Critical Care Toxicology

2916 Pages·67.778 MB·English

by  Jeffrey Brent, Keith Burkhart, Paul Dargan, Benjamin Hatten, Bruno Megarbane, Robert Palmer (eds.)

Cocaine
Ruben Olmedo, Christopher Yates, and Robert S. Hoffman
Contents Cocainehasbeenusedforthousandsofyearsfor
its recognized medicinal properties and for its
CocaineChemistry................................... 2
personally gratifying qualities. The first
PathophysiologyofCocaineEffects................ 3 archeologicalfindingofhumanuseofcocaleaves
Pharmacokinetics...................................... 3
dates back to 3000 b.c. among pre-Colombian
MechanismofAction................................. 4
Andean societies [1]. The leaves were chewed
ClinicalPresentation................................. 5
by chasquis (on-foot mail carriers of the Incan
Hyperthermia.......................................... 5
NeurologicalManifestations.......................... 6 empire) to decrease fatigue and enhance endur-
CardiacManifestations................................ 8 anceastheydeliveredroyalmessagesbyrunning
PulmonaryManifestations............................ 9
fromtowntotown.
GastrointestinalManifestations....................... 10
Chewing the coca leaf was the preferred
RenalManifestations.................................. 11
Rhabdomyolysis....................................... 11 method of use until Niemann isolated cocaine in
UteroplacentalComplications........................ 12 1859. In thelate 1800s, Freud advocated theuse
Diagnosis.............................................. 12 ofcocaineformanyailments,includingthetreat-
mentofopioidaddiction.Duringthissameperiod,
Treatment............................................. 16
the renowned John Hopkins’ surgeon Halsted
GradingSystemforLevelsofEvidenceSupporting reported the local anesthetic effects of cocaine.
RecommendationsinCriticalCareToxicology,
By the end of the nineteenth century, cocaine
2ndEdition........................................ 20
became widely used in various medicinal pastes
References............................................ 20
andremedies[2].Itwasthemainactiveingredient
in the soft drink Coca-Cola until 1903 [1]. As
accounts of addiction multiplied, legislation was
R.Olmedo(*)
enactedthatcurtaileditsusealthoughcocainewas
MedicalToxicology–EmergencyMedicine,TheMount
stillsoldover-the-counterintheUSAuntil1916.
SinaiHospital,NewYork,NY,USA
e-mail:[email protected] CocainecontinuestobeaScheduleIIdruginthe
USAwithlimiteduseespeciallyinotorhinolaryn-
C.Yates(*)
EmergencyMedicineDepartment,ClinicalToxicology gological interventions including in the UK and
Unit,HospitalUniversitariSonEspases,Palmade USA[3–5].
Mallorca,Spain
Although a resurgence of cocaine use in the
e-mail:[email protected]
USA occurred in the 1970s, useleveled offuntil
R.S.Hoffman(*) 1983, when “crack” appeared, providing a fast
RonaldO.PerelmanDepartmentofEmergencyMedicine,
and inexpensive method of self-administration.
NYULangoneMedicalCenter,NewYork,NY,USA
e-mail:[email protected] By 1985, the US National Household Survey on
#SpringerInternationalPublishingSwitzerland2016 1
J.Brentetal.(eds.),CriticalCareToxicology,
DOI10.1007/978-3-319-20790-2_1-1
2 R.Olmedoetal.
Drug Abuse from the US National Institute on isemerginguseinareasofSouthernandWestern
DrugAbuseestimatedthat25to40millionAmer- Africa,aswellasinAsia[16].
icanshadusedcocaineatsometimeintheirlives Cocaine toxicity involves all of the body’s
(1.5 million of whom were first-time cocaine organsystems. Its use brings patients to the hos-
users)[6].Cocaineusereachedepidemicpropor- pitalwithavarietyofclinicalfeatures.Complica-
tionsinthemid-1980s,whenitwasreportedtobe tions include medical, psychiatric, and surgical
the most frequent cause of illicit drug-related emergencies. In 1995 in the USA, the estimated
visits to emergency departments [7]. In the last health-carecostofpatientswithmyocardialische-
15 years of the twentieth century, the use of the mia alone secondary to cocaine was greater than
crystallized freebase form of cocaine became $80 million [17]. A retrospective study reported
widespread, resulting in many cocaine-related 1.1 % incidence of positive urine screens for
hospitalizations and deaths [8]. Results from the cocaine among all hospitalized non-newborn
National Institute of Drug Abuse indicate that patientsduringa12-monthperiod.Thesepatients
cocaine use has been declining since 1992 to a were predominantly young (average age
plateau of 1.8 million regular users in 1998 (5.7 31.8 years) crack users and required admission
million in 1985) [9, 10]. This trend continued to the intensive care unit 20 % of the time
duringthefirstdecadeofthetwenty-firstcentury. [9].Anunderstandingofcocaine’spharmacology
In2013,itwasreportedthattherewere1.5million and its pathophysiology is beneficial in identify-
currentcocaineusers,aged12orolder(0.6 %of ingandtreatingpatientswiththehighestrisksof
the population) and an estimate of 601,000 per- complications.
sonswhohadusedcocaineforthefirsttimewithin
the past 12 months in the USA [11]. Also for
2013, an estimated 3.1 million European adults Cocaine Chemistry
hadusedcocaineinthepreviousyear(0.9 %the
population),withhigheruseinthesouthandwest The natural tropane alkaloid cocaine is extracted
ofEurope.Especiallyhighprevalenceofusewas from the leaves of the plant Erythroxylum coca.
reportedintheUKandSpain,thoughadeclinein Coca paste is obtained by alkaline extraction of
use has been reported since peaking in 2008 the leaves, using ammonia and organic solvents.
[12]. Despite the decline, the incidence of Theactivecocainealkaloidsarecontainedwithin
cocaine-related deaths in the USA increased by theorganicphaseoftheextractionmedium,which
14 % from 1992 to 1995 [8, 13]. Cocaine con- isthentreatedwithhydrochloricacidtocreatethe
tinues to be the most commonly illicit drug of water-soluble cocaine hydrochloride (HCl) salt.
abuse involved in drug-related ED visits in the Cocaine hydrochloride (Fig. 1), often referred to
USA per year as reported by the Drug Abuse as “powder cocaine,” is used intranasally and
Warning Network, with 162.1 visits per 100,000 intravenously. This salt cannot be smoked, as it
population in 2013 [14]. European data from the undergoes pyrolysis at the temperatures required
EuropeanMonitoringCentreforDrugsandDrug forvaporization[18].
Addictionreport oncocaine usehealthemergen-
cies portrays a similarly high burden on emer-
gency services in European countries, especially
intheUKandSpainalthoughthelackofsystem-
atic data collection limits comparison [15]. The
UnitedNationsOfficeonDrugsandCrime2015
World Drug Report data reflects that the use of
cocaine as a recreational drug is concentrated in
Fig.1 Chemicalstructureofthesaltcocainehydrochlo-
North and South America (especially Brazil),
ride (HCl). When the hydrochloride salt is treated with
Europe, and to a more limited extent Oceania, base, the hydrochloride is removed, leaving cocaine in
despite recent declines in demand but that there thealkaloid(“freebase”)form
Cocaine 3
In order to be smoked, cocaine hydrochloride Table1 Toxicokineticparametersofcocaine
is converted back to its base (non-salt) form, Peakonsetof Durationof
called “crack” or “freebase” cocaine. To convert Methodofuse symptoms(min) effect(hr)
cocainehydrochloridetocrack,thehydrochloride Oral(cocaine 60–90 >3
saltisheatedinsodiumbicarbonateorammonia, HCl)
creating a hard crystallized substance. This crys- Intranasal 30 1–2
(cocaineHCl)
tallizedbaseofcocaineiscalled“crack”becausea
Smoking 0.5–1.0 0.25–0.5
poppingorcrackingsoundisoftenheardwhenit
(freebasing,
issmoked.Anotherprocesscalledfreebasingalso crack)
gives rise to smokable alkaloidal cocaine. First, Intravenous 0.5–2.0 0.25–0.5
the cocaine hydrochloride salt is dissolved in (cocaineHCl)
water mixed with an alkaline substance. The HClhydrochloride
base alkaloid is then is extracted into ether or
another organic solvent, which is separated from parent compound is cleared in the urine
theaqueouslayer.Thefinalproductisobtainedby [23]. More than 11 metabolites of cocaine have
evaporation of the organic phase. This final been described, and some deserve mention.
extraction is hazardous as many of the solvents Cocaineismetabolizedrapidlybyacombination
used are volatile and flammable. Facial and tra- of enzymatic and nonenzymatic hydrolysis
cheal burn injuries are reported in freebase [24]. Enzymatic hydrolysis by plasma and liver
cocaineusers,andfiresinclandestinelaboratories esterases yields ecgonine methyl ester. Ecgonine
duringtheproductionprocesshavebeenreported methylesterhasmildvasodilatingpropertiesand
[19]. For the sake of simplicity, in this text all has a plasma half-life of approximately 5 h
alkaloidalformsof cocainewill be referred toas [25–27].Decreasedplasmacholinesteraseactivity
crack. enhancescocainetoxicityinmice[28].Similarly,
patients with relative plasma cholinesterase defi-
ciency seem to be at increased risk of adverse
Pathophysiology of Cocaine Effects consequencesfromcocainetoxicity[29].
Another metabolite, benzoylecgonine, is
Pharmacokinetics formed mostly via nonenzymatic (chemical)
hydrolysis. Although an enzymatic hydrolysis
Cocaine is absorbed rapidly from all mucous pathwayproducingbenzoylecgonineisknown,it
membranes,includingtherespiratory,gastrointes- probablyaccountsforonlyasmallpercentageof
tinal,andgenitourinarytracts,givingrisetomul- thismetabolite[24].Benzoylecgoninehaspotent
tiple potential routes of abuse [20]. Its onset of vasoconstrictiveproperties,althoughlessthanthe
action is almost immediate from the intravenous parent compound. It has a plasma half-life of
or inhalational route (0.5–2 min) and is delayed approximately 8 h [26, 28, 30]. One important
20–30 min after nasal insufflation [21, 22]. Gas- factaboutbenzoylecgonineisthatthismetabolite
trointestinal absorption is delayed further by a is tested in most urine immunoassays. It is
minimum of 90 min. The duration of effect is detectedfor48–72hafterinfrequentcocaineuse
related closely to the onset of action, with intra- or3weeksinhigh-dosechroniccocaineusers[31,
venousandinhalationalexposurelastingapprox- 32].
imately 30 min, nasal insufflation lasting about Together, ecgonine methyl ester and
1h,andgastrointestinaluselastingatleast2–3h benzoylecgonine constitute approximately 85 %
(Table1). of cocaine’s metabolism [33]. Less than 10 % of
The physiological effects of cocaine are the cocaine ismetabolized byN-demethylationmedi-
summationoftheeffectsoftheparentcompound, atedbyCYP3A4 in the liver, formingnorcocaine
itsmetabolites,andtheirrespectivepharmacody- [34,35].Thismetaboliteishighlyvasoconstrictive
namics. Once absorbed, less than 5 % of the
4 R.Olmedoetal.
andinanimalmodelsproducesclinicaleffectssim- Table2 Mechanismofactionandclinicalmanifestations
ilartothoseoftheparentcompound[26]. ofcocainepoisoning
Additionally, in the presence of ethanol, Mechanism Clinicalmanifestation
cocaine is transesterified by liver esterases to Sodiumchannel Localanesthesia
ethylcocaine, which is also known as blockade QRSwideningonECG
cocaethylene [36]. Cocaethylene has a longer Decreasedcardiacmuscle
half-life (2.5–6 h) than cocaine [35]. In humans, contractility
Respiratorydepression
coadministrationofcocaineandethanolproduces
Monoaminereuptake
prolonged euphoria [37]. This metabolite has
inhibition
pharmacologicallysignificantcentralandperiph-
Epinephrine Tachycardia
eral effects that are similar to those of cocaine
Norepinephrine Hypertension
[38–41]. Additionally, animal studies with
Dopamine Psychomotoragitationwith
cocaethylene show a dose-dependent myocardial attendantelevationin
depression effect and more potent Na+ channel temperature.Rewardleading
todependence.Movement
blockadethancocaine[40,42].
disorders
Althoughsomedatashowsthatcocainepurity
Serotonin Variouseffectsonmoodand
is on the rise in Western Europe [43], average behavior
purityisgenerallybelow50 %andonthefallin Excitatoryamino Seizures
the USA, with indication that increased cocaine acids
puritymaybeassociatedwithadversehealth-care Plateletactivationand Thrombogenesis
alterationsinplasma
outcomes[44,45].Manyadulterantsarefoundin
thrombogenic
cocaine including some with pharmacological
constituents
activity (phenacetin, lidocaine, tetracaine, diltia-
ECGelectrocardiogram
zem,caffeine),mostofwhichhaveminimaltoxic
effects but may include seizures and nephrotoxi-
city [46]. Special mention should be made of
(sodium channel-blocking), membrane-stabiliz-
levamisole, an antihelminthic agent no longer
ing properties that result in QRS widening and
used in human medicine that recently has been decreased contractility [57–59]. In large doses,
reportedworldwideasacocaineadulterantandis
sodiumchannelblockadeinthemedullarycenters
foundinupto69 %[47]ofcocaineintheUSA,in
producesrespiratorydepressionandsuddendeath
Europe [48, 49], and in 54 % of samples of
(Table2).
cocaine destined to international trafficking in Cocaine’s second mechanism of action (inhi-
Brazil [50]. Patients presenting with oropharyn-
bitionofmonoaminereuptake)increasesthecon-
geal symptoms, agranulocytosis, leukoence-
centrations of norepinephrine, dopamine,
phalopathy, and vasculitis [47, 51–55] are
serotonin,andexcitatoryneurotransmittersinthe
reported after using levamisole-adulterated
synaptic space [58, 60, 61]. This mechanism is
cocaine.
responsibleformanyofthestimulatoryeffectson
thesympatheticnervoussystem.Someofthecen-
trallymediatedeffectsareeuphoria,psychomotor
MechanismofAction
agitation,andrespiratorystimulation.
The increase in synaptic and circulating con-
Cocaine’seffectsderivefromitssodiumchannel
centrationsofcatecholaminesstimulatesadrener-
blockadeanditscentralandperipheralinhibition
gic nerve terminals, resulting in an increase in
of monoamine reuptake. Sodium channel block-
sympathetic activity [60]. Typically, sympathetic
ade is responsible for cocaine’s local anesthetic
nervous system stimulation manifests as hyper-
effects by inhibiting nerve conduction [56]. The
tension, tachycardia, diaphoresis, mydriasis, and
effectisalsoimportantinthemyocardialconduc-
hyperthermia. Pressor effects are mediated by
tion system, where it produces quinidine-like
Cocaine 5
norepinephrine of sympathetic neural origin, flow.Thislattereffectiswell-describedinpatients
whereas tachycardia is secondary to epinephrine chewing coca leaf during exercise [76–78]. As a
derivedfromtheadrenalmedulla[60]. result, intravascular thrombosis after cocaine use
Other effects of cocaine are secondary to its occursinavarietyofvascularbeds[79–84],both
dopamine reuptake inhibition. Dopamine D /D indiseasedandnondiseasedvessels.
1 5
antagonists attenuate the euphoric effects of
cocaine [62]. Administration of cocaine directly
into motor centers produces an increase in loco- Clinical Presentation
motion that is reversed by coadministration of
dopamine antagonists [63]. Restlessness, agita- Cocainetoxicitymayinvolvemultipleorgansys-
tion, and seizures can occur from motor center tems.Althoughmostpatientswithacutecocaine-
stimulationaftercocaineadministration.Thispsy- associatedtoxicitymaybemanagedintheemer-
chomotorstimulationaftercocaineadministration gency department, some require hospitalization
isabsentinmicelackingthedopaminetransporter due to catastrophic complications. Most com-
[64].Chroniccocaineusealsodepletesdopamine plaintsarecardiopulmonary(56.2 %),neurologic
fromrewardcentersinthebrain.Thismechanism (39.1 %), and psychiatric (36.8 %), although
isthoughttobethebasisforitsreinforcementand multiple systems often are involved
addictiveproperties[65]. (57.5 %)[85].
Theserotonergiceffectsofcocaineareunclear. The effects of cocaine on the different organ
Serotonin modulates certain biologic processes, systemsareacombinationoftheoverallintrinsic
such as mood, personality, temperature regula- effect of cocaine on vascular tone and
tion,affect,appetite,motorfunction,sexualactiv- thrombogenicity and the specific physiologic
ity, sleep induction, hallucinations, and response of the involved organ system. Arterial
vasospasm.Alloftheseprocessesmaybeaffected vasoconstriction and spasm and intravascular
during chronic cocaine abuse and thrombosis occur in vascular beds throughout
withdrawal[66]. the body [79–84, 86–88]. Some of the clinical
Cocaine increases excitatory amino acid con- manifestations of cocaine-induced vasospasm
centrationsinthenucleusaccumbensbyenhanc- includecerebralinfarction,myocardialinfarction,
ing dopamine stimulation of the N-methyl-D- blindness,centralretinalarteryocclusion,mesen-
aspartate (NMDA) receptor [60]. In animal teric ischemia, and renal infarction [82, 83,
models, NMDA antagonists attenuate the effect 89–93]. Secondary effects of cocaine that affect
of cocaine on the nucleus accumbens [67] and multiple organ systems are hypertension and
preventcocaine-inducedseizuresanddeath[68]. tachycardia, which increase tissue oxygen
Cocaine has several hematological actions, demandandfurtherimpairorganperformance.
which may promote thrombogenesis. Tonga and
colleagues [69] first noted an increase in rabbit
plateletaggregationandthromboxaneproduction Hyperthermia
in vitro. Similar results of platelet activation are
reported in in vitro human volunteer studies [70, Cocaineusecanresultinserioustoxiceffectsand
71]andinaninvivocaninemodel[72].Cocaine deathinpartbecauseofhyperthermia.Evenrela-
also alters plasma constituents (increases tissue tivelylowdosesofcocainecanelevatecoretem-
plasminogen activator type I activity, increases perature and hamper cardiac reserve [94]. High
von Willebrand factor) that regulate thrombus ambient temperature is associated with a signifi-
formation [73,74]. An additional direct effectof cant increase in mortality from cocaine
cocaine on the vascular endothelium causes overdose[95].
release of endothelin-1, a potent endogenous Cocainecauseshyperthermiainseveralways.
vasoconstrictor [75]. Lastly, cocaine induces a It increases psychomotor agitation,which results
transient erythrocytosis, further restricting blood inincreasedheatproduction.Asavasoconstrictor
6 R.Olmedoetal.
oftheperipheralvasculature,cocaineimpairsheat Table 3 Cocaine-induced central nervous system
dissipation.Additionally,becausethethermoreg- complications
ulatorycentersinthehypothalamusaredopamine CNS
modulated,cocainehasdirecteffectsontempera- complications Etiology References
ture control [96]. Several case reports describe Ischemic Vasospasm, [87,88,91,
strokes thrombosis 101,103,105,
fatal hyperthermia without severe agitation or
109,110]
rhabdomyolysis in cocaine users [97, 98]. This
Hemorrhagic Hypertension, [87,88,91,
modelofhyperthermia asamajorcauseofacute stroke vasospasm, 101,103,105,
cocaine fatality is well established in cocaine- thrombosis 106,109–112]
poisoned dogs [99]. When ambient temperature Seizures Reuptakeinhibition [109,110,
increasedfrom(cid:1)5(cid:3)Cto5(cid:3)C(23(cid:3)Fto41(cid:3)F)in ofexcitatoryamino 113–118]
acids,CNS
this animal model, the survival rate decreased
hemorrhage,or
from100 %to57 %[99].Ofallvitalsignabnor- infarction
malities, hyperthermia seems to correlate most Cerebral Directeffects [100]
withfatality. vasculitis
Migraine Dopaminereuptake [108]
headaches inhibition,
vasospasm
NeurologicalManifestations
Movement Dopaminereuptake [102]
disorders inhibition [85,119–121]
Cocaineisapopularillicitdrugofabusebecause Agitation Diverse
Delirium/ mechanisms
of its stimulatory effects on the central nervous
psychosis
system (CNS).Its usealso generates avarietyof
untoward effects on the CNS. These CNS com-
plicationsoccurwithallformsofcocaineadmin- neurologic deficits. Clinical features in these
istration and include cerebrovascular ischemia patientsaretypicalofpatientswithcerebrovascu-
and infarction, transient ischemic attacks, sub- lar accidents, with aphasia, hemiplegia, dysar-
arachnoid hemorrhage, intraparenchymal hemor- thria,and/orparesthesiae/sensoryloss.
rhage, seizures, cerebrovascular thrombosis, Cocaine-inducedcerebralhemorrhagemaybe
cerebral vasculitis, migraine headache, anterior intraparenchymal or subarachnoid; however,
spinal artery syndrome, and movement disorders cocaine-positive patients with intracerebral hem-
(Table3)[87,88,91,100–108]. orrhage are more likely to have intraventricular
hemorrhage, subcortical localization, seizures,
CerebrovascularAccidents andapoorerprognosis[112,123].Theincidence
Cocaine-related strokes were first reported in of neurovascular complications among cocaine-
1977 [101]. Epidemiological studies clearly sup- related hospital admissions is low (0.35–3 %)
port cocaine as a risk factor for stroke, although [109, 113]. However, autopsy studies of fatal
the magnitude of this association is not easily nontraumatic intracranial hemorrhage reported
estimated with available studies [122]. Strokes an incidence of cocaine abuse to be 7–59 %
can be either ischemic or hemorrhagic though [124,125].Headacheisthemostcommonsymp-
limited data shows that the form ofcocaineused tom on presentation. Other presenting signs
might have an influence on the predominant eti- include meningismus, altered mental status, sei-
ology. The incidence of ischemic and hemor- zures,andfocalneurologicdeficits[105].
rhagic strokes secondary to crack cocaine is The mechanisms of cocaine-related ischemic
approximately the same [87], whereas 80 % of strokes are multiple and overlapping and have
cocaine HCl-induced strokes are been related to focal vascular disease. Proposed
hemorrhagic[88]. causes include vasospasm (either pharmacologi-
Patients with cerebrovascular ischemia or cally induced or secondary to hypertension),
infarction may present with focal lateralizing thrombosis, and vasculitis. Cerebral
Cocaine 7
vasoconstriction, documented by magnetic reso- seizures occur secondary to a large CNS hemor-
nance angiography, occurs within 15 min of rhage or infarction, most are not associated with
cocaine administration in asymptomatic human anylastingneurologicdeficits[110,117].
volunteers [126]. In head computed tomography Most cocaine-induced seizures occur within
(CT) scan-proven cerebral infarctions, angiogra- 90 min of use [117]. Similar to cocaine-induced
phy revealed evidence of vasospasm and throm- strokes, this corresponds temporally to peak
bosis[91].Biopsy-provencerebralvasculitisasa plasma cocaine concentrations [104, 116,
cause of ischemic stroke is also rarely 117]. Delayed seizures may be caused by
reported[100]. benzoylecgonine because this metabolite is also
Alternatively,acutesystemichypertensionasa apotentCNSvasoconstrictor[129].
result of the sympathomimetic effects of cocaine Cocaine also lowers theseizurethresholdand
is the proposed mechanism for cocaine-related precipitates seizures in patients with known sei-
hemorrhagic strokes. The sudden increase in zuredisorders[118].Patientswithapriorhistory
blood pressure may precipitate the rupture of a of epilepsy have a higher frequency of cocaine-
preexisting vascular malformation or aneurysm inducedseizuresthanpatientswithoutahistoryof
[87].Arteriographyhasshownbothofthesevas- seizures [116]. Partial or multiple seizures occur
cular abnormalities in many cases of cocaine- more often in patients with prior history of epi-
induced subarachnoid hemorrhage and in some lepsy [118]. Additionally, animal studies and
cases of intraparenchymal hemorrhage [105, human case reports suggest seizures “kindle”
109, 111, 113]. Patients suffering from aneurys- afterhabitualcocaineuse[116,117].Thisprocess
mal subarachnoid hemorrhage after cocaine use increases the sensitivity of the brain following
haveahigherriskofaneurysmalre-ruptureanda repeateddoses.
higherhospitalmortality[127].
Although most strokes occur either immedi- NeuropsychiatricFeatures
ately or within the first 3 h after cocaine use, A wide range of neuropsychiatric features are
Levine andassociates[87]reported that 18 %of common complaints in cocaine-associated emer-
strokesoccurafteranabstinenceperiodofatleast gencydepartmentepisodes[85,119].Theserange
2 days following a period of heavy crack use. from anxiety [120] to psychosis [121], including
Possible explanations for these delayed events suicidalintent.Agitationandaggressionarehall-
are the prolonged half-life of cocaine’s metabo- marksofseverecocainetoxicityandposeariskto
lites (benzoylecgonine) and cocaine’s intrinsic patientandcaregiversafety.
thrombogeniceffect.
OtherNeurologicalEffects
Seizures Cocaineinducesavarietyofmovementdisorders,
Although seizures are well associated with whicharepresumedtobedopaminergicinorigin.
cocaine use, they are a relatively uncommon These movement disorders include dystonia,
presentingfeatureofemergencydepartmentvisits choreoathetosis (commonly known as crack
andhospitalizationsamongpatientswithcocaine- dancing), akathisia, buccolingual dyskinesia
relatedcomplaints(2.8–8.4 %)[110,114,115].A (risussardonicus),andexacerbationofTourette’s
systematic review of evidence however did not syndrome. The high incidence of acute dystonic
find an association between cocaine and seizure reactionsincocaine-addictedpatientstreatedwith
activity [128]. Most cocaine-induced seizures antipsychotic medications suggests a dysfunc-
occur astheonly manifestation ofcocaine toxic- tional dopamine-mediated basal ganglia
ity. They are predominantly single, generalized, effect[102].
and tonic–clonic. Approximately 20 % are focal Inadditiontothekindlingeffect,chronicuseof
inonset.Seizures thatarefocal ormultipleoften cocaineisassociatedwithanincreaseincerebral
are associated with acute intracerebral complica- atrophy[130].Becauserewardcentersinthebrain
tions [116]. Although some cocaine-induced areundercontrolofdopaminergictone,depletion
8 R.Olmedoetal.
ofdopaminergictransmissionintheseareasafter elevation)upto6weeksafteraninpatientdetox-
repeated administration of cocaine produces a ification admission in cocaine-addicted patients
cravingforthedrug. (in8/21patientsvs.1/42controls)[138].
Cocaine causes myocardial infarction by sev-
eral mechanisms. Acutely, cocaine use leads to
CardiacManifestations hypertension, tachycardia, and vasoconstriction,
allofwhichincreasemyocardialoxygendemand.
Cardiac manifestations of cocaine poisoning are First,anelevationinheartrateandbloodpressure
commonandhavebeenwellrecognizedforyears. increases myocardial workload. More dramatic
Mostsymptomsrelatingtoacutecocaineusesug- elevations in blood pressure may intensify the
gest a cardiovascular etiology, with 40 % of shearingforcesinthemajorvessels,causingaor-
cocaine-relatedvisitstothehospitalhavingchest tic dissection and rupture [140–145]. Dissection
pain as the leading single presenting symptom ofcoronaryarterieshasoccurred[146,147].Sec-
[85]. Other symptoms that occur at presentation ond, cocaine causes local vasoconstrictionof the
and could be related to cardiac events include coronary vasculature. In human volunteers, this
diaphoresis, palpitations, and dyspnea [85, effect occurs within 15 min of cocaine adminis-
119]. Because of cocaine’s multiple effects on tration, as is well documented by angiography
the coronary vasculature, evaluation of patients [87]. This arterial vasoconstriction is markedly
formyocardialischemiaorinfarctionisimportant worse in coronary artery segments previously
withanyofthesepresentingsymptoms. narrowedbyatherosclerosis[148].Inthepresence
Myocardial infarction as a complication of ofcocaineanditsincreasedsympatheticactivity,
cocaineabusewasfirstreportedin1982[131].It the normal coronary vasodilating response to a
isnowwellrecognizedthatmyocardialinfarction diminishedoxygensupplyisoverwhelmed.
occurs with intranasal, intravenous, and inhala- The vasoconstrictive effects of cocaine are
tionaluseofcocaine[132].Retrospectivestudies establishedtobeα-adrenergicallymediated.Pro-
ofcocaine-associatedchestpainreportedaninci- pranolol, a β-adrenergic antagonist, exacerbates
denceofmyocardialinfarctionrangingfrom0 % coronary narrowing after cocaine infusion,
to 31 %. Subsequent prospective studies indi- whereas phentolamine, an α-adrenergic antago-
cated that the frequency of infarction defined by nist,reversesthiseffect[149,150].
creatine kinase–MB fraction (CK-MB) or tropo- Acuteandchroniceffectsofcocaineareasso-
nin criteria more likely approximates 0.7–6 % ciated with its thrombogenicity and ability to
[132–136]. accelerateatherosclerosis.Coronaryangiography
Thetypicalpatientwithcocaine-inducedmyo- performed in patients after cocaine-associated
cardial infarction is a male, 18–52 years old myocardial infarction often shows intracoronary
(medianage33yearsold)withahistoryofregular thrombus and atherosclerotic lesions at different
tobacco smoking and frequent cocaine use. The stages of stenosis in any of the coronaries [137,
quality of the chest pain is usually atypical of 151, 152]. Autopsy and coronary catheterization
ischemia, and the location of the pain does not reportsofchroniccocaineabusersshowadvanced
predictmyocardialinfarction[132]. atherosclerosis despite a young age [90, 145,
Two thirds of patients with chest pain experi- 153–156].Additionally,rabbitsfeda0.5 %cho-
ence it within 3 h, and 93 % have chest pain lesterol diet and injected with cocaine develop
within 24 h of cocaine use [90, 132, 137]. A atherosclerotic lesions in the aorta [157]. In
greaterdelayintheonsetofsymptomsisexperi- humans, chronic cocaine use is said to increase
enced rarely but has been documented the prevalence of aortic atherosclerotic lesions
[138].Myocardialinfarction3daysaftercocaine independent of traditional cardiac risk factors
use was reported by Del Aguila and Rosman [158]. In contrast, more recent studies in symp-
[139]. Additionally, Holter monitoring detected tomatic patients with low to intermediate risk of
ECG changes (ST-T changes, ST-segment acutecoronarysyndromes(ACS)whounderwent
Cocaine 9
coronary computerized tomography angiography theactionpotentialincocaineintoxicationissec-
havefailedtofindanassociationbetweencocaine ondary to the direct sodium channel-blocking
useandadvancedatherosclerosis.Thepresenceof effects of cocaine [171]. Cocaine-induced
coronary lesions as measured by the extent of Brugada-type ECG findings are reported and are
vesselstenosis((cid:4)25 %,(cid:4)50 %)[159],extentof alsolikelyrelatedtothesodiumchannelactionof
calcifiedandnoncalcifiedcoronaryplaques[160], cocaine[172].Additionally,ventriculardysrhyth-
andcoronarycalciumscores[159,161]werenot mias may develop secondary to cocaine-induced
different among patients who use cocaine and ischemiaorinfarction.AlthoughQTprolongation
thosewhodonot. is common, torsade de pointes is uncommonly
Cocaineusealsohasglobalcardiaceffectsthat reported [168, 173–175]. Numerous reports doc-
may produce ischemia. Data from both echocar- ument sudden prehospital cardiac arrest second-
diography and cardiac catheterization reveal that ary to cocaine use, which may be related to
cocaine use depresses myocardial function. cocaine ion-channel blockade or secondary to
Dilated cardiomyopathy is reported with normal cocaine-mediatedischemia[145,152,167,176].
coronaryarteriesinpatientswithhabitualcocaine A rare but devastating cause of chest pain in
use [162, 163]. Ventricular angiography showed cocaine users is aortic dissection. In the Interna-
myocardial dysfunction as measured by worsen- tionalRegistryofAcuteAorticDissectionof3584
ing hemodynamic parameters in patients infused patients with aortic dissection, 1.8 % had
with cocaine[164]. Left ventricularsystolicdys- documentedrecentcocaineuse,andthesepatients
function, secondary to cocaine’s myocardial were relatively younger (47 years old in cocaine
depressant effect, presents as congestive heart positive patients with type A and type B dissec-
failureandcardiomyopathy[151,163].Thesecar- tions, 61 and 64 years old for cocaine-negative
diovascular hemodynamic changes alter the typeAandtypeB,respectively)[177].
genetic expression of contractile proteins in
cocaine-treatedrats[165].Inflammatorylympho-
cytic and eosinophilic infiltrates consistent with PulmonaryManifestations
myocarditis are found in myocardial tissue from
some patients with cocaine-related deaths [166, Thepulmonarycomplicationsofcocaineusearise
167]. These anatomic alterations may provide a from its pharmacological effects on pulmonary
substrate for reentrant dysrhythmias and other physiology and from the various methods of
conductionabnormalities. administering the drug. Cocaine-induced vaso-
Cocainemayproducecardiacdysrhythmiasin constriction and platelet aggregation, pulmonary
severalways,includingdirecteffectsonthecon- hemorrhage,andpulmonarythrombuscanoccur.
duction system and release of endogenous cate- Hemoptysisisreportedtooccurin5.7 %ofhabit-
cholamines. In low doses, cocaine may result in ual smokers of freebase cocaine [178]. Histopa-
bradycardia. Higher doses cause all types of thology of fiber-optic bronchoscopic lavage and
tachydysrhythmias, with sinus tachycardia being autopsy reports of acutely cocaine-intoxicated
the most common. Other rhythm disturbances patients reveal diffuse interstitial and alveolar
frequently associated with cocaine use are atrial hemorrhage, bronchial arterial constriction, and
fibrillation, narrow-complex and wide-complex ischemic damage [179, 180]. Pulmonary infarc-
supraventricular tachycardias, ventricular tachy- tion is encountered less often [181], mainly
cardia and fibrillation, and torsade de pointes because of the dual blood supply to the lungs
[57,59,137,168–170].Animalmodelsandcase fromthepulmonaryandbronchialarteries.
reports of wide-complex supraventricular tachy- Sincethe1990s,habitualsmokingofcrackhas
cardiassuggestthatthesedysrhythmiasresemble replaced nasal insufflation of cocaine HCl as the
those following poisoning from other sodium most common method of use in the USA likely
channel blockers such as type I antidysrhythmic becauseofthefasteronsetandgreaterintensityof
ortricyclicantidepressants.Slowingofphase0of effects achievable with smoking. Each of these
10 R.Olmedoetal.
routesofadministrationisassociatedwithunique patientspresentingwithspontaneouspneumome-
pulmonary complications. Thermal burns of the diastinumfoundthat76 %ofthecaseswereasso-
upper airway, including the tongue, epiglottis, ciated with illicit inhalational drug use. Of these
vocal cords, and subglottic area, occur after cases,53 %weresecondarytococaineuse.Eval-
smokingcocaine[182];thisisfrominhalationof uation of the presenting clinical symptoms
either hot cocaine or ether used to prepare the revealedthat82 %ofthepatientshadacomplaint
alkaloidformofcocaine.Acuterespiratorysymp- of chest pain or shortness of breath or both. The
toms(cough,blacksputum,chestpain,shortness absence of an abnormal physical finding was
of breath, asthma) [183] occur with high fre- uncommon:mostpatients(88 %)hadsubcutane-
quency in temporal association with crack ous emphysema, Hamman’s crunch, or
smoking. both[195].
Functional disorders of the lungs, gas Chronic cocaine smokers develop gas diffu-
exchange abnormalities, and reactive airway dis- sion abnormalities at the alveolar-capillary level
easealsooccurcommonly[184].Subsequentpul- [178].Thecauseofthediffusiondefectisconsis-
monaryarterymedialhypertrophyoccursin20 % tent with increased lung epithelial permeability
of individuals who chronically abuse cocaine. secondary to damage to the alveolar-capillary
This condition occurs in the absence of foreign membrane. This crack-related lung injury,
particle embolization and is independent of the reflected by abnormally rapid 99mTc-DTPA
dose,frequency,orrouteofadministration[185]. (diethylenetriamine pentaacetate aerosol) lung
The condition known as “crack lung” that clearance, is at least partially reversible after a
resultsfrominhalationofcocaineisdescribedas 3-month period of abstinence from smoking
pulmonary infiltrates, fever, and bronchospasm. crack[198].
An immunologic etiology of these effects is
supported by the findings of eosinophilia, ele-
vated IgE concentrations, and pruritus, all of GastrointestinalManifestations
which resolve with abstinence of drug use
[186–188]. These findings suggest that heavy Gastric and mesenteric arteries have abundant
crack smoking produces respiratory tract injury α-adrenergic receptors [199], which constrict in
manifested by acute respiratory symptoms and responsetococaine.Theintensityandlocationof
evidence of chronic airflow obstruction in large vasoconstriction determine the extent of injury.
airways. Acute gastrointestinal ischemia occurs with all
Acutepulmonaryedemasecondarytococaine routes of cocaine administration. Patients who
use is also encountered due to both cardiogenic smuggle cocaine in the gastrointestinal tract in
and noncardiogenic causes. Noncardiogenic pul- wrapped packets can suffer from local effects
monary edema (acute respiratory distress syn- (obstruction, perforation), but the most cata-
drome) results from either the direct effect of strophicoutcomesareaconsequenceofsystemic
cocaine or adulterants on the pulmonary alveoli toxicityduetorupturedpackets[200,201].
and endothelium by increasing their Pathophysiologically, cocaine’s decrease in
permeability[189]. mesenteric blood flow results in bowel edema,
Barotrauma occurs in individuals who use a ulceration, and ultimately necrosis. Perforation
Valsalva-type maneuver for rapid absorption of of the duodenum, jejunum, ileum, and colon are
cocaine. There are numerous case reports of allwelldescribed[82,202–205].Largeintestinal
patients presenting to the emergency department ischemia from localized vasoconstriction may
with pneumomediastinum, pneumothorax, or presentascolitis[82,83].
pneumopericardium. These abnormalities occur Kramandcolleagues[204]comparedpatients
secondary to the mechanics of drug administra- with cocaine-induced gastroduodenal ulceration
tion rather than directly related to cocaine itself and perforations with patients with perforations
[190–197]. A retrospective study that evaluated and ulcerations secondary to peptic