1, 2017
ABSTRACT
Cocaine is the leading cause for drugabuse-related visits to emergency departments, most of which are due to
cardiovascular complaints. Through its diverse pathophysiological mechanisms, cocaine exerts various adverse effects on
the cardiovascular system, many times with grave results. Described here are the varied cardiovascular effects of cocaine,
areas of controversy, and therapeutic options. (J Am Coll Cardiol 2017;70:10113) 2017 by the American College of
Cardiology Foundation.
The use of chewed coca leaves, either as a powerful cocaine cardiotoxicity (Central Illustration).
stimulant or as a spiritual communication instrument
with the Gods (through Incan Kuka Moma, Mother PHARMACOKINETICS AND
Coca, the goddess of health and joy), can be traced PHARMACODYNAMICS
back as early as 2500 BC (2). Cocaine acceptance in Eu-
ropean culture was somewhat delayed, though, prob- Cocaine (chemically: benzoylmethylecgonine; struc-
ably because of its reduced effect after drying before turally: 2-b-carbomethoxy-3-b-benzoxytropane) is a
shipment across the Atlantic. By the end of the 19th naturally occurring alkaloid extracted from the leaves
century, cocaine regained its former publicity when of Erythroxylum coca, rst isolated by the chemists
well known physicians such as Dr. Sigmund Freud Dr. Gaedcke and Dr. Nieman in 1860 (6). Cocaine is
recommended its routine use: I take very small cleared through tissue uptake and is metabolized by
doses of it regularly against depression and against liver and plasma esterases into active (e.g., norco-
indigestion, and with the most brilliant success (3). caine) and inactive metabolites (7) that are eventually
Unfortunately, despite the Harrison Narcotics Act of excreted in the urine (8). The onset and duration of
1914 (banning the nonprescription use of cocaine), cocaines effects depend on its route of use (Table 1),
this misconception was present even in the 1970s consequently varying its cardiovascular and hemo-
(4), allowing a culmination of cocaine abuse with dynamic effects. In general, the intravenous and
staggering numbers of more than 2 million users inhaled (i.e., smoked) routes have a very rapid onset
in the United States alone by 2007 (5). The myriad of action (seconds) and short-lived (30 min) duration
deleterious effects of cocaine on the cardiovascular compared with the mucosally absorbed (e.g., oral,
system were soon recognized, whereas the patho- nasal [i.e., snorted], rectal, vaginal) routes (9). The
physiological mechanisms by which cocaine exerts excretion of cocaine and its metabolites is not
Listen to this manuscripts its harmful effect continue to be explored (Figure 1). affected by cocaines route of ingestion; the half-life
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aDepartment of Cardiology, Keck School of Medicine, University of Southern California, Los Angeles, California; bDepartment
of Cardiology, Tel Aviv Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; cDepartment of Cardiology and
Marsheld Clinic Research Institute, Marsheld, Wisconsin; and the dHuntington Medical Research Institute, Los Angeles, California.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received March 17, 2017; revised manuscript received April 26, 2017, accepted May 8, 2017.
102 Havakuk et al. JACC VOL. 70, NO. 1, 2017
Cardiac arrhythmias
Impaired
Pulmonary
calcium cocaine
hypertension?
handling
Increased
Impaired CBF,
Catecholamine endothelin-1, Prothrombotic Vessel wall
cerebral
surge reduced NO, state injury
vasoconstriction
stimulation
Increase
myocardial
oxygen demand
Myocardial
stroke
ischemia and
infarction Aortic dissection
The ample cardiovascular effects of cocaine are exerted through a multitude of mechanisms, with possible consequent deleterious impact on
almost every aspect of the cardiovascular system. CBF cerebral blood ow; NO nitrous oxide.
cocaine-related sudden deaths, despite a mean age of unnecessary hospitalizations and interventions in
34 7 years (28) (although 81% were also cigarette these patients. Weber et al. (61) conducted a pro-
smokers). An unusual mechanism for coronary spective study in 344 cocaine abusers evaluated
thrombosis, plaque erosion, was also found in cocaine for chest pain; patients with high-risk features (i.e.,
abusers (28). ST-segment deviation >1 mm, elevated cardiac
Considering the deleterious effect cocaine can troponin, recurrent ischemic chest pain, and hemo-
have on the oxygen supply/demand balance, it is not dynamic instability) (Figure 2) were directly admitted
surprising that chest pain is the chief complaint in (of whom 23% eventually developed MI). The
cocaine abusers presenting to emergency de- remaining 302 patients were monitored in the emer-
partments (59), and that the risk of myocardial gency department with ECG and repeated cardiac
infarction (MI) was found to increase up to 24-fold in troponin for a 12-h period before discharge. During a
the rst hour after cocaine abuse (60). The correct 30-day follow-up, no mortality occurred in the low-
diagnosis of cocaine-related MI, however, can be risk group, and only 1.6% developed MI (although
challenging; the majority of patients who present 46 patients were lost to follow-up) (61). Because
with cocaine-related chest pain demonstrate both an complications tend to occur early in the course of
abnormal electrocardiogram (ECG) (61,62) and presentation, even when MIs do develop (68), these
elevated creatinine kinase levels (62,63) (although and other data (69) supported the safety of a 12-h
cardiac troponin was found to more accurately iden- observational approach in cocaine-related chest
tify cases of MIs (64)). Additionally, not all cocaine- pain, an approach also suggested by the 2012 Amer-
related chest pain is cardiac; 2 large-scale registries ican College of Cardiology/American Heart Associa-
(62,65) showed that the incidence of MI among tion (ACC/AHA) guidelines on MI (70). It is important
cocaine abusers who presented with chest pain was to note, however, that ST-segment elevations
only 6%, a nding that might correspond to extrac- (from early repolarization) are prevalent in the de-
ardiac cocaine-related causes of chest pain (e.g., mographic of cocaine users, making the denition of
pleuritic, musculoskeletal) (66,67). Accordingly, a high-risk patients less reliable. The added value
systematic approach has been offered to reduce of more sophisticated tests in the investigation of
104 Havakuk et al. JACC VOL. 70, NO. 1, 2017
Cocaine may provoke a variety of cardiovascular complications. A systematic approach toward the patients clinical status including simple yet
important initial tests can help with identifying and appropriately addressing these potential complications. AD aortic dissection; BDZ
benzodiazepines; IV intravenous; MI myocardial infarction.
cocaine-related chest pain is questionable; results clinical studies actually developed chest pain, and,
suggestive of clinically signicant coronary artery notably, each of these agents (including verapamil)
disease were infrequently demonstrated with the use induced a signicant increase in heart rate
of either myocardial perfusion scans (2.3%, [71]) or (23,73,74), an effect that might further aggravate
coronary computed tomography angiography (10%, myocardial oxygen demand in cocaine-exposed
(72)), and did not signicantly alter the management patients.
approach.
The mechanistic basis for treating cocaine-related b -BLOCKER THERAPY. Considering the known
chest pain with nitrates (73), phentolamine (an benecial hemodynamic effects of b-blockers, the
a-receptor blocker) (23), or verapamil (a calcium- general approach toward b-blocker treatment after
channel blocker) (74) is derived from studies cocaine exposure was initially positive (75,76). Then,
showing reversal of cocaine-induced coronary vaso- a case report in 1985 (77) suggested that the selective
constriction with the use of each of these agents in blocking of b-receptors might produce a paradoxical
the controlled setting of a cardiac catheterization hypertension as a result of unopposed a -receptor
laboratory. However, it is important to note that stimulation. Animal studies (78,79) investigating
although cocaine-induced coronary vasoconstriction possible protective agents against cocaine lethality in
was demonstrated, none of the participants in these the early 1980s, which showed that pretreatment with
JACC VOL. 70, NO. 1, 2017 Havakuk et al. 105
JULY 4, 2017:10113 The Cardiovascular Effects of Cocaine
the b1/ b2/a 1 -blocker labetalol was used in patients Bradycardia, conduction Inhibition of voltage-gated sodium channels
disturbances (i.e., Class IC antiarrhythmic effect) (36,39),
who were initially treated with intranasal cocaine nerve-blocking effect (40)
(82), and although labetalol did not worsen the Brugada-type ECG Inhibition of SCN5A sodium channels (41)
cocaine-induced coronary vasoconstriction, its lack of Pulmonary hypertension Possibly through the adulterant levamisole (42,43)
Stroke Acute hypertension as a result of an abrupt
effect further contributed to the growing perception
catecholamine surge (1315)
of the inappropriateness of b -blocker therapy in Endothelial dysfunction (17)
Vessel wall injury (17)
cocaine intoxication. A case report describing car-
Prothrombotic effect (2426)
diovascular collapse and death in a patient treated Sodium-blocking effect (44)
Impaired cerebral blood ow (45)
with metoprolol after consuming 1,000 mg of cocaine
(83) has been suggested to exemplify the possible AF atrial brillation; BP blood pressure; CNS central nervous system; ECG electrocardiogram; HF heart
deleterious relation between cocaine and b-blockers, failure; NO nitric oxide; SVT supraventricular tachycardia; TDP torsade de pointes; VT ventricular
tachycardia.
even though the patient did not experience a BP
elevation after the metoprolol treatment and was
106 Havakuk et al. JACC VOL. 70, NO. 1, 2017
Cocaine related
chest pain
STE*?
High risk no yes Brief trial of
features? nitrates
resolved?
yes no yes no
To safely and effectively discriminate between benign and life-threatening chest pain in cocaine abusers, the evaluation of the patients clinical
condition along with electrocardiographic changes and elevation in cardiac troponin is suggested. Patients should be accordingly referred for
urgent coronary angiography, hospitalization, or 12-h monitoring. *STE is dened as ST-segment elevation of $2 mm. High-risk features:
hemodynamic instability, positive cardiac troponin, recurrent chest pain. BB b-receptor blocker; BDZ benzodiazepines; ECG electrocar-
diogram; Hx history; Px physical examination; STE ST-segment elevation; STEMI ST-segment elevation myocardial infarction.
also exposed to a high dose of cocaine (which might considered lifesaving therapies in ischemic heart
have been responsible for his late collapse). As a disease, heart failure (HF), and cardiomyopathies.
result of this notion, a scientic statement by the The suggested hypertensive response as a result of an
ACC/AHA on the management of cocaine-associated unopposed a -stimulation after b -blocker therapy in
chest pain and MI in 2008 recommended against the cocaine-exposed patients is either rarely seen or even
use of b-blocker therapy in these patients (Class III, usually found to be opposite. Interestingly, the se-
Level of Evidence: C) (84). However, either because of vere hypertensive response found in 1 patient treated
lack of adherence to guidelines or that not all patients with the b1 -selective agent esmolol was successfully
disclose cocaine abuse when they are being treated by reversed by labetalol (90). Furthermore, indirect
emergency teams, reports on large numbers of pa- evidence for the safety of nonselective b-blockers in
tients treated with b-blockers after cocaine exposure cocaine-induced coronary vasoconstriction can be
have been published and generally showed neutral or drawn from a retrospective study in which the
even benecial effects on cardiovascular outcomes troponin rise was similar in patients who were or
(8587). Furthermore, prospective studies examining were not treated with b -blockers (86).
the safety of b-blockers in cocaine-exposed patients
showed similar favorable results (88,89). The APPROACH TO COCAINE-INDUCED CHEST PAIN.
2012 ACC/AHA guidelines state that nonselective Patients who present with cocaine-related chest pain
b-blockers might be considered in persistently hy- should be rst evaluated by history, physical exami-
pertensive or tachycardic patients after cocaine use, nation, and vital signs, followed by an ECG and
provided that they were treated with a vasodilator cardiac troponin. Patients who continue to have
(Class IIb, Level of Evidence: C) (Table 3) (70). ST-segment elevation on their ECGs should be
b-blockers represent an essential therapy in the directly referred for coronary angiography with
mitigation of hyperadrenergic states, are known to possible angioplasty and stent implantation (70). In
reduce myocardial oxygen demand, and are cocaine abusers who received stent implantation,
JACC VOL. 70, NO. 1, 2017 Havakuk et al. 107
JULY 4, 2017:10113 The Cardiovascular Effects of Cocaine
cooling should be initiated. Sodium bicarbonate were shown to have an equivocal effect on pulmo-
treatment may target 2 important components of nary vascular resistance (130,131). Third, addressing
cocaine toxicity, counteracting cocaines sodium- the specic effect of smoked crack on pulmonary
blocking effect, while simultaneously correcting artery pressures, levamisole, an adulterant often
increased acidity (120). The heightened sympathetic found in the mixed powder of crack, is converted
tone, which is both central and peripheral, should be after inhalation to aminorex, a substrate strongly
addressed with benzodiazepines, with varying de- related to drug-induced pulmonary hypertension
grees of sedation according to the patients condition (43). Finally, both the increased prevalence of
(84). We believe that nonselective b-blockers repre- cigarette smoking and the inhaled crack might
sent a useful treatment option in that scenario. predispose cocaine users to chronic lung injury,
Because most patients will react well to the afore- with subsequent increased risk for pulmonary
mentioned approach, antiarrhythmic drugs will not hypertension.
usually be needed, and should be used with caution.
VASCULITIS
Because of the similar mechanism of action of Class
1A/1C drugs with cocaine, these medications should
Cocaine-induced midline destructive lesions have
be avoided (112). Lidocaine might represent a safe
been infrequently described (132,133) and can be
alternative in the case of protracted ventricular ar-
attributed to severe vasoconstriction, ischemic nasal
rhythmias (121). Data on the safety and efcacy of
mucosa, repeated traumatic damage caused by
amiodarone is lacking (122). Intravenous lipid emul-
insufated cocaine crystals and recurrent local in-
sion therapy, originally attempted in severe local
fections, but also to antineutrophil cytoplasmic
anesthetic poisoning (123), was also shown to be
antibody (ANCA)-positive vasculitis, with local nd-
helpful in extreme cases of cocaine intoxication (124).
ings similar to granulomatosis with polyangiitis
The therapy works by lipid compartmentalization of a
(formerly Wegener) disease (133). Another type of
lipophilic agent, and might also offer an abundant
ANCApositive cocaine-related vasculitis takes a
source of energy to the exhausted myocardium.
more systemic form, with fever, purpuric skin lesions,
Because cocaine is lipophilic and acts as a local
acute kidney injury, and glomerulonephritis (134).
anesthetic, it seems reasonable to apply this therapy
Importantly, the correlation between cocaine and
in severe cases of cocaine poisoning. However,
vasculitis is confounded as both types of vasculitis
although current cardiopulmonary resuscitation
were found to be related to the adulterant levamisole,
guidelines recommend consideration of this therapy
an agent that was shown to induce the production of
in severe local anesthetic poisoning, it is not sug-
autoantibodies (133,134). A more exclusive associa-
gested for cocaine intoxication (125).
tion between cocaine and vasculitis awaits further
investigation.
PULMONARY HYPERTENSION
STROKE
A retrospective study in 340 patients with pulmo-
nary hypertension (126) demonstrated that patients Single-center registries have demonstrated an
with idiopathic pulmonary hypertension were 10 increased prevalence of cocaine abuse in both
times more likely to have a history of stimulant ischemic and hemorrhagic stroke patients (135,136),
drug use compared with patients with pulmonary which tended to be more signicant in the young
hypertension and a known risk factor. Nevertheless, (<60 years) age group. Similarly, a logistic regression
specic data on cocaine-induced pulmonary hyper- model in >3,000,000 hospitalized patients identied
tension are less conclusive. A study examining the cocaine abuse as a risk factor for either ischemic (odds
acute effect of intravenous cocaine on the pulmo- ratio: 2.03; 95% condence interval: 1.48 to 2.79)
nary vasculature showed that cocaine did not pro- or hemorrhagic (odds ratio: 2.33; 95% condence
duce an elevation in pulmonary artery pressure interval: 1.74 to 3.11) stroke (137). The mechanisms
(127); however, chronic crack cocaine smokers were involved in cocaine-related stroke include acute hy-
found to be at an increased risk of pulmonary hy- pertension (15), endothelial dysfunction and vascular
pertension (128). This inconsistency might be settled injury (17), a prothrombotic state (24), impaired ce-
through several mechanisms. First, in contrast to rebral blood ow (45), and cerebral artery vasocon-
other stimulants (e.g., methamphetamines), cocaine striction induced by cocaines sodium-blocking effect
only mildly elevates the level of serotonin (129), a (Table 2) (44). A case-control study comparing 1,090
known agent in the induction of pulmonary hyper- stroke patients with 1,152 controls showed that
tension. Second, both noradrenaline and dopamine although an overall similar proportion of participants
110 Havakuk et al. JACC VOL. 70, NO. 1, 2017
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