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Cocaine: History, SocialImplications, and Toxicity—A Review
Rachel A. Goldstein, MSc, DO, FACOI,Carol DesLauriers, PHARM D, and
Anthony M. Burda, BS PHARM, DABAT
ackground/History of Useocaine is a naturally occurring substance found in the leaves of therythroxylum coca plant. The plant is endogenous to South America,exico, Indonesia, and the West Indies. Peoples of ancient civilizations
sed the coca leaves for religious and ceremonial reasons. Remains ofoca leaves in the cheeks of Peruvian mummies have been found.1 Thesencient civilizations used a mixture of coca leaves and saliva as a localnesthetic for ritual trephinations.2,3 Trephinations involved removing aircular section of bone from the skull. It is not entirely clear whetherhese procedures were done for ritual purposes or for treatment of variousonditions including head trauma.When the Spaniards conquered South America in 1492, they ignored the
laims of “the power the leaf gave” and abolished its use. Shortly afterhis, they discovered the claims of the coca leaf; it became legal and a0% tax was added to the value of the crop. The Spanish needed nativeorkers for the silver mines after they conquered the New World. Work
n the silver mines was arduous and taking coca reduces appetite andncreases physical stamina. Hence there was a great surge in coca use andhe number of coqueros (coca-chewers).4
It was not until the mid-1800s that a PhD student achieved the isolationf the cocaine alkaloid in Germany. In 1884 it was used as the firstnesthetic. Albert Niemann, the student who perfected the purificationrocess, noted its anesthetic properties. He noted its “bitter taste and theesultant peculiar numbness when applied to the tongue.” By the late800s, cocaine was widely used for its analgesic properties to includeerve block anesthesia, epidural, and spinal anesthesia. In 1863, a chemistamed Angelo Mariani marketed a wine called Vin Mariani. When
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ombined with alcohol, it yielded a further potently reinforcing com-ound, now known to be cocaethylene. Thus cocaine was a popularngredient in wines, notably Vin Mariani. Coca wine received endorse-ent from prime ministers, royalty, and even the Pope. He used the
thanol in wine as a solvent and extracted the cocaine from the cocaeaves. Vin Mariani was competing with beverages sold in the Unitedtates such as John Styth Pemberton’s original 1886 recipe for Coca-ola. At that time, it was sold as a patent medicine. It was promoted astemperance drink offering the virtues of coca without the vices of
lcohol. The new beverage was invigorating and popular. By 1906, whenhe Pure Food and Drug Act was passed, the company began usingecocainized leaves. Originally, the stimulant mixed in the beverage wasoca leaves from South America, which the drug cocaine is derived from.n addition, the drink was flavored using kola nuts, also acting as theeverage’s source of caffeine. Pemberton called for 5 oz of coca leaf perallon of syrup, a significant dose, whereas, in 1891, Candler claimed hisormula (altered extensively from Pemberton’s original) contained onlyne-tenth of this amount. Coca-Cola did once contain an estimated 9 mgf cocaine per glass, but in 1903 it was removed. After 1904, Coca-Colatarted using, instead of fresh leaves, “spent” leaves—the leftovers of theocaine-extraction process with cocaine trace levels left over at aolecular level. To this day, Coca-Cola uses as an ingredient a nonnar-
otic coca leaf extract prepared at a Stepan Company plant in Maywood,ew Jersey. In the United States, Stepan Company is the only manufac-
uring plant authorized by the federal government to import and processhe coca plant, which it obtains mainly from Peru and, to a lesser extent,olivia. Besides producing the coca flavoring agent for Coca-Cola,tepan extracts cocaine from the coca leaves, which it sells to Mallinck-odt Inc., a St. Louis pharmaceutical manufacturer that is the onlyompany in the United States licensed to purify the product for medicinalse.5 Stepan buys about 100 metric tons of dried Peruvian coca leavesach year, said Marco Castillo, spokesman for Peru’s state-ownedational Coca Co.6,7 In 1879 cocaine was used to treat morphine
ddiction. In 1885 the U.S. manufacturer Parke-Davis sold various formsf cocaine including powder, cigarettes, and even a cocaine mixture fornjection, complete with the needle.In the U.S., cocaine was sold over the counter until 1916. It was widelysed in tonics, toothache cures, patent medicines, and chocolate cocaineablets. Prospective buyers were advised (in the words of pharmaceuticalrm Parke-Davis) that cocaine “could make the coward brave, the silent
loquent, and render the sufferer insensitive to pain.”M, January 2009 7
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Sigmund Freud, the father of psychoanalysis, in the early 1880’s begano experiment with cocaine. At a time when he was undergoing a loweriod in his life, he reported that cocaine lifted his spirits and took hisind off his professional and financial difficulties. He sent cocaine to hisancée, telling her it would make her strong and give her cheeks a redolor. Freud was to play a significant role in the development of the
estern cocaine industry. “I take very small doses of it regularly andgainst depression and against indigestion, and with the most brilliantuccess,” he observed. Drug giants Merck and Parke-Davis both paidreud to endorse their rival brands. He published several papers onocaine, his most famous and well-read Umber coca (1884). An excerpteads:
“A few minutes after taking cocaine, one experiences a certain exhilarationand feeling of lightness. One feels a certain furriness on the lips and palate,followed by a feeling of warmth in the same areas; if one now drinks coldwater; it feels warm on the lips and cold in the throat. One other occasion thepredominant feeling is a rather pleasant coolness in the mouth and throat.Often, at the outset of the cocaine effect, the subjects alleged that theyexperienced an intense feeling of heat in the head. I noticed this in myself aswell in the course of some later experiments, but on other occasions it wasabsent. In only two cases did coca give rise to dizziness. On the whole thetoxic effects of coca are of short duration, and much less intense than thoseproduced by effective doses of quinine or salicylate of soda; they seem tobecome even weaker after repeated use of cocaine.”
By the turn of the twentieth century cocaine’s addictive propertiesecame well-known and The Harrison Narcotics Tax Act was passed in914 and included cocaine among other substances. The Harrison billowever did not appear to be a prohibition law at all. Its official title was:An Act to provide for the registration of, with collectors of internalevenue, and to impose a special tax upon all persons who produce,mport, manufacture, compound, deal in, dispense, sell, distribute, or giveway opium or coca leaves, their salts, derivatives, or preparations, andor other purposes.” Far from appearing to be a prohibition law, thearrison Narcotic Act on the surface was merely a law for the orderlyarketing of opium, morphine, heroin, and other drugs—in small
uantities over the counter, and in larger quantities on a physician’srescription. Indeed, the right of a physician to prescribe was spelled outn apparently unambiguous terms: “Nothing contained in this section shallpply . . . to the dispensing or distribution of any of the aforesaid drugs topatient by a physician, dentist, or veterinary surgeon registered under
his Act in the course of his professional practice only.”8,9 In the 1920socaine use declined, and that decline was to become more so in the
930s, when amphetamine (speed) became popular among drug users.DM, January 2009
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oday’s Use of CocaineIn 2006, six million Americans age 12 and older had abused cocaine in
ny form and 1.5 million had abused crack at least once in the year prioro being surveyed.10 The National Institute on Drug Abuse (NIDA)-unded 2007 Monitoring the Future Study showed that 2.0% of 8thraders, 3.4% of 10th graders, and 5.2% of 12th graders had abusedocaine in any form and 1.3% of 8th graders, 1.3% of 10th graders, and.9% of 12th graders had abused crack at least once in the year prior toeing surveyed.Cocaine is the most frequent drug-related cause of emergency depart-ent (ED) visits in the United States. Of an estimated 106 million ED
isits in the U.S. during 2004, the Drug Abuse Warning NetworkDAWN) estimates that 1,997,993 (95% confidence interval (CI):,708,205 to 2,287,781) were drug-related. Data for 2004, DAWNstimates 940,953 (CI: 773,124 to 1,108,782) drug-related ED visitsnvolved a major substance of abuse. DAWN estimates that cocaine wasnvolved in 383,350 (CI: 284,170 to 482,530) ED visits.11 In summary,ocaine is the most commonly used illicit drug among those seeking caren EDs or drug-treatment centers. It is the most frequent cause ofrug-related deaths reported by medical examiners.12
Along with other illicit substances, cocaine is frequently used for theurposes of body packing and body stuffing. While these two phrases areometimes used interchangeably, they represent distinctly different enti-ies. Body packers (also called “mules” or “couriers”) ingest a largemount (commonly about 1 kg, or 50-100 packets) of carefully packagedrug-containing packets, in attempts to illegally smuggle the drugshrough customs and border crossings.13,14 The packets are later removedrom the body through fecal elimination, and the drugs are recovered andold. Body stuffers internally conceal fewer and more hastily packagedrug packets, in order to avoid being arrested for possession of the drugr other offenses. Body stuffing of drugs may occur through oral, anal, oraginal orifices.15 Both body stuffers and packers are subject to toxicityrom leakage or rupture of drug-containing packets.
rocessing and ProductionMost of the world’s current cocaine supply is produced in Southmerican countries such as Peru, Colombia, Ecuador, or Bolivia.16
olombia and Peru export the most cocaine to the United States.17
ocaine is an alkaloid extracted from the E. coca bush, which grows in
he Andes Mountains in western South America.17 Of all plants in theM, January 2009 9
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rythroxylon genus (so named because of their reddish color), the E. cocaush’s leaves yield the highest amounts of cocaine, approximately 1% byeight.1 However, cocaine is found in all parts of the coca plant. Because
he amount of cocaine present in the harvested leaves decreases over time,he leaves are typically processed into cocaine paste and/or powder asoon as possible.18
To extract cocaine from the plant, the harvested leaves are soaked witholvents such as kerosene until a thick pasty substance (called “cocaineaste”) is isolated. This paste, which contains 40-80% cocaine, is thenreated with hydrochloric acid to form cocaine hydrochloride salt (orcocaine powder”) before it is exported from South America.16,19
ocaine hydrochloride is water soluble and is well absorbed throughsnorting” through the nasal mucosa, and by intravenous injection. Its also absorbed through all mucous membranes. When “snorted,” aypical “line” of cocaine contains approximately 50-100 mg of parentompound, although it is often “cut” or adulterated with otherubstances.20 Because it has a high melting point and decomposeshen burned, cocaine hydrochloride cannot be smoked.18 Cocaineydrochloride must be converted into an alkaline form of eitherreebase or crack cocaine before it can be smoked. Both freebase andrack cocaine share the same chemical form and are synthesized fromhe same coca plant but have different physical characteristics and arerepared using different techniques.18
To make freebase cocaine, cocaine hydrochloride powder is dissolvedn water and a base (such as ammonia) is added. Ether or a similar solvents added to dissolve the cocaine base. The “free” base is then extractedrom the ether solution through evaporation. Freebase cocaine is subjecto adulteration; many local anesthetics and stimulants can be extractedhrough the ether solution as well.19 If the freebase is removed before thextraction process is completed, some residual ether may remain in therug. This remaining ether is highly flammable and may cause facialurns when the freebase is smoked.16 This risk of fire limits the popularityf freebase as a smokable drug.Crack cocaine is also synthesized from cocaine hydrochloride powder,hich has been dissolved in water. The drug is then mixed with baking
oda or sodium bicarbonate and heated, which allows the cocaine base toolidify into a soft mass that hardens into a rock-like state after drying.he hard product, known as “crack,” is not flammable because ether is notsed in its production. The name “crack” is derived from the cracking oropping sound heard when the drug is smoked. Crack cocaine is cheap to
ake, has a high profit margin, and is highly addictive when smoked.0 DM, January 2009
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ecause of these characteristics, dealers more frequently sell it thanocaine hydrochloride or freebase.21 Like freebase and cocaine hydro-hloride, crack cocaine is also frequently adulterated with other sub-tances. Crack is sold as “rocks,” which are off-white in color and ofrregular size, approximately one-quarter to three-eighths of an inch iniameter.22 For marketing, crack cocaine is packaged into vials contain-ng one to three rocks of the drug, which weigh 100 mg each; vials areold for 5 to 10 dollars by street dealers.21 Currently, crack is the mostommonly used form of cocaine.16
Both freebase and crack cocaine have a lower melting point thanocaine hydrochloride; thus, both formulations can be easily smoked inipes (glass “crack pipes” or traditional pipes) or cigarettes.18 Smokingauses a rapid absorption of the drug into the central nervous systemCNS), which causes intense euphoria and subsequent craving sensations.ocaine is sometimes also mixed with heroin and sold on the street; thisombination is referred to as a “speedball.” Other street names for cocainenclude Snow, Nose Candy, Bernice, Dama Blanca, Baseball, and Goldust.
ocaine AdulterantsAlcohol and cocaine are commonly used together; between 50 and 90%f cocaine users also concurrently ingest ethanol during their binges.23
ocaine users frequently report that the use of ethanol and cocaineogether prolongs the “high” and minimizes the dysphoric feelingsssociated with the use of cocaine. These reports may be due to theresence of cocaethylene, which is formed in vivo after use of concurrentse of alcohol and cocaine. In the presence of ethanol, cocaine isransesterified by a hepatic carboxyesterase into cocaethylene. Likeocaine, cocaethylene causes increases in heart rate and blood pressure asell as euphoric effects.24 In rats, cocaethylene induces reinforcingroperties and increased motor activities.23 Cocaethylene has an elimi-ation half-life of 150 minutes (compared to approximately 90 minutesor cocaine), which explains the prolonged euphoric effects reported afterse of cocaine and ethanol.17 The sympathomimetic effects of cocainend ethanol may be additive and contribute to the high mortality ratebserved in individuals who use the two drugs together.24 In addition toromoting the formation of cocaethylene, the use of ethanol and cocaineogether also inhibits cocaine metabolism. This may explain the higheroncentrations of cocaine that are frequently noted in patients withoncurrent cocaine and ethanol abuse.23
Analysis of street samples of cocaine has found an average purity rate
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f 40%.19 Therefore, adulterants represent more than half of the compo-ition of all cocaine sold. Adulterants are added to cocaine to promote theerceived potency of the drug, to increase the volume of the drug, or toncrease the toxicity associated with the drug.Local anesthetics are among the most frequent contaminants of co-
aine.19 Local anesthetics have psychoactive and reinforcing propertiesimilar to cocaine and can thus potentiate these effects when combinedlong with cocaine.19 The symptoms of local anesthetic toxicity includearesthesias, tremors, and seizures, which are similar to some of the toxicffects of cocaine. The contamination of cocaine with benzocaine hasesulted in methemoglobinemia.25
Many compounds are added to cocaine to increase the available volumef the drug. These include sugars, talc, and cornstarch. These compoundsan have variable pharmacologic action or toxicity. Sugar can causerritation of nasal passages when inhaled. Talc and cornstarch can causeulmonary fibrosis and hypertension.19
Toxins such as quinine and strychnine are sometimes used to adulterateocaine and other illicit drugs.19 Quinine is an alkaloid, which is used forreatment of nocturnal cramps and drug-resistant Plasmodium falciparumalaria.26 Historically, quinine has been recognized as a common
ontaminant of heroin. The toxicity of quinine includes gastrointestinalymptoms, cardiac dysrhythmias, and blindness. Strychnine, which haseen commercially marketed in the past as a rodenticide, inhibits theeurotransmitter glycine. This causes increased neuronal activity of theNS. Symptoms of strychnine toxicity include muscle spasms and
eizures during which the patient remains conscious.27,28 Treatment ofatients with strychnine poisoning is supportive and symptomatic; ben-odiazepines have been successfully used in the past to treat theonvulsions associated with strychnine toxicity.29
aboratory Detection of CocaineTesting for cocaine and its metabolites can be performed on manyiologic specimens. Blood, urine, hair, perspiration, meconium, saliva,nd amniotic fluid have all been used for testing of cocaine use.The initial screening test for cocaine is usually performed on urine.rine is commonly used for initial screening because samples are easy tobtain, the testing is noninvasive, and many cost-effective commercialits are available.29 Urine testing is commonly performed by thenzyme-multiplied immunoassay technique; other analytic screeningethods include radioimmunoassay and thin-layer chromatography.
ince cocaine has a short elimination half-life of about 1 hour, urine2 DM, January 2009
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ssays for cocaine use typically measure the cocaine metabolite benzo-lecgonine, which has an elimination half-life of 6 hours.18 Urinemmunoassays have a lower limit of detection of approximately 300g/mL. Positive results are commonly confirmed with gas chromatogra-hy/mass spectroscopy (GC/MS), which can detect as little as 1 ng/mL ofenzoylecgonine.18 Urine testing for benzoylecgonine is typically re-orted to give positive results for 1 to 2 days after recent cocaine use.owever, two case series have shown that patients who use high amountsf cocaine (�0.5 g per day) over many years can have positive urinecreens for weeks after their last use of the drug.30 For example, a patientho used up to 30 g of cocaine a day for 10 years had a positive urine test
or 22 days after his last use of cocaine.31 This may be secondary toltered kinetics of cocaine tissue deposition and metabolic rates inatients who use high amounts of the drug.Although urine testing is a frequently used screening method byospitals for cocaine abuse, limitations exist in terms of how results (bothositive and negative) should be interpreted. With the exception ofxcessively high doses of prilocaine, no drugs other than cocaine and itsetabolites are recognized to cause a false-positive urine immunoassay
or cocaine.32 Ingestion of coca tea, which is made from the leaves of the. coca plant and is sold over the internet and in some restaurants in thenited States, can result in a positive urinary immunoassay for cocaine.33
oth Drano (or bleach) and sodium chloride solution, when added torine assays for benzoylecgonine, can cause false-negative results; otherdulterants such as vinegar, liquid hand soap, Visine, lemon juice, andoldenseal tea did not cause a false-negative benzoylecgonine assay whendded to urine.34 A false-negative result may also occur if urine is testedery soon after cocaine use, before metabolism to benzoylecgonine hasccurred. Additionally, since urine assays usually screen for cocaine’snactive metabolite benzoylecgonine, a positive urine screen cannot besed to extrapolate the degree of intoxication after cocaine use. Labora-ory tests for cocaine and its metabolites are best used as a marker forecent use, but not abuse or intoxication.Blood testing for cocaine is typically performed using GC/MS. Cocaine
n blood samples undergoes spontaneous hydrolysis to benzoylecgoninenless the samples are preserved with sodium fluoride or a similarseudocholinesterase inhibitor.22 Changes in pH and temperature can alsoffect breakdown of cocaine in these specimens.29 Newborns achieveigher blood levels of cocaine than adults after the same amount of therug is used; this is likely due to lower levels of plasma pseudocholines-
erase (and thus decreased ability to metabolize cocaine) in newborns.35M, January 2009 13
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dults with plasma cholinesterase deficiency, which can affect up to 4%f the population in its mild forms, can also have prolonged high bloodocaine levels due to the same decreased metabolic activity. Pseudocho-inesterase deficiency does not appear to confer a higher rate of mortalityfter cocaine use.35
Analysis of hair can be used to determine exposure to cocaine. The maindvantage of testing hair over blood or urine is that drugs persist in hairor longer time intervals than they are present in blood and urine.36 Inddition, collection of hair is noninvasive and easy to perform; approxi-ately 50-100 strands are required for analysis of a hair sample.33 Both
ocaine and benzoylecgonine deposit in the hair shaft and can beeasured approximately 1 day after intranasal cocaine use.29 Cocaethyl-
ne has also been reported to be present in hair samples of cocaine users,lthough the significance of this is uncertain.36 Because hair grows at axed rate (approximately one-half inch each month), analysis of cocaineatterns along the length of a hair sample can be used to determinehether use was episodic or chronic. External contamination of hair haseen shown to occur after passive exposure to crack cocaine vapors. Hairashing after passive exposure results in an undetectable level of cocaine
n the hair.20 Patients with passive exposures to cocaine do not haveeasurable amounts of cocaine metabolites such as benzoylecgonine in
heir hair samples.20 Thus, the presence of benzoylecgonine in a hairample can be used to differentiate passive exposure to cocaine fromllicit use of the drug.In certain inner-city areas, the prevalence of maternal cocaine use is
stimated to be between 10 and 30%. Since maternal cocaine use hasultiple medical, social, and economic implications, determination of
etal exposure to cocaine is important. Both meconium and amniotic fluidave been utilized as markers of intrauterine fetal cocaine exposure.nalysis of meconium can detect drug exposure as early as 17 weeks ofestation; collection of meconium is limited by its small time period forollection (the first 3 days of life).29 Amniotic fluid, collected either atetal delivery or during amniocentesis, can also be used to measure fetalxposure to cocaine. Amniotic fluid examination can provide a qualita-ive, but not quantitative, measurement of cocaine exposure.29 Similar toeconium testing, amniotic fluid analysis is limited by its small window
f collection time.A coca leaf typically contains between 0.1 and 0.9% cocaine. If chewed
n the leaf form, it rarely presents the user with any social or medicalroblems. When the leaves are soaked and mashed, however, cocaine is
xtracted as a coca-paste. The paste is 60 to 80% pure. It is usually4 DM, January 2009
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xported in the form of the salt, cocaine hydrochloride. This is theowdered cocaine most common, until recently, in the West. Drug testingor cocaine aims to detect the presence of its major metabolite, thenactive benzoylecgonine. Benzoylecgonine can be detected for up to 5ays in casual users. In chronic users, urinary detection is possible for asong as 3 weeks.37
hemistry/PharmacologyAs a local anesthetic, cocaine blocks voltage-gated sodium channels in
he neuronal membrane. This inhibits depolarization and blocks both thenitiation and the conduction of nerve impulses. Cocaine exhibits itsasoconstrictive action therapeutically by inhibiting local reuptake oforepinephrine.38 Cocaine is an ester type of local anesthetic; it is an esterf methyl-ecgonine and benzoic acid.38,16 Ecgonine is also the parentompound of atropine16 (Fig 1).The ester link is rapidly hydrolyzed by plasma cholinesterases, which
ontributes to cocaine’s short half-life (see kinetics section).38 Structuresf the local anesthetics are shown in Fig 2 for comparison. All local
IG 1. Chemical structure of (A) cocaine, (B) ecgonine, and (C) atropine. (Color version of figures available online.)
nesthetics comprise both a hydrophobic and a hydrophilic moiety
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IG 2. Chemical structure of (A) lidocaine, (B) mepivacaine, (C) prilocaine, and (D) procaine.
Color version of figure is available online.)6 DM, January 2009
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eparated by an ester (eg, cocaine) or amide (eg, lidocaine) linkage.ncreased lipophilicity leads to a greater affinity for the sodium channeleceptor and increased toxicity of the drug. Local anesthetics with a largerolecule size results in increased duration of time on the receptor;
maller molecules escape the receptor site more rapidly. Local anestheticsan also block the potassium channel, especially in large doses.38,39
Of the local anesthetics, cocaine stands alone in causing markedehavioral responses, including euphoria and addictive behavior.40 Co-aine is abused in either of two following chemical forms.
ocaine Hydrochloride (also known as “coke”)The cocaine alkaloid is extracted from the leaves and then converted to
ocaine hydrochloride using hydrochloric acid.16,41 This crystalline whiteowder is usually insufflated but can also be dissolved in water andnjected. Cocaine salt is not smokable, as it breaks down during pyrolysis.
ree BaseCocaine hydrochloride is dissolved in water, mixed with a strong base,
nd heated. The cocaine base is extracted by the addition of an organicolvent. The free base will dry into a hard rock upon evaporation. Crackocaine is then usually smoked out of a glass pipe.16,41 The word “crack”omes from the cracking or popping noise it makes when it is smoked.
echanism of Toxic ActionCocaine exhibits profound CNS and cardiovascular toxicity. Cocaine
nd some of its metabolites exert activity at many receptors throughouthe CNS and cardiovascular system. Receptor activity is described below.
NSCocaine blocks the reuptake of catecholamines (dopamine, norepineph-
ine) and serotonin.16,41 Increased serotenergic activity can result ineizures and may be involved in the addiction and reward effects ofocaine.16,40,42,43 It is excess dopamine activity, however, that is believedo cause the majority of CNS symptoms, both the “desired” and the toxicffects. CNS symptoms include euphoria, increased self-confidence andlertness at lower doses, and aggressiveness, disorientation, and halluci-ations at higher doses. Repetitive use of cocaine results in the depletionf the dopamine stores. This can result both in an intense craving forocaine and in what is referred to as a “washed-out” syndrome.16,41
atients experiencing “washed-out” syndrome experience lethargy and
nhedonia and have difficulty with muscle movement.41 Cocaine alsoM, January 2009 17
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ffects the heat regulation center in the hypothalamus and can causeyperthermia,40 which is considered a poor prognostic indicator. Effectsn excitatory amino acids/glutamatergic system and muscarinic andigma receptors are also believed to contribute to CNS toxicity.16,40,42
ardiovascularCocaine’s reuptake inhibition of biogenic amines results in a powerful
ympathomimetic effect. As a sodium channel blocking drug, cocaine islassified as a type I antidysrhythmic agent.16,41 Cocaine exhibits “slow”n–off kinetics at the sodium channel. Ventricular arrhythmias and wideRS complex or QT/QTc prolongation can occur.16,40,44
Cocaine is also known to cause vasoconstriction, which can result inypertension, cerebrovascular accident (CVA), cardiac ischemia, andnd-organ and tissue infarcts. There are several mechanisms and media-ors responsible for cocaine-induced vasoconstriction: increased neuronalorepinephrine, a direct effect of benzoylecgonine on the blood vesselspossibly calcium mediated, see kinetics section for a more detailedescription of the metabolite benzoylecgonine), increased levels ofndothelin-1 (a powerful vasoconstrictor), and decreased production ofitric oxide (a vasodilator).45,46
rug Interactions
idocaineLidocaine is also a local anesthetic and possesses the same sodium
hannel blockade action as cocaine. However, lidocaine exhibits “fast”n–off binding kinetics and is thought to displace cocaine from theodium channel receptor through competitive binding. It has been useduccessfully to shorten cocaine-induced QRS prolongation.44
One animal study suggested that lidocaine exacerbated cocaine-inducedeizures and arrhythmias; however, the American Heart AssociationAHA) recommends use of lidocaine for persistent ventricular arrhyth-ias.45 (Lidocaine may be less useful in a patient with low heart rate.)44
lass Ia and Ic AntiarrhythmicsAdditive sodium channel blockade can exacerbate or precipitate co-
aine-induced QRS prolongation or cardiac arrhythmias.
eta-Adrenergic AntagonistsThe use of beta-adrenergic antagonists in the setting of cocaine toxicityas produced increased vasoconstriction with resultant increase in blood
ressure, coronary artery spasm, increased seizure frequency, and in-8 DM, January 2009
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reased mortality.44,47 These effects are caused by unopposed alpha-drenergic effect when the beta-adrenergic receptors are blocked. Duallpha- and beta-blockers (eg, labatelol) have also caused toxicity. Aecent retrospective study found that the administration of beta-adrenergicntagonists were associated with reduction in incidence of myocardialnfarction after cocaine use.44 However, all toxicology reference texts asell as the AHA advise that beta-antagonists are contraindicated in the
etting of cocaine-induced toxicity. Deaths from cocaine-associatedyocardial infarction are “exceedingly low” per the AHA.
uccinylcholinePlasma cholinesterase (PChE) metabolizes both succinylcholine and
ocaine. Using any drug that is metabolized by PChE can potentiallyncrease the toxicity of cocaine or the other PChE substrate.
henothiazines/ButyrophenonesAnimal studies have shown that these drugs enhance toxicity and/oreath. These medications can affect body temperature, precipitate dys-onic reactions and seizures, and contribute to cardiotoxicity (by addi-ionally blocking sodium and potassium channels).41
ntidepressant DrugsMonoamine oxidase inhibitors (eg, tranylcypromine) inhibit metabo-
ism of endogenous catecholamines and would be expected to have andditive effect on cocaine’s catecholamine-induced toxicity. Selectiveerotonin reuptake inhibitors (SSRIs) (eg, fluoxetine), which inhibiteuptake of serotonin, have increased the incidence of seizures in theetting of cocaine toxicity. Antidepressants with dopamine reuptakenhibition (eg, bupropion) have increased the incidence of death in theetting of cocaine toxicity.43
rugs of AbuseCocaine is often abused with other substances, and treating clinicians
hould anticipate synergistic toxicity when used with the followingubstances.40
Ethanol. Through a transesterification reaction, cocaine and ethanolombine to produce an entirely new compound known as cocaethylenebenzoylethylecgonine). Cocaethylene has a much longer duration ofction than cocaine and is neuro- and cardiotoxic.41,48 Cocaethylene canause enhanced cardiodepression by affecting calcium and is thought to
e less potent than cocaine for causing tachycardia and euphoria.40M, January 2009 19
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Marijuana. Simultaneous use of cocaine and marijuana significantlyncreases heart rate than either drug alone (up to 50 bpm).49,50 Theseffects are noted especially during exertion.40,50 One study also suggestedn increase in blood pressure of up to 20 mm Hg with concomitant use.49
uggestions for this mechanism include increased cocaine absorptionhrough cannabinoid-induced nasal epithelium vasodilation, and an addi-ive effect in catecholamine concentration.50
Nicotine. Using nicotine and cocaine concomitantly increases heart ratend vasoconstriction more so than either cocaine or nicotine alone.45 Theocaine and nicotine combination is also postulated to affect dopaminend euphoria, but to what extent remains unclear.40
Cocaine is also a CYP3A4 substrate, and a strong CYP2D6 inhibitor.rugs that inhibit CYP3A4 may increase cocaine toxicity (eg, azole
ntifungals, ciprofloxacin, verapamil, propofol, erythromycin/clarithro-ycin) and cocaine may increase toxicity of CYP2D6 substrates (eg,
isperidone, ritonavir, dextromethorphan, amphetamines, tricyclic antide-ressants, codeine/hydrocodone/oxycodone).50
harmacokinetics
ummaryThe pharmacokinetics of cocaine are dependent on multiple factors such
s physical/chemical form, route of administration, genetics, and concur-ent consumption of alcohol. Cocaine, chemically known as benzoylm-thylecgonine, exists in several forms, ie, cocaine hydrochloride, a saltorm, and free base alkaloid, also known as “crack.”44 Cocaine may bedministered via multiple routes: insufflation (snorting), intravenousnjection, smoking, ingestion, or mucousal application. The half-life ofocaine is approximately 0.7-1.5 hours and most of the administered doses eliminated within a few hours.51-54
Cocaine and its major metabolite, benzoylecgonine (BE), may beetected in urine, blood, saliva, and meconium. BE may be detected inrine up to 3 days after last drug usage by enzyme-multiplied immuno-ssay technique or GC/MS and up to 7 days by radioimmunoassay.52 Itay be detected up to 10 days following chronic heavy daily usage.55
bsorptionCocaine is generally very rapidly absorbed by all routes with the
xception of ingestion and topical application.41,51,52 Topical applicationroduces vasoconstriction causing delayed peak, while oral administra-
ion is delayed due to time to reach distal stomach or duodenum.520 DM, January 2009
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The bioavailability of cocaine varies depending on the route ofdministration. Intravenous and smoked cocaine may be greater than 90%ioavailable, while insufflated drug is approximately 80% bioavailable.41
ne reference states the following bioavailability data: cocaine smoked inlass pipes: 70%; cocaine smoked in corncob pipes: 60%; intranasaloute: dose dependent: 25-94%; oral: 30%.53
Table 1 shows the onset, peak action, and duration of cocaine admin-stered by the topical, intranasal, intravenous, and inhalation routes.53
istributionCocaine undergoes rapid distribution following absorption. The proteininding of cocaine is approximately 90%.41,53 The volume of distributions 1.96-2.7 L/kg in volunteer studies.51,53
Following an administration of 20 mg cocaine, the detection time inerum was 4-6 hours, and 12 hours following a 100 mg dose. BE wasound in serum for an average of 5 days in chronic cocaine users.55
etabolismCocaine undergoes metabolism through multiple enzymatic path-ays.41,51,52,55-59 The three major pathways are as follows: (a) Approx-
mately half the absorbed dose is hydrolyzed by carboxylesterase in theuman liver to form BE. It is the major metabolite following all routes ofdministration. BE may be quantified in urine after 1-4 hours and mayersist up to 144 hours.52 The reported half-lives of BE and ecgonineethyl ester (EME) are approximately 5-6 hours.57 BE has been demon-
trated to have vasoconstrictive properties; however, it does not appear toross the blood–brain barrier readily. (b) Hepatic N-demethylation ofocaine forms norcocaine, which accounts for no more than 5% ofbsorbed drug. This metabolite does cross the blood–brain barrier anday produce clinical effects similar to its parent compound. It has been
uggested that reactive cocaine metabolites are responsible for cocaine-nduced cytotoxic effects such as hepatotoxicity.58 Norcocaine can be
able 1. Onset, Peak, and Duration of Cocaine by Route
Route Onset Peak Duration
opical* Within 5 minutes — —ntranasal* Within 5 minutes 15-20 minutes 60-90 minutesntravenous 10-60 seconds 3-5 minutes 20-60 minutesnhalation 3-5 seconds 1-3 minutes 5-15 minutes
These values represent therapeutic use.
etabolized to N-hydroxynorcocaine and norcocaine nitroxide. Chemi-
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ally reactive intermediates of these compounds may covalently bond toellular proteins, causing cellular damage.52 PChE, eg, butyrylcholines-erase, reacts with cocaine to form EME. Approximately one-third tone-half of cocaine is metabolized to EME. This metabolite poorlyrosses the blood–brain barrier. It is thought that EME possesses littleharmacologic activity. It has been demonstrated that patients withenetic low PChE activity show greater sensitivity to the effects ofocaine.Other minor metabolites of cocaine that have been identified include-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine, m-
hydroxybenzoylecgonine, and norbenzoylecgonine.57,59 In one study-hydroxybenzoylecgonine was the most prevalent and abundantinor metabolite.59
A clinically significant interaction occurs between cocaine and simul-aneously ingested ethanol.41,52,53 Transesterification of these two com-ounds produces cocaethylene, also known as ethyl cocaine, and benzo-lethylecgonine. The duration of effect of cocaethylene is longer thanocaine, with a half-life of 148 � 15 minutes. It may be moreuphorigenic and reinforcing than cocaine, while demonstrating similaroxicity.52
Other multiple metabolic pathways have been identified. For instance,moked crack cocaine yields the metabolites anhydroecgonine methylster (AEME) or methylecgonide, methylecgonidine, and carbomethoxy-ycloheptatriene derivatives.52,54,58 Measurement of this metabolite cane used as a means of determining the route of administration followingocaine use. It should be noted that AEME may be formed in the injectionort of most gas chromatographs; this test is not a unique identifier forocaine smokers.54 AEME, which is an end product of pyrolysis duringmoking, may produce bronchospasm as a result of muscarinic effects.
xcretionLittle cocaine is eliminated unchanged in the urine (approximately.5-20%).52 Unchanged cocaine may be detected in urine up to 24-36ours. Following metabolism, the two major metabolites of cocainexcreted in the urine are BE and EME. EME and BE, which is furtheretabolized to ecgonine, account for 80-90% of urinary metabolites in
umans. One to 3% of urinary metabolites are the N-demethylationroducts ecgonine, norbenzoylecgonine, and norecgonine.52 Fecal excre-ion represents a minor route of elimination of cocaine and its metabo-ites.51
In one study, following single-dose cocaine administration by the
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ntravenous, intranasal, and smoked routes, cocaine and BE sho-ed average detection times in oral fluid of 4.7, 6.3, and 4.1 hours (overall
verage equals 5.0 hours) for cocaine and 6.7, 8.7, and 5.0 hours (overallverage equals 6.8 hours) for BE.56 Detection time of BE in urine to autoff concentration of 100 ng/mL was 47.4, 48.5, and 44.2 hours with anverall average of 46.7 hours.56 Repeated cocaine dosing extendedverage oral fluid cocaine detection times by a factor of approximately 4nd for BE by a factor of 7. BE detection times were only extended by aactor of 2 in urine. The authors explained this observation in that cocaines a lipophilic substance more easily stored in bodily tissues than the moreater-soluble BE metabolite following repeated dosing.In a study published in 2007, it was shown that ecognine appears later
han the other metabolites in the urine and can be detected up to 80 hourshen the smoked cocaine dose is 20-40 mg.57 EME had the longestetection time of up to 164 hours following a 40 mg dose and using autoff concentration of 10 ng/mL.
oxicity
ardiacChest pain is the most frequent cocaine-related symptom and accounts
or up to 40% of cocaine-related ED visits. Chest pain following use cane caused by several factors such as myocardial infarction and aorticissection. Chest pain can also be dependent on the route of drug use, ie,nhalation can cause pneumomediastinum and pneumothorax. Intrave-ous injection can cause septic emboli, which can manifest as chest painnd other cardiopulmonary symptoms. The cocaine-associated chest painrial has been the largest retrospective multicenter study of patientsresenting to EDs with chest pain after cocaine use. The study found thencidence of cocaine-associated myocardial infarction ranged from 0 to1%, with pain frequently described as substernal pressure and associatediaphoresis and shortness of breath. Patients ranged in age from 19 to 40ho most commonly smoked cigarettes and repeatedly used cocaine.ost commonly these individual experienced chest pain about 60 minutes
fter use and pain lasted up to 120 minutes. The period for cocaine-ssociated myocardial infarction can persist for weeks following cessa-ion of the drug.37 With the use of Holter monitors in patients admitted to
detoxification center, spontaneous episodes of ST-segment elevationccurred for up to 6 weeks after cessation of cocaine use.60 Theechanism for this may be because during cocaine withdrawal there is a
opamine-depleted state that results in intermittent coronary spasm. It has
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lso been postulated that increased adrenergic receptor sensitivity andatecholamine replenishment during withdrawal time may also contributeo myocardial/coronary sensitivity.Cocaine-related cardiovascular events include angina pectoris, myocar-ial infarction, cardiomyopathy, and sudden death from cardiac causes.he occurrence of myocardial infarction after cocaine use is unrelated to
he amount ingested, route of ingestion, or frequency of use. There is noausal relationship between casual users and habitual users.61 Youngerersons presenting with chest pain, dilated cardiomyopathy, myocarditis,r cardiac arrhythmias to EDs should be asked whether they have usedocaine.62,63 Avoidance of clot-busting drugs in the setting of cocaine-nduced ischemia is prudent, as these drugs carry an extra risk of cerebralemorrhage in patients who have elevated blood pressure secondary toocaine use.64 Of patients with nontraumatic chest pain, 14-25% in urbanospitals and 7% in suburban hospitals have detectable levels of cocainer cocaine metabolites in their urine.65 Approximately 6% of patientseen in the ED with cocaine-associated chest pain have enzymaticvidence of myocardial infarction.65 This was reinforced in a prospectiveulticenter evaluation of cocaine-associated chest pain.66 Patients who
resent with myocardial infarction are at highest risk the first 24 hoursfter cocaine use.67 Patients may also present with atypical chest pain orhest pain that is delayed for hours to days after their most recent use.65
he pathogenesis of cocaine-related myocardial ischemia and infarctions most likely multifactorial and can include increased oxygen demand,asoconstriction of the coronary arteries that can be marked, andnhanced platelet aggregation and thrombus formation. Cocaine directlynduces and causes an increase in the three major determinants ofyocardial oxygen demand: the heart rate, systemic arterial pressure, and
eft ventricular contractility. Although cocaine caused vasoconstriction inoth healthy and diseased coronary vessels, its effect is most pronouncedn the diseased vessels.68 This of course leaves those patients withnderlying atherosclerotic coronary artery disease at greater risk for anschemic event after cocaine use. Cocaine-induced vasoconstriction of theoronary arteries is mostly a result of stimulation of coronary arteriallpha-adrenergic receptors. This action can be reversed with phentol-mine (an alpha-adrenergic antagonist)69-71 and has been shown to bexacerbated by propanolol (a beta-adrenergic antagonist). Cocaine alsoauses increased endothelial production of endothelin (a potent vasocon-trictor) and decreased production of nitric oxide (a potent vasodilator),ll of which may promote vasoconstriction. Aside from the effects of cell
ediators on vasospasm, various neurotransmitters in the form of4 DM, January 2009
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atecholamines also contribute to the cardiac toxicity of cocaine. (Cat-cholamines are hormones that are released by the adrenal glands inituations of stress such as psychological stress or low blood sugar levels.atecholamines include epinephrine (adrenaline), norepinephrine (nor-drenaline), and dopamine, all of which are produced from phenylalaninend tyrosine). Vasoconstriction is caused by preventing the reuptake ofatecholamines in the CNS and stimulating the release of norepinephrinerom adrenergic nerve terminals. Norepinephrine (or noreadrenaline)ncreases myocardial oxygen demand and coronary artery spasm. Thepasm decreases the size of vessels leading to myocardial infarction. Thisbviously occurs with greater incidence in those vessels that are alreadyiseased. This effect is seen more often in chronic users due to acceleratedoronary atherosclerosis and increased platelet aggregation as aforemen-ioned. With chronic use, dopamine stores in the peripheral nerve terminalre depleted. With depletion of these stores is cardiovascular sensitivity toatecholamines, which results in a variant of angina-like syndrome andtypical chest pain with ST elevations that may develop with cocaineithdrawal as seen in some detoxification patients.72 For the most part
ocaine users who present with chest pain do so within an hour aftersing, when the blood concentration of cocaine is the highest. At this timehe coronary artery diameter is directly proportional to the drug concen-ration, ie, as drug concentration increases, the diameter of coronaryessels gets smaller and then returns to baseline as concentration of drugeclines. Even with this said, onset of chest pain symptoms can occureveral hours after cocaine use when blood concentration of the drug isery low or even undetectable. This is a slightly different mechanism thanhe aforementioned action of the coronary vessels. The delayed onset ofhest pain is due to cocaine’s metabolites (benzoylecgonine and ecgonineethyl ester). In summary, the delayed or recurrent vasoconstriction of
he coronary arteries appears to be related to major metabolites ofocaine, therefore, causing myocardial ischemia or infarction severalours after ingestion.67 Aside from vasoconstriction, cocaine may inducehrombus formation via enhanced platelet activation, aggregability, andncreasing plasminogen-activator inhibitor.73-76 All of the aforemen-ioned have caused premature atherosclerotic coronary artery disease aseen in postmortem studies of chronic, long-term cocaine users.77 Furthertudies have shown that the progression of atherosclerosis can be causedy cocaine’s ability to cause structural defects in the endothelial cellarrier, thereby increasing its permeability to low-density lipoproteins
nd enhancing endothelial adhesion molecules.78,79M, January 2009 25
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reatment of Myocardial Ischemia and InfarctionUse of oxygen, aspirin, nitrates, and benzodiazepines is recommendedn all patients with cocaine-induced ischemic changes. Aspirin is used tonhibit platelet aggregation. Nitrates reverse cocaine-induced hyperten-ion and vasoconstriction of the coronary arteries and are the agents ofhoice for these patients. Verapamil and cardizem also ameliorateasoconstrictive effects and are of benefit. Nifedipine should not be useds this agent may potentiate seizures and death. Benzodiazepines (ie,orazepam and Diazepam) are recommended to control cocaine-inducedympathetic tone such as heart rate and the systemic arterial pressure.ocaine-induced vasoconstriction or the coronary arteries can be reversedith phentolamine, an alpha-adrenergic antagonist. Beta-blockers shouldot be used in the setting of cocaine-induced vasoconstriction as it mayorsen the coronary artery spasm. Pharmacologic effects of cocaine
nclude both alpha- and beta-receptor stimulation. Beta-stimulation leadso vasodilatation of the coronary arteries; therefore, using a beta-blockers counterintuitive and may block this vasodilatation. This has beeneasured physiologically by reduced coronary blood flow and increased
oronary vascular resistance. There is some evidence that the benefit ofeta-blockers with the reduction of myocardial infarction may offset theisk of coronary artery spasm due to unopposed alpha-effects of co-aine.80 Thrombolytics should be avoided in patients with cocaine-relatednfarction because of the increased risk of bleeding in these patients asell as the unreliable electrocardiographic criteria to identify myocardial
nfarction.61 Hypertension in the setting of the cocaine patient is causedy alpha-mediated vasoconstriction secondary to norepinephrine gener-ted by the CNS and responds to benzodiazepines (benzos) as well.enzos are useful with or without chest pain. If benzos fail to control theypertension, then nitrates can be used. In the event of a contraindicationo nitrates, phentolamine is the next agent of choice, which blocks theasomotor effects of norepinephrine.
ysrhythmiasDysrhythmias have a wide range of types, varying from bradycardias to
achydysrhythmias, depending on the quantity of cocaine used. Lowoses of cocaine are more commonly associated with bradycardias,hereas high doses are associated with all types of tachydysrhythmias, ie,
inus tachycardia (tach), atrial fibrillation (A-fib)/atrial flutter (A-flutter),
upraventricular tachycardias, premature ventricular contractions (PVCs),6 DM, January 2009
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ccelerated idioventricular, ventricular tachycardia (V-tach), torsades deointes, and ventricular fibrillation (V-fib).Bradycardia may be secondary to stimulation of vagal nuclei of therain, myocardial infarction, and acidosis. Tachycardias may be causedy cocaine’s ability to stimulate central and peripheral sympatheticystem, hyperacidosis, and other effects, ie, catecholamines.72 The effectsf endogenous catecholamines are potentiated, yielding tachycardia,ypertension, vasoconstriction, and increased myocardial consumption.eople who abuse cocaine are exposed to very high levels of circulationatecholamines as approximately 48 mg of cocaine more than doubledirculating levels of norepinephrine. However, most cocaine-relatedysrhythmic fatalities occur in patients with low or moderate levels ofocaine use. This suggests that the mechanism of death may be differentn low-level cocaine users, in which sudden death may be a result ofdrenergic effects and long-term catecholamine toxicity. In rat studies,ong-term use of cocaine markedly increased norepinephrine content ofhe left ventricle. This brings attention the fact that long-term cocainesers may also accumulate excess norepinephrine and may be at risk foralignant arrhythmias. A physiologic attempt to decrease sympathetic
one secondary to chronic cocaine stimulation has also been found in theresence of increased ventricular catecholamine concentrations.81 Highoses of cocaine have been shown to cause infranodal and intraventricularonduction delays as well as lethal ventricular dysrhythmias secondary torolonged QRS and QT intervals. These effects are similar to type IA andC antidysrhythmic agents and may be mediated by the local anestheticroperties that result in sodium channel blockade. This may be the reasonscalating doses of cocaine yield direct myocardial depressant effects.82
reatmentSinus tachycardia is treated with observation and benzodiazepines. If
he tachycardia continues, then initiation of verapamil or cardizem shoulde used. Ventricular arrhythmias are thought to be due to cocaine’s effectn the sodium channels. Sodium bicarbonate is the general treatment forodium channel blockade; therefore, the ventricular arrhythmia mayespond to this. Lidocaine may also be of use due to its competition withocaine for fast sodium channel binding kinetics on the sodium channel.RS duration will shorten as lidocaine displaces cocaine from sodium
hannels. Using lidocaine in combination with benzodiazepines seems toe the best combination. Torsades is treated with intravenous magnesiumulfate and overdrive pacing if necessary as per protocol even without
ocaine. Cocaine-induced atrial tachycardias respond to benzos byM, January 2009 27
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educing sympathetic tone. If this fails, diltiazem and verapamil should besed as first-line agents. Adenosine is not useful with cocaine-inducedupraventricular tachycardias. V-tach should be treated with defibrillationer advanced cardiac life support (ACLS) protocol.
ardiomyopathyDilated cardiomyopathy is the most common form of cardiomyopathy
een in chronic cocaine users. The mechanism is unclear, but it is thoughto develop from recurrent or diffuse ischemia or from a direct effect onontractility unrelated to ischemia.83,84
ortic DissectionAortic dissection is a known complication of cocaine use and is thought
o occur due to increased shear forces on the vascular wall produced byhe drug. Most patients with aortic dissection also had underlyingypertension and cocaine-induced vascular damage.
ulmonary EffectsThe pulmonary vasculature is innervated by adrenergic nerves with
lpha- and beta-adrenergic receptors on the vascular smooth muscle.Adrenergic nerves release norepinephrine as the neurotransmitter for theympathetic nervous system. The sympathetic system activates andrepares the body for vigorous muscular activity, stress, and emergencies.here are at least two adrenergic receptor sites (alpha or beta). Norepi-ephrine activates primarily alpha-receptors and epinephrine activatesrimarily beta-receptors, although it may also activate alpha-receptors.timulation of alpha-receptors is associated with constriction of smalllood vessels in the bronchial mucosa and relaxation of smooth musclesf the intestinal tract. Beta-receptor activation relaxes bronchial smoothuscles, which cause the bronchi of the lungs to dilate.) Cocaine has been
hown to cause adrenergic agonists responses in the pulmonary circula-ion. Intrapulmonary arteries are more sensitive to this than extrapulmo-ary segments. Therefore, the effects of cocaine on the pulmonaryasculature may be mediated by the effect on alpha-adrenergic receptors.ocaine-induced pulmonary edema may result from changes in centraldrenergic outflow. Increased adrenergic outflow therefore could affectulmonary vasculature permeability.85 Pulmonary effects of cocaine cane dependent on the route of use, ie, smoking crack has the greatestulmonary effects, which includes acute bronchoconstriction. The bron-hoconstriction is found to be mediated by either foreign material or
irect injury.86 In general, acute cocaine lung injury can cause a wide8 DM, January 2009
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ariety of lung complications aside from bronchoconstriction, to includehe following: exacerbation of asthma, pneumothorax, pneumomediasti-um, diffuse alveolar hemorrhage, recurrent pulmonary infiltrates withosinophilia, Goodpasture’s syndrome, bronchiolitis obliterans, acuteung injury, and possibly, upper airway burns and abscess formation.Chronic pulmonary effects have not been shown to have significant
ffects on lung mechanics. There is some evidence that chronic cocainemokers may be at increased risk for lung cancers. This has been shownue to early cellular abnormalities in the bronchial epithelium.82
ocaine-Associated RhabdomyolysisCase reports have suggested a syndrome associated with chronic use of
ocaine, which includes rhabdomyolysis and excited delirium. Excitedelirium can be described as a prolonged period of increasingly bizarreehavior, usually over several days or weeks. In those who haveonsumed cocaine or amphetamines, the course can last several hours.Those signs/symptoms typically associated with excited delirium are as
ollows: bizarre and violent behavior, most commonly violence towardslass, removal of clothing, public nudity (even in cold weather), aggres-ion, hyperactivity, paranoia, incoherent speech or shouting, increasedtrength, imperviousness to pain, and hyperthermia. In early reports ofocaine-associated rhabdomyolysis in 1987, there have been manyescriptions of similar syndromes in the literature. This has includedocaine-induced delirium. Because these two cocaine-associated condi-ions exhibit many similar characteristics, including hyperthermia, bizarrend psychotic behavior, and hyperactivity, it can be concluded that theyre different stages in the same pathologic process, ie, cocaine-associatedhabdomyolysis and excited delirium.Long-term cocaine use more so than short-term cocaine use placesersons at risk for excited delirium and cocaine-associated rhabdomyol-sis. This is due to alterations in dopamine function on a more chronicasis that can affect the physiology of skeletal muscle.81 Rhabdomyolysiss also caused by skeletal muscle ischemia through the same mechanismhat affects other vascular beds. Renal failure and myoglobinuria occur as
sequelae for rhabdomyolysis as would be expected via any mecha-ism.82 Hyperthermia is also a contributing factor and a marker of severeoxicity and aside from rhabdomyolysis can cause disseminated intravas-ular coagulation (DIC), acidosis, hepatic injury, and renal failure.emperatures can run as high as 45.6°C. The hyperthermia can bettributed to increased dopamine neurotransmission, as dopamine is
nown to play a role in regulation of core body temperature. ThisM, January 2009 29
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ncrease in dopamine is also responsible for excited delirium that canccompany cocaine use. Dopamine 2 receptors are involved withecreases in core temperature. In excited delirium the number of D2eceptors in the hypothalamus is substantially reduced, thereby caus-ng hyperthermia, although hyperthermia is not a necessary componentor the induction of rhabdomyolysis.87 Aberrant processing of dopa-ine as well as changes in dopamine processing can be attributed to
hronic cocaine use, yielding symptoms of increased creatine kinasend paranoid psychosis that persists long after cessation of cocainese. The proposed mechanism of cocaine-associated rhabdomyolysiss the blockade of synaptic catecholamine reuptake and induction ofdrenergic agonism, yielding vasoconstriction and ischemia, causinguscle tissue damage. It has also been proposed that cocaine for theost part may directly increase the release of catecholamines. This
hen causes increased intracellular calcium or vasoconstriction ofnknown mechanism. These mechanisms explain the induction ofhabdomyolysis, although it does not explain the onset of delirium. Airect toxic effect of cocaine upon muscle tissue has been proposedased on animal models. Cocaine has been shown to induce creatineinase leakage from muscle tissue, although the exact mechanism isnknown.88,89 The victims of cocaine-associated rhabdomyolysis areimilar to victims of fatal excited delirium with regard to age, gender,nd race; both groups were found to be different from victims of acuteocaine toxicity with respect to these demographics variables. Studiesf victims with fatal excited delirium linked black race, male gender,nd use of cocaine via a route other than nasal insufflation with aattern of chronic and intense cocaine use. Many of the articlesiscussing rhabdomyolysis describe patterns of chronic cocaine use oringing that preceded the onset of rhabdomyolysis. Therefore the datauggest that victims of cocaine-associated rhabdomyolysis and fatalxcited delirium had a pattern of chronic cocaine use more frequentlyhan those deaths associated with acute cocaine toxicity. The connec-ion of cocaine-associated rhabdomyolysis, excited delirium, andhronic cocaine use is supported by a temporal coincidence betweenhe appearance of these two conditions and the epidemic of crackocaine use in the U.S. Crack is associated more often with chronicinge use than insufflation of cocaine hydrochloride. To support this,he first report of excited delirium and early description of rhabdomy-lysis came from Miami. Miami was the first metropolitan area in the.S. to experience an influx of cheap and highly pure cocaine
ydrochloride in the early 1980s due to transport routes through the0 DM, January 2009
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aribbean.90 Treatment of hyperthermia, psychomotor agitation, andonvulsions is achieved with rapid cooling and generous use ofenzodiazepines in escalating doses. Diazepam and Lorazepam are thereferred agents. If a total dose of 8-10 mg Lorazepam fails to controleizures, barbiturates such as pentobarbital (short-acting) or amobar-ital may be used. These agents demonstrate synergistic effects withenzodiazepines. If this approach fails, neuromuscular blockadevecuronium preferred agent) and intubation as per any uncontrollableeizure are then recommended.
reatment of RhabdomyolysisTreatment consists of maintaining urine output as 3 mL/kg/h andreventing the precipitation of myoglobin in the kidneys and infusion ofV fluids, mannitol, and even hemodialysis. The use of urine alkaliniza-ion should be cautioned as this may slow cocaine excretion but is anxcellent modality to promote myoglobin and uric acid excretion.
erinatal Cocaine ExposureEarly pregnancy is a time of rapid embryonic development, making the
etus especially vulnerable to toxic insult. Most abnormalities of the fetusre determined in the very early stages of pregnancy before the motheray even know she is pregnant. The most sensitive period for causing
irth defects is the 5th to the 10th week after the last menstrual period (therd to 8th week of gestation). Damage to the fetus also includes injurieshat are not birth defects, such as low birth weight, premature delivery,espiratory problems, developmental delays, or even death. Only aftermplantation does the embryo begin to receive toxins, as well as nutrients,rom the woman’s bloodstream. Cocaine transport in the first and earlyecond trimester may in part be across the placental chorion. Lacking akin barrier, the fetus (mid-pregnancy) may come in direct contact withigh concentrations of cocaine in the amniotic fluid. Studies withregnant guinea pigs receiving daily subcutaneous cocaine from day 50 to9 showed amniotic fluid cocaine levels at the end of the exposure periodere three to four times higher than fetal plasma cocaine concentrations.he in vitro half-life of cocaine in amniotic fluid is 30 times longer than
he in vivo plasma half-life. This raises the possibility that the fetus mayngest cocaine by swallowing amniotic fluid or absorb through the skin orucosa in contact with the amniotic fluid.85 Cocaine is cleared slowly
rom the amniotic fluid, prolonging exposure during critical fetal neuro-ransmitter formation.91
Studies of fetal cocaine exposure and newborn neurologic function have
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btained conflicting results. Studies of fetal cocaine exposure andewborn neurologic function have obtained conflicting results in thatome studies identify abnormalities, others find no differences betweenewborns that were assessed by a pediatric neurologist that was blindedo exposure study. Gestational age was determined by Ballard’s exami-ation. To determine the effects of prenatal cocaine exposure on intra-terine growth and neurologic function in infants, 253 infants wererospectively evaluated shortly after birth. Cocaine exposure was deter-ined for the last trimester by radioimmunoassay of maternal hair.ompared with unexposed controls, cocaine-exposed infants exhibitedigher rates of intrauterine growth retardation (24% versus 8%), smallead circumference (�10th percentile) (20% versus 5%), and neuro-ogic abnormalities: global hypertonia (32% versus 11%), coarseremor (40% versus 15%), and extensor leg posturing. Therefore thistudy concluded that adverse neonatal effects associated with fetalocaine exposure follow a dose–response relationship: newborns withigher levels of prenatal cocaine exposure show higher rates ofmpairments in fetal head growth and abnormalities of muscle tone,ovements, and posture. Significant relationships between cocaine
xposure and these outcomes remain in controlled analyses.92
Prenatal cocaine exposure has been linked to numerous adverse neona-al outcomes, affecting fetal growth (ie, low birth weight, intrauterinerowth retardation, and small head size) and neurobehavior. Theseeurobehavior effects span the gamut from no abnormalities to impair-ents in arousal, neurological function, neurophysiological function, and
tate regulation. Strokes and possibly seizures are also noted. Dose–esponse effects of fetal cocaine exposure on fetal growth and neonataleurobehavior are reported using quantitative methods. In early infancy,rritability and hypertonia are also described. Most cocaine associationsre transient and resolve in infancy and early childhood. Whether suchransient abnormalities place infants at increased risk for later neurode-elopmental impairments is not known. Controlled studies have found noognitive differences related to prenatal cocaine exposure among toddlersr school-age children, except as mediated through effects on headrowth. Anecdotally, cocaine-exposed children seem to suffer fromeurobehavioral abnormalities, but to date controlled studies have notstablished an association between cocaine and behavioral disorders,xcept for inattentiveness. Despite encouraging reports, the question ofhether cocaine exerts long-term adverse effects on the developinguman nervous system has not yet been resolved, largely because of the
imitations of existing studies.932 DM, January 2009
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Prenatal cocaine exposure lowers IQ and language performance scoresnd results in thousands of new children each year who enter schooleeding special education services, according to a study by three Brownrofessors. An analysis of information on more than 800 school-agedhildren in eight studies found that cocaine-exposed children had subtlyower intelligence scores than other children, placing them at risk forailure in school. It is estimated that up to 80,550 new cocaine-exposedhildren annually will need special education services at a cost of up to352 million.The results are in sharp contrast to the popular image of hopelesslyrain-damaged cocaine-exposed children predicted a few years ago.owever, the results still show that prenatal cocaine use significantly
ffects society. Children in the cocaine-exposed group, on average, hadQ scores 3.26 points lower than the control group. The cocaine effectas even more pronounced on language skills. For many people three IQoints would be negligible—the average IQ is 100 points. However, thatubtle difference must be taken in context with cocaine use as thosehildren are also likely to be living in poverty and have other known riskactors that depress IQ scores, therefore making the results more dra-atic. Between 1688 and 37,612 children each year will need special
ducation services because of the IQ difference caused by cocainexposure. Because those services cost $6,335 for each child per year, thateans an additional $4 to $80 million in special education costs annually.hose numbers are even larger for children whose speaking ability isffected. There will be 4432 to 80,550 children who will need specialducation services each year, at a cost of $22 to $352 million, accordingo the study. Although the effects of cocaine exposure on intelligencere more subtle than originally believed, the results are significant.A study to identify associations between cocaine exposure duringregnancy and medical conditions in newborn infants from birth throughospital discharge was carried out by Bauer and coworkers with theollowing results. Cocaine-exposed infants were about 1.2 weeksounger, weighed 536 g less, measured 2.6 cm shorter, and had headircumference 1.5 cm smaller than nonexposed infants. Central andutonomic nervous system symptoms were more frequent in the exposedroup: jittery/tremor, high-pitched cry, irritability, excessive suck, hype-alertness, and autonomic instability. No differences were detected inrgan systems by ultrasound examination. Exposed infants had morenfections’ including hepatitis, syphilis, and human immunodeficiencyirus exposure; were less often breastfed; had more child protective
ervices referrals; and were more often not living with their biologicalM, January 2009 33
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other.94 Cocaine alters the placental production of prostaglandins initro, favoring thromboaxane production, which may cause vasoconstric-ion and decrease uteroplacental blood flow.95
uthor’s ExcerptI currently work in a busy urban Emergency Department in Chicago.he amount of positive cocaine results is staggering. The ages of use areore commonly in late 30’s to many patients in their 60’s. Most of these
atients have underlying medical conditions including end-stage renalisease (on hemodialysis), heart, and lung disease. Most of the visits areor cocaine exacerbation of an underlying chronic condition, addingxponentially to health care dollars.
REFERENCES1. Altman AJ, Albert DM, Fournier GA. Cocaine’s use in ophthalmology: our 100
year heritage. Surv Ophthalmol 1985;29:300-7.2. Gay GR, Inaba DS, Sheperd CW, et al. Cocaine: history, epidemiology, human
pharmacology and treatment. A perspective on a new debut for an old girl. ClinToxicol 1975;8:149-78.
3. Piek J, Lidke G, Terberger Th. Chirurgische Universitatsklinik Rostock, Abeilungfur Neurochirurgie, Rostock. Ancient trephinations in Neolithic people—evidencefor stone age neurosurgery? Nat Proc hdl:10101/npre.2008.1615.1. Posted 21 Feb2008.
4. Monardes N. Joyfull Newes Out of the Newe Founde Worlde. New York, NY:Alfred Knopf, 1925.
5. May CD. How Coca-Cola obtains its coca. The New York Times, July 1 1998.Accessed December 4, 2007.
6. Benson D. Coca kick in drinks spurs export fears. The Washington Times, April 202004.
7. Johnson C. The Legal Importation of Coca Leaf. http://www.uic.edu/classes/osci/osci590/9_3%20The%20Legal%20Importation%20of%20Coca%20Leaf.htm.Accessed on February 11, 2007.
8. Brecher EM, Editors of Consumer Reports Magazine. The Consumers UnionReport on licit and illicit drugs. Consumer Reports Magazine, 1972.
9. 63rd Congress. The Harrison Narcotic Act (1914). Public Law No. 223, approvedDecember 17, 1914.
0. National Survey on Drug Use and Health. http://www.samhsa.gov/. Accessed June1, 2008.
1. Drug Abuse Warning Network, 2004: National estimates of drug-related emer-gency department visits. U.S. Department of Health and Human Services. Sub-stance Abuse and Mental Health Services Administration. http://DAWNinfo.samhsa.gov/.
2. Office of Applied Studies. Year-end 1999 emergency department data from drugabuse warning network. Rockville, MD: Substance Abuse and Mental Health
Services Administration, August 2000. DHSS publication no. (SMA)00-3462.4 DM, January 2009
1
1
1
1
1
11
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
D
3. Traub SJ, Hoffman RS, Nelson LS. Body packing—the internal concealment ofillicit drugs. New Engl J Med 2003;349(26):2519-26.
4. Caruana DS, Weinbach B, Goerg D, et al. Cocaine-packet ingestion. Ann InternMed 1984;100(1):73-4.
5. Kashani J, Ruha AM. Methamphetamine toxicity secondary to intravaginal bodystuffing. J Toxicol Clin Toxicol 2004;42(7):987-9.
6. Shanti CM, Lucas CE. Cocaine and the critical care challenge. Crit Care Med2003;31(6):1851-9.
7. Boghdadi MS, Henning RJ. Cocaine: pathophysiology and clinical toxicology.Heart Lung 1997;26(6):466-83.
8. Warner EA. Cocaine abuse. Ann Intern Med 1993;119(3):226-35.9. Shannon M. Clinical toxicity of cocaine adulterants. Ann Emerg Med
1988;17(11):1243-7.0. Koren G, Klein J, Forman R, et al. Hair analysis of cocaine: differentiation between
systemic exposure and external contamination. J Clin Pharmacol 1992;32:671-5.1. Chychula NM, Okore C. The cocaine epidemic: a comprehensive review of use,
abuse and dependence. Nurse Pract 1990;15(7):31-9.2. Stephens BG, Jentzen JM, Karch S, et al. Criteria for the interpretation of cocaine
levels in human biological samples and their relation to the cause of death. Am JForensic Med Pathol 2004;25(1):1-10.
3. Jatlow P. Cocaethylene: pharmacologic activity and clinical significance. TherDrug Monit 1993;15(6):533-6.
4. McCance EF, Price LH, Kosten TR, et al. Cocaethylene: pharmacology, physiologyand behavioral effects in humans. J Pharmacol Exp Ther 1995;274:215-23.
5. McKinney CD, Postiglione KF, Herold DA. Benzocaine-adulterated street cocainein association with methemoglobinemia. Clin Chem 1992;38(4):596-7.
6. Prasad RS, Kodali VR, Kuraijam GS, et al. Acute confusion and blindness fromquinine toxicity. Eur J Emerg Med 2003;10:353-6.
7. Wood DM, Webster E, Martinez D, et al. Case report: survival after deliberatestrychnine self-poisoning, with toxicokinetic data. Crit Care 2002;6(5):456-9.
8. O’Callaghan WG, Joyce N, Counihan HE. Unusual strychnine poisoning and itstreatment: report of eight cases. BMJ 1982;285:478.
9. Ursitti F, Klein J, Koren G. Confirmation of cocaine use during pregnancy: acritical review. Ther Drug Monit 2001;23(4):347-53.
0. Burke WM, Ravi NV, Dhopesh V, et al. Prolonged presence of metabolite in urineafter compulsive cocaine use. J Clin Psychiatry 1990;51(4):145-48.
1. Weiss RD, Gawin FH. Protracted elimination of cocaine metabolites in long-term,high-dose cocaine abusers. Am J Med 1988;85:879-80.
2. Baselt RC, Baselt DR. Little cross-reactivity of local anesthetics with Abuscreen,EMIT d.a.u., and TDX immunoassays for cocaine metabolite (letter). Clin Chem1987;33(5):747.
3. Mazor SS, Mycyk MB, Wills BK, et al. Coca tea consumption causes positive urinecocaine assay. Eur J Emerg Med 2006;13:340-1.
4. Mikkelsen SL, Ash KO. Adulterants causing false negatives in illicit drug testing.Clin Chem 1988;34(11):2233-6.
5. Karch SB. Introduction to the forensic pathology of cocaine. Am J Forensic MedPathol 1991;12(2):126-31.
6. Gruszecki AC, Robinson CA, Embry JH, et al. Correlation of the incidence of
M, January 2009 35
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
3
cocaine and cocaethylene in hair and postmortem biologic samples. Am J ForensicMed Pathol 2000;21(2):166-71.
7. Roldan CJ. Toxicity, Cocaine. http://www.emedicine.com/med/topic400.htm. Ac-cessed June 1, 2008.
8. Catterall WA, Mackie K. Local anesthetics. In: Brunton LJ, Parker KL, Buxton I,et al., editors. Goodman and Gilman’s the Pharmacological Basis of Therapeutics,11th ed. New York, NY: McGraw Hill, 2006.
9. Leshner AI. Molecular mechanisms of cocaine addiction (letter). New Engl J Med1996;335(2):128-9.
0. Knuepfer M. Cardiovascular disorders associated with cocaine use: myths andtruths. Pharmacol Ther 2003;97(3):181-222.
1. Hoffman RS. Cocaine. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, et al.,editors. Goldfrank’s Toxicologic Emergencies, 8th ed. New York, NY: McGrawHill, 2006. p. 1133-46.
2. Lason W. Neurochemical and pharmacological aspects of cocaine-induced sei-zures. Pol J Pharmacol 2001;53:57-60.
3. O’Dell L, George FR, Ritz MC. Antidepressant drugs appear to enhance cocaine-induced toxicity. Exp Clin Psychpharmacol 2000;8(1):133-41.
4. Liu D, Hariman RJ, Bauman JL. Cocaine concentration-effect relationship in thepresence and absence of lidocaine: evidence of competitive binding betweencocaine and lidocaine. J Pharmacol Exp Ther 1996;276(2):568-77.
5. McCord J, Hani J, Hollander JE. Management of cocaine-associated chest pain andmyocardial infarction: a scientific statement from the American Heart Associationacute cardiac care committee of the council on clinical cardiology. Circulation2008;117(14):1897-907.
6. Tella SR, Schindler CW, Goldberg SR. Cocaine: cardiovascular effects inrelation to inhibition of peripheral neuronal monoamine uptake and centralstimulation of the sympathoadrenal system. J Pharmacol Exp Ther1993;267(1):153-62.
7. Dattilo PB, Hailpern SM, Fearon K, et al. Beta blockers are associated with reducedrisk of myocardial infarction after cocaine use. Ann Emerg Med 2008;51(2):117-25.
8. Laizure SC, Mandrell T, Gades NM, et al. Cocaethylene metabolism and interac-tion with cocaine and ethanol: role of carboxylesterases. Drug Metab Dispos2003;31(1):16-20.
9. Foltin W, Fischman MW, Pedroso JJ, et al. Marijuana and cocaine interactions inhumans: cardiovascular consequences. Pharmacol Biochem Behav 1987;28(4):459-64.
0. Lexi-comp Online. Lexi-Interact. 1978-2008 Lexi-Comp, Inc. Retrieved June2008.
1. Jeffcoat A, Perez-Reyes M, Hill J. Cocaine disposition in humans after intravenousinjection, nasal insufflation (snorting), or smoking. Am Soc Pharmacol ExpTherapeut 17(2):153-9.
2. Klasco RK, editor. Cocaine. POISINDEX System. Thomson Healthcare, Green-wood Village, CO (Edition expired 9/2008).
3. Leikin J, Paloucek F. Cocaine. Poisoning and Toxicology Handbook, 4th ed. New
York, NY: CRC Press, 2008. p. 213.6 DM, January 2009
5
5
5
5
5
5
6
6
6
6
66
6
6
6
6
7
7
7
7
7
D
4. Baslet R. Cocaine. Disposition of Toxic Drugs and Chemicals in Man, 6th ed.Foster City, CA: Biomedical Publications, 2002. p. 247-53.
5. Maurer H, Sauer C, Theobald D. Toxicokinetics of drugs of abuse: current knowledgeof the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine,heroin, morphine, and codeine. Drug Monit 2006;28(3):447-53.
6. Jufer R, Walsh S, Cone E, et al. Effect of repeated cocaine administration ondetection times in oral fluid and urine. J Anal Toxicol 2006;30:458-62.
7. Huestis M, Darwin W, Shimomura E, et al. Cocaine and metabolites urinaryexcretion after controlled smoked administration. J Anal Toxicol 2007;21:462-68.
8. Cone E, Tsadic A, Oyler H, et al. Cocaine metabolism and urinary excretion afterdifferent routes of administration. Ther Drug Monit 1998;20(5):556-60.
9. Kolbrich E, Barnes A, Gorelick D, et al. Major and minor metabolites of cocainein human plasma following controlled subcutaneous cocaine administration. J AnalToxicol 2006;30:501-11.
0. Nedamanee K, Gorelick DA, Josephson MA, et al. Myocardial ischemia duringcocaine withdrawal. Ann Int Med 1989;111:876-80.
1. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. New EnglJ Med 2001;345:351-8.
2. Tennant CC. Cocaine use and cardiovascular complications. Department of AgedCare and Rehab, Hornsby Kur-Ring-Gai Hospital, Hornsby, NSW. Med J Aust2002;177(5):260-2.
3. Hollander J, Todd K, Green G, et al. Chest pain associated with cocaine: Anassessment of prevalence in suburban and urban emergency departments. AnnEmerg Med 1995;26:671-6.
4. http://www.cnn.com/2008/HEALTH/03/17/cocaine.heart.ap/index.html.5. Hollander JE. Management of cocaine-associated myocardial ischemia. N Engl
J Med 1995;333:1267-72.6. Hollander JE, Hoffman RS, Gennis P, et al. Prospective multicenter evaluation of
cocaine-associated chest pain. Cocaine Associated Chest Pain (COCHPA) StudyGroup. Acad Emerg Med 1994;1:330-9.
7. Mittleman MA, Mintzewr D, Maclure M, et al. Triggering of myocardial infarctionby cocaine. Circulation 1999;99:2737-41.
8. Lange RA, Cigarroa RG, Yancy CW Jr, et al. Cocaine-induced coronary arteryvasoconstriction. N Engl J Med 1989;321:1557-62.
9. Flores ED, Lange RA, Cigarrora RG, et al. Effects of cocaine on coronary arterydimensions in atherosclerotic coronary artery disease: enhanced vasoconstriction atsites of significant stenoses. J Am Coll Cardiol 1990;16:74-9.
0. Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine induced coronaryvasoconstriction by beta-adrenergic vasoconstriction by beta-adrenergic blockade.Ann Int Med 1990;112:897-903.
1. Mo W, Singh AK, Arruda JA, et al. Role of nitric oxide in cocaine induced acutehypertension. Am J Hypertens 1998;11:708-14.
2. Roldan CJ, Habal R. Toxicity, Cocaine, WebMD, Sep 22, 2006. http://www.emedicine.com/med/topic400.htm.
3. Rezkella SH, Mazza JJ, Kloner RA, et al. Effects of cocaine on human platelets inhealthy subjects. Am J Cardiol 1993;72:243-6.
4. Kugelmass AD, Oda A, Monahan K, et al. Activation of human platelets by
cocaine. Circulation 1993;88:876-83.M, January 2009 37
7
7
7
7
7
8
88
8
8
8
8
8
8
8
9
9
9
9
9
9
3
5. Rinder HM, Ault KA, Jatlow PI, et al. Platelet alpha-granule release in cocaineusers. Circulation 1994;90:1162-7.
6. Moliterno DJ, Lange RA, Gerard RD, et al. Influence of intranasal cocaine onplasma constituents associated with endogenous thrombosis and thrombolysis.Am J Med 1994;96:492-6.
7. Kolodgie FD, Virmani R, Cornhill JF, et al. Increases in atherosclerosis and adventitialmast cells in cocaine abusers: an alternative mechanism of cocaine-associated coronaryvasospasm and thrombosis. J Am Coll Cardiol 1991;17:1553-60.
8. Kolodgie FD, Wilson PS, Mergner WJ, et al. Cocaine-induced increase in thepermeability function of human vascular endothelial cell monolayers. Exp MolPathol 1999;66:109-22.
9. Gan X, Zhang L, Berger O, et al. Cocaine enhances brain endothelial adhesionmolecules and leukocyte migration. Clin Immunol 1999;91:68-76.
0. Dattilo PB, Fearon K, Sohal D. B-blockers are associated with reduced risk ofmyocardial infarction after cocaine use. Ann Emerg Med 2008;51:117-25.
1. Burnett LB. Toxicity, Cocaine. http://www.emedicine.com/EMERG/topic102.htm.2. Goldfrank LR, Flomenbaum NE, Lewin NA, et al. Goldfranks toxicologic emergen-
cies, 7th ed. New York: McGraw-Hill, 2002. p. 1007-8.3. Weiner RS, Lockhart JT, Schwartz RG. Dilated cardiomyopathy and cocaine abuse.
Am J Med 1986;81:699-701.4. Johnson MN, Karas SP, Hursey TL, et al. Cocaine binging produces left ventricular
dysfunction. Circulation 1989;80:94(suppl 21):15.5. Konkol RJ, Olsen GD. Prenatal cocaine exposure. Boca Raton, FL: CRC Press,
1996. p. 47, 84.6. Tashkin DP, Kleerup EC, Koyal SN, et al. Acute effects of inhaled and IV cocaine
on airway dynamics. Chest 1996;110:904-10.7. Callaway C, Clark RF. Hyperthermia in psychostimulant overdose. Ann Emerg
Med 1994;24:68-76.8. Pagala M, Amaladevi B, Azad D, et al. Effect of cocaine in leakage of creatine
kinase from isolated fast and slow muscles of rat. Life Sci 1995;57:1569-78.9. Brazeau G, McArdles A, Jackson M. Effects of cocaine on leakage of creatine
kinase from skeletal muscle; in vitro and in vivo studies in mice. Life Sci1995;57:751-6.
0. Ruttenber JA, McNally HB, Weitl CV, et al. Cocaine-associated rhabdomyolysisand excited delirium: different stages of the same syndrome. Am J Forensic MedPathol 1999;20(2):120-7.
1. Woods JR Jr. Maternal and transplacental effects of cocaine. Ann NY Acad Sci1998;846(1):1-11.
2. Chiriboga CA, Brust JC, Bateman D, et al. Dose-response effect of fetal cocaineexposure on newborn neurologic function. Pediatrics 1999;103(1):79-85.
3. Chiriboga CA. Neurological correlates if fetal cocaine exposure: cocaine effects onthe developing brain. Ann NY Acad Sci 1998;846:109-25.
4. Bauer CR, Shankaren S, Bada HS, et al. Acute neonatal effects of cocaine exposureduring pregnancy. Arch Pediatr Adolesc Med 2005;159:824-34.
5. Manju M, Chmielowiec S, Andres R, et al. Cocaine alters placental production ofthromboxane and prostacyclin. Am J Obstet Gynecol 1994;171:965-9.
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