Cocaine: History, Social Implications, and ToxicityA Review

Rachel A. Goldstein, MSc, DO, FACOI, Carol DesLauriers, PHARM D, and Anthony M. Burda, BS PHARM, DABAT Background/History of Use
Cocaine is a naturally occurring substance found in the leaves of the Erythroxylum coca plant. The plant is endogenous to South America, Mexico, Indonesia, and the West Indies. Peoples of ancient civilizations used the coca leaves for religious and ceremonial reasons. Remains of coca leaves in the cheeks of Peruvian mummies have been found.1 These ancient civilizations used a mixture of coca leaves and saliva as a local anesthetic for ritual trephinations.2,3 Trephinations involved removing a circular section of bone from the skull. It is not entirely clear whether these procedures were done for ritual purposes or for treatment of various conditions including head trauma. When the Spaniards conquered South America in 1492, they ignored the claims of the power the leaf gave and abolished its use. Shortly after this, they discovered the claims of the coca leaf; it became legal and a 10% tax was added to the value of the crop. The Spanish needed native workers for the silver mines after they conquered the New World. Work in the silver mines was arduous and taking coca reduces appetite and increases physical stamina. Hence there was a great surge in coca use and the number of coqueros (coca-chewers).4 It was not until the mid-1800s that a PhD student achieved the isolation of the cocaine alkaloid in Germany. In 1884 it was used as the rst anesthetic. Albert Niemann, the student who perfected the purication process, noted its anesthetic properties. He noted its bitter taste and the resultant peculiar numbness when applied to the tongue. By the late 1800s, cocaine was widely used for its analgesic properties to include nerve block anesthesia, epidural, and spinal anesthesia. In 1863, a chemist named Angelo Mariani marketed a wine called Vin Mariani. When
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combined with alcohol, it yielded a further potently reinforcing compound, now known to be cocaethylene. Thus cocaine was a popular ingredient in wines, notably Vin Mariani. Coca wine received endorsement from prime ministers, royalty, and even the Pope. He used the ethanol in wine as a solvent and extracted the cocaine from the coca leaves. Vin Mariani was competing with beverages sold in the United States such as John Styth Pembertons original 1886 recipe for CocaCola. At that time, it was sold as a patent medicine. It was promoted as a temperance drink offering the virtues of coca without the vices of alcohol. The new beverage was invigorating and popular. By 1906, when the Pure Food and Drug Act was passed, the company began using decocainized leaves. Originally, the stimulant mixed in the beverage was coca leaves from South America, which the drug cocaine is derived from. In addition, the drink was avored using kola nuts, also acting as the beverages source of caffeine. Pemberton called for 5 oz of coca leaf per gallon of syrup, a signicant dose, whereas, in 1891, Candler claimed his formula (altered extensively from Pembertons original) contained only one-tenth of this amount. Coca-Cola did once contain an estimated 9 mg of cocaine per glass, but in 1903 it was removed. After 1904, Coca-Cola started using, instead of fresh leaves, spent leavesthe leftovers of the cocaine-extraction process with cocaine trace levels left over at a molecular level. To this day, Coca-Cola uses as an ingredient a nonnarcotic coca leaf extract prepared at a Stepan Company plant in Maywood, New Jersey. In the United States, Stepan Company is the only manufacturing plant authorized by the federal government to import and process the coca plant, which it obtains mainly from Peru and, to a lesser extent, Bolivia. Besides producing the coca avoring agent for Coca-Cola, Stepan extracts cocaine from the coca leaves, which it sells to Mallinckrodt Inc., a St. Louis pharmaceutical manufacturer that is the only company in the United States licensed to purify the product for medicinal use.5 Stepan buys about 100 metric tons of dried Peruvian coca leaves each year, said Marco Castillo, spokesman for Perus state-owned National Coca Co.6,7 In 1879 cocaine was used to treat morphine addiction. In 1885 the U.S. manufacturer Parke-Davis sold various forms of cocaine including powder, cigarettes, and even a cocaine mixture for injection, complete with the needle. In the U.S., cocaine was sold over the counter until 1916. It was widely used in tonics, toothache cures, patent medicines, and chocolate cocaine tablets. Prospective buyers were advised (in the words of pharmaceutical rm Parke-Davis) that cocaine could make the coward brave, the silent eloquent, and render the sufferer insensitive to pain.
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Sigmund Freud, the father of psychoanalysis, in the early 1880s began to experiment with cocaine. At a time when he was undergoing a low period in his life, he reported that cocaine lifted his spirits and took his mind off his professional and nancial difculties. He sent cocaine to his ance, telling her it would make her strong and give her cheeks a red color. Freud was to play a signicant role in the development of the Western cocaine industry. I take very small doses of it regularly and against depression and against indigestion, and with the most brilliant success, he observed. Drug giants Merck and Parke-Davis both paid Freud to endorse their rival brands. He published several papers on cocaine, his most famous and well-read Umber coca (1884). An excerpt reads:
A few minutes after taking cocaine, one experiences a certain exhilaration and 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 cold water; it feels warm on the lips and cold in the throat. One other occasion the predominant feeling is a rather pleasant coolness in the mouth and throat. Often, at the outset of the cocaine effect, the subjects alleged that they experienced an intense feeling of heat in the head. I noticed this in myself as well in the course of some later experiments, but on other occasions it was absent. In only two cases did coca give rise to dizziness. On the whole the toxic effects of coca are of short duration, and much less intense than those produced by effective doses of quinine or salicylate of soda; they seem to become even weaker after repeated use of cocaine.

By the turn of the twentieth century cocaines addictive properties became well-known and The Harrison Narcotics Tax Act was passed in 1914 and included cocaine among other substances. The Harrison bill however did not appear to be a prohibition law at all. Its ofcial title was: An Act to provide for the registration of, with collectors of internal revenue, and to impose a special tax upon all persons who produce, import, manufacture, compound, deal in, dispense, sell, distribute, or give away opium or coca leaves, their salts, derivatives, or preparations, and for other purposes. Far from appearing to be a prohibition law, the Harrison Narcotic Act on the surface was merely a law for the orderly marketing of opium, morphine, heroin, and other drugsin small quantities over the counter, and in larger quantities on a physicians prescription. Indeed, the right of a physician to prescribe was spelled out in apparently unambiguous terms: Nothing contained in this section shall apply . . . to the dispensing or distribution of any of the aforesaid drugs to a patient by a physician, dentist, or veterinary surgeon registered under this Act in the course of his professional practice only.8,9 In the 1920s cocaine use declined, and that decline was to become more so in the 1930s, when amphetamine (speed) became popular among drug users.
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Todays Use of Cocaine

In 2006, six million Americans age 12 and older had abused cocaine in any form and 1.5 million had abused crack at least once in the year prior to being surveyed.10 The National Institute on Drug Abuse (NIDA)funded 2007 Monitoring the Future Study showed that 2.0% of 8th graders, 3.4% of 10th graders, and 5.2% of 12th graders had abused cocaine in any form and 1.3% of 8th graders, 1.3% of 10th graders, and 1.9% of 12th graders had abused crack at least once in the year prior to being surveyed. Cocaine is the most frequent drug-related cause of emergency department (ED) visits in the United States. Of an estimated 106 million ED visits in the U.S. during 2004, the Drug Abuse Warning Network (DAWN) estimates that 1,997,993 (95% condence interval (CI): 1,708,205 to 2,287,781) were drug-related. Data for 2004, DAWN estimates 940,953 (CI: 773,124 to 1,108,782) drug-related ED visits involved a major substance of abuse. DAWN estimates that cocaine was involved in 383,350 (CI: 284,170 to 482,530) ED visits.11 In summary, cocaine is the most commonly used illicit drug among those seeking care in EDs or drug-treatment centers. It is the most frequent cause of drug-related deaths reported by medical examiners.12 Along with other illicit substances, cocaine is frequently used for the purposes of body packing and body stufng. While these two phrases are sometimes used interchangeably, they represent distinctly different entities. Body packers (also called mules or couriers) ingest a large amount (commonly about 1 kg, or 50-100 packets) of carefully packaged drug-containing packets, in attempts to illegally smuggle the drugs through customs and border crossings.13,14 The packets are later removed from the body through fecal elimination, and the drugs are recovered and sold. Body stuffers internally conceal fewer and more hastily packaged drug packets, in order to avoid being arrested for possession of the drug or other offenses. Body stufng of drugs may occur through oral, anal, or vaginal orices.15 Both body stuffers and packers are subject to toxicity from leakage or rupture of drug-containing packets.

Processing and Production

Most of the worlds current cocaine supply is produced in South American countries such as Peru, Colombia, Ecuador, or Bolivia.16 Colombia and Peru export the most cocaine to the United States.17 Cocaine is an alkaloid extracted from the E. coca bush, which grows in the Andes Mountains in western South America.17 Of all plants in the
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Erythroxylon genus (so named because of their reddish color), the E. coca bushs leaves yield the highest amounts of cocaine, approximately 1% by weight.1 However, cocaine is found in all parts of the coca plant. Because the amount of cocaine present in the harvested leaves decreases over time, the leaves are typically processed into cocaine paste and/or powder as soon as possible.18 To extract cocaine from the plant, the harvested leaves are soaked with solvents such as kerosene until a thick pasty substance (called cocaine paste) is isolated. This paste, which contains 40-80% cocaine, is then treated with hydrochloric acid to form cocaine hydrochloride salt (or cocaine powder) before it is exported from South America.16,19 Cocaine hydrochloride is water soluble and is well absorbed through snorting through the nasal mucosa, and by intravenous injection. It is also absorbed through all mucous membranes. When snorted, a typical line of cocaine contains approximately 50-100 mg of parent compound, although it is often cut or adulterated with other substances.20 Because it has a high melting point and decomposes when burned, cocaine hydrochloride cannot be smoked.18 Cocaine hydrochloride must be converted into an alkaline form of either freebase or crack cocaine before it can be smoked. Both freebase and crack cocaine share the same chemical form and are synthesized from the same coca plant but have different physical characteristics and are prepared using different techniques.18 To make freebase cocaine, cocaine hydrochloride powder is dissolved in water and a base (such as ammonia) is added. Ether or a similar solvent is added to dissolve the cocaine base. The free base is then extracted from the ether solution through evaporation. Freebase cocaine is subject to adulteration; many local anesthetics and stimulants can be extracted through the ether solution as well.19 If the freebase is removed before the extraction process is completed, some residual ether may remain in the drug. This remaining ether is highly ammable and may cause facial burns when the freebase is smoked.16 This risk of re limits the popularity of freebase as a smokable drug. Crack cocaine is also synthesized from cocaine hydrochloride powder, which has been dissolved in water. The drug is then mixed with baking soda or sodium bicarbonate and heated, which allows the cocaine base to solidify into a soft mass that hardens into a rock-like state after drying. The hard product, known as crack, is not ammable because ether is not used in its production. The name crack is derived from the cracking or popping sound heard when the drug is smoked. Crack cocaine is cheap to make, has a high prot margin, and is highly addictive when smoked.
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Because of these characteristics, dealers more frequently sell it than cocaine hydrochloride or freebase.21 Like freebase and cocaine hydrochloride, crack cocaine is also frequently adulterated with other substances. Crack is sold as rocks, which are off-white in color and of irregular size, approximately one-quarter to three-eighths of an inch in diameter.22 For marketing, crack cocaine is packaged into vials containing one to three rocks of the drug, which weigh 100 mg each; vials are sold for 5 to 10 dollars by street dealers.21 Currently, crack is the most commonly used form of cocaine.16 Both freebase and crack cocaine have a lower melting point than cocaine hydrochloride; thus, both formulations can be easily smoked in pipes (glass crack pipes or traditional pipes) or cigarettes.18 Smoking causes a rapid absorption of the drug into the central nervous system (CNS), which causes intense euphoria and subsequent craving sensations. Cocaine is sometimes also mixed with heroin and sold on the street; this combination is referred to as a speedball. Other street names for cocaine include Snow, Nose Candy, Bernice, Dama Blanca, Baseball, and Gold Dust.

Cocaine Adulterants
Alcohol and cocaine are commonly used together; between 50 and 90% of cocaine users also concurrently ingest ethanol during their binges.23 Cocaine users frequently report that the use of ethanol and cocaine together prolongs the high and minimizes the dysphoric feelings associated with the use of cocaine. These reports may be due to the presence of cocaethylene, which is formed in vivo after use of concurrent use of alcohol and cocaine. In the presence of ethanol, cocaine is transesteried by a hepatic carboxyesterase into cocaethylene. Like cocaine, cocaethylene causes increases in heart rate and blood pressure as well as euphoric effects.24 In rats, cocaethylene induces reinforcing properties and increased motor activities.23 Cocaethylene has an elimination half-life of 150 minutes (compared to approximately 90 minutes for cocaine), which explains the prolonged euphoric effects reported after use of cocaine and ethanol.17 The sympathomimetic effects of cocaine and ethanol may be additive and contribute to the high mortality rate observed in individuals who use the two drugs together.24 In addition to promoting the formation of cocaethylene, the use of ethanol and cocaine together also inhibits cocaine metabolism. This may explain the higher concentrations of cocaine that are frequently noted in patients with concurrent cocaine and ethanol abuse.23 Analysis of street samples of cocaine has found an average purity rate
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of 40%.19 Therefore, adulterants represent more than half of the composition of all cocaine sold. Adulterants are added to cocaine to promote the perceived potency of the drug, to increase the volume of the drug, or to increase the toxicity associated with the drug. Local anesthetics are among the most frequent contaminants of cocaine.19 Local anesthetics have psychoactive and reinforcing properties similar to cocaine and can thus potentiate these effects when combined along with cocaine.19 The symptoms of local anesthetic toxicity include paresthesias, tremors, and seizures, which are similar to some of the toxic effects of cocaine. The contamination of cocaine with benzocaine has resulted in methemoglobinemia.25 Many compounds are added to cocaine to increase the available volume of the drug. These include sugars, talc, and cornstarch. These compounds can have variable pharmacologic action or toxicity. Sugar can cause irritation of nasal passages when inhaled. Talc and cornstarch can cause pulmonary brosis and hypertension.19 Toxins such as quinine and strychnine are sometimes used to adulterate cocaine and other illicit drugs.19 Quinine is an alkaloid, which is used for treatment of nocturnal cramps and drug-resistant Plasmodium falciparum malaria.26 Historically, quinine has been recognized as a common contaminant of heroin. The toxicity of quinine includes gastrointestinal symptoms, cardiac dysrhythmias, and blindness. Strychnine, which has been commercially marketed in the past as a rodenticide, inhibits the neurotransmitter glycine. This causes increased neuronal activity of the CNS. Symptoms of strychnine toxicity include muscle spasms and seizures during which the patient remains conscious.27,28 Treatment of patients with strychnine poisoning is supportive and symptomatic; benzodiazepines have been successfully used in the past to treat the convulsions associated with strychnine toxicity.29

Laboratory Detection of Cocaine

Testing for cocaine and its metabolites can be performed on many biologic specimens. Blood, urine, hair, perspiration, meconium, saliva, and amniotic uid have all been used for testing of cocaine use. The initial screening test for cocaine is usually performed on urine. Urine is commonly used for initial screening because samples are easy to obtain, the testing is noninvasive, and many cost-effective commercial kits are available.29 Urine testing is commonly performed by the enzyme-multiplied immunoassay technique; other analytic screening methods include radioimmunoassay and thin-layer chromatography. Since cocaine has a short elimination half-life of about 1 hour, urine
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assays for cocaine use typically measure the cocaine metabolite benzoylecgonine, which has an elimination half-life of 6 hours.18 Urine immunoassays have a lower limit of detection of approximately 300 ng/mL. Positive results are commonly conrmed with gas chromatography/mass spectroscopy (GC/MS), which can detect as little as 1 ng/mL of benzoylecgonine.18 Urine testing for benzoylecgonine is typically reported to give positive results for 1 to 2 days after recent cocaine use. However, two case series have shown that patients who use high amounts of cocaine ( 0.5 g per day) over many years can have positive urine screens for weeks after their last use of the drug.30 For example, a patient who used up to 30 g of cocaine a day for 10 years had a positive urine test for 22 days after his last use of cocaine.31 This may be secondary to altered kinetics of cocaine tissue deposition and metabolic rates in patients who use high amounts of the drug. Although urine testing is a frequently used screening method by hospitals for cocaine abuse, limitations exist in terms of how results (both positive and negative) should be interpreted. With the exception of excessively high doses of prilocaine, no drugs other than cocaine and its metabolites are recognized to cause a false-positive urine immunoassay for cocaine.32 Ingestion of coca tea, which is made from the leaves of the E. coca plant and is sold over the internet and in some restaurants in the United States, can result in a positive urinary immunoassay for cocaine.33 Both Drano (or bleach) and sodium chloride solution, when added to urine assays for benzoylecgonine, can cause false-negative results; other adulterants such as vinegar, liquid hand soap, Visine, lemon juice, and goldenseal tea did not cause a false-negative benzoylecgonine assay when added to urine.34 A false-negative result may also occur if urine is tested very soon after cocaine use, before metabolism to benzoylecgonine has occurred. Additionally, since urine assays usually screen for cocaines inactive metabolite benzoylecgonine, a positive urine screen cannot be used to extrapolate the degree of intoxication after cocaine use. Laboratory tests for cocaine and its metabolites are best used as a marker for recent use, but not abuse or intoxication. Blood testing for cocaine is typically performed using GC/MS. Cocaine in blood samples undergoes spontaneous hydrolysis to benzoylecgonine unless the samples are preserved with sodium uoride or a similar pseudocholinesterase inhibitor.22 Changes in pH and temperature can also affect breakdown of cocaine in these specimens.29 Newborns achieve higher blood levels of cocaine than adults after the same amount of the drug is used; this is likely due to lower levels of plasma pseudocholinesterase (and thus decreased ability to metabolize cocaine) in newborns.35
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Adults with plasma cholinesterase deciency, which can affect up to 4% of the population in its mild forms, can also have prolonged high blood cocaine levels due to the same decreased metabolic activity. Pseudocholinesterase deciency does not appear to confer a higher rate of mortality after cocaine use.35 Analysis of hair can be used to determine exposure to cocaine. The main advantage of testing hair over blood or urine is that drugs persist in hair for longer time intervals than they are present in blood and urine.36 In addition, collection of hair is noninvasive and easy to perform; approximately 50-100 strands are required for analysis of a hair sample.33 Both cocaine and benzoylecgonine deposit in the hair shaft and can be measured approximately 1 day after intranasal cocaine use.29 Cocaethylene has also been reported to be present in hair samples of cocaine users, although the signicance of this is uncertain.36 Because hair grows at a xed rate (approximately one-half inch each month), analysis of cocaine patterns along the length of a hair sample can be used to determine whether use was episodic or chronic. External contamination of hair has been shown to occur after passive exposure to crack cocaine vapors. Hair washing after passive exposure results in an undetectable level of cocaine in the hair.20 Patients with passive exposures to cocaine do not have measurable amounts of cocaine metabolites such as benzoylecgonine in their hair samples.20 Thus, the presence of benzoylecgonine in a hair sample can be used to differentiate passive exposure to cocaine from illicit use of the drug. In certain inner-city areas, the prevalence of maternal cocaine use is estimated to be between 10 and 30%. Since maternal cocaine use has multiple medical, social, and economic implications, determination of fetal exposure to cocaine is important. Both meconium and amniotic uid have been utilized as markers of intrauterine fetal cocaine exposure. Analysis of meconium can detect drug exposure as early as 17 weeks of gestation; collection of meconium is limited by its small time period for collection (the rst 3 days of life).29 Amniotic uid, collected either at fetal delivery or during amniocentesis, can also be used to measure fetal exposure to cocaine. Amniotic uid examination can provide a qualitative, but not quantitative, measurement of cocaine exposure.29 Similar to meconium testing, amniotic uid analysis is limited by its small window of collection time. A coca leaf typically contains between 0.1 and 0.9% cocaine. If chewed in the leaf form, it rarely presents the user with any social or medical problems. When the leaves are soaked and mashed, however, cocaine is extracted as a coca-paste. The paste is 60 to 80% pure. It is usually
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FIG 1. Chemical structure of (A) cocaine, (B) ecgonine, and (C) atropine. (Color version of gure is available online.)

exported in the form of the salt, cocaine hydrochloride. This is the powdered cocaine most common, until recently, in the West. Drug testing for cocaine aims to detect the presence of its major metabolite, the inactive benzoylecgonine. Benzoylecgonine can be detected for up to 5 days in casual users. In chronic users, urinary detection is possible for as long as 3 weeks.37

Chemistry/Pharmacology
As a local anesthetic, cocaine blocks voltage-gated sodium channels in the neuronal membrane. This inhibits depolarization and blocks both the initiation and the conduction of nerve impulses. Cocaine exhibits its vasoconstrictive action therapeutically by inhibiting local reuptake of norepinephrine.38 Cocaine is an ester type of local anesthetic; it is an ester of methyl-ecgonine and benzoic acid.38,16 Ecgonine is also the parent compound of atropine16 (Fig 1). The ester link is rapidly hydrolyzed by plasma cholinesterases, which contributes to cocaines short half-life (see kinetics section).38 Structures of the local anesthetics are shown in Fig 2 for comparison. All local anesthetics comprise both a hydrophobic and a hydrophilic moiety
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FIG 2. Chemical structure of (A) lidocaine, (B) mepivacaine, (C) prilocaine, and (D) procaine. (Color version of gure is available online.) 16 DM, January 2009

separated by an ester (eg, cocaine) or amide (eg, lidocaine) linkage. Increased lipophilicity leads to a greater afnity for the sodium channel receptor and increased toxicity of the drug. Local anesthetics with a larger molecule size results in increased duration of time on the receptor; smaller molecules escape the receptor site more rapidly. Local anesthetics can also block the potassium channel, especially in large doses.38,39 Of the local anesthetics, cocaine stands alone in causing marked behavioral responses, including euphoria and addictive behavior.40 Cocaine is abused in either of two following chemical forms.

Cocaine Hydrochloride (also known as coke)

The cocaine alkaloid is extracted from the leaves and then converted to cocaine hydrochloride using hydrochloric acid.16,41 This crystalline white powder is usually insufated but can also be dissolved in water and injected. Cocaine salt is not smokable, as it breaks down during pyrolysis.

Free Base
Cocaine hydrochloride is dissolved in water, mixed with a strong base, and heated. The cocaine base is extracted by the addition of an organic solvent. The free base will dry into a hard rock upon evaporation. Crack cocaine is then usually smoked out of a glass pipe.16,41 The word crack comes from the cracking or popping noise it makes when it is smoked.

Mechanism of Toxic Action

Cocaine exhibits profound CNS and cardiovascular toxicity. Cocaine and some of its metabolites exert activity at many receptors throughout the CNS and cardiovascular system. Receptor activity is described below.

CNS
Cocaine blocks the reuptake of catecholamines (dopamine, norepinephrine) and serotonin.16,41 Increased serotenergic activity can result in seizures and may be involved in the addiction and reward effects of cocaine.16,40,42,43 It is excess dopamine activity, however, that is believed to cause the majority of CNS symptoms, both the desired and the toxic effects. CNS symptoms include euphoria, increased self-condence and alertness at lower doses, and aggressiveness, disorientation, and hallucinations at higher doses. Repetitive use of cocaine results in the depletion of the dopamine stores. This can result both in an intense craving for cocaine and in what is referred to as a washed-out syndrome.16,41 Patients experiencing washed-out syndrome experience lethargy and anhedonia and have difculty with muscle movement.41 Cocaine also
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affects the heat regulation center in the hypothalamus and can cause hyperthermia,40 which is considered a poor prognostic indicator. Effects on excitatory amino acids/glutamatergic system and muscarinic and sigma receptors are also believed to contribute to CNS toxicity.16,40,42

Cardiovascular
Cocaines reuptake inhibition of biogenic amines results in a powerful sympathomimetic effect. As a sodium channel blocking drug, cocaine is classied as a type I antidysrhythmic agent.16,41 Cocaine exhibits slow on off kinetics at the sodium channel. Ventricular arrhythmias and wide QRS complex or QT/QTc prolongation can occur.16,40,44 Cocaine is also known to cause vasoconstriction, which can result in hypertension, cerebrovascular accident (CVA), cardiac ischemia, and end-organ and tissue infarcts. There are several mechanisms and mediators responsible for cocaine-induced vasoconstriction: increased neuronal norepinephrine, a direct effect of benzoylecgonine on the blood vessels (possibly calcium mediated, see kinetics section for a more detailed description of the metabolite benzoylecgonine), increased levels of endothelin-1 (a powerful vasoconstrictor), and decreased production of nitric oxide (a vasodilator).45,46

Drug Interactions
Lidocaine
Lidocaine is also a local anesthetic and possesses the same sodium channel blockade action as cocaine. However, lidocaine exhibits fast on off binding kinetics and is thought to displace cocaine from the sodium channel receptor through competitive binding. It has been used successfully to shorten cocaine-induced QRS prolongation.44 One animal study suggested that lidocaine exacerbated cocaine-induced seizures and arrhythmias; however, the American Heart Association (AHA) recommends use of lidocaine for persistent ventricular arrhythmias.45 (Lidocaine may be less useful in a patient with low heart rate.)44

Class Ia and Ic Antiarrhythmics

Additive sodium channel blockade can exacerbate or precipitate cocaine-induced QRS prolongation or cardiac arrhythmias.

Beta-Adrenergic Antagonists
The use of beta-adrenergic antagonists in the setting of cocaine toxicity has produced increased vasoconstriction with resultant increase in blood pressure, coronary artery spasm, increased seizure frequency, and in18 DM, January 2009

creased mortality.44,47 These effects are caused by unopposed alphaadrenergic effect when the beta-adrenergic receptors are blocked. Dual alpha- and beta-blockers (eg, labatelol) have also caused toxicity. A recent retrospective study found that the administration of beta-adrenergic antagonists were associated with reduction in incidence of myocardial infarction after cocaine use.44 However, all toxicology reference texts as well as the AHA advise that beta-antagonists are contraindicated in the setting of cocaine-induced toxicity. Deaths from cocaine-associated myocardial infarction are exceedingly low per the AHA.

Succinylcholine
Plasma cholinesterase (PChE) metabolizes both succinylcholine and cocaine. Using any drug that is metabolized by PChE can potentially increase the toxicity of cocaine or the other PChE substrate.

Phenothiazines/Butyrophenones
Animal studies have shown that these drugs enhance toxicity and/or death. These medications can affect body temperature, precipitate dystonic reactions and seizures, and contribute to cardiotoxicity (by additionally blocking sodium and potassium channels).41

Antidepressant Drugs
Monoamine oxidase inhibitors (eg, tranylcypromine) inhibit metabolism of endogenous catecholamines and would be expected to have an additive effect on cocaines catecholamine-induced toxicity. Selective serotonin reuptake inhibitors (SSRIs) (eg, uoxetine), which inhibit reuptake of serotonin, have increased the incidence of seizures in the setting of cocaine toxicity. Antidepressants with dopamine reuptake inhibition (eg, bupropion) have increased the incidence of death in the setting of cocaine toxicity.43

Drugs of Abuse
Cocaine is often abused with other substances, and treating clinicians should anticipate synergistic toxicity when used with the following substances.40 Ethanol. Through a transesterication reaction, cocaine and ethanol combine to produce an entirely new compound known as cocaethylene (benzoylethylecgonine). Cocaethylene has a much longer duration of action than cocaine and is neuro- and cardiotoxic.41,48 Cocaethylene can cause enhanced cardiodepression by affecting calcium and is thought to be less potent than cocaine for causing tachycardia and euphoria.40
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Marijuana. Simultaneous use of cocaine and marijuana signicantly increases heart rate than either drug alone (up to 50 bpm).49,50 These effects are noted especially during exertion.40,50 One study also suggested an increase in blood pressure of up to 20 mm Hg with concomitant use.49 Suggestions for this mechanism include increased cocaine absorption through cannabinoid-induced nasal epithelium vasodilation, and an additive effect in catecholamine concentration.50 Nicotine. Using nicotine and cocaine concomitantly increases heart rate and vasoconstriction more so than either cocaine or nicotine alone.45 The cocaine and nicotine combination is also postulated to affect dopamine and euphoria, but to what extent remains unclear.40 Cocaine is also a CYP3A4 substrate, and a strong CYP2D6 inhibitor. Drugs that inhibit CYP3A4 may increase cocaine toxicity (eg, azole antifungals, ciprooxacin, verapamil, propofol, erythromycin/clarithromycin) and cocaine may increase toxicity of CYP2D6 substrates (eg, risperidone, ritonavir, dextromethorphan, amphetamines, tricyclic antidepressants, codeine/hydrocodone/oxycodone).50

Pharmacokinetics
Summary
The pharmacokinetics of cocaine are dependent on multiple factors such as physical/chemical form, route of administration, genetics, and concurrent consumption of alcohol. Cocaine, chemically known as benzoylmethylecgonine, exists in several forms, ie, cocaine hydrochloride, a salt form, and free base alkaloid, also known as crack.44 Cocaine may be administered via multiple routes: insufation (snorting), intravenous injection, smoking, ingestion, or mucousal application. The half-life of cocaine is approximately 0.7-1.5 hours and most of the administered dose is eliminated within a few hours.51-54 Cocaine and its major metabolite, benzoylecgonine (BE), may be detected in urine, blood, saliva, and meconium. BE may be detected in urine up to 3 days after last drug usage by enzyme-multiplied immunoassay technique or GC/MS and up to 7 days by radioimmunoassay.52 It may be detected up to 10 days following chronic heavy daily usage.55

Absorption
Cocaine is generally very rapidly absorbed by all routes with the exception of ingestion and topical application.41,51,52 Topical application produces vasoconstriction causing delayed peak, while oral administration is delayed due to time to reach distal stomach or duodenum.52
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Table 1. Onset, Peak, and Duration of Cocaine by Route Route Topical* Intranasal* Intravenous Inhalation Onset Within 5 minutes Within 5 minutes 10-60 seconds 3-5 seconds Peak 15-20 minutes 3-5 minutes 1-3 minutes Duration 60-90 minutes 20-60 minutes 5-15 minutes

*These values represent therapeutic use.

The bioavailability of cocaine varies depending on the route of administration. Intravenous and smoked cocaine may be greater than 90% bioavailable, while insufated drug is approximately 80% bioavailable.41 One reference states the following bioavailability data: cocaine smoked in glass pipes: 70%; cocaine smoked in corncob pipes: 60%; intranasal route: dose dependent: 25-94%; oral: 30%.53 Table 1 shows the onset, peak action, and duration of cocaine administered by the topical, intranasal, intravenous, and inhalation routes.53

Distribution
Cocaine undergoes rapid distribution following absorption. The protein binding of cocaine is approximately 90%.41,53 The volume of distribution is 1.96-2.7 L/kg in volunteer studies.51,53 Following an administration of 20 mg cocaine, the detection time in serum was 4-6 hours, and 12 hours following a 100 mg dose. BE was found in serum for an average of 5 days in chronic cocaine users.55

Metabolism
Cocaine undergoes metabolism through multiple enzymatic pathways.41,51,52,55-59 The three major pathways are as follows: (a) Approximately half the absorbed dose is hydrolyzed by carboxylesterase in the human liver to form BE. It is the major metabolite following all routes of administration. BE may be quantied in urine after 1-4 hours and may persist up to 144 hours.52 The reported half-lives of BE and ecgonine methyl ester (EME) are approximately 5-6 hours.57 BE has been demonstrated to have vasoconstrictive properties; however, it does not appear to cross the blood brain barrier readily. (b) Hepatic N-demethylation of cocaine forms norcocaine, which accounts for no more than 5% of absorbed drug. This metabolite does cross the blood brain barrier and may produce clinical effects similar to its parent compound. It has been suggested that reactive cocaine metabolites are responsible for cocaineinduced cytotoxic effects such as hepatotoxicity.58 Norcocaine can be metabolized to N-hydroxynorcocaine and norcocaine nitroxide. ChemiDM, January 2009 21

cally reactive intermediates of these compounds may covalently bond to cellular proteins, causing cellular damage.52 PChE, eg, butyrylcholinesterase, reacts with cocaine to form EME. Approximately one-third to one-half of cocaine is metabolized to EME. This metabolite poorly crosses the blood brain barrier. It is thought that EME possesses little pharmacologic activity. It has been demonstrated that patients with genetic low PChE activity show greater sensitivity to the effects of cocaine. Other minor metabolites of cocaine that have been identied include p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine, mhydroxybenzoylecgonine, and norbenzoylecgonine.57,59 In one study p-hydroxybenzoylecgonine was the most prevalent and abundant minor metabolite.59 A clinically signicant interaction occurs between cocaine and simultaneously ingested ethanol.41,52,53 Transesterication of these two compounds produces cocaethylene, also known as ethyl cocaine, and benzoylethylecgonine. The duration of effect of cocaethylene is longer than cocaine, with a half-life of 148 15 minutes. It may be more euphorigenic and reinforcing than cocaine, while demonstrating similar toxicity.52 Other multiple metabolic pathways have been identied. For instance, smoked crack cocaine yields the metabolites anhydroecgonine methyl ester (AEME) or methylecgonide, methylecgonidine, and carbomethoxycycloheptatriene derivatives.52,54,58 Measurement of this metabolite can be used as a means of determining the route of administration following cocaine use. It should be noted that AEME may be formed in the injection port of most gas chromatographs; this test is not a unique identier for cocaine smokers.54 AEME, which is an end product of pyrolysis during smoking, may produce bronchospasm as a result of muscarinic effects.

Excretion
Little cocaine is eliminated unchanged in the urine (approximately 9.5-20%).52 Unchanged cocaine may be detected in urine up to 24-36 hours. Following metabolism, the two major metabolites of cocaine excreted in the urine are BE and EME. EME and BE, which is further metabolized to ecgonine, account for 80-90% of urinary metabolites in humans. One to 3% of urinary metabolites are the N-demethylation products ecgonine, norbenzoylecgonine, and norecgonine.52 Fecal excretion represents a minor route of elimination of cocaine and its metabolites.51 In one study, following single-dose cocaine administration by the
22 DM, January 2009

intravenous, intranasal, and smoked routes, cocaine and BE showed average detection times in oral uid of 4.7, 6.3, and 4.1 hours (overall average equals 5.0 hours) for cocaine and 6.7, 8.7, and 5.0 hours (overall average equals 6.8 hours) for BE.56 Detection time of BE in urine to a cutoff concentration of 100 ng/mL was 47.4, 48.5, and 44.2 hours with an overall average of 46.7 hours.56 Repeated cocaine dosing extended average oral uid cocaine detection times by a factor of approximately 4 and for BE by a factor of 7. BE detection times were only extended by a factor of 2 in urine. The authors explained this observation in that cocaine is a lipophilic substance more easily stored in bodily tissues than the more water-soluble BE metabolite following repeated dosing. In a study published in 2007, it was shown that ecognine appears later than the other metabolites in the urine and can be detected up to 80 hours when the smoked cocaine dose is 20-40 mg.57 EME had the longest detection time of up to 164 hours following a 40 mg dose and using a cutoff concentration of 10 ng/mL.

Toxicity
Cardiac
Chest pain is the most frequent cocaine-related symptom and accounts for up to 40% of cocaine-related ED visits. Chest pain following use can be caused by several factors such as myocardial infarction and aortic dissection. Chest pain can also be dependent on the route of drug use, ie, inhalation can cause pneumomediastinum and pneumothorax. Intravenous injection can cause septic emboli, which can manifest as chest pain and other cardiopulmonary symptoms. The cocaine-associated chest pain trial has been the largest retrospective multicenter study of patients presenting to EDs with chest pain after cocaine use. The study found the incidence of cocaine-associated myocardial infarction ranged from 0 to 31%, with pain frequently described as substernal pressure and associated diaphoresis and shortness of breath. Patients ranged in age from 19 to 40 who most commonly smoked cigarettes and repeatedly used cocaine. Most commonly these individual experienced chest pain about 60 minutes after use and pain lasted up to 120 minutes. The period for cocaineassociated myocardial infarction can persist for weeks following cessation of the drug.37 With the use of Holter monitors in patients admitted to a detoxication center, spontaneous episodes of ST-segment elevation occurred for up to 6 weeks after cessation of cocaine use.60 The mechanism for this may be because during cocaine withdrawal there is a dopamine-depleted state that results in intermittent coronary spasm. It has
DM, January 2009 23

also been postulated that increased adrenergic receptor sensitivity and catecholamine replenishment during withdrawal time may also contribute to myocardial/coronary sensitivity. Cocaine-related cardiovascular events include angina pectoris, myocardial infarction, cardiomyopathy, and sudden death from cardiac causes. The occurrence of myocardial infarction after cocaine use is unrelated to the amount ingested, route of ingestion, or frequency of use. There is no causal relationship between casual users and habitual users.61 Younger persons presenting with chest pain, dilated cardiomyopathy, myocarditis, or cardiac arrhythmias to EDs should be asked whether they have used cocaine.62,63 Avoidance of clot-busting drugs in the setting of cocaineinduced ischemia is prudent, as these drugs carry an extra risk of cerebral hemorrhage in patients who have elevated blood pressure secondary to cocaine use.64 Of patients with nontraumatic chest pain, 14-25% in urban hospitals and 7% in suburban hospitals have detectable levels of cocaine or cocaine metabolites in their urine.65 Approximately 6% of patients seen in the ED with cocaine-associated chest pain have enzymatic evidence of myocardial infarction.65 This was reinforced in a prospective multicenter evaluation of cocaine-associated chest pain.66 Patients who present with myocardial infarction are at highest risk the rst 24 hours after cocaine use.67 Patients may also present with atypical chest pain or chest pain that is delayed for hours to days after their most recent use.65 The pathogenesis of cocaine-related myocardial ischemia and infarction is most likely multifactorial and can include increased oxygen demand, vasoconstriction of the coronary arteries that can be marked, and enhanced platelet aggregation and thrombus formation. Cocaine directly induces and causes an increase in the three major determinants of myocardial oxygen demand: the heart rate, systemic arterial pressure, and left ventricular contractility. Although cocaine caused vasoconstriction in both healthy and diseased coronary vessels, its effect is most pronounced in the diseased vessels.68 This of course leaves those patients with underlying atherosclerotic coronary artery disease at greater risk for an ischemic event after cocaine use. Cocaine-induced vasoconstriction of the coronary arteries is mostly a result of stimulation of coronary arterial alpha-adrenergic receptors. This action can be reversed with phentolamine (an alpha-adrenergic antagonist)69-71 and has been shown to be exacerbated by propanolol (a beta-adrenergic antagonist). Cocaine also causes increased endothelial production of endothelin (a potent vasoconstrictor) and decreased production of nitric oxide (a potent vasodilator), all of which may promote vasoconstriction. Aside from the effects of cell mediators on vasospasm, various neurotransmitters in the form of
24 DM, January 2009

catecholamines also contribute to the cardiac toxicity of cocaine. (Catecholamines are hormones that are released by the adrenal glands in situations of stress such as psychological stress or low blood sugar levels. Catecholamines include epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine, all of which are produced from phenylalanine and tyrosine). Vasoconstriction is caused by preventing the reuptake of catecholamines in the CNS and stimulating the release of norepinephrine from adrenergic nerve terminals. Norepinephrine (or noreadrenaline) increases myocardial oxygen demand and coronary artery spasm. The spasm decreases the size of vessels leading to myocardial infarction. This obviously occurs with greater incidence in those vessels that are already diseased. This effect is seen more often in chronic users due to accelerated coronary atherosclerosis and increased platelet aggregation as aforementioned. With chronic use, dopamine stores in the peripheral nerve terminal are depleted. With depletion of these stores is cardiovascular sensitivity to catecholamines, which results in a variant of angina-like syndrome and atypical chest pain with ST elevations that may develop with cocaine withdrawal as seen in some detoxication patients.72 For the most part cocaine users who present with chest pain do so within an hour after using, when the blood concentration of cocaine is the highest. At this time the coronary artery diameter is directly proportional to the drug concentration, ie, as drug concentration increases, the diameter of coronary vessels gets smaller and then returns to baseline as concentration of drug declines. Even with this said, onset of chest pain symptoms can occur several hours after cocaine use when blood concentration of the drug is very low or even undetectable. This is a slightly different mechanism than the aforementioned action of the coronary vessels. The delayed onset of chest pain is due to cocaines metabolites (benzoylecgonine and ecgonine methyl ester). In summary, the delayed or recurrent vasoconstriction of the coronary arteries appears to be related to major metabolites of cocaine, therefore, causing myocardial ischemia or infarction several hours after ingestion.67 Aside from vasoconstriction, cocaine may induce thrombus formation via enhanced platelet activation, aggregability, and increasing plasminogen-activator inhibitor.73-76 All of the aforementioned have caused premature atherosclerotic coronary artery disease as seen in postmortem studies of chronic, long-term cocaine users.77 Further studies have shown that the progression of atherosclerosis can be caused by cocaines ability to cause structural defects in the endothelial cell barrier, thereby increasing its permeability to low-density lipoproteins and enhancing endothelial adhesion molecules.78,79
DM, January 2009 25

Treatment of Myocardial Ischemia and Infarction

Use of oxygen, aspirin, nitrates, and benzodiazepines is recommended on all patients with cocaine-induced ischemic changes. Aspirin is used to inhibit platelet aggregation. Nitrates reverse cocaine-induced hypertension and vasoconstriction of the coronary arteries and are the agents of choice for these patients. Verapamil and cardizem also ameliorate vasoconstrictive effects and are of benet. Nifedipine should not be used as this agent may potentiate seizures and death. Benzodiazepines (ie, Lorazepam and Diazepam) are recommended to control cocaine-induced sympathetic tone such as heart rate and the systemic arterial pressure. Cocaine-induced vasoconstriction or the coronary arteries can be reversed with phentolamine, an alpha-adrenergic antagonist. Beta-blockers should not be used in the setting of cocaine-induced vasoconstriction as it may worsen the coronary artery spasm. Pharmacologic effects of cocaine include both alpha- and beta-receptor stimulation. Beta-stimulation leads to vasodilatation of the coronary arteries; therefore, using a beta-blocker is counterintuitive and may block this vasodilatation. This has been measured physiologically by reduced coronary blood ow and increased coronary vascular resistance. There is some evidence that the benet of beta-blockers with the reduction of myocardial infarction may offset the risk of coronary artery spasm due to unopposed alpha-effects of cocaine.80 Thrombolytics should be avoided in patients with cocaine-related infarction because of the increased risk of bleeding in these patients as well as the unreliable electrocardiographic criteria to identify myocardial infarction.61 Hypertension in the setting of the cocaine patient is caused by alpha-mediated vasoconstriction secondary to norepinephrine generated by the CNS and responds to benzodiazepines (benzos) as well. Benzos are useful with or without chest pain. If benzos fail to control the hypertension, then nitrates can be used. In the event of a contraindication to nitrates, phentolamine is the next agent of choice, which blocks the vasomotor effects of norepinephrine.

Dysrhythmias
Dysrhythmias have a wide range of types, varying from bradycardias to tachydysrhythmias, depending on the quantity of cocaine used. Low doses of cocaine are more commonly associated with bradycardias, whereas high doses are associated with all types of tachydysrhythmias, ie, sinus tachycardia (tach), atrial brillation (A-b)/atrial utter (A-utter), supraventricular tachycardias, premature ventricular contractions (PVCs),
26 DM, January 2009

accelerated idioventricular, ventricular tachycardia (V-tach), torsades de pointes, and ventricular brillation (V-b). Bradycardia may be secondary to stimulation of vagal nuclei of the brain, myocardial infarction, and acidosis. Tachycardias may be caused by cocaines ability to stimulate central and peripheral sympathetic system, hyperacidosis, and other effects, ie, catecholamines.72 The effects of endogenous catecholamines are potentiated, yielding tachycardia, hypertension, vasoconstriction, and increased myocardial consumption. People who abuse cocaine are exposed to very high levels of circulation catecholamines as approximately 48 mg of cocaine more than doubled circulating levels of norepinephrine. However, most cocaine-related dysrhythmic fatalities occur in patients with low or moderate levels of cocaine use. This suggests that the mechanism of death may be different in low-level cocaine users, in which sudden death may be a result of adrenergic effects and long-term catecholamine toxicity. In rat studies, long-term use of cocaine markedly increased norepinephrine content of the left ventricle. This brings attention the fact that long-term cocaine users may also accumulate excess norepinephrine and may be at risk for malignant arrhythmias. A physiologic attempt to decrease sympathetic tone secondary to chronic cocaine stimulation has also been found in the presence of increased ventricular catecholamine concentrations.81 High doses of cocaine have been shown to cause infranodal and intraventricular conduction delays as well as lethal ventricular dysrhythmias secondary to prolonged QRS and QT intervals. These effects are similar to type IA and IC antidysrhythmic agents and may be mediated by the local anesthetic properties that result in sodium channel blockade. This may be the reason escalating doses of cocaine yield direct myocardial depressant effects.82

Treatment
Sinus tachycardia is treated with observation and benzodiazepines. If the tachycardia continues, then initiation of verapamil or cardizem should be used. Ventricular arrhythmias are thought to be due to cocaines effect on the sodium channels. Sodium bicarbonate is the general treatment for sodium channel blockade; therefore, the ventricular arrhythmia may respond to this. Lidocaine may also be of use due to its competition with cocaine for fast sodium channel binding kinetics on the sodium channel. QRS duration will shorten as lidocaine displaces cocaine from sodium channels. Using lidocaine in combination with benzodiazepines seems to be the best combination. Torsades is treated with intravenous magnesium sulfate and overdrive pacing if necessary as per protocol even without cocaine. Cocaine-induced atrial tachycardias respond to benzos by
DM, January 2009 27

reducing sympathetic tone. If this fails, diltiazem and verapamil should be used as rst-line agents. Adenosine is not useful with cocaine-induced supraventricular tachycardias. V-tach should be treated with debrillation per advanced cardiac life support (ACLS) protocol.

Cardiomyopathy
Dilated cardiomyopathy is the most common form of cardiomyopathy seen in chronic cocaine users. The mechanism is unclear, but it is thought to develop from recurrent or diffuse ischemia or from a direct effect on contractility unrelated to ischemia.83,84

Aortic Dissection
Aortic dissection is a known complication of cocaine use and is thought to occur due to increased shear forces on the vascular wall produced by the drug. Most patients with aortic dissection also had underlying hypertension and cocaine-induced vascular damage.

Pulmonary Effects
The pulmonary vasculature is innervated by adrenergic nerves with alpha- and beta-adrenergic receptors on the vascular smooth muscle. (Adrenergic nerves release norepinephrine as the neurotransmitter for the sympathetic nervous system. The sympathetic system activates and prepares the body for vigorous muscular activity, stress, and emergencies. There are at least two adrenergic receptor sites (alpha or beta). Norepinephrine activates primarily alpha-receptors and epinephrine activates primarily beta-receptors, although it may also activate alpha-receptors. Stimulation of alpha-receptors is associated with constriction of small blood vessels in the bronchial mucosa and relaxation of smooth muscles of the intestinal tract. Beta-receptor activation relaxes bronchial smooth muscles, which cause the bronchi of the lungs to dilate.) Cocaine has been shown to cause adrenergic agonists responses in the pulmonary circulation. Intrapulmonary arteries are more sensitive to this than extrapulmonary segments. Therefore, the effects of cocaine on the pulmonary vasculature may be mediated by the effect on alpha-adrenergic receptors. Cocaine-induced pulmonary edema may result from changes in central adrenergic outow. Increased adrenergic outow therefore could affect pulmonary vasculature permeability.85 Pulmonary effects of cocaine can be dependent on the route of use, ie, smoking crack has the greatest pulmonary effects, which includes acute bronchoconstriction. The bronchoconstriction is found to be mediated by either foreign material or direct injury.86 In general, acute cocaine lung injury can cause a wide
28 DM, January 2009

variety of lung complications aside from bronchoconstriction, to include the following: exacerbation of asthma, pneumothorax, pneumomediastinum, diffuse alveolar hemorrhage, recurrent pulmonary inltrates with eosinophilia, Goodpastures syndrome, bronchiolitis obliterans, acute lung injury, and possibly, upper airway burns and abscess formation. Chronic pulmonary effects have not been shown to have signicant effects on lung mechanics. There is some evidence that chronic cocaine smokers may be at increased risk for lung cancers. This has been shown due to early cellular abnormalities in the bronchial epithelium.82

Cocaine-Associated Rhabdomyolysis
Case reports have suggested a syndrome associated with chronic use of cocaine, which includes rhabdomyolysis and excited delirium. Excited delirium can be described as a prolonged period of increasingly bizarre behavior, usually over several days or weeks. In those who have consumed cocaine or amphetamines, the course can last several hours. Those signs/symptoms typically associated with excited delirium are as follows: bizarre and violent behavior, most commonly violence towards glass, removal of clothing, public nudity (even in cold weather), aggression, hyperactivity, paranoia, incoherent speech or shouting, increased strength, imperviousness to pain, and hyperthermia. In early reports of cocaine-associated rhabdomyolysis in 1987, there have been many descriptions of similar syndromes in the literature. This has included cocaine-induced delirium. Because these two cocaine-associated conditions exhibit many similar characteristics, including hyperthermia, bizarre and psychotic behavior, and hyperactivity, it can be concluded that they are different stages in the same pathologic process, ie, cocaine-associated rhabdomyolysis and excited delirium. Long-term cocaine use more so than short-term cocaine use places persons at risk for excited delirium and cocaine-associated rhabdomyolysis. This is due to alterations in dopamine function on a more chronic basis that can affect the physiology of skeletal muscle.81 Rhabdomyolysis is also caused by skeletal muscle ischemia through the same mechanism that affects other vascular beds. Renal failure and myoglobinuria occur as a sequelae for rhabdomyolysis as would be expected via any mechanism.82 Hyperthermia is also a contributing factor and a marker of severe toxicity and aside from rhabdomyolysis can cause disseminated intravascular coagulation (DIC), acidosis, hepatic injury, and renal failure. Temperatures can run as high as 45.6C. The hyperthermia can be attributed to increased dopamine neurotransmission, as dopamine is known to play a role in regulation of core body temperature. This
DM, January 2009 29

increase in dopamine is also responsible for excited delirium that can accompany cocaine use. Dopamine 2 receptors are involved with decreases in core temperature. In excited delirium the number of D2 receptors in the hypothalamus is substantially reduced, thereby causing hyperthermia, although hyperthermia is not a necessary component for the induction of rhabdomyolysis.87 Aberrant processing of dopamine as well as changes in dopamine processing can be attributed to chronic cocaine use, yielding symptoms of increased creatine kinase and paranoid psychosis that persists long after cessation of cocaine use. The proposed mechanism of cocaine-associated rhabdomyolysis is the blockade of synaptic catecholamine reuptake and induction of adrenergic agonism, yielding vasoconstriction and ischemia, causing muscle tissue damage. It has also been proposed that cocaine for the most part may directly increase the release of catecholamines. This then causes increased intracellular calcium or vasoconstriction of unknown mechanism. These mechanisms explain the induction of rhabdomyolysis, although it does not explain the onset of delirium. A direct toxic effect of cocaine upon muscle tissue has been proposed based on animal models. Cocaine has been shown to induce creatine kinase leakage from muscle tissue, although the exact mechanism is unknown.88,89 The victims of cocaine-associated rhabdomyolysis are similar to victims of fatal excited delirium with regard to age, gender, and race; both groups were found to be different from victims of acute cocaine toxicity with respect to these demographics variables. Studies of victims with fatal excited delirium linked black race, male gender, and use of cocaine via a route other than nasal insufation with a pattern of chronic and intense cocaine use. Many of the articles discussing rhabdomyolysis describe patterns of chronic cocaine use or binging that preceded the onset of rhabdomyolysis. Therefore the data suggest that victims of cocaine-associated rhabdomyolysis and fatal excited delirium had a pattern of chronic cocaine use more frequently than those deaths associated with acute cocaine toxicity. The connection of cocaine-associated rhabdomyolysis, excited delirium, and chronic cocaine use is supported by a temporal coincidence between the appearance of these two conditions and the epidemic of crack cocaine use in the U.S. Crack is associated more often with chronic binge use than insufation of cocaine hydrochloride. To support this, the rst report of excited delirium and early description of rhabdomyolysis came from Miami. Miami was the rst metropolitan area in the U.S. to experience an inux of cheap and highly pure cocaine hydrochloride in the early 1980s due to transport routes through the
30 DM, January 2009

Caribbean.90 Treatment of hyperthermia, psychomotor agitation, and convulsions is achieved with rapid cooling and generous use of benzodiazepines in escalating doses. Diazepam and Lorazepam are the preferred agents. If a total dose of 8-10 mg Lorazepam fails to control seizures, barbiturates such as pentobarbital (short-acting) or amobarbital may be used. These agents demonstrate synergistic effects with benzodiazepines. If this approach fails, neuromuscular blockade (vecuronium preferred agent) and intubation as per any uncontrollable seizure are then recommended.

Treatment of Rhabdomyolysis
Treatment consists of maintaining urine output as 3 mL/kg/h and preventing the precipitation of myoglobin in the kidneys and infusion of IV uids, mannitol, and even hemodialysis. The use of urine alkalinization should be cautioned as this may slow cocaine excretion but is an excellent modality to promote myoglobin and uric acid excretion.

Perinatal Cocaine Exposure

Early pregnancy is a time of rapid embryonic development, making the fetus especially vulnerable to toxic insult. Most abnormalities of the fetus are determined in the very early stages of pregnancy before the mother may even know she is pregnant. The most sensitive period for causing birth defects is the 5th to the 10th week after the last menstrual period (the 3rd to 8th week of gestation). Damage to the fetus also includes injuries that are not birth defects, such as low birth weight, premature delivery, respiratory problems, developmental delays, or even death. Only after implantation does the embryo begin to receive toxins, as well as nutrients, from the womans bloodstream. Cocaine transport in the rst and early second trimester may in part be across the placental chorion. Lacking a skin barrier, the fetus (mid-pregnancy) may come in direct contact with high concentrations of cocaine in the amniotic uid. Studies with pregnant guinea pigs receiving daily subcutaneous cocaine from day 50 to 59 showed amniotic uid cocaine levels at the end of the exposure period were three to four times higher than fetal plasma cocaine concentrations. The in vitro half-life of cocaine in amniotic uid is 30 times longer than the in vivo plasma half-life. This raises the possibility that the fetus may ingest cocaine by swallowing amniotic uid or absorb through the skin or mucosa in contact with the amniotic uid.85 Cocaine is cleared slowly from the amniotic uid, prolonging exposure during critical fetal neurotransmitter formation.91 Studies of fetal cocaine exposure and newborn neurologic function have
DM, January 2009 31

obtained conicting results. Studies of fetal cocaine exposure and newborn neurologic function have obtained conicting results in that some studies identify abnormalities, others nd no differences between newborns that were assessed by a pediatric neurologist that was blinded to exposure study. Gestational age was determined by Ballards examination. To determine the effects of prenatal cocaine exposure on intrauterine growth and neurologic function in infants, 253 infants were prospectively evaluated shortly after birth. Cocaine exposure was determined for the last trimester by radioimmunoassay of maternal hair. Compared with unexposed controls, cocaine-exposed infants exhibited higher rates of intrauterine growth retardation (24% versus 8%), small head circumference ( 10th percentile) (20% versus 5%), and neurologic abnormalities: global hypertonia (32% versus 11%), coarse tremor (40% versus 15%), and extensor leg posturing. Therefore this study concluded that adverse neonatal effects associated with fetal cocaine exposure follow a doseresponse relationship: newborns with higher levels of prenatal cocaine exposure show higher rates of impairments in fetal head growth and abnormalities of muscle tone, movements, and posture. Signicant relationships between cocaine exposure and these outcomes remain in controlled analyses.92 Prenatal cocaine exposure has been linked to numerous adverse neonatal outcomes, affecting fetal growth (ie, low birth weight, intrauterine growth retardation, and small head size) and neurobehavior. These neurobehavior effects span the gamut from no abnormalities to impairments in arousal, neurological function, neurophysiological function, and state regulation. Strokes and possibly seizures are also noted. Dose response effects of fetal cocaine exposure on fetal growth and neonatal neurobehavior are reported using quantitative methods. In early infancy, irritability and hypertonia are also described. Most cocaine associations are transient and resolve in infancy and early childhood. Whether such transient abnormalities place infants at increased risk for later neurodevelopmental impairments is not known. Controlled studies have found no cognitive differences related to prenatal cocaine exposure among toddlers or school-age children, except as mediated through effects on head growth. Anecdotally, cocaine-exposed children seem to suffer from neurobehavioral abnormalities, but to date controlled studies have not established an association between cocaine and behavioral disorders, except for inattentiveness. Despite encouraging reports, the question of whether cocaine exerts long-term adverse effects on the developing human nervous system has not yet been resolved, largely because of the limitations of existing studies.93
32 DM, January 2009

Prenatal cocaine exposure lowers IQ and language performance scores and results in thousands of new children each year who enter school needing special education services, according to a study by three Brown professors. An analysis of information on more than 800 school-aged children in eight studies found that cocaine-exposed children had subtly lower intelligence scores than other children, placing them at risk for failure in school. It is estimated that up to 80,550 new cocaine-exposed children annually will need special education services at a cost of up to $352 million. The results are in sharp contrast to the popular image of hopelessly brain-damaged cocaine-exposed children predicted a few years ago. However, the results still show that prenatal cocaine use signicantly affects society. Children in the cocaine-exposed group, on average, had IQ scores 3.26 points lower than the control group. The cocaine effect was even more pronounced on language skills. For many people three IQ points would be negligiblethe average IQ is 100 points. However, that subtle difference must be taken in context with cocaine use as those children are also likely to be living in poverty and have other known risk factors that depress IQ scores, therefore making the results more dramatic. Between 1688 and 37,612 children each year will need special education services because of the IQ difference caused by cocaine exposure. Because those services cost $6,335 for each child per year, that means an additional $4 to $80 million in special education costs annually. Those numbers are even larger for children whose speaking ability is affected. There will be 4432 to 80,550 children who will need special education services each year, at a cost of $22 to $352 million, according to the study. Although the effects of cocaine exposure on intelligence are more subtle than originally believed, the results are signicant. A study to identify associations between cocaine exposure during pregnancy and medical conditions in newborn infants from birth through hospital discharge was carried out by Bauer and coworkers with the following results. Cocaine-exposed infants were about 1.2 weeks younger, weighed 536 g less, measured 2.6 cm shorter, and had head circumference 1.5 cm smaller than nonexposed infants. Central and autonomic nervous system symptoms were more frequent in the exposed group: jittery/tremor, high-pitched cry, irritability, excessive suck, hyperalertness, and autonomic instability. No differences were detected in organ systems by ultrasound examination. Exposed infants had more infections including hepatitis, syphilis, and human immunodeciency virus exposure; were less often breastfed; had more child protective services referrals; and were more often not living with their biological
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mother.94 Cocaine alters the placental production of prostaglandins in vitro, favoring thromboaxane production, which may cause vasoconstriction and decrease uteroplacental blood ow.95

Authors Excerpt
I currently work in a busy urban Emergency Department in Chicago. The amount of positive cocaine results is staggering. The ages of use are more commonly in late 30s to many patients in their 60s. Most of these patients have underlying medical conditions including end-stage renal disease (on hemodialysis), heart, and lung disease. Most of the visits are for cocaine exacerbation of an underlying chronic condition, adding exponentially to health care dollars.

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