Cardiovascular complications of cocaine abuse
James P Morgan, MD, PhD
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INTRODUCTION — Cocaine is the second most commonly used illicit drug in the
United States, ranking after marijuana. It is most frequently used by males between
the ages of 18 and 25 [1]. The 1998 National Household Survey on Drug Abuse
(NHDSA) estimated that approximately 11 percent of the population has used
cocaine at some point in their lifetime [1]. Another 1998 report estimated that about
2000 people use cocaine for the first time every day [2,3].
The great epidemic of cocaine abuse in the United States peaked in 1985, when 5.7
million people were current users of cocaine (3 percent of the population); the
number of current users decreased to 1.4 million (0.7 percent of the population) by
1992, and by 1998 had not significantly changed, especially among persons over the
age of 35 [1,4]. Crack cocaine use has also remained unchanged since 1988.
Because even casual use of cocaine may be associated with acute or chronic toxicity,
these large numbers of exposed individuals represent a reservoir of patients who
may present with sequelae related to the cardiovascular or other systems in the
body. Thus, identification of cocaine exposure is a legitimate goal of cardiovascular
history taking, particularly with regard to the occurrence of symptoms associated
with ischemic heart disease.
The most common complaints from cocaine users entering emergency departments
are related to the cardiovascular system [5], although a variety of other organ
systems may be involved [6-8]. The vascular complications of cocaine toxicity
include:

Cardiac — myocardial ischemia, coronary vasospasm, myocardial infarction
(MI), arrhythmias, myocarditis, and cardiomyopathy

Neurologic — intracerebral hemorrhage, cerebral infarction, seizures,
migraine headache, and vasculitis [9]

Vascular — aortic dissection and rupture, hypertension, vasculitis [ 10]

Gastrointestinal — mesenteric ischemia and infarction, gastrointestinal
perforation [11]


Pulmonary — pulmonary edema, infarction, hemoptysis [12] (see "Pulmonary
complications of cocaine abuse").
Musculoskeletal — rhabdomyolysis, which can lead to acute renal failure [13]
(see "Clinical features and prevention of heme pigment-induced acute tubular necrosis")


Dermatologic (ischemia)
Uterine, placental, obstetric and neonatal — abruptio placentae, spontaneous
abortion, prematurity, developmental delays, growth retardation, and congenital
abnormalities

Genitourinary — renal and testicular infarction

Venous — superficial and deep venous thrombosis and thrombophlebitis
Among the cardiac complications, myocardial ischemia and infarction have been
most commonly reported in clinical and autopsy studies, although their exact
incidence is difficult to state with certainty since only a fraction of symptomatic
patients come to medical attention. When not attributed to trauma or infection with
HIV, the marked increase in fatalities among cocaine abusers is due to
cardiovascular causes. There is no evidence to suggest that preexistent vascular
disease or other abnormalities are essential prerequisites for the development of a
cocaine-related cardiovascular event [7]. However, certain subgroups of patients
may be at increased risk of manifesting cardiovascular toxicity if exposed to cocaine,
including those who consume alcohol, are pregnant, or infected with HIV.
PHARMACOLOGY OF COCAINE — Cocaine (benzoylmethylecgonine, C17, H21, NO4)
is an alkaloid prepared from the leaves of the Erythroxylon coca plant. The crystalline
form of cocaine is prepared by dissolving the alkaloid in hydrochloric acid to form the
water soluble salt, cocaine hydrochloride. Street cocaine is typically in the form of
hydrochloride salt. Crack is unpurified free base cocaine, which is formed by
combining cocaine hydrochloride with an alkaline substance, such as sodium
bicarbonate, and cooking it in water. This forms an oil-like substance that separates
from water and solidifies into small pieces, or "rocks." These pieces can be combined
with tobacco to form a cigarette or can be smoked in a water pipe. Free base is a
purer form of cocaine that is ether-extracted and is not as widely available as crack
[14].
Absorption — Cocaine is absorbed from mucus membranes, and the respiratory,
gastrointestinal and genitourinary tracts in both the hydrochloride and base forms.
Onset of action — The peak onset of action for the intravenous and inhalation routes
is approximately one-half to two minutes. In comparison, the peak effect occurs later
with the intranasal (up to 20 minutes) and gastrointestinal routes (up to 90
minutes).
Half-life — After intravenous or inhalation administration, the plasma half-life
approximates 60 minutes; cocaine's vasoconstrictive properties inhibit absorption by
the intranasal route, prolonging the apparent plasma half-life to two to three hours
[7].
Duration of action — The duration of effect is approximately 15 to 30 minutes by
intravenous or inhalation routes, one hour by intranasal exposure, and as long as
three hours after gastrointestinal absorption.
Metabolism — Cocaine is detoxified by plasma and hepatic cholinesterase and
nonenzymatic hydrolysis to the inactive water-soluble metabolites benzoylecgonine
and ecgonine methyl ester, which are excreted in the urine along with small amounts
of unchanged cocaine (10 to 20 percent).
Cholinesterase activity is lower in the fetus, infants, pregnant women, the elderly,
and those with liver disease or pseudocholinesterase deficiency. Thus, the use of
cocaine by individuals in any of these categories carries increased risks.
Metabolites — After administration, the urine remains positive for cocaine
metabolites for 72 hours, which is useful for documenting recent exposure to the
drug [15,16]. Norcocaine is the only known active metabolite of cocaine that is
present in significant concentration in the blood. It is formed by an N-demethylation
reaction and usually represents less than 5 percent of the total quantity of cocaine
metabolites, but may mediate delayed effects of cocaine via enterohepatic
recirculation [17].
When cocaine is administered as a smoke in "crack," another group of compounds is
produced, either as by-products of the smoking procedure or as metabolites.
Anhydroecgonine methyl ester (AEME) and noranhydroecgonine methyl ester
(NAEME) are pyrolysis products of cocaine that have pharmacologic activity [18]. As
a result, the potential influence of these products must be considered when
evaluating the effects of cocaine on cardiovascular function.
MECHANISM OF CARDIOVASCULAR EFFECTS — The major cardiovascular effects of
cocaine and its active metabolite, norcocaine, appear to be caused by the inhibition
of norepinephrine reuptake into the synaptic cleft by sympathetic neurons. Since
reuptake is the major mechanism by which neurotransmitter is removed from its
active receptor sites, this inhibition results in potentiation of the response to
sympathetic stimulation of innervated organs and to infused catecholamine. Cocaine
may also enhance the release of catecholamines from central and peripheral stores
[19].
In addition to its effects as a sympathomimetic agent, cocaine is the only known
naturally occurring local anesthetic. However, its use in ear, nose, eye, and throat
surgery has steadily declined due to its perceived arrhythmogenic potential [20].
The cardiovascular responses produced by intravenous, intranasal, and inhaled
cocaine are the same. The drug induces a dose-dependent increase in blood pressure
and heart rate, which in usual recreational doses is, in most cases, relatively modest
and well within the range of physiologic changes observed in normal humans.
Fortunately, MIs and life-threatening arrhythmias are rare, even in patients with
advanced coronary disease [19].
At the cellular level, cocaine's sympathomimetic actions are mediated by stimulation
of the alpha- and beta-adrenergic receptors. Cocaine may also interact with the
muscarinic receptors, and is known to inhibit reuptake of dopamine and serotonin by
dopaminergic and serotonergic nerve endings, respectively [ 21]. As with other local
anesthetic agents, cocaine inhibits sodium currents in excitable cells [ 22].
CARDIOVASCULAR SYNDROMES ASSOCIATED WITH COCAINE USE — Cocaine use is
associated with a number of cardiac problems, including ischemia, myocarditis and
the development of a cardiomyopathy, and arrhythmias.
Myocardial ischemia — An acute coronary ischemic syndrome is the most common
cardiac pathology associated with cocaine abuse and can occur with all routes of
cocaine intake [23,24]. The precise incidence of myocardial ischemia, with or without
infarction, is difficult to quantitate. It is probably safe to say that the number of
patients in whom cocaine use is identified as a potential causative factor and who
come to medical attention is small relative to the total population of abusers. In
some cases, the relationship of the ischemic event to cocaine use is unclear based
upon the time of onset of symptoms versus the known pharmacokinetics of cocaine
and it metabolites [25].
Myocardial infarction — MI is a well-described complication among patients
presenting with cocaine-induced ischemic symptoms. In one study of 246 patients
presenting to an emergency department with cocaine-associated chest pain, 5.7
percent had an MI documented by elevated serum CK-MB [26]. One survey of
10,085 adults between the age of 18 and 45 found that 25 percent of nonfatal MIs
were attributable to frequent cocaine use [27]. (See "Coronary heart disease and
myocardial infarction in young men and women").
Most patients have their infarction within three hours of using cocaine, but the range
varies from one minute to four days [24]. In a series of 3946 patients who had had
an acute MI, 1 percent had used cocaine within the previous year [28]. In the latter
group, approximately 25 percent used cocaine within the 60 minutes prior to the
infarct. It was estimated that the risk of an MI was increased 24 times over baseline
in the 60 minutes after cocaine use (show figure 1).
The occurrence of MI after cocaine use is unrelated to the dose or frequency of use.
The anterior wall is the most frequent site of infarction (77 percent in one review)
among the patients with cocaine-associated infarction in whom coronary anatomy
has been defined [29].
MI associated with cocaine abuse often occurs in patients with normal coronary
arteries [24,29]. Most patients smoke cigarettes but many have no other cardiac risk
factors [25,28-30]. Approximately one-half have noted previous episodes of chest
pain [24].
These observations illustrate the importance of questioning all patients with an acute
chest pain syndrome in the absence of trauma about possible cocaine use [ 31,32].
This is particularly true in younger patients [28]. (See "Pathophysiology and clinical
presentation of ischemic chest pain").
Mechanisms — Four mechanisms have been proposed for cocaine-induced ischemia.
It is difficult or even impossible to determine a predominant mechanism in most
patients, and it is likely that more than one may be contributing to the clinical
syndrome.

Increased myocardial oxygen demand — Increased myocardial oxygen
demand occurs secondary to the sympathomimetic actions of cocaine that increase
myocardial inotropy, heart rate and systemic blood pressure [33]. This may pose a
significant problem to patients in whom coronary blood flow is compromised by the
presence of fixed stenoses. As noted above, however, most patients do not have
significant underlying coronary disease [24,29].

Coronary artery vasoconstriction and spasm — Cocaine induces constriction of
the large and small coronary vessels under some circumstances [33-35]. The
vasoconstrictor effects of cocaine on the large coronary arteries are mediated
primarily through stimulation of the alpha-adrenergic receptors [33]; cholinergic
stimulation of microvessel contraction appears to play a role in some animal models
of cocaine toxicity [36]. Cocaine also causes endothelial dysfunction and impairs
endothelium-dependent vasorelaxation [37].

Coronary artery thrombosis — Pathologic and angiographic studies have
demonstrated coronary thrombi in some patients with cocaine-related MI [26]. In
vitro studies have demonstrated that cocaine can activate platelets, increase platelet
aggregability, and potentiate thromboxane production; each of these changes can
promote thrombus formation [38-40].

Coronary artery aneurysm — Coronary artery aneurysms may be relatively
common in cocaine users who undergo angiography. This was illustrated in a review
of 112 consecutive patients with a history of cocaine use who underwent coronary
angiography, mostly for an acute coronary syndrome, stable angina or a positive
stress test, heart failure, or atypical chest pain [41]. The patients were compared to
a matched control group of similar age and risk factors in whom angiography was
performed in the same time. Coronary artery aneurysms were noted in 34 of the
cocaine users (30.4 percent) compared to 7.6 percent of controls.
Myocarditis and cardiomyopathy — Myocarditis is a common autopsy finding among
subjects dying from cocaine abuse, affecting as many as 20 to 30 percent of patients
in some series [42-44]. Myocarditis has also been reported on myocardial biopsies of
active users [43]. The precise mechanism of the myocarditis is not clear, and
hypotheses range from hypersensitivity reactions leading to vasculitis and
myocarditis to catecholamine-induced toxicity. In its early stages, cocaine induced
myocarditis is fully reversible [45].
Several cases of dilated cardiomyopathy have been documented among cocaine
users, although a cause and effect relationship has not as yet been definitively
established [46]. The precise mechanism is not known but the following may
contribute [47]:

Cocaine exerts direct toxic effects on the heart, which lead to the destruction
of myofibrils, interstitial fibrosis, myocardial dilation, and heart failure [ 44].

The cocaine-induced hyperadrenergic state may contribute via production of
contraction band necrosis in the heart.

Both myocarditis and cardiomyopathy may be caused by infectious agents in
subjects who abuse cocaine parentally, either through direct invasion of the
myocardium or stimulation of an autoimmune reaction. (See "Etiology and pathogenesis
of myocarditis").
Cardiomegaly with otherwise unexplained heart failure in a young person should
raise the possibility of cocaine abuse [47]. Abstinence usually leads to complete
reversal of the myocardial dysfunction [48-50].
Arrhythmias and conduction abnormalities — The arrhythmogenic potential of
cocaine is poorly understood, but because of its pharmacological profile and ability to
induce a hyperadrenergic state, it is likely that the drug can produce or exacerbate
arrhythmias and conduction abnormalities under some circumstances [ 25,42]. Sinus
tachycardia and bradycardia, bundle-branch block, sudden death (ventricular
fibrillation or asystole), ventricular tachycardia and accelerated idioventricular
rhythm, heart block, torsade de pointes, a variety of supraventricular arrhythmias,
and an ECG pattern typical of Brugada syndrome (a pseudo-right bundle branch
block and persistent ST segment elevation in V1 to V3), and QT prolongation have all
been observed with cocaine use [5,23,51-56].
Cocaine acts like a class I antiarrhythmic agent, producing local anesthetic effects via
sodium channel blockade in the heart [57]. When cocaine is used as a local
anesthetic during laryngoscopy, the frequency of premature ventricular complexes
increases.
The potential mechanisms for arrhythmogenesis include:





Altering automaticity by a direct effect on myocardium
Altering autonomic balance by increasing circulating catecholamine levels
Inducing ischemia with resultant electrical inhomogeneity
Creating an anatomic substrate for reentrant arrhythmia
Altering repolarization with QT prolongation
Unless an MI occurs, the rhythm disturbances associated with cocaine abuse are
transient and disappear when the drug is metabolized.
Stroke — Cocaine abuse significantly increases the risk of ischemic stroke [ 58,59].
The etiology of cocaine-induced brain ischemia is multifactorial:

Cocaine stimulates vasospasm, presumably by increasing levels of
extracellular monoamines, particularly dopamine [60,61].

Cocaine may cause thrombus formation in the cerebral vasculature, in the
same way that it causes coronary artery thrombosis (see above) [62].

Long-term cocaine use may cause pathologic changes in the cerebral
vasculature (vasculitis) that impair cellular oxygenation by exacerbating nonlaminar
blood flow and sludging in the vessels, with consequent increase in platelet
aggregation and thrombus formation [10,63].
Regardless of the precise mechanism, cocaine-induced cerebral ischemia can cause
marked hypoperfusion abnormalities associated with severe neurologic deficits. More
subtle cognitive deficits also can occur [64]. Over time, repeated ischemic episodes
and subsequent reperfusion can weaken vessel walls, thereby increasing the
likelihood of cerebral hemorrhage [65].
The dihydropyridine calcium channel antagonists may prevent cocaine-induced
cerebral vasospasm [65]; this requires further study.
Miscellaneous cardiac complications — Cocaine abuse can produce a variety of other
complications, including left ventricular hypertrophy, infectious endocarditis among
intravenous users, and mesenteric ischemia [7]. In addition, an acute aortic
dissection can result from the use of crack cocaine; it is a frequent cause of
dissection in a young, inner city population (37 percent in one report) [ 66]. (See
"Clinical manifestations and diagnosis of aortic dissection").
SPECIAL CONSIDERATIONS — There are several clinical situations in which the
cardiovascular toxicity of cocaine may be exacerbated and thereby raise additional
concerns.
Pregnancy — Cocaine use during pregnancy has been associated with abruption
placentae, premature labor and delivery, and fetal and neonatal neurologic
abnormalities. The basic mechanism of these effects have not been elucidated, but
because cocaine has significant cardiovascular actions, these may include direct
actions upon the fetal heart and circulation in addition to maternal vasoconstriction
and impairment of uterine blood flow [67]. Pregnant animals show accentuated heart
rate and blood pressure responses to cocaine administration, an effect that may be
mediated in part by reduced cholinesterase activity which reduces cocaine
metabolism.
Alcohol — A variety of epidemiologic, observational, and toxicology studies have
suggested that the combination of alcohol and cocaine produces increased toxicity in
addition to behavioral change. Alcohol alters cocaine kinetics and metabolism and
results in the generation of new and pharmacologically active metabolites, such as
cocaethylene. The pharmacologic properties of cocaethylene are similar to those of
cocaine, and it has been hypothesized that the enhanced toxicity of the cocaine plus
alcohol combination is due primarily to generation of this long-lasting metabolite
[68,69].
Adulterants — All street forms of cocaine contain adulterants, some of which may
have pharmacologic activity. The most common cocaine adulterants are sugars and
stimulants, including ephedrine, phenylpropanolamine, caffeine, and amphetamines.
Quinine and strychnine may be added, which can produce rhabdomyolysis and acute
renal failure. Local anesthetics are common adulterants that may cause central
stimulation or cardiovascular depression in large doses [14].
Human immunodeficiency virus — Patients with HIV infection can develop cardiac
dysfunction via a variety of mechanisms. Among the complications in such patients
are pericarditis, myocarditis, ventricular tachycardia, infective endocarditis,
metastatic involvement from Kaposi's sarcoma, and dilated cardiomyopathy. ( See
"Cardiac involvement in HIV-infected patients").
Since cocaine use increases libido and impairs judgment, it may lead to an increased
incidence of sexually transmitted diseases, including HIV-infection and AIDS [14].
Whether or not cocaine increases the risk of cardiac involvement in patients with
HIV-infection, and, in particular, myocarditis, is currently under active investigation.
MANAGEMENT OF COCAINE-RELATED CHEST PAIN — Chest pain is the most common
cocaine-related medical problem, and has been estimated to result in the emergency
department evaluation of over 64,000 patients annually for possible MI. ( See
"Diagnostic approach to chest pain in adults"). Of these patients, 57 percent are admitted
to the hospital [26]. In 2002, an ACC/AHA Task Force published guidelines for the
management of patients with chest pain after cocaine use (show table 1) [70].
Diagnosis — As noted above, the typical patient with a cocaine-related MI is a young
man with a history of repetitive cocaine use but without cardiac risk factors other
than tobacco smoking [25,28-30]. The chest pain is often accompanied by anxiety,
dyspnea, palpitations, and nausea. The risk of infarction is greatest within the first
hour after cocaine use, elevated almost 24-fold over baseline, and decreases
progressively thereafter (show figure 1) [28]. As a result, all patients with an acute
coronary syndrome, particularly those with the above characteristics, should be
carefully questioned about cocaine use [31,32]. Toxicology assays for the drug or its
metabolites may be useful if exposure to cocaine is suspected or requires
confirmation.
Electrocardiogram — The electrocardiogram (ECG) is particularly difficult to interpret
in young patients who have a relatively high incidence of early repolarization
changes and left ventricular hypertrophy. As an example, up to 84 percent of
patients with cocaine-associated chest pain may have abnormal electrocardiograms;
up to 43 percent of cocaine abusers without an MI may have ST segment elevation
0.1 mV in two or more contiguous ECG leads [26,30]. On the other hand, MIs occur
in some patients with an ECG that is normal or has only nonspecific findings.
Because of the difficulty in identifying cocaine users with chest pain who are at low
risk of infarction, most are admitted to the hospital [26].
Serum markers — Some of the newer markers of ischemia, such as serum troponin I
or troponin T, appear to be specific for cardiac damage [70,71]. In contrast, chemical
markers such as myoglobin, CK, and CK-MB may be elevated in the absence of
infarction if skeletal muscle injury, rhabdomyolysis, or increased motor activity have
occurred. This was illustrated in a study of 97 patients presenting with chest pain, 20
percent of whom had recent cocaine use [72]:



The specificity of myoglobin was altered by recent cocaine use
The specificity of CK-MB was affected less
The specificity of cardiac troponin I was unaffected
(See "Troponins, creatine kinase, and CK isoforms as biomarkers of cardiac injury" and see
"Biomarkers of cardiac injury other than troponins and creatine kinase").
Treatment — There have been no well-designed, randomized, prospective clinical
trials to compare treatment strategies for cocaine-associated coronary ischemia.
However, a general approach to such patients has been proposed by an ACC/AHA
task force, based upon well-controlled trials in animals, experimental trials in the
catheterization laboratory, observational studies, case series, and case reports ( show
table 1) [30,70].

The three first-line drugs are benzodiazepines, aspirin, and nitrates.
Benzodiazepines reduce blood pressure and heart rate in part through their anxiolytic
effects and are therefore recommended for patients with cocaine-associated ischemia
who are hypertensive, tachycardic, or anxious. Aspirin should be administered to
prevent thrombus formation and nitrates to reverse cocaine-induced coronary artery
vasoconstriction. The administration of oxygen should also be considered as a
measure to limit ischemia.

Several other therapies can be considered if the patient continues to have
chest pain or ischemic changes after initial therapy. Calcium channel blockers and
alpha-blockers (phentolamine), which are coronary vasodilators, are reasonable
additions to, or replacements for, therapy with nitrates. As noted above, the
coronary vasoconstriction induced by cocaine is largely mediated by alpha-adrenergic
stimulation [33]. On the other hand, beta blockers and drugs with mixed alpha and
beta-adrenergic blocking properties should probably be avoided, since these drugs
may exacerbate cocaine-induced vasoconstriction, increase the incidence of
complications, and, perhaps, even decrease survival [73]. (See "Antiischemic agents in
the management of unstable angina and acute non-ST elevation (non-Q wave) myocardial
infarction").
Acute myocardial infarction — Patients in whom acute myocardial infarction is likely
or definitively diagnosed may require cardiac catheterization for diagnosis followed
by primary angioplasty or thrombolytic therapy [74]. (See "Overview of the
management of acute ST elevation (Q wave) myocardial infarction").
Patients with an acute MI secondary to cocaine use have similar complications to
those seen in the absence of drug abuse. As an example, one study of 130 patients
with cocaine-associated acute MI found that 36 percent had a complication, including
heart failure and sustained ventricular and supraventricular tachyarrhythmias; these
complications typically within the first 12 hours [75].
Antiarrhythmic agents should be used with caution during the early period after
exposure to cocaine, since the proarrhythmic and proconvulsant effects of these
drugs may be additive to that of cocaine. However, the use of lidocaine or related
drugs is rational after the immediate period of exposure has passed. Sodium
bicarbonate may be a safer approach to reversing cocaine-mediated conduction
abnormalities and rhythm disturbances, but this modality is still under investigation
[26].
Undifferentiated chest pain — Short-term evaluation of patients for 12 to 24 hours in
a chest pain observation unit is becoming an increasingly popular approach to
patients with chest pain who have a low likelihood of significant coronary disease.
(See "Evaluation and management of suspected acute coronary syndrome in the emergency
department").
A similar approach can be taken to cocaine-related chest pain, since the incidence of
late complications among patients who have been ruled out for an MI appears to be
extremely low. This was illustrated in a study of 203 patients with cocaine-associated
chest pain; the one-year survival was 98 percent and the incidence of late MI was
only 1 percent [76].
Further confirmation of the value of a chest pain observation unit for such patients
was provided by a subsequent prospective study that evaluated 344 patients
presenting with chest pain who reported cocaine use within the prior week and/or
had a positive urine test for cocaine metabolites [77]. Forty-two patients (12
percent) were directly admitted due to ST segment elevation or depression of 1 mm
or more for at least one minute, elevated cardiac enzyme levels, recurrent ischemic
chest pain, or hemodynamic instability. The remaining 302 patients were evaluated
in a chest pain observation unit for nine to twelve hours. None of these patients
developed heart failure or dysrhythmias during observation; 158 underwent exercise
testing, which led to catheterization in four. At 30 days, there were no cardiovascular
deaths and no sustained ventricular arrhythmias. There were four subsequent MIs,
all in patients who continued to use cocaine.
Cessation of cocaine use — Cessation of cocaine use is obviously essential for
secondary prevention, although modification of other risk factors, in particular,
tobacco smoking, may also play a role. Unfortunately, among patients with cocaineassociated chest pain, approximately 60 percent admit to continued cocaine use in
the year after a symptomatic episode [76]. (See "Overview of the recognition and
management of the drug abuser").
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65.
GRAPHICS
Risk of MI with cocaine
ACC AHA chest pain cocaine