Mechanisms for the cardiotoxic effects of cocaine - The FASEB Journal

5 downloads 117 Views 2MB Size Report
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:

FASEBJ

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-

2475