Cocaine: History, Social Implications, and Toxicity—A 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 first anesthetic. Albert Niemann, the student who perfected the purification 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 Pemberton’s 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 flavored using kola nuts, also acting as the beverage’s source of caffeine. Pemberton called for 5 oz of coca leaf per gallon of syrup, a significant dose, whereas, in 1891, Candler claimed his formula (altered extensively from Pemberton’s 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” leaves—the 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 flavoring 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 Peru’s 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 firm 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 1880’s 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 financial difficulties. He sent cocaine to his fiancée, telling her it would make her strong and give her cheeks a red color. Freud was to play a significant 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 cocaine’s 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 official 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 drugs—in small quantities over the counter, and in larger quantities on a physician’s 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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708.17 Of all plants in the DM. January 2009 9 .S. Of an estimated 106 million ED visits in the U. and the drugs are recovered and sold.287.11 In summary.530) ED visits. cocaine is the most commonly used illicit drug among those seeking care in EDs or drug-treatment centers.17 Cocaine is an alkaloid extracted from the E.9% of 12th graders had abused crack at least once in the year prior to being surveyed.2% of 12th graders had abused cocaine in any form and 1. 3. It is the most frequent cause of drug-related deaths reported by medical examiners.350 (CI: 284. the Drug Abuse Warning Network (DAWN) estimates that 1.782) drug-related ED visits involved a major substance of abuse. Body stuffers internally conceal fewer and more hastily packaged drug packets.0% of 8th graders. Data for 2004.170 to 482.10 The National Institute on Drug Abuse (NIDA)funded 2007 Monitoring the Future Study showed that 2.13. and 5.953 (CI: 773. or 50-100 packets) of carefully packaged drug-containing packets. they represent distinctly different entities.3% of 10th graders.108. Colombia.993 (95% confidence interval (CI): 1. anal. or vaginal orifices. Cocaine is the most frequent drug-related cause of emergency department (ED) visits in the United States.12 Along with other illicit substances. six million Americans age 12 and older had abused cocaine in any form and 1.16 Colombia and Peru export the most cocaine to the United States.4% of 10th graders. Body stuffing of drugs may occur through oral. Ecuador. cocaine is frequently used for the purposes of body packing and body stuffing.5 million had abused crack at least once in the year prior to being surveyed.124 to 1. DAWN estimates that cocaine was involved in 383.205 to 2.3% of 8th graders. Body packers (also called “mules” or “couriers”) ingest a large amount (commonly about 1 kg. or Bolivia.997. Processing and Production Most of the world’s current cocaine supply is produced in South American countries such as Peru. in order to avoid being arrested for possession of the drug or other offenses. in attempts to illegally smuggle the drugs through customs and border crossings. DAWN estimates 940. While these two phrases are sometimes used interchangeably.15 Both body stuffers and packers are subject to toxicity from leakage or rupture of drug-containing packets. during 2004. 1.14 The packets are later removed from the body through fecal elimination. coca bush. which grows in the Andes Mountains in western South America.781) were drug-related. and 1.Today’s Use of Cocaine In 2006.

The name “crack” is derived from the cracking or popping sound heard when the drug is smoked. approximately 1% by weight.19 If the freebase is removed before the extraction process is completed. which allows the cocaine base to solidify into a soft mass that hardens into a rock-like state after drying. is then treated with hydrochloric acid to form cocaine hydrochloride salt (or “cocaine powder”) before it is exported from South America. coca bush’s leaves yield the highest amounts of cocaine. the leaves are typically processed into cocaine paste and/or powder as soon as possible.” a typical “line” of cocaine contains approximately 50-100 mg of parent compound. The hard product. known as “crack. the harvested leaves are soaked with solvents such as kerosene until a thick pasty substance (called “cocaine paste”) is isolated. This paste. 10 DM.19 Cocaine hydrochloride is water soluble and is well absorbed through “snorting” through the nasal mucosa. The drug is then mixed with baking soda or sodium bicarbonate and heated. It is also absorbed through all mucous membranes. has a high profit margin. cocaine hydrochloride powder is dissolved in water and a base (such as ammonia) is added.” is not flammable because ether is not used in its production. some residual ether may remain in the drug. Because the amount of cocaine present in the harvested leaves decreases over time. Ether or a similar solvent is added to dissolve the cocaine base. Crack cocaine is cheap to make. which has been dissolved in water. although it is often “cut” or adulterated with other substances. Freebase cocaine is subject to adulteration.20 Because it has a high melting point and decomposes when burned.1 However.18 Cocaine hydrochloride must be converted into an alkaline form of either freebase or crack cocaine before it can be smoked. and is highly addictive when smoked.18 To make freebase cocaine. which contains 40-80% cocaine. cocaine hydrochloride cannot be smoked. When “snorted. Crack cocaine is also synthesized from cocaine hydrochloride powder. the E. and by intravenous injection.16 This risk of fire limits the popularity of freebase as a smokable drug. This remaining ether is highly flammable and may cause facial burns when the freebase is smoked. many local anesthetics and stimulants can be extracted through the ether solution as well. The “free” base is then extracted from the ether solution through evaporation.18 To extract cocaine from the plant.16. January 2009 . cocaine is found in all parts of the coca plant.Erythroxylon genus (so named because of their reddish color). 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.

which is formed in vivo after use of concurrent use of alcohol and cocaine. between 50 and 90% of cocaine users also concurrently ingest ethanol during their binges. Dama Blanca. which explains the prolonged euphoric effects reported after use of cocaine and ethanol.22 For marketing. approximately one-quarter to three-eighths of an inch in diameter.21 Like freebase and cocaine hydrochloride.24 In addition to promoting the formation of cocaethylene.24 In rats.23 Cocaethylene has an elimination half-life of 150 minutes (compared to approximately 90 minutes for cocaine). dealers more frequently sell it than cocaine hydrochloride or freebase.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. vials are sold for 5 to 10 dollars by street dealers.21 Currently. which causes intense euphoria and subsequent craving sensations. Like cocaine. In the presence of ethanol. Cocaine Adulterants Alcohol and cocaine are commonly used together. thus.16 Both freebase and crack cocaine have a lower melting point than cocaine hydrochloride. crack cocaine is packaged into vials containing one to three rocks of the drug.” which are off-white in color and of irregular size. cocaethylene induces reinforcing properties and increased motor activities. both formulations can be easily smoked in pipes (glass “crack pipes” or traditional pipes) or cigarettes. this combination is referred to as a “speedball. This may explain the higher concentrations of cocaine that are frequently noted in patients with concurrent cocaine and ethanol abuse. Bernice. cocaethylene causes increases in heart rate and blood pressure as well as euphoric effects.18 Smoking causes a rapid absorption of the drug into the central nervous system (CNS). Baseball.Because of these characteristics.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. These reports may be due to the presence of cocaethylene. cocaine is transesterified by a hepatic carboxyesterase into cocaethylene. Nose Candy.” Other street names for cocaine include Snow. which weigh 100 mg each. crack is the most commonly used form of cocaine. the use of ethanol and cocaine together also inhibits cocaine metabolism. and Gold Dust. January 2009 11 . Cocaine is sometimes also mixed with heroin and sold on the street.23 Analysis of street samples of cocaine has found an average purity rate DM. Crack is sold as “rocks. crack cocaine is also frequently adulterated with other substances.

hair.26 Historically. quinine has been recognized as a common contaminant of heroin. or to increase the toxicity associated with the drug. January 2009 .19 Quinine is an alkaloid.19 Toxins such as quinine and strychnine are sometimes used to adulterate cocaine and other illicit drugs. The toxicity of quinine includes gastrointestinal symptoms.28 Treatment of patients with strychnine poisoning is supportive and symptomatic. Sugar can cause irritation of nasal passages when inhaled.19 Therefore. This causes increased neuronal activity of the CNS.25 Many compounds are added to cocaine to increase the available volume of the drug. Urine is commonly used for initial screening because samples are easy to obtain. and seizures. The contamination of cocaine with benzocaine has resulted in methemoglobinemia.of 40%. These include sugars.19 Local anesthetics have psychoactive and reinforcing properties similar to cocaine and can thus potentiate these effects when combined along with cocaine. Strychnine. These compounds can have variable pharmacologic action or toxicity. meconium. urine. Since cocaine has a short elimination half-life of about 1 hour. tremors. The initial screening test for cocaine is usually performed on urine. and blindness.19 The symptoms of local anesthetic toxicity include paresthesias. cardiac dysrhythmias. saliva. the testing is noninvasive. Local anesthetics are among the most frequent contaminants of cocaine. Symptoms of strychnine toxicity include muscle spasms and seizures during which the patient remains conscious. and amniotic fluid have all been used for testing of cocaine use. Adulterants are added to cocaine to promote the perceived potency of the drug. and many cost-effective commercial kits are available. Blood. adulterants represent more than half of the composition of all cocaine sold. urine 12 DM.29 Laboratory Detection of Cocaine Testing for cocaine and its metabolites can be performed on many biologic specimens. perspiration. benzodiazepines have been successfully used in the past to treat the convulsions associated with strychnine toxicity. talc. which has been commercially marketed in the past as a rodenticide. which are similar to some of the toxic effects of cocaine. other analytic screening methods include radioimmunoassay and thin-layer chromatography. Talc and cornstarch can cause pulmonary fibrosis and hypertension. inhibits the neurotransmitter glycine. to increase the volume of the drug. which is used for treatment of nocturnal cramps and drug-resistant Plasmodium falciparum malaria.27. and cornstarch.29 Urine testing is commonly performed by the enzyme-multiplied immunoassay technique.

Positive results are commonly confirmed with gas chromatography/mass spectroscopy (GC/MS). Cocaine in blood samples undergoes spontaneous hydrolysis to benzoylecgonine unless the samples are preserved with sodium fluoride or a similar pseudocholinesterase inhibitor. but not abuse or intoxication. However.5 g per day) over many years can have positive urine screens for weeks after their last use of the drug. coca plant and is sold over the internet and in some restaurants in the United States. other adulterants such as vinegar. limitations exist in terms of how results (both positive and negative) should be interpreted. liquid hand soap. With the exception of excessively high doses of prilocaine.33 Both Drano (or bleach) and sodium chloride solution.assays for cocaine use typically measure the cocaine metabolite benzoylecgonine.32 Ingestion of coca tea. Although urine testing is a frequently used screening method by hospitals for cocaine abuse. 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. since urine assays usually screen for cocaine’s inactive metabolite benzoylecgonine.22 Changes in pH and temperature can also affect breakdown of cocaine in these specimens. two case series have shown that patients who use high amounts of cocaine ( 0. Blood testing for cocaine is typically performed using GC/MS. Additionally.18 Urine immunoassays have a lower limit of detection of approximately 300 ng/mL. lemon juice.18 Urine testing for benzoylecgonine is typically reported to give positive results for 1 to 2 days after recent cocaine use. Visine. a positive urine screen cannot be used to extrapolate the degree of intoxication after cocaine use. and goldenseal tea did not cause a false-negative benzoylecgonine assay when added to urine.30 For example.35 DM.34 A false-negative result may also occur if urine is tested very soon after cocaine use. can result in a positive urinary immunoassay for cocaine.29 Newborns achieve higher blood levels of cocaine than adults after the same amount of the drug is used. which can detect as little as 1 ng/mL of benzoylecgonine. no drugs other than cocaine and its metabolites are recognized to cause a false-positive urine immunoassay for 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. this is likely due to lower levels of plasma pseudocholinesterase (and thus decreased ability to metabolize cocaine) in newborns. before metabolism to benzoylecgonine has occurred. Laboratory tests for cocaine and its metabolites are best used as a marker for recent use. January 2009 13 . which has an elimination half-life of 6 hours. which is made from the leaves of the E. when added to urine assays for benzoylecgonine. can cause false-negative results.

35 Analysis of hair can be used to determine exposure to cocaine. although the significance of this is uncertain.33 Both cocaine and benzoylecgonine deposit in the hair shaft and can be measured approximately 1 day after intranasal cocaine use. If chewed in the leaf form.20 Patients with passive exposures to cocaine do not have measurable amounts of cocaine metabolites such as benzoylecgonine in their hair samples. determination of fetal exposure to cocaine is important. measurement of cocaine exposure. It is usually 14 DM. analysis of cocaine patterns along the length of a hair sample can be used to determine whether use was episodic or chronic. Amniotic fluid examination can provide a qualitative.29 Cocaethylene has also been reported to be present in hair samples of cocaine users. Since maternal cocaine use has multiple medical.20 Thus. In certain inner-city areas.1 and 0.Adults with plasma cholinesterase deficiency. External contamination of hair has been shown to occur after passive exposure to crack cocaine vapors. When the leaves are soaked and mashed. A coca leaf typically contains between 0. January 2009 . social. however. collected either at fetal delivery or during amniocentesis. The paste is 60 to 80% pure. can also be used to measure fetal exposure to cocaine. amniotic fluid analysis is limited by its small window of collection time. can also have prolonged high blood cocaine levels due to the same decreased metabolic activity. which can affect up to 4% of the population in its mild forms. Analysis of meconium can detect drug exposure as early as 17 weeks of gestation.36 In addition.36 Because hair grows at a fixed rate (approximately one-half inch each month). approximately 50-100 strands are required for analysis of a hair sample. Pseudocholinesterase deficiency does not appear to confer a higher rate of mortality after cocaine use. collection of hair is noninvasive and easy to perform. and economic implications. it rarely presents the user with any social or medical problems. the prevalence of maternal cocaine use is estimated to be between 10 and 30%. collection of meconium is limited by its small time period for collection (the first 3 days of life). 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. Hair washing after passive exposure results in an undetectable level of cocaine in the hair.9% cocaine. the presence of benzoylecgonine in a hair sample can be used to differentiate passive exposure to cocaine from illicit use of the drug. cocaine is extracted as a coca-paste.29 Amniotic fluid. but not quantitative.29 Similar to meconium testing. Both meconium and amniotic fluid have been utilized as markers of intrauterine fetal cocaine exposure.

until recently.37 Chemistry/Pharmacology As a local anesthetic.38 Structures of the local anesthetics are shown in Fig 2 for comparison.FIG 1. Chemical structure of (A) cocaine. (B) ecgonine. This inhibits depolarization and blocks both the initiation and the conduction of nerve impulses. Drug testing for cocaine aims to detect the presence of its major metabolite. The ester link is rapidly hydrolyzed by plasma cholinesterases. (Color version of figure is available online. and (C) atropine. in the West. January 2009 15 . cocaine hydrochloride.) exported in the form of the salt. Cocaine exhibits its vasoconstrictive action therapeutically by inhibiting local reuptake of norepinephrine.16 Ecgonine is also the parent compound of atropine16 (Fig 1). it is an ester of methyl-ecgonine and benzoic acid. In chronic users.38. Benzoylecgonine can be detected for up to 5 days in casual users. urinary detection is possible for as long as 3 weeks. This is the powdered cocaine most common.38 Cocaine is an ester type of local anesthetic. which contributes to cocaine’s short half-life (see kinetics section). the inactive benzoylecgonine. All local anesthetics comprise both a hydrophobic and a hydrophilic moiety DM. cocaine blocks voltage-gated sodium channels in the neuronal membrane.

Chemical structure of (A) lidocaine. (Color version of figure is available online. (B) mepivacaine. and (D) procaine.FIG 2.) 16 DM. (C) prilocaine. January 2009 .

as it breaks down during pyrolysis.16. The free base will dry into a hard rock upon evaporation. Mechanism of Toxic Action Cocaine exhibits profound CNS and cardiovascular toxicity. and aggressiveness.16.40 Cocaine is abused in either of two following chemical forms. Repetitive use of cocaine results in the depletion of the dopamine stores. Increased lipophilicity leads to a greater affinity for the sodium channel receptor and increased toxicity of the drug.41 Increased serotenergic activity can result in seizures and may be involved in the addiction and reward effects of cocaine.43 It is excess dopamine activity. Free Base Cocaine hydrochloride is dissolved in water.41 Cocaine also DM. increased self-confidence and alertness at lower doses. lidocaine) linkage.41 This crystalline white powder is usually insufflated but can also be dissolved in water and injected. disorientation. cocaine stands alone in causing marked behavioral responses. especially in large doses. The cocaine base is extracted by the addition of an organic solvent. Crack cocaine is then usually smoked out of a glass pipe.41 Patients experiencing “washed-out” syndrome experience lethargy and anhedonia and have difficulty with muscle movement. norepinephrine) and serotonin. Local anesthetics with a larger molecule size results in increased duration of time on the receptor. smaller molecules escape the receptor site more rapidly. This can result both in an intense craving for cocaine and in what is referred to as a “washed-out” syndrome. mixed with a strong base. CNS symptoms include euphoria. Cocaine and some of its metabolites exert activity at many receptors throughout the CNS and cardiovascular system. Receptor activity is described below.16. Cocaine Hydrochloride (also known as “coke”) The cocaine alkaloid is extracted from the leaves and then converted to cocaine hydrochloride using hydrochloric acid.39 Of the local anesthetics. Local anesthetics can also block the potassium channel.41 The word “crack” comes from the cracking or popping noise it makes when it is smoked.separated by an ester (eg. both the “desired” and the toxic effects. Cocaine salt is not smokable. cocaine) or amide (eg. and heated.42.40. CNS Cocaine blocks the reuptake of catecholamines (dopamine.16. January 2009 17 .38. that is believed to cause the majority of CNS symptoms. including euphoria and addictive behavior. however.16. and hallucinations at higher doses.

41 Cocaine exhibits “slow” on– off kinetics at the sodium channel.44 One animal study suggested that lidocaine exacerbated cocaine-induced seizures and arrhythmias.16.45.40 which is considered a poor prognostic indicator. and decreased production of nitric oxide (a vasodilator).42 Cardiovascular Cocaine’s reuptake inhibition of biogenic amines results in a powerful sympathomimetic effect. cardiac ischemia. and end-organ and tissue infarcts. cerebrovascular accident (CVA).16.45 (Lidocaine may be less useful in a patient with low heart rate.16.40. There are several mechanisms and mediators responsible for cocaine-induced vasoconstriction: increased neuronal norepinephrine. cocaine is classified as a type I antidysrhythmic agent. the American Heart Association (AHA) recommends use of lidocaine for persistent ventricular arrhythmias. increased seizure frequency. increased levels of endothelin-1 (a powerful vasoconstrictor). Effects on excitatory amino acids/glutamatergic system and muscarinic and sigma receptors are also believed to contribute to CNS toxicity.44 Cocaine is also known to cause vasoconstriction. January 2009 .)44 Class Ia and Ic Antiarrhythmics Additive sodium channel blockade can exacerbate or precipitate cocaine-induced QRS prolongation or cardiac arrhythmias. a direct effect of benzoylecgonine on the blood vessels (possibly calcium mediated. coronary artery spasm. It has been used successfully to shorten cocaine-induced QRS prolongation. 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. which can result in hypertension.affects the heat regulation center in the hypothalamus and can cause hyperthermia.46 Drug Interactions Lidocaine Lidocaine is also a local anesthetic and possesses the same sodium channel blockade action as cocaine. Ventricular arrhythmias and wide QRS complex or QT/QTc prolongation can occur. and in18 DM. however. lidocaine exhibits “fast” on– off binding kinetics and is thought to displace cocaine from the sodium channel receptor through competitive binding.40. see kinetics section for a more detailed description of the metabolite benzoylecgonine). However. As a sodium channel blocking drug.

41. Through a transesterification reaction. Dual alpha. These medications can affect body temperature.43 Drugs of Abuse Cocaine is often abused with other substances. have increased the incidence of seizures in the setting of cocaine toxicity. Antidepressants with dopamine reuptake inhibition (eg. January 2009 19 . Selective serotonin reuptake inhibitors (SSRIs) (eg.creased mortality.41 Antidepressant Drugs Monoamine oxidase inhibitors (eg. fluoxetine). Succinylcholine Plasma cholinesterase (PChE) metabolizes both succinylcholine and cocaine.and beta-blockers (eg. Using any drug that is metabolized by PChE can potentially increase the toxicity of cocaine or the other PChE substrate. labatelol) have also caused toxicity.40 Ethanol. and contribute to cardiotoxicity (by additionally blocking sodium and potassium channels).and cardiotoxic. 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. Deaths from cocaine-associated myocardial infarction are “exceedingly low” per the AHA. cocaine and ethanol combine to produce an entirely new compound known as cocaethylene (benzoylethylecgonine). all toxicology reference texts as well as the AHA advise that beta-antagonists are contraindicated in the setting of cocaine-induced toxicity.44 However. bupropion) have increased the incidence of death in the setting of cocaine toxicity. and treating clinicians should anticipate synergistic toxicity when used with the following substances. Cocaethylene has a much longer duration of action than cocaine and is neuro. precipitate dystonic reactions and seizures. tranylcypromine) inhibit metabolism of endogenous catecholamines and would be expected to have an additive effect on cocaine’s catecholamine-induced toxicity.48 Cocaethylene can cause enhanced cardiodepression by affecting calcium and is thought to be less potent than cocaine for causing tachycardia and euphoria. Phenothiazines/Butyrophenones Animal studies have shown that these drugs enhance toxicity and/or death. which inhibit reuptake of serotonin.47 These effects are caused by unopposed alphaadrenergic effect when the beta-adrenergic receptors are blocked.40 DM.

5 hours and most of the administered dose is eliminated within a few hours.50 One study also suggested an increase in blood pressure of up to 20 mm Hg with concomitant use. propofol.7-1. may be detected in urine.50 Pharmacokinetics Summary The pharmacokinetics of cocaine are dependent on multiple factors such as physical/chemical form.49.50 These effects are noted especially during exertion.52 20 DM. also known as “crack. genetics. codeine/hydrocodone/oxycodone). ciprofloxacin. and concurrent consumption of alcohol. and free base alkaloid.40 Cocaine is also a CYP3A4 substrate. ritonavir. Simultaneous use of cocaine and marijuana significantly increases heart rate than either drug alone (up to 50 bpm). Using nicotine and cocaine concomitantly increases heart rate and vasoconstriction more so than either cocaine or nicotine alone. and meconium.49 Suggestions for this mechanism include increased cocaine absorption through cannabinoid-induced nasal epithelium vasodilation. or mucousal application. benzoylecgonine (BE). azole antifungals.50 Nicotine. ingestion.Marijuana.41. risperidone.55 Absorption Cocaine is generally very rapidly absorbed by all routes with the exception of ingestion and topical application. and an additive effect in catecholamine concentration. intravenous injection.45 The cocaine and nicotine combination is also postulated to affect dopamine and euphoria. erythromycin/clarithromycin) and cocaine may increase toxicity of CYP2D6 substrates (eg. smoking. 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. ie. cocaine hydrochloride.51.52 It may be detected up to 10 days following chronic heavy daily usage.”44 Cocaine may be administered via multiple routes: insufflation (snorting). verapamil. January 2009 . The half-life of cocaine is approximately 0. route of administration. amphetamines. and a strong CYP2D6 inhibitor. Cocaine. saliva.40.52 Topical application produces vasoconstriction causing delayed peak. a salt form.51-54 Cocaine and its major metabolite. chemically known as benzoylmethylecgonine. dextromethorphan. but to what extent remains unclear. Drugs that inhibit CYP3A4 may increase cocaine toxicity (eg. tricyclic antidepressants. blood. while oral administration is delayed due to time to reach distal stomach or duodenum. exists in several forms.

Onset. however.53 Distribution Cocaine undergoes rapid distribution following absorption. cocaine smoked in corncob pipes: 60%.55 Metabolism Cocaine undergoes metabolism through multiple enzymatic pathways. It has been suggested that reactive cocaine metabolites are responsible for cocaineinduced cytotoxic effects such as hepatotoxicity. it does not appear to cross the blood– brain barrier readily. Intravenous and smoked cocaine may be greater than 90% bioavailable. This metabolite does cross the blood– brain barrier and may produce clinical effects similar to its parent compound.53 Table 1 shows the onset. and 12 hours following a 100 mg dose. ChemiDM.41.53 Following an administration of 20 mg cocaine.52. oral: 30%.52 The reported half-lives of BE and ecgonine methyl ester (EME) are approximately 5-6 hours.51. and inhalation routes. the detection time in serum was 4-6 hours. intranasal.41 One reference states the following bioavailability data: cocaine smoked in glass pipes: 70%.41. while insufflated drug is approximately 80% bioavailable.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.7 L/kg in volunteer studies. intranasal route: dose dependent: 25-94%. which accounts for no more than 5% of absorbed drug. The protein binding of cocaine is approximately 90%. 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.53 The volume of distribution is 1.Table 1. (b) Hepatic N-demethylation of cocaine forms norcocaine. BE was found in serum for an average of 5 days in chronic cocaine users. January 2009 21 . Peak.96-2. The bioavailability of cocaine varies depending on the route of administration. peak action. intravenous.51. and duration of cocaine administered by the topical. It is the major metabolite following all routes of administration.57 BE has been demonstrated to have vasoconstrictive properties.58 Norcocaine can be metabolized to N-hydroxynorcocaine and norcocaine nitroxide. BE may be quantified in urine after 1-4 hours and may persist up to 144 hours.

54 AEME. It should be noted that AEME may be formed in the injection port of most gas chromatographs. also known as ethyl cocaine.51 In one study. Approximately one-third to one-half of cocaine is metabolized to EME. January 2009 . while demonstrating similar toxicity. causing cellular damage.59 In one study p-hydroxybenzoylecgonine was the most prevalent and abundant minor metabolite. p-hydroxybenzoylecgonine. This metabolite poorly crosses the blood– brain barrier. m-hydroxycocaine. Excretion Little cocaine is eliminated unchanged in the urine (approximately 9. account for 80-90% of urinary metabolites in humans.59 A clinically significant interaction occurs between cocaine and simultaneously ingested ethanol. Following metabolism. Other minor metabolites of cocaine that have been identified include p-hydroxycocaine. smoked crack cocaine yields the metabolites anhydroecgonine methyl ester (AEME) or methylecgonide.57. the two major metabolites of cocaine excreted in the urine are BE and EME. and benzoylethylecgonine.cally reactive intermediates of these compounds may covalently bond to cellular proteins. butyrylcholinesterase. methylecgonidine. For instance. with a half-life of 148 15 minutes.52 Unchanged cocaine may be detected in urine up to 24-36 hours.52 PChE. and norbenzoylecgonine.52.58 Measurement of this metabolite can be used as a means of determining the route of administration following cocaine use. One to 3% of urinary metabolites are the N-demethylation products ecgonine. reacts with cocaine to form EME.52.52 Fecal excretion represents a minor route of elimination of cocaine and its metabolites. may produce bronchospasm as a result of muscarinic effects. eg.41. mhydroxybenzoylecgonine. which is an end product of pyrolysis during smoking.52 Other multiple metabolic pathways have been identified. following single-dose cocaine administration by the 22 DM. It has been demonstrated that patients with genetic low PChE activity show greater sensitivity to the effects of cocaine.54. and carbomethoxycycloheptatriene derivatives.53 Transesterification of these two compounds produces cocaethylene.5-20%). The duration of effect of cocaethylene is longer than cocaine. norbenzoylecgonine. and norecgonine. this test is not a unique identifier for cocaine smokers. EME and BE. It may be more euphorigenic and reinforcing than cocaine. which is further metabolized to ecgonine. It is thought that EME possesses little pharmacologic activity.

56 Detection time of BE in urine to a cutoff concentration of 100 ng/mL was 47. spontaneous episodes of ST-segment elevation occurred for up to 6 weeks after cessation of cocaine use.56 Repeated cocaine dosing extended average oral fluid cocaine detection times by a factor of approximately 4 and for BE by a factor of 7.4. Chest pain can also be dependent on the route of drug use. The period for cocaineassociated myocardial infarction can persist for weeks following cessation of the drug. 8. ie. and 4. and 5. It has DM.2 hours with an overall average of 46. Patients ranged in age from 19 to 40 who most commonly smoked cigarettes and repeatedly used cocaine. inhalation can cause pneumomediastinum and pneumothorax. 6.57 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. In a study published in 2007. The study found the incidence of cocaine-associated myocardial infarction ranged from 0 to 31%.8 hours) for BE.7 hours. with pain frequently described as substernal pressure and associated diaphoresis and shortness of breath.intravenous.1 hours (overall average equals 5. The cocaine-associated chest pain trial has been the largest retrospective multicenter study of patients presenting to EDs with chest pain after cocaine use.37 With the use of Holter monitors in patients admitted to a detoxification center. intranasal. 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. 48. and 44. January 2009 23 . Most commonly these individual experienced chest pain about 60 minutes after use and pain lasted up to 120 minutes. Chest pain following use can be caused by several factors such as myocardial infarction and aortic dissection.3. cocaine and BE showed average detection times in oral fluid of 4. which can manifest as chest pain and other cardiopulmonary symptoms. Toxicity Cardiac Chest pain is the most frequent cocaine-related symptom and accounts for up to 40% of cocaine-related ED visits.7.60 The mechanism for this may be because during cocaine withdrawal there is a dopamine-depleted state that results in intermittent coronary spasm.7.0 hours) for cocaine and 6. and smoked routes.5. Intravenous injection can cause septic emboli. 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.7.0 hours (overall average equals 6. BE detection times were only extended by a factor of 2 in urine.

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

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

This has been measured physiologically by reduced coronary blood flow and increased coronary vascular resistance. Dysrhythmias Dysrhythmias have a wide range of types. In the event of a contraindication to nitrates.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. nitrates. Verapamil and cardizem also ameliorate vasoconstrictive effects and are of benefit. Cocaine-induced vasoconstriction or the coronary arteries can be reversed with phentolamine. sinus tachycardia (tach). Low doses of cocaine are more commonly associated with bradycardias. then nitrates can be used.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. and benzodiazepines is recommended on all patients with cocaine-induced ischemic changes. Nifedipine should not be used as this agent may potentiate seizures and death. therefore. atrial fibrillation (A-fib)/atrial flutter (A-flutter). 26 DM. Beta-stimulation leads to vasodilatation of the coronary arteries. which blocks the vasomotor effects of norepinephrine. Pharmacologic effects of cocaine include both alpha. ie. There is some evidence that the benefit of beta-blockers with the reduction of myocardial infarction may offset the risk of coronary artery spasm due to unopposed alpha-effects of cocaine. supraventricular tachycardias. depending on the quantity of cocaine used. using a beta-blocker is counterintuitive and may block this vasodilatation. January 2009 .and beta-receptor stimulation.Treatment of Myocardial Ischemia and Infarction Use of oxygen. If benzos fail to control the hypertension. phentolamine is the next agent of choice. premature ventricular contractions (PVCs). an alpha-adrenergic antagonist. aspirin. Benzodiazepines (ie. whereas high doses are associated with all types of tachydysrhythmias. Beta-blockers should not be used in the setting of cocaine-induced vasoconstriction as it may worsen the coronary artery spasm. Lorazepam and Diazepam) are recommended to control cocaine-induced sympathetic tone such as heart rate and the systemic arterial pressure. varying from bradycardias to tachydysrhythmias. Nitrates reverse cocaine-induced hypertension and vasoconstriction of the coronary arteries and are the agents of choice for these patients. Benzos are useful with or without chest pain. Aspirin is used to inhibit platelet aggregation.

Sodium bicarbonate is the general treatment for sodium channel blockade. most cocaine-related dysrhythmic fatalities occur in patients with low or moderate levels of cocaine use. and other effects. Torsades is treated with intravenous magnesium sulfate and overdrive pacing if necessary as per protocol even without cocaine. the ventricular arrhythmia may respond to this. yielding tachycardia. ie. catecholamines.82 Treatment Sinus tachycardia is treated with observation and benzodiazepines. Cocaine-induced atrial tachycardias respond to benzos by DM. hyperacidosis.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. then initiation of verapamil or cardizem should be used. This brings attention the fact that long-term cocaine users may also accumulate excess norepinephrine and may be at risk for malignant arrhythmias. Tachycardias may be caused by cocaine’s ability to stimulate central and peripheral sympathetic system. This may be the reason escalating doses of cocaine yield direct myocardial depressant effects.72 The effects of endogenous catecholamines are potentiated. and increased myocardial consumption. and ventricular fibrillation (V-fib). Ventricular arrhythmias are thought to be due to cocaine’s effect on the sodium channels. ventricular tachycardia (V-tach). However. Bradycardia may be secondary to stimulation of vagal nuclei of the brain. myocardial infarction. vasoconstriction. January 2009 27 . A physiologic attempt to decrease sympathetic tone secondary to chronic cocaine stimulation has also been found in the presence of increased ventricular catecholamine concentrations. 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. 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. torsades de pointes. Using lidocaine in combination with benzodiazepines seems to be the best combination. and acidosis.accelerated idioventricular. hypertension. This suggests that the mechanism of death may be different in low-level cocaine users. QRS duration will shorten as lidocaine displaces cocaine from sodium channels. If the tachycardia continues. therefore. In rat studies. long-term use of cocaine markedly increased norepinephrine content of the left ventricle. Lidocaine may also be of use due to its competition with cocaine for fast sodium channel binding kinetics on the sodium channel. in which sudden death may be a result of adrenergic effects and long-term catecholamine toxicity.

Most patients with aortic dissection also had underlying hypertension and cocaine-induced vascular damage. If this fails. January 2009 . Adenosine is not useful with cocaine-induced supraventricular tachycardias.86 In general. diltiazem and verapamil should be used as first-line agents. Cocaine-induced pulmonary edema may result from changes in central adrenergic outflow. but it is thought to develop from recurrent or diffuse ischemia or from a direct effect on contractility unrelated to ischemia. There are at least two adrenergic receptor sites (alpha or beta).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.) Cocaine has been shown to cause adrenergic agonists responses in the pulmonary circulation. which includes acute bronchoconstriction. 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.and beta-adrenergic receptors on the vascular smooth muscle. ie. Norepinephrine activates primarily alpha-receptors and epinephrine activates primarily beta-receptors. smoking crack has the greatest pulmonary effects. Pulmonary Effects The pulmonary vasculature is innervated by adrenergic nerves with alpha. and emergencies.83. the effects of cocaine on the pulmonary vasculature may be mediated by the effect on alpha-adrenergic receptors.reducing sympathetic tone. although it may also activate alpha-receptors. The sympathetic system activates and prepares the body for vigorous muscular activity. The bronchoconstriction is found to be mediated by either foreign material or direct injury. which cause the bronchi of the lungs to dilate. Increased adrenergic outflow therefore could affect pulmonary vasculature permeability. Intrapulmonary arteries are more sensitive to this than extrapulmonary segments.85 Pulmonary effects of cocaine can be dependent on the route of use. Cardiomyopathy Dilated cardiomyopathy is the most common form of cardiomyopathy seen in chronic cocaine users. Therefore. Beta-receptor activation relaxes bronchial smooth muscles. acute cocaine lung injury can cause a wide 28 DM. V-tach should be treated with defibrillation per advanced cardiac life support (ACLS) protocol. stress. (Adrenergic nerves release norepinephrine as the neurotransmitter for the sympathetic nervous system. The mechanism is unclear.

82 Hyperthermia is also a contributing factor and a marker of severe toxicity and aside from rhabdomyolysis can cause disseminated intravascular coagulation (DIC).82 Cocaine-Associated Rhabdomyolysis Case reports have suggested a syndrome associated with chronic use of cocaine. Chronic pulmonary effects have not been shown to have significant effects on lung mechanics. There is some evidence that chronic cocaine smokers may be at increased risk for lung cancers. and renal failure.81 Rhabdomyolysis is also caused by skeletal muscle ischemia through the same mechanism that affects other vascular beds. and hyperactivity. public nudity (even in cold weather). recurrent pulmonary infiltrates with eosinophilia. as dopamine is known to play a role in regulation of core body temperature. most commonly violence towards glass. The hyperthermia can be attributed to increased dopamine neurotransmission. Because these two cocaine-associated conditions exhibit many similar characteristics. and possibly. to include the following: exacerbation of asthma. bizarre and psychotic behavior. it can be concluded that they are different stages in the same pathologic process. imperviousness to pain. cocaine-associated rhabdomyolysis and excited delirium. aggression. bronchiolitis obliterans. January 2009 29 . In early reports of cocaine-associated rhabdomyolysis in 1987. acidosis. usually over several days or weeks. and hyperthermia. Temperatures can run as high as 45. hyperactivity. This is due to alterations in dopamine function on a more chronic basis that can affect the physiology of skeletal muscle. In those who have consumed cocaine or amphetamines. Renal failure and myoglobinuria occur as a sequelae for rhabdomyolysis as would be expected via any mechanism. This has been shown due to early cellular abnormalities in the bronchial epithelium. Goodpasture’s syndrome.variety of lung complications aside from bronchoconstriction. acute lung injury. pneumothorax. pneumomediastinum. This has included cocaine-induced delirium. Those signs/symptoms typically associated with excited delirium are as follows: bizarre and violent behavior. hepatic injury. including hyperthermia. the course can last several hours. paranoia. This DM. which includes 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. ie. removal of clothing. there have been many descriptions of similar syndromes in the literature.6°C. increased strength. upper airway burns and abscess formation. incoherent speech or shouting. diffuse alveolar hemorrhage. Excited delirium can be described as a prolonged period of increasingly bizarre behavior.

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

developmental delays. the fetus (mid-pregnancy) may come in direct contact with high concentrations of cocaine in the amniotic fluid. making the fetus especially vulnerable to toxic insult. Cocaine transport in the first and early second trimester may in part be across the placental chorion. January 2009 31 . Diazepam and Lorazepam are the preferred agents.85 Cocaine is cleared slowly from the amniotic fluid. 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.90 Treatment of hyperthermia. from the woman’s bloodstream. These agents demonstrate synergistic effects with benzodiazepines. This raises the possibility that the fetus may ingest cocaine by swallowing amniotic fluid or absorb through the skin or mucosa in contact with the amniotic fluid. mannitol. Damage to the fetus also includes injuries that are not birth defects. barbiturates such as pentobarbital (short-acting) or amobarbital may be used. 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). Most abnormalities of the fetus are determined in the very early stages of pregnancy before the mother may even know she is pregnant. If a total dose of 8-10 mg Lorazepam fails to control seizures. 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 fluids.Caribbean. If this approach fails. Studies with pregnant guinea pigs receiving daily subcutaneous cocaine from day 50 to 59 showed amniotic fluid cocaine levels at the end of the exposure period were three to four times higher than fetal plasma cocaine concentrations. prolonging exposure during critical fetal neurotransmitter formation. psychomotor agitation. and even hemodialysis. and convulsions is achieved with rapid cooling and generous use of benzodiazepines in escalating doses. as well as nutrients. respiratory problems.91 Studies of fetal cocaine exposure and newborn neurologic function have DM. Lacking a skin barrier. or even death. neuromuscular blockade (vecuronium preferred agent) and intubation as per any uncontrollable seizure are then recommended. The in vitro half-life of cocaine in amniotic fluid is 30 times longer than the in vivo plasma half-life. premature delivery. Perinatal Cocaine Exposure Early pregnancy is a time of rapid embryonic development. such as low birth weight. Only after implantation does the embryo begin to receive toxins.

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

Cocaine-exposed infants were about 1.26 points lower than the control group. The results are in sharp contrast to the popular image of hopelessly brain-damaged cocaine-exposed children predicted a few years ago. were less often breastfed. hyperalertness. There will be 4432 to 80. Children in the cocaine-exposed group. and had head circumference 1. For many people three IQ points would be negligible—the average IQ is 100 points. according to the study. January 2009 33 . However.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. and were more often not living with their biological DM. Central and autonomic nervous system symptoms were more frequent in the exposed group: jittery/tremor. and autonomic instability. had IQ scores 3. Although the effects of cocaine exposure on intelligence are more subtle than originally believed. the results are significant. 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. that means an additional $4 to $80 million in special education costs annually. on average.6 cm shorter. had more child protective services referrals. high-pitched cry. Between 1688 and 37. syphilis. 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. irritability.550 new cocaine-exposed children annually will need special education services at a cost of up to $352 million. The cocaine effect was even more pronounced on language skills. therefore making the results more dramatic. excessive suck.335 for each child per year. It is estimated that up to 80. However. the results still show that prenatal cocaine use significantly affects society. No differences were detected in organ systems by ultrasound examination. Because those services cost $6. Those numbers are even larger for children whose speaking ability is affected.550 children who will need special education services each year. weighed 536 g less. Exposed infants had more infections’ including hepatitis. at a cost of $22 to $352 million. according to a study by three Brown professors. placing them at risk for failure in school.612 children each year will need special education services because of the IQ difference caused by cocaine exposure. measured 2.2 weeks younger. 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.5 cm smaller than nonexposed infants. and human immunodeficiency virus exposure.

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