the sarcoplasmic reticulum protein, phospholamban (29). This results in increased calcium entry and release from cytosolic stores, eliciting an increased force of contraction and elevation of intracellular free calcium levels. In a similar manner, a-adrenergic
stimulation
of the
phospholipase
heart
that
results
hydrolyzes
in the
activation
of a
phosphatidyl-inositol
into two second messengers: diacylglycerol and inositol trisphosphate (30). Inositol trisphosphate stimulates calcium effiux channels in the sarcoplasmic reticulum, facilitating greater calcium release. Diacylglycerol stimulates the calcium-dependent activation of the calcium phospholipid-stimulated kinase, protein kinase C. This kinase, which is also activated by phorbol esters, is known to phosphorylate and regulate calcium channels, /3-adrenergic receptors, and G proteins in order to modulate cellular excitability and the response to hormones (30). The overall effect of a-adrenergic stimulation of the heart is a rise in cytosolic calcium and positive inotrophy. Thus, a- and 13-adrenergic stimulation
may act synergistically to elicit a positive inotropic response (which increases oxygen demand) and to increase cytosolic calcium level (Fig. 1). Elevations in intracellular calcium can provoke oscillatory after-potentials (also known as delayed afterdepolarizations, transient depolarizations, or late afterdepolarizations). These after-depolarizations are oscillations of membrane voltage that occur after repolarization of the cardiac action potential, that is, during diastole (21). If the amplitude of the after-potential is sufficient to reach threshold voltage, a repetitively sustained action potential generation results (21). In 1943 Bozler (31) found that catecholamines augmented the development of after-depolarizations and proposed that this
triggered
for coupled
activity
extrasystoles
provided
“a simple
explanation
and
paroxysmal tachycardia.” Clusin (32) further proposed that calcium overload and resulting calcium-dependent ionic currents contributed to both the initiation and maintenance of ventricular fibrillation.
In isolated myocardial tissue, calcium loading has been shown to induce spontaneous after-depolarizations and after-contractions of the cells (21). In general, it has been
found
that
interventions
calcium loading enhance tricular fibrillation (21). agonists have been shown of cellular calcium (33), to
that
favor
intracellular
triggered activity and venFor example, a-adrenergic to elicit large accumulations induce after-depolarizations 2471
Alpha
tracellular calcium could cantly to the development
Beta
DAG +
‘P /3 PKA
Ca
__________
j
Other
PL Figure 1.A schematic representation of adrenergic modulation of myocardial calcium. 13-Adrenergic receptor stimulation activates a stimulatory 0 protein (G,), which interacts with adenylate cyclase (AC)
to modulate
dependent phorylates
CAMP
levels.
Cyclic-AMP
kinase, protein kinase A (PKA), membrane calcium channel and
located
on the sarcoplasmic
reticulum
(SR)
activates
a cAMP-
which in turn phospholamban
to increase
phos(PL)
cytosolic
calcium levels. a-Adrenergic receptors stimulate G proteins, which activate a membrane-bound phospholipase (L) to hydrolyze phosphatidylinositol into diacylglycerol (DAG) and inositol trisphosphate (1P3). The DAG activates protein kinase C (PKC), which can phosphorylate and regulate calcium channels, fl-adrenergic receptors, and G proteins. The 1P3 stimulates calcium efflux mechanisms in the SR, facilitating an increasein cytosolic calcium.
(34),
and
a similar
to provoke
manner,
spontaneous
the calcium
8644 has been shown ing after-depolarization (35, 36). Conversely,
arrhythmias
channel
to promote
calcium
arrhythmias agents
that
buffer
(26).
agonist entry,
in isolated against
In
Bay K elicit-
tissue calcium
overload have been shown to prevent triggered activity and the accompanying arrhythmias. Ryanodine, a drug that blocks calcium release from the sarcoplasmic reticulum, has been shown to attenuate arrhythmias resulting from ischemia (37) or digitalis toxicity (38), whereas the intracellular calcium-specific chelator, BAPTA-AM [the acetoxymethyl ester of 1,2 bis (0-aminophenoxy ethane)-N, N, -N’, N’ tetraacetic acid], can prevent after-depolarizations and after-contractions induced by catecholamines or cardiac glycosides in isolated ferret papillary muscle (36). Similar findings have been noted in intact preparations. Billman (39) demonstrated that both organic (verapamil, nifedipine) and inorganic (magnesium) calcium channel antagonists could prevent ventricular fibrillation induced by the combination of exercise and ischemia, whereas the calcium channel agonist Bay K 8644 provoked malignant arrhythmias in animals resistant to sudden death. Billman and co-workers (40) further demonstrated that BAPTA-AM significantly protected against either Bay K 8644 or ischemically induced ventricular fibrillation. An accumulation of in-
2472
Vol. 4
May 1990
therefore contribute of cocaine-induced
signifimalig-
nant arrhythmias. If this hypothesis is correct, one would predict that interventions designed to lower cellular calcium levels would protect against the cardiotoxic effects of cocaine. Indeed, the calcium channel antagonist nitrendipine prevented ventricular arrhythmias and counteracted the lethal effects of very high (toxic) doses of cocaine (16, 17). The authors concluded that this protection was probably afforded by the vascular effects of this drug; that is, nitrendipine elicited a vasodilation and thereby prevented coronary vasospasm and the resulting ischemia. In a similar manner, the calcium channel antagonist nimodipine prevented cardiac arrhythmias and blood pressure increases produced by cocaine injections in squirrel monkeys (41). More recently, Billman and Hoskins (19) found that verapamil, a calcium channel antagonist with significant myocardial effects, prevented cocaine-induced ventricular fibrillation during the combination of exercise and acute ischemia. Briefly, the left circumflex coronary artery was occluded for 2 mm, beginning during the last minute of exercise in mongrel dogs.
None
of the
13 animals
developed
ventricular
ar-
rhythmias during control exercise plus ischemia tests. On a subsequent day, the exercise plus ischemia test was repeated after cocaine (1.0 mg/kg, i.v.). Cocaine elicited ventricular arrhythmias in 12 of 13 animals; 11 animals had ventricular fibrillation (Fig. 2). Previous treatment with verapamil prevented the cocaine-induced ventricular fibrillation. The authors concluded that verapamil prevented these lethal arrhythmias by attenuating catecholamineinduced increases in cellular calcium, thereby reducing the potential for oscillatory after-depolarizations. Pathological changes believed to reflect changes in calcium homeostasis (namely, myocardial contraction bands) are more frequently noted in the hearts of individuals who died from acute cocaine toxicity compared to other drug-related deaths (10, 42). Tazelaar et al. (42) found significantly greater numbers of myocardial contraction bands in the hearts of cocaine users compared with sedative-hypnotic overdose victims. They concluded that these “contraction bands may supply the anatomic substrate for the arrhythmias and sudden death associated with cocaine use” (42). Studies of isolated tissue further support this calcium overload hypothesis. Cocaine was shown to increase intracellular calcium levels, as measured by the calcium-sensitive fluorescent dye aequorin (43), as well as to enhance spontaneous release of calcium from the sarcoplasmic reticulum (44). Therefore, the adrenergic effects of cocaine could lead. to the accumulation of cytosolic calcium and the generation of after-depolarization and triggered ventricular arrhythmias. Since intracellular calcium levels are known to increase during myocardial ischemia (21, 32), cocaine-induced reductions in coronary blood flow (as noted above) would tend to exacerbate this accumulation of cytosolic calcium.
The FASEB Journal
BILLMAN
CONTROL
-
-
1s:{
ECO
1k1
f
+600011rd1, .11,k 1 -6000
HR
240
Ill II !L1300 IAll OCCLUSION
COCAINE
..i.iiiii:
(;:4E)
ECO
+6000 d(LVP)/dt (mrnl$gIs.c)
-eooo
11
HR
+ COCAINE
336
300 OCCLUSION
COCAINE
VERAPAMIL
+
____________________________________
ECO
I
ii
I I
Ii
I
ww
(mniHg/uc)
-
HR
4
336
270
COCAINE
OCCLUSION
Figure 2. Representative recordings obtained during an exercise plus ischemia test during control (saline), cocaine (1.0 mg/kg), and verapamil (250 pg/kg) plus cocainetestconditions.Note thatthe combination of cocaine plus ischemia-inducedventricularflutter that was prevented by the previous treatment with the calcium channel antagonist verapamil. LVP, left ventricular pressure; HR, heart rate in beats/mm.
LOCAL ANESTHETIC PROPERTIES OF COCAINE AND CARDIAC ARRHYTHMIAS As noted above, cocaine also acts as a potent local anesthetic, which could profoundly affect cardiac electrical properties, particularly impulse conduction. These conduction changes could, in turn, contribute significantly to the development and maintenance of cardiac rhythm disorders. A variety of local anesthetics, including cocaine, have been shown to block sodium or fast channels in nervous and cardiac tissue (12, 24, 25). Conduction velocity in cardiac tissue is dependent on the rate of depolarization (dV/dt max or Vmax) and the amplitude of the action potential, factors resulting from the opening of fast sodium channels (20). When an impulse is propagated into a region in which the opening of the fast channels is impaired, conduction is depressed and a unidirectional block often results. The combination of a decremental conduction and a unidirectional block of the impulse creates a reentrant circuit that forms a substrate for sustained ventricular arrhythmias (20). Many local anesthetic agents, particularly bupivacaine, have been shown to impair impulse conduction and elicit ventricular arrhythmias (45). The cardiac electrophysiological effects of cocaine have not been extensively investigated. In isolated tissue preparations, cocaine has been shown to reduce COCAINE
AND
VENTRICULAR
FIBRILLATION
phase 0 amplitude and to decrease the phase 0 rate of depolarization (Vm) factors that would alter action potential conduction (24, 25). In whole animals, cocaine has been reported to increase the duration of the QRS complex, lengthen the P-R interval, and prolong the His to ventricle conduction time (H-V interval on His
bundle
(46,
47).
tole
have
cate alter
recordings)
in
a dose-dependent
Cocaine-induced also
that local ventricular
velopment
been
conduction
reported
anesthetic conduction,
of reentrant
(6,
48).
properties which
fashion
block These
and
asys-
data
indi-
of cocaine could may lead to the de-
circuits.
Local anesthetics have also been shown to affect the ventricular repolarization process (49), which can also contribute to the development of reentrant circuits (20). The ability of a local anesthetic to influence the duration of the cardiac action potential gives rise to the
possibility
that excitability
of the
heart
rized.
In
this
before
could recover
adjacent
situation,
the
areas tissue
have that
in one region fully has
repola-
remained
depolarized longer than the surrounding tissue may reexcite the fully repolarized regions such that a second (premature) impulse can be generated. This phenomenon is known as inhomogeneity of repolarization (20). Lidocaine and bupivacaine have been shown to prolong in a nonuniform
of the cardiac
manner
tissue
the
(49). That
effective
refractory
is, the refractory
period
period 2473
was shown to lengthen to a different extent in different recording sites, and was in fact shown to decrease in some regions. This temporal dispersion of refractory period results in an inhomogeneity of repolarization, and forms the substrate for reentrant arrhythmias (20). The magnitude of the refractory period dispersion has been shown to correlate with ventricular fibrillation threshold; i.e., the greater the temporal dispersion, the lower the ventricular fibrillation threshold (ventricular fibrillation was easier to induce) (20, 49). Cocaine has been shown to prolong repolarization due to inhibition of potassium effiux channels in isolated cardiac tissue (25) and to increase effective refractory period in intact animals (46, 47). The effects of cocaine on the temporal dispersion of effective refractory period (i.e., regional differences in refractory period) have not been investigated. However, one would predict that the sodium channel-blocking properties of cocaine should result in a temporal dispersion of refractory period similar to that noted for other local anesthetics.
-‘)-Cocaine
I
Ift Na
4 -
.
-
COCAINE-INDUCED SUMMARY AND
The combination of the anesthetic properties (decremental conduction with unidirectional inhomogeneity
of
repolarization)
with
of cocaine block and
its
adrenergic
properties (increased intracellularcalcium, calcium overload, after-depolarization, and triggered events) may explain the potent arrhythmogenic properties of the drug. This hypothesis is graphically illustrated in Fig. 3. For example, the temporal dispersion of refractory period produced by sodium and potassium channel blockade would allow some areas of the ventricle to repolarize before others, which when combined with slowed conduction, creates the substrate likely to cause reentrant ventricular arrhythmias. Under these conditions, if a premature depolarization (due to calciummediated oscillatory after-potentials) should occur in an area of slowed conduction and/or early repolarization, sustained ventricular tachyarrhythmias would likely result. Thus, the adrenergic and anesthetic properties of cocaine could act synergistically to elicit and maintain ventricular fibrillation. Adrenergic receptor stimulation would trigger the event while sodium channel blockade would create the reentrant substrate to perpetuate the ventricular arrhythmias. In addition, myocardial ischemia has been shown to accentuate the effects of local anesthetics on conduction and repolarization (45, 49) while also increasing the potential for slow responses (calcium channel effects) (21). Therefore, acute myocardial ischemia elicited by a-adrenergically
-,
ARRHYTHMIAS: HYPOTHESIS
mediated
reductions
in coronary
blood
flow
in
the face of increased metabolic demand (myocardial adrenergic effects)would tend to exacerbate the conditions necessary to induce the lethal cardiac events. This hypothesis
suggests
that
a
multifactorial
approach
should be used in the management of cocaine-induced arrhythmias; both the adrenergic and local anesthetic properties of this drug should be considered before treatment begins for these patients.
1 Figure for
3.A schematicrepresentation
cocaine-induced
ventricular
The author would like to thank Terry Carsner for typing this manuscript. This work was supported by National Institutes of Health grant
.TT1
of a mechanism
fibrillation.
The
tering bined
and
extra-systoles. right)
Cocaine
blocking
impulse conduction. with unidirectional
This impulse
also has local
fast sodium
channels,
leads to conduction blockade in some
left-hand
anesthetic thereby
delays regions
al-
comof the
heart, creating a substrate for reentrant circuits. Thus when an extra-systole istriggeredby oscillatory after-potentials in a region of delayed conduction with unidirectional conduction block, lethal tachyarrhythmias can result (bottom of figure).
2474
Vol. 4
May 1990
36336
and
responsible
upper
neuronal uptake of NE accentuating the catecholamine effects postsynaptically. By activating both a- and $-adrenergic receptors, cytosolic calcium levels increase, triggering oscillatory after(upper
HL
National
Institute
on
Drug
Abuse
REFERENCES
portion represents the effects of cocaine on the neuronal uptake of the neurotransmitter norepinephrine (NE). Cocaine blocks the
potentials properties
grant
DA 05917.
1. Abelson, H. I., and Miller, cocaine use in the household Res. Mongr Ser. 61, 35-49 2. Levine, S. R., Washington,
J. D. (1985) A decade of trends population.
J.
M.,
Kieran,
Feit, N., and Welch, K. M. A. (1987) ‘Crack” stroke. Neurology 37, 1849-1853
in Nati. Inst. Drug Abuse S. N., Moen, M., cocaine-associated
J. M., Estes, M., and Thompson, P.D. (1986)CostanzoNordin, M. R., Subramanian, R., Miller, G., Katsas, G., Sweeney, K., and Sturner, W. Q Acute cardiac events temporarily related to cocaine abuse. N Engl. j Med. 315,
3. Isner,
1438-1443 4. Ascher, E. K.,
Stauffer, J. C. E., and Gaasch, W. H. (1988) Coronary artery spasm, cardiac arrest transient electrocardiographic Q waves and stunned myocardium in cocaine-associated acute myocardial infarction. Am. j Cardiol. 61, 939-941
The FASEB Journal
BILLMAN
-
-
5. Benchimol,
A., Bartal,
ventricular 519-521
rhythm
and
H., and Desser, K. B. (1978) Accelerated cocaine abuse. Ann. Intern. Med. 88,
S22-S29
6. Nanji, A. A., and Fiipenko, J. D. (1984) Asystole and ventricular fibrillation associated with cocaine intoxication. C/zest 85, 132-133
D., and resulting
Glauber, J. J. (1947) Electrocardiographic from acute cocaine intoxication. Am. Heartj
979._97Q
8. Price, F. W., and Leaky, A. B. (1911) Grave and prolonged cardiac failure following the use of cocaine in dental surgery. Lancet 1, 797-799 9. Wiener, R. S., Lockhart, J. T., and Schwartz, R. G. (1986) Dilated cardiomyopathy and cocaine abuse. Am. J. Med. 81, 699-701
10.Peng, S-K., French, W. J., and Pelikan,P. C. D. (1989) Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy. Arch. Pathol. Lab. Med. 113, 842-845 11.Byck, R. (1974)The Cocaine Papers by Sigmund Freud. New York, StonehillPublish Co. 12. Van Dyke, C., and Byck, R. (1982) Cocaine. Sci. Am. 246, 128-141 13. Kleber, H. D. (1988)Cocaine abuse historical, epidemiological and psychological perspectives. j Clin. Psychiatry 49, 3-6 14. Mathias,
D. W. (1988)
Cocaine-associated
myocardial
review of clinical and angiographic findings.Am. j
ischemia:
Med. 81,
675-678
15.Ruben, H., and Morris, L. E. (1957) Effect of cocaine on cardiac automaticityin the dog. j PharmacoL Exp. Ther. 106, 55-64 16. Nahas,
0.
G., Trouve,
J.
R., Demus,
F., and
Sitbon,
M. (1985)
A calcium channel blocker as an antidote to cardiac effects of cocaine intoxication. N Engl. j Med. 313, 519-520 17. Trouve, R., Nahas, 0. 0., and Maillet, M. (1987) Nitrendipine as an antagonist to cardiac toxicityof cocaine. j Cardiovasc. Pharmacol.
9 (Suppl.
4), S49-S53
18. Inoue,
H., and Zipes, D. P. (1988) Cocaine-induced supersensitivity and arrhythmogenesis. j Am. Coil. Cardiol. 11, 867-874 19. Singer, D. H., Baumgarten, C. M., and Ten Eick, R. E. (1981) Cellularelectrophysiology of ventricularand other dysrhythmias studies on diseased and ischemic heart. Prog. Cardiovasc. Dis. 24, 97-156 20. Levy, M. N. (1989)Role ofcalcium in arrhythmogenesis.Circulation
80 (Suppi.
IV),
IV 23-IV
30
21. Billman,G. E., and Hoskins, R. S. (1988) Cocaine-induced ventricular fibrillation: protection afforded by the calcium antagonist verapamil. FASEB j 2, 2990-2995 22. Wilkerson, conscious
D. R. (1988) dogs: importance
Cardiovascular effects of cocaine in of fully functional autonomic and systems. J. Pharmacol. Exp. Therap. 246, 466-47 1
central nervous 23. Resnick,R. B.,Keslenbaum, R. S., and Schwartz, L. K. (1977) Acute systemic effects of cocaine in man: a controlled study by intranasal and intravenous routes. Science 195, 696-698 24. Weidmann, S. (1955) Effect of calcium ions and local anaesthetics on electrical properties of Purkinje fibres. j PhysioL (London) 129, 568-582 25. Przywara, cocaine
D. A., and
on cardiac
Dambach,
cellular
0.
E. (1989) Direct actions of activity. Circ. Res. 65,
electrical
184-193 26.Corr, P. B., Yamada, K. A., and Witkowski, F. X. (1986) Mechanisms controlling cardiac autonomic function and their relationships to arrhythmogenesis. In The Heart and Cardiovascular System (Fozzard,H. A., Haber, E., Jennings, R. B., Katz, A. M., and Morgan, H. E.,eds) 1597-1612,New York, Raven 27.Vargas, R., Zukowska-Grojec, Z., Gillis, R. A., and Ramwell, R. W. (1988)
Cocaine
and
coronary
artery
reactivity.
Circulation
79 (Suppl. II) 11-223 (abstr.) 28. Lange, R. A., Cigarro, R. 0., Yancy, C. W., Jr., Willard, J. E., Popma, J. J., Sills, M. N., McBride, W., Kim, A. S., and Hillis, L. D. (1989)Cocaine-induced coronary-artery vasoconstriction. N EngL j Med. 321, 1557-1562
COCAINE
30. Berridge, M. J. (1987) Inositol trisphosphate two interacting second messengers. Am.
and
Rev.
diacylglycerol: Biochem. 56,
159-193
7. Young, changes .;4
29. Evans, D. B. (1986) Modulation of CAMP: mechanism for positive inotropic action. j Cardiovasc. Pharmacoi. 8 (Suppl. 9)
AND
VENTRICULAR
FIBRILLATION
31. Bozler,E. (1943) The initiation Am. j Physiol. 138, 273-282 32. Clusin, B. 0.,
W. T., Bristow, and Schroeder,
of impulses
in cardiac
muscle.
M. R., Karagueuzian, H. S., Katzung, S. (1982) Do calcium-dependent ionic
J.
currents mediate ischemic Cardiol. 49, 606-612 33. Auffermann, W., Stefenelli,
ventricular T., Wu,
fibrillation?
Am.
S. T., Parmley,
j
W. W.,
Wikman-Coffett, J., and Mason, D. T. (1989) Influence tive inotropic agents on intracellular calcium transients: normal rat heart. Am. Heartj 118, 1219-1227
of posi-
Part 1,
34. Kimura, S., Cameron, J. S., Kozlovskis, P. L., Bassett, A. L., and Myerberg, R. J. (1984) Delayed afterdepolarizations and triggered activity induced in feline Purkinje fibers by alphaadrenergic stimulation in the presence of elevated calcium levels. Circulation 70, 1074-1082 35. January, C. T., Riddle, J. M., and Salata,J. J. (1988) A model for early
afterdepolarizations:
agonist
induction
with
the Ca2’
channel
Bay K 8644. Circ. Res. 62, 563-571
36. Marban,
E., Robinson,
S. W., and
Wier,
W. 0.
(1986)
Mecha-
nisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J. Clin. Invest. 78, 1185-1192 37. Thandroyen, F. T, McCarthy, J., Burton, K. P.,and Opie, L. H.
(1988)
rhythmias rat heart.
Ryanodine
and
caffeine
during acute myocardial Circ. Res. 62, 306-314
prevent
ischemia
ventricular
ar-
and reperfusion
in
M. D., Wittingham, D. J., and Wiesner, K. (1964) Effects of ryanodine in normal dogs and in those with digitalis induced arrhythmias. Am. j Cardiol. 14, 658-668 39. Billman, 0. E. (1989) Effect of calcium channel antagonists on 38. Kahn,
susceptibility to sudden cardiac death: protection from ventricular fibrillation. j PharmacoL Ex1t,. Therap. 248, 1334-1342 40. Billman, 0. E., Mcllroy, B., and Johnson, J. D. (1990) The role of elevated intracellular calcium in the susceptibility to ventricular fibrillation. In Frontiers in Smooth Muscle Research (Sperelakis, N., and Wood, J. D., eds) pp. 755-764, Wiley-Liss, New York 41. Manger, W. M., Nahas, 0. 0., Trouve, R., Vinyard, C., and Goldberg, S. R. (1989) Nimodipine as an antidote to cocaine induced cardiac changes in squirrel monkey. FASEBJ. 3, A883 (abstr.) 42. Tazelaar, H. D., Karch, S. B., Stephens, B. G., and Billingham, M. E. (1987)Cocaine and the heart. Human PathoL 18, 195-199
43. Hague, N., Perreault, C.,and Morgan,J. P.(1988)Effects of cocaine on intracellular Ca handling in mammalian myocardium. 44. Neeley, enhances papillary
45. Block, agents
Circulation 79 (Suppl. II), 11-359 (abstr.) B. H., Urthaler, F., and Walker, A. A. (1989) Cocaine spontaneous SR Ca2’ release in length-clamped ferret muscle. Circulation 80 (Suppl. II), 11-16 (abstr.) A., and Covino, B. G. (1981) Effect of local anesthetic on cardiac conduction and contractility. Reg. Anesth. 8,
55-61
46. Kabas, J. S., Blanchard, S. M., Matsuyama, Y.,Long, E. J. D., Hoffman, G. W., Ellinwood, E. H., Smith, P. K., and Strauss, H. C. (1990)Cocaine mediated impairment of cardiacconduction in the conscious dog: a potential mechanism for sudden death after cocaine. j PharmacoL Exp. Therap. 252, 185-191 47. Schwartz, A. B., Janzen, D., Jones, R. T, and Boyle, W. (1989) Electrocardiographic and hemodynamic effects of intravenous cocaine in awake and anesthetized dog. j ElectrocardioL 22, 159-166
48. Watt, T. B., and Pruitt, R. D. (1964) Cocaine-induced incomplete bundle branch block in dogs. Circ. Res. 15, 234-239 49. Kasten, G. W. (1986)Amide local anesthetic alterations of effective refractory period tricular arrhythmias.
temporal dispersion: relationship Anesthesiology 65, 61-66
to ven-
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