Cocaine
T1/2: 0.7-1.5 hours
Vd: 1.2-1.9 L/kg
Fb: ?
pKa: 8.6
Occurrence and Usage. Cocaine is the most potent of the naturally occurring central nervous system stimulants. The compound is found in the leaves of Erythroxylon coca, a South American shrub, in amounts of up to 2% by weight. It was first isolated in pure form in 1855, and has been widely utilized in medicine as a local anesthetic and increasingly by drug abusers for its stimulant properties. For anesthetic uses cocaine is administered topically as the hydrochloride in 1%-4% solutions for ophthalmological procedures and in 10%-20% solutions for the membranes of the nose and throat. When self-administered it is commonly taken as the hydrochloride by nasal insufflation or intravenous injection or as the free base by smoking, in doses of 10-120 mg.
Blood Concentrations. The chewing of powdered coca leaves containing 17-48 mg of cocaine produced peak plasma concentrations of 0.011-0.149 mg/L within 0.4-2 hours in 6 volunteers (Holmstedt et al., 1979). A 2 mg/kg (140 mg/ 70 kg) intranasal application of cocaine to 4 subjects yielded an average peak plasma concentration of 0.161 mg/L after 1 hour; an equivalent oral dose given to the same volunteers produced an average peak concentration of 0.210 mg/L at 1 hour, declining with an average half-life of 0.9 hour (Van Dyke et al., 1978). The intravenous injection of 32 mg of cocaine resulted in an average peak plasma concentration of 0.308 mg/L after 5 minutes (Javaid et al., 1978a). Following the nasal topical application of 1.5 mg/kg (105 mg/70 kg) of cocaine to surgical patients, plasma concentrations of the drug reached an average peak of 0.308 mg/L (range, 0.120-0.474) at 1 hour and declined to 0.206 mg/L by 3 hours (Van Dyke et al., 1976). Wilkinson et al. (1980) observed half-lives of 0.8 and 1.25 hours for cocaine after oral and intranasal administration, respectively. Barnett et al. (1981) reported dose-dependent pharmacokinetics for the drug over the range of 1-3 mg/kg.
Chronic cocaine abusers given free access to cigarettes containing 75 mg each of cocaine paste developed and maintained plasma concentrations of 0.253-0.932 mg/L over a 90-minute smoking period, during which they smoked 8-10 cigarettes (Paly et al., 1982).
Metabolism and Excretion. Cocaine is rapidly inactivated in man by the hydrolysis of one or both of the ester linkages. Even in water, at pH values greater than neutrality, the drug is readily hydrolyzed to benzoylecgonine. In blood or plasma, cocaine is hydrolyzed to ecgonine methyl ester by cholinesterase;the reaction rate is highly dependent on drug concentrations and may be inhibited by freezing or by the addition of fluoride or cholinesterase inhibitors (Stewart et al., 1977). With storage at 4 C., blood containing 1 mg/L of cocaine lost 100% of the drug in 21 days, whereas with 0.5% sodium fluoride 70% of the cocaine was still intact (Baselt, 1983). A similar rate of decline was observed in stored postmortem tissues (Price, 1974).
Benzoylecgonine is believed to arise spontaneously in vivo, since neither liver nor serum esterases produce this compound from cocaine. The further production of ecgonine from benzoylecgonine, however, may be the result of enzymatic hydrolysis (Stewart et al., 1979). Each of these metabolites is highly polar and, when formed outside the central nervous system, is without pharmacological activity (Misra et al., 1975). Norcocaine, an active metabolite, has not been detected in plasma after therapeutic administration, but is found in trace amounts in urine (Jatlow and Bailey, 1975; Mule et al., 1976; Jindal et al., 1978). Phenolic hydroxylation has been shown to produce a series of minor cocaine metabolites in man (Smith, 1984).
Cocaine is eliminated in the urine primarily as unchanged drug (1%-9%, dependent on urine pH), benzoylecgonine (35%-54%), ecgonine methyl ester (32%-49%), and ecgonine (not quantitated) in a 24-hour period (Fish and Wilson, 1969; Inaba et al., 1978). After a 1.5 mg/kg intranasal application, cocaine concentrations in urine averaged 6.7 mg/L during the first hour and declined rapidly to undetectable levels by 12 hours; benzoylecgonine urine concentrations reached an average peak of 35 mg/L during the 4-8 hour period and diminished slowly to an average of 0.4 mg/L for the 48-72 hour collection period (Hamilton et al., 1977). In a similar study involving 2 subjects, ecgonine methyl ester concentrations peaked at 29-36 mg/L during the 0-8-hour period and declined rapidly to 0.1-0.2 mg/L for the 24-48-hour period (Ambre et al., 1984).
Drinking 1 cup of herbal tea containing 2.2 mg cocaine produced a peak urine benzoylecgonine concentration of 1.3 mg/L in a subject after 2 hours, declining to 0.1 mg/L by 29 hours (ElSohly et al., 1986). The oral ingestion of 25 mg of cocaine by a volunteer resulted in a peak urine benzoylecgonine level of 7.9 mg/L in the 6-12-hour collection period, with a decline to 0.4 mg/L by 48 hours (Baselt and Chang, 1987).
Toxicity. Overdosage with cocaine has resulted in a relatively small number of serious intoxications, considering its popularity as a recreational drug. The symptoms of acute toxicity are similar to those for amphetamine, although it is believed that a direct cardiotoxic effect may be a contributory factor in cocaineinduced deaths. Myocardial infarction, ventricular tachycardia and fibrillation, and cerebrovascular accident may occur with acute or chronic abuse and even with medical usage (Chiu et al., 1986; Cregler and Mark, 1986; Isner et al., 1986); control of seizure activity with diazepam, correction of acidosis to stabilize heart rhythm, and administration of a calcium-channel blocker such as nitrendipine have been recommended as treatment (Jonsson et al., 1983; Nahas et al., 1985). One case was reported in which the unintentional rupture in the stomach of a 5 g packet of cocaine produced unconsciousness and massive convulsions; a maximal blood concentration of 5.2 mg/L was observed, but with treatment the patient survived (Suarez et al., 1977).
Cocaine concentrations observed in the tissues of victims who succumb to the drug vary greatly depending on the dosage, route of administration, period of survival, and manner of storage of the specimens. Intense paranoia, bizarre and violent behavior, hyperthermia, and sudden collapse were observed in 7 individuals, whose postmortem blood cocaine concentrations averaged 0.6 mg/L (range, 0.1-0.9) (Wetli and Fishbain, 1985). Blood cocaine concentrations in 53 cocaine-related fatalities ranged from 0-26 mg/L (Finkle and McCloskey, 1978). Postmortem blood concentrations averaged 3.0 mg/L in those who administered the drug intravenously, 4.4 mg/L in those practicing insufflation, and 9.2 mg/L in victims of oral overdosage (Wetli and Wright, 1979). 
The unusually high blood cocaine concentrations of 52 and 211 mg/L were reported in 2 victims of acute massive oral overdosage (Amon et al., 1986; Winek et al., 1987). The following data summarize the analytical results of 19 fatal cases that occurred after the ingestion, inhalation, or injection of from 160 mg (intravenously) to as much as 26 g (orally) of cocaine (McCurdy and Jones, 1973; Price, 1974; Griffin, 1975; Gottschalk, 1977; Lundberg et al., 1977; Prouty, 1977; Di Maio and Garriott, 1978; Bednarczyk et al., 1980; Poklis et al., 1985):
Analysis. Cocaine usage is often detected by thin-layer chromatographic screening of urine specimens for cocaine metabolites (Valanju et al., 1973; Bastos et al., 1974; Wallace et al., 1975; Clark and Hajar, 1987). The published procedures for the quantitative determination of low levels of cocaine in blood or plasma have relied on gas chromatography with nitrogen-selective detection (Jatlow and Bailey, 1975; Dvorchik et al., 1977), electron-capture detection (Javaid et al., 1978b), or mass spectrometric detection (Chine et al., 1980). For higher concentrations, flame-ionization detection is quite satisfactory (Valentour et al., 1978). Gas chromatographic techniques for the analysis of the drug and its metabolites in urine require derivatization of the polar metabolites and have used either flame-ionization or electron-capture detection (Javaid et al., 1975; Wallace et al., 1976; Jain et al., 1977; Kogan et al., 1977; von Minden and D’Amato, 1977). Liquid chromatographic techniques have been recently reported (Jatlow et al., 1978; Evans and Morarity, 1980; Masoud and Krupski, 1980). Both radioimmunoassay and enzyme immunoassay methods are commercially available for the quantitative detection of benzoylecgonine in urine. The radioimmunoassay cross-reacts with cocaine, but the enzyme immunoassay reportedly shows only minimal cross-reactivity (Mule et al., 1977; Van Dyke et al., 1977)