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Crack Whips the Heart: A Review of the CardiovascularToxicity of Cocaine

Luis Afonsob,*, Tamam Mohammada, and Deepak Thataib

Cocaine is an extremely powerful reinforcing psychostimulant with highly addictive prop-erties. Over the last few decades, cocaine addiction has attained epidemic proportions inNorth America, imposing a tremendous burden on society and the health care system. Thecardiovascular complications of cocaine abuse are adrenergic mediated and range fromcocaine-associated acute coronary syndromes to aortic dissection and sudden cardiacdeath. Concomitant alcohol and cigarette smoking exacerbate the cardiotoxicity of cocaine.This contemporary review discusses the spectrum of cardiac complications arising fromcocaine use, operant pathophysiologic mechanisms and controversies surrounding thepharmacotherapy of cocaine-associated acute coronary syndromes. © 2007 Elsevier Inc.

All rights reserved. (Am J Cardiol 2007;100:1040–1043)

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he local anesthetic, stimulatory, medicinal, aphrodisiac,nd salutary effects of the “coca leaf” have been commonnowledge for centuries, mystically revered as a “gift of theods” by the ancient Incan civilizations of Peru and otherre-Columbian Andean societies. In the modern world, co-aine has been a feature of the counterculture for over aentury, afflicting celebrities and public figures alike. It hasemained the most feared illicit drug in the United Statesince the 1920s. Over the last few decades, its recreationalse has attained epidemic proportions, being increasinglyntertwined with violence and crime, particularly in theower socioeconomic stratum. Cocaine is a highly addictivend potent sympathomimetic drug with potentially lethalardiovascular effects. This review focuses on the pharma-ology of this drug, its mechanism of action and addresseshe wide spectrum of cardiovascular complications associ-ted with cocaine.

pidemiologic Perspective and Scope of the Problem

n the United States, 5 million people report using cocainennually on a regular basis,1,2 and in 2003 alone, 34.9 millionmericans, �12 years reported using cocaine at least once.ocaine is reportedly the most commonly abused drug inatients presenting to emergency departments and accounts forquarter of all nonfatal myocardial infarction (MI) in young

dults.3 Cocaine also happens to be the most frequent cause ofrug-related deaths reported by medical examiners. The eco-omic burden on the health system, stemming from the car-iovascular toxicity of cocaine is substantial.

harmacologic Considerations

ocaine (or “crack” in its impure freebase form) is a crys-alline tropane alkaloid that is obtained from the leaves of

Divisions of aInternal Medicine and bCardiology, Wayne State Univer-ity, Detroit, Michigan. Manuscript received April 4, 2007; revised manu-cript received and accepted April 16, 2007.

*Corresponding author: Telephone: 313-745-2620; fax: 313-993-8627.

dE-mail address: lafonso@med.wayne.edu (L. Afonso).

002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2007.04.049

he coca plant (Erythroxylon coca), which grows primarilyn South America. Cocaine is available in 2 forms: theydrochloride salt and the “free base.” Cocaine hydrochlo-ide is prepared by dissolving the alkaloid in hydrochloriccid to form a water-soluble powder or granule that decom-oses when heated. Freebase cocaine is a form producedhen the user mixes cocaine hydrochloride with a liquidase, such as baking soda or ammonia; dissolves the result-nt alkaloidal cocaine in a solvent, such as ether; and finallyeats it to evaporate the liquid. The result is pure smokeableocaine or crack (heat stable, melting point 98°C). Cocainehalf-life 0.5 to 1.5 hours) is metabolized by plasma andiver cholinesterases to water-soluble metabolites, primarilyenzoylecgonine and ecgonine methyl ester; these havealf-lives of 5 to 8 and 3.5 to 6 hours, respectively,4 and arexcreted in the urine. Although cocaine can be detected inlood or urine for a only few hours, its metabolites areetectable in blood or urine for 24 to 36 hours after inges-ion.5 Biochemical analysis of hair (radioimmunoassay) isouted to be a very sensitive marker of cocaine use in thereceding weeks or months.6

athophysiologic Mechanisms

uring depolarization, cocaine inhibits membrane perme-bility to sodium, thereby blocking the initiation and trans-ission of electrical signals, a property that accounts for its

nesthetic effects. Regardless of the route of administration,high blood concentration of cocaine is achieved due to its

xcellent absorption via mucous membranes.

Genesis of ischemia: A variety of mechanisms have beenmplicated in the development of cocaine-induced myocardialschemia and necrosis. Cocaine blocks the presynaptic uptakef catecholamines and dopamine, leading to post-synapticympathetic activation and dopaminergic receptor stimula-ion.5 These sympathomimetic effects result in an augmenta-ion of ventricular contractility, blood pressure, heart rate, andscalating myocardial oxygen demand. The ensuing supply–

emand deficit may manifest as angina.

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1041Review/Cocaine and Cardiac Complications

Prothrombotic effects: Cocaine increases platelet ag-regability and may incite intracoronary thrombosis in theetting of hypoxia compounded by vasoconstriction of largepicardial and small coronary resistance vessels.7 Intranasalocaine administration is associated with an increase inlasma plasminogen activator inhibitor (PAI-1), conceiv-bly potentiating vascular thrombosis.8

Mechanisms of vasospasm: Cocaine has been shown torovoke coronary vasospasm in several small studies per-ormed in the catheterization laboratory.9,10 Even minuteoses used for topical anesthesia have been shown to lead tooronary vasoconstriction, increases in heart rate and bloodressure, as well as reduction of coronary sinus bloodow.10 Cocaine-induced vasoconstriction has been shown toe �-adrenergic receptor mediated, more pronounced intenotic as opposed to nonstenotic coronary segments, ands generally believed to be accentuated by �-adrenergiclockade (unopposed �-adrenergic effects). Cocaine-in-uced vasoconstriction may be facilitated by additionalechanisms, including the release of plasma endothelin-1

vasoconstrictor effects) and an impairment of the periph-ral production of nitric oxide (local vasodilator effects).nterestingly, a reduction of coronary flow velocity andncreased coronary resistance has also been demonstrated inocaine users in the absence of significant epicardial vesselpasm, coronary artery disease (CAD) or MI. Recurrentpasm occurring approximately 90 minutes after initial ad-inistration is temporally related to increasing blood con-

entration of the main cocaine metabolite ethyl methylcgonine.

ccelerated Coronary Atherosclerosis

remature coronary atherosclerosis is common in youngocaine abusers and appears to further elevate their risk ofecurrent ischemic events. Obstructive CAD is typicallyound in 35% to 55% of patients undergoing coronaryngiography for cocaine-associated chest pain, with no par-icular predilection to coronary vascular territories. This haslso been demonstrated quantitatively (cross-sectional cor-nary plaque area) in a case-controlled necropsy study ofocaine addicts.11 Cocaine has also been reported to causeoronary artery aneurysms and ectasia, suggesting yet an-ther potential mechanism for MI in these patients.

ocaine-Associated Chest Pain

ocaine may be imbibed by smoking, nasal insufflation, orntravenous injection; the occurrence of an ischemic event isot related to the amount ingested, the route, or frequency ofdministration.5,12 The association between cocaine use andyocardial ischemia and infarction is well recognized.emporally, these events typically occur when the bloodocaine concentration is at its highest, but may manifesthen the concentration is low or undetectable, as attributed

o the vasoconstrictive effects of cocaine’s major metabo-ites.9 Chest pain characteristics and presence of traditionalisk factors for atherosclerosis do not help identify patientsho have cocaine-related MI. It is noteworthy that although

hest pain is the most common presenting symptom, the

ncidence of enzymatic or biomarker evidence of acute MI t

r myonecrosis is relatively low and reported to be approx-mately 6% in patients presenting with chest pain.13 Myo-ardial ischemia, infarction, and occasionally rhabdomyol-sis or cocaine-related barotraumas (pneumomediastinum,neumothorax, or pneumopericardium) explain the pres-nce of chest pain in a small fraction of patients; however,he etiology of chest pain remains largely obscure andoorly understood in most patients. Finally, although ap-roximately a third of patients with cocaine-induced MIevelop complications such as congestive heart failure orrrhythmias, the overall mortality in hospitalized patientsemains exceedingly low.14

herapeutic Recommendations for Cocaine-Associatedhest PainCalcium channel blockers: Trouve and Nahas15 first

eported the benefit of calcium channel blockers andhowed that nitrendipine increased the survival and pro-ected rat hearts from arrhythmias and other toxic effects ofocaine. Negus and colleagues16 later reported alleviation ofocaine-induced coronary vasoconstriction with intravenouserapamil. Cocaine-induced coronary vasospasm in boththerosclerotic and normal segments can be abolished byublingual nitroglycerin, calcium channel antagonists, andorphine sulfate,17 and blocked by the adrenergic-receptor

locker phentolamine.10,18 The American College of Cardi-logy/American Heart Association 2002 guidelibes recom-end nitroglycerin and oral calcium antagonists for patientsith ST-segment elevation or depression that accompanies

schemic chest discomfort (class I indication), and intrave-ous calcium antagonists for patients with ST-segment de-iation suggestive of ischemia (class IIa indication).19

The beta-blocker controversy: There is considerableebate as to the role of � blockers in the setting of cocaine-elated chest pain or MI. The use of � blockers in thisetting is fraught with controversy largely stemming largelyrom the paucity of clinical trials addressing this issue.20,21

ased on the results of a single, double-blind, randomized,lacebo-controlled trial, some observers believe that �-ad-energic blockers be avoided altogether as they accentuateocaine-induced coronary spasm.20 In this study, 30 patientolunteers who underwent cardiac catheterization for the eval-ation of chest pain were randomized to topically administeredntranasal cocaine or saline followed by intracoronary propran-lol or placebo in blinded fashion. Intranasal cocaine-inducedoronary vasoconstriction with further increases in coronaryascular resistance were noted after the administration of in-racoronary propranolol. Labetalol, which has both �- and-adrenergic blocking activity, in comparison, reverses theocaine-induced increase in arterial pressure but does notlleviate cocaine-induced coronary vasoconstriction.22 Themerican College of Cardiology/American Heart Associationuidelines19 advocate the use of � blockers (class II A indica-ion, level of evidence: C) for cocaine-associated chest pain inhe presence of hypertension or sinus tachycardia. No data onhe effects of � blockers in the setting of cocaine-related MIould be found in the literature.

Benzodiazepines reduce heart rate and systemic arterialressure, and in animals, attenuate cocaine’s toxic effects on

he heart; thus, representing a viable alternative to nitro-

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1042 The American Journal of Cardiology (www.AJConline.org)

lycerin. Finally, it is reasonable to administer aspirin toatients with cocaine-induced myocardial ischemia to in-ibit platelet aggregation.

Role of thrombolytics: There are limited data on theafety of thrombolytic therapy and reports of severe com-lications associated with its use in cocaine users.23 Therequent presence of contraindications to thrombolysis, in-luding severe hypertension, seizures, intracerebral hemor-hage, and aortic dissection in cocaine abusers precludes theiberal use of thrombolytic agents. Moreover, the lack ofpecificity of standard electrocardiographic criteria (ST el-vation) to identify cocaine-induced MI predicates the cau-ious use of thrombolytics, after treatment with oxygen,spirin, nitrates, and benzodiazepines have failed, particu-arly, if immediate coronary angiography and angioplastyre not feasible.5 The American College of Cardiology/merican Heart Association guidelines19 advocate the usef thrombolytic therapy if ST segments remain elevatedespite nitroglycerin and calcium antagonists and coronaryrteriography is not possible (class II A indication).

Recommendations for coronary arteriography: Im-ediate coronary angiography is advisable in patients withT-segment elevation persisting after administration of ni-

roglycerine and calcium antagonists (Class I, level of evi-ence C). If available, angiography is also recommended ife novo ST-segment depression or isolated T-wave changeso not respond to the previously mentioned medical therapyclass II a, level of evidence C).19

ocaine-Related Myocardial Dysfunction

ocaine may cause an acute or chronic deterioration of leftentricular performance. Acute left ventricular systolic andiastolic function has been attributed to the effects of co-aine or its metabolites in myocyte calcium handling andas been documented after binge use.24 Focal myocyte ne-rosis, focal myocarditis, sarcoplasmic vacuolization, andyofibrillar loss have been variably demonstrated in myo-

ardial biopsy specimens obtained in the setting of acuteocaine toxicity.

Acute myocardial depression may also manifest as leftentricular apical ballooning syndrome or Tako-tsubo Syn-rome an entity associated with high circulating levels ofatecholamines, myocyte injury, and microvascular dysfunc-ion with close histopathologic resemblances to cocaine-medi-ted cardiotoxicity. Studies in animals have shown that cocainelters cytokine production in the endothelium and in circulat-ng leukocytes, inducing the transcription of genes responsibleor changes in the composition of myocardial collagen andyosin, and myocyte apoptosis. Chronic left ventricular sys-

olic dysfunction is also a well-known occurrence in a smallercent (7%) of asymptomatic long-term abusers.24

lectrocardiographic Changes and Dysrythmias

he interpretation of electrocardiograms in patients withocaine-associated chest pain can be challenging. Cocaine-nduced MI has been documented in patients with normal asell as abnormal electrocardiograms.Conversely, a signifi-

ant proportion of patients without MI meet the electrocar- b

iographic criteria for ST-elevation MI. The sensitivity ofhe electrocardiogram for detecting MI is reportedly as lows 36%.25

Cocaine has direct effects on blocking the sodium chan-els and may produce or exacerbate cardiac arrhythmias,ncluding sinus tachycardia, sinus bradycardia, supraven-ricular tachycardias, asystole, accelerated idioventricularhythm, ventricular tachycardia, ventricular fibrillation, andorsade de pointes.5 In canine experiments, cocaine haseen demonstrated to reduce ventricular fibrillation thresh-lds. It is speculated that the increase in left ventricularass (associated with long-term cocaine use) and the de-

elopment of contraction band necrosis serve as the under-ying anatomic substrate, increasing the propensity for isch-mia and arrhythmias.

The cocaine-associated long QTc interval might be re-ated to the effects of cocaine and its metabolites on con-uction in the Human Ether-a-go-go Related Gene (HERG)-ncoded potassium channel.26 A Brugada pattern (rightundle branch block with ST elevation in leads V1,V2,V3)rovoked by cocaine has recently gained recognition and iselieved to occur from modulation or unmasking of theodium channels.27 Wide-complex dysrhythmias respond-ng to sodium bicarbonate (pH-dependency) may also occurfter exposure to cocaine as a result of the direct effects ofocaine on the sodium channels.

olysubstance Abuse: Cocaine, Tobacco,nd Alcohol Interactions

oncomitant cigarette smoking has been shown to exacer-ate the deleterious effects (adrenergically-mediated) of co-aine on myocardial supply–demand balance.28 This com-ination increases the myocardial metabolic requirementsor oxygen while simultaneously decreasing the diameter ofhe diseased coronary artery.21 Likewise, the combination ofocaine and ethanol is considered be more lethal than eitherubstance alone as it increases myocardial oxygen demandnd is reported to be the most frequent substance abuseombination encountered in the emergency department. Theransesterification of cocaine and ethanol to the metaboliteocaethylene occurs in the liver. Cocaethylene is consideredore lethal than cocaine because it blocks the re-uptake of

opamine and appears to mediate the increase in cata-trophic cardiovascular complications observed with thisombination.

ndocarditis

ocaine, because it is administered intravenously more thanny other illicit drug, causes endocarditis, particularly in-olving the left-sided cardiac valves.29 The mechanism ofhis propensity for endocarditis is unclear, but may relate to

hemodynamically-mediated injury of cardiac valves, fa-ilitating bacterial invasion,5 possibly compounded by theurported immunosuppressive effects of cocaine.

ortic Dissection

his is a diagnosis that should be considered in patients withevere cocaine-associated chest pain. Most patients tend to

e young and have poorly controlled or untreated hyperten-

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1043Review/Cocaine and Cardiac Complications

ion. The cocaine-induced surge in catecholamine levelsresumably leads to elevated shear-stress forces, increasinghe proclivity for intimal tears and aortic dissection. In aetrospective study by Hsue and colleagues,30 cocaine wasmplicated in 37% of aortic dissections studied in an innerity population. The location of dissection seems to bequally distributed between types A and B, as is the caseith dissections not related to cocaine. Aortic intramuralematoma and coronary artery dissection have also beeneported to be associated with cocaine abuse.

1. Cregler LL, Mark H. Relation of acute myocardial infarction to co-caine abuse. Am J Cardiol 1985;56:794.

2. Hughes AL. The prevalence of illicit drug use in six metropolitan areasin the United States: results from the 1991 National Household Surveyon Drug Abuse. Br J Addict 1992;87:1481–1485.

3. Qureshi AI, Suri MF, Guterman LR, Hopkins LN. Cocaine use and thelikelihood of nonfatal myocardial infarction and stroke: data from theThird National Health and Nutrition Examination Survey. Circulation2001;103:502–506.

4. Hollander JE, Hollander RS. In: Goldfrank LR, ed. Goldfrank’s Tox-icologic Emergencies. New York: McGraw-Hill Medical Pub. Divi-sion, 2002:1004–1019.

5. Lange RA, Hillis LD. Cardiovascular complications of cocaine use.N Engl J Med 2001;345:351–358.

6. Ness RB, Grisso JA, Hirschinger N, Markovic N, Shaw LM, Day NL,Kline J. Cocaine and tobacco use and the risk of spontaneous abortion.N Engl J Med 1999;340:333–339.

7. Minor RL, Jr., Scott BD, Brown DD, Winniford MD. Cocaine-inducedmyocardial infarction in patients with normal coronary arteries. AnnIntern Med 1991;115:797–806.

8. Moliterno DJ, Lange RA, Gerard RD, Willard JE, Lackner C, HillisLD. Influence of intranasal cocaine on plasma constituents associatedwith endogenous thrombosis and thrombolysis. Am J Med 1994;96:492–496.

9. Brogan WC III, Lange RA, Glamann DB, Hillis LD. Recurrent coro-nary vasoconstriction caused by intranasal cocaine: possible role formetabolites. Ann Intern Med 1992;116:556–561.

0. Lange RA, Cigarroa RG, Yancy CW, Jr., Willard JE, Popma JJ, SillsMN, McBride W, Kim AS, Hillis LD. Cocaine-induced coronary-artery vasoconstriction. N Engl J Med 1989;321:1557–1562.

1. Dressler FA, Malekzadeh S, Roberts WC. Quantitative analysis ofamounts of coronary arterial narrowing in cocaine addicts. Am JCardiol 1990;65:303–308.

2. Kloner RA, Rezkalla SH. Cocaine and the heart. N Engl J Med2003;348:487–488.

3. Weber JE, Chudnofsky CR, Boczar M, Boyer EW, Wilkerson MD,Hollander JE. Cocaine-associated chest pain: how common is myo-cardial infarction? Acad Emerg Med 2000;7:873–877.

4. Hollander JE, Hoffman RS, Burstein JL, Shih RD, Thode HC, Jr.Cocaine-associated myocardial infarction. Mortality and complica-tions. Cocaine-Associated Myocardial Infarction Study Group. Arch

Intern Med 1995;155:1081–1086.

5. Trouve R, Nahas G. Nitrendipine: an antidote to cardiac and lethaltoxicity of cocaine. Proc Soc Exp Biol Med 1986;183:392–397.

6. Negus BH, Willard JE, Hillis LD, Glamann DB, Landau C, SnyderRW, Lange RA. Alleviation of cocaine-induced coronary vasocon-striction with intravenous verapamil. Am J Cardiol 1994;73:510–513.

7. Saland KE, Hillis LD, Lange RA, Cigarroa JE. Influence of morphinesulfate on cocaine-induced coronary vasoconstriction. Am J Cardiol2002;90:810–811.

8. Brogan WC III, Lange RA, Kim AS, Moliterno DJ, Hillis LD. Alle-viation of cocaine-induced coronary vasoconstriction by nitroglycerin.J Am Coll Cardiol 1991;18:581–586.

9. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD,Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, et al.ACC/AHA 2002 guideline update for the management of patients withunstable angina and non-ST-segment elevation myocardial infarction–summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Com-mittee on the Management of Patients With Unstable Angina). J AmColl Cardiol 2002;40:1366–1374.

0. Lange RA, Cigarroa RG, Flores ED, McBride W, Kim AS, Wells PJ,Bedotto JB, Danziger RS, Hillis LD. Potentiation of cocaine-inducedcoronary vasoconstriction by beta-adrenergic blockade. Ann InternMed 1990;112:897–903.

1. Moliterno DJ, Willard JE, Lange RA, Negus BH, Boehrer JD, Gla-mann DB, Landau C, Rossen JD, Winniford MD, Hillis LD. Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both.N Engl J Med 1994;330:454–459.

2. Boehrer JD, Moliterno DJ, Willard JE, Hillis LD, Lange RA. Influenceof labetalol on cocaine-induced coronary vasoconstriction in humans.Am J Med 1993;94:608–610.

3. Hoffman RS, Hollander JE. Thrombolytic therapy and cocaine-in-duced myocardial infarction. Am J Emerg Med 1996;14:693–695.

4. Bertolet BD, Freund G, Martin CA, Perchalski DL, Williams CM,Pepine CJ. Unrecognized left ventricular dysfunction in an apparentlyhealthy cocaine abuse population. Clin Cardiol 1990;13:323–328.

5. Hollander JE, Hoffman RS, Gennis P, Fairweather P, DiSano MJ,Schumb DA, Feldman JA, Fish SS, Dyer S, Wax P, et al. Prospectivemulticenter evaluation of cocaine-associated chest pain. Cocaine As-sociated Chest Pain (COCHPA) Study Group. Acad Emerg Med 1994;1:330–339.

6. Ferreira S, Crumb WJ, Jr., Carlton CG, Clarkson CW. Effects ofcocaine and its major metabolites on the HERG-encoded potassiumchannel. J Pharmacol Exp Ther 2001;299:220–226.

7. Daga B, Minano A, de la Puerta I, Pelegrin J, Rodrigo G, Ferreira I.Electrocardiographic findings typical of Brugada syndrome unmaskedby cocaine consumption. Rev Esp Cardiol 2005;58:1355–1357.

8. Winniford MD, Wheelan KR, Kremers MS, Ugolini V, van den BergE, Jr., Niggemann EH, Jansen DE, Hillis LD. Smoking-induced cor-onary vasoconstriction in patients with atherosclerotic coronary arterydisease: evidence for adrenergically mediated alterations in coronaryartery tone. Circulation 1986;73:662–667.

9. Chambers HF, Morris DL, Tauber MG, Modin G. Cocaine use and therisk for endocarditis in intravenous drug users. Ann Intern Med 1987;106:833–836.

0. Hsue PY, Salinas CL, Bolger AF, Benowitz NL, Waters DD. Acute aortic

dissection related to crack cocaine. Circulation 2002;105:1592–1595.