Cocaine

Cocaine is a naturally occurring alkaloid obtained from the plant Erythroxylon coca L. This plant grows in the Andes region of South America, ideally at elevations between 1,500 to 5,000 ft.1

A second closely related species has been identified , Erythroxylon novogranatense H., and each species has one variety known as E. coca var. ipadu Plowman and E. coca novogranatense var. truxilllense, respectively. Cocaine may also be chemically synthesized with cold aqueous succinaldehyde and cold aqueous methylamine, methylamine hydrochloride, and the potassium salt of acetone-dicarboxylic acid monomethyl ester.2

Cocaine is used medically by otorhinolaryngologists and plastic surgeons as an epinephrine cocaine mixture. Solutions for topical application are typically less than 4% cocaine hydrochloride. In the U.S. cocaine is a scheduled drug under the federal Controlled Substances Act of 1970. Refined cocaine, in the form of the base or hydrochloride salt, is self-administered by many routes, including snorting, smoking, genital application, and by injection.

3.6.9.1 Pharmacology

Cocaine inhibits the presynaptic reuptake of the neurotransmitters norepinehrine, serotonin, and dopamine at synaptic junctions. This results in increased concentrations in the synaptic cleft. Since norepinephrine acts within the sympathetic nervous system, increased sympathetic stimulation is produced. Physiological effects of this stimulation include tachycardia, vasoconstriction, mydriasis, and hyperthermia.3 Central nervous system stimulation results in increased alertness, diminished appetite, and increased energy. The euphoria or psychological stimulation produced by cocaine is thought to be related to the inhibition of serotonin and dopamine re-uptake. Cocaine also acts as a local anesthetic due to its ability to block sodium channels in neuronal cells.3

3.6.9.2 Absorption

Cocaine is rapidly absorbed from mucous membranes and the pulmonary vasculature. However, differences in the rate of appearance of cocaine in blood is dependent on the route of administration. Coca leaves were chewed by native South Americans over 3,000 years ago. Recent studies of the oral route of administration found that chewing powdered coca leaves containing between 17 and 48 mg of cocaine produced peak plasma concentrations of 11 to 149 ng/mL (N=6) at 0.4 to 2 h after administration.4 In another study, healthy male volunteers were administered cocaine hydrochloride (2 mg/kg) in gelatin capsules. Peak plasma concentrations of 104 to 424 ng/mL were achieved at 50 to 90 min. One of the most common routes of self-administration of cocaine in North America is the intranasal route. Wilkinson et al.5 found that peak plasma concentrations of cocaine were reached 35 to 90 min after "snorting" but another study using equivalent doses found that peak plasma concentrations were achieved between 120 and 160 min.6 Intravenous administration of 32-mg cocaine hydrochloride resulted in an average peak plasma concentration of 308 ng/mL at 5 min.6 Cocaine may also be self-administered by the smoked route in the form of cocaine base, commonly called "crack" or by a process known as "free-basing" in which powdered cocaine hydrochloride is converted to its base form. In a study in which 6 subjects smoked 50 mg of cocaine, the average peak plasma cocaine concentration of 203 ng/mL was achieved at 5 min.7 The bioavailability of cocaine after smoking depends on several factors including the temperature of volatilization and losses of drug in main and sidestream smoke.

Perez-Reyes et al.8 estimated that only 32% of a dose of cocaine base in a pipe is inhaled by the smoker. Cone9 compared the pharmacokinetics and pharmacodynamics of cocaine by the intravenous, intranasal, and smoked routes of administration in the same subjects. Venous plasma cocaine concentrations peaked within 5 min by the intravenous and smoked routes. Estimated peak cocaine concentrations ranged from 98 to 349 ng/mL and 154 to 345 ng/ mL after intravenous administration of 25-mg cocaine hydrochloride and 42-mg cocaine base by the smoked route, respectively. After dosing by the intranasal route (32-mg cocaine hydrochloride) estimated peak plasma cocaine concentrations ranged from 40 to 88 ng/mL

Cocaine Metabolic Metabolism
3.6.9 Metabolic pathway of cocaine.

after 0.39 to 0.85 h.9 In this study, the average bioavailability of cocaine was 70.1% by the smoked route, and 93.7% by the intranasal route.

3.6.9.3 Distribution

After an intravenous dose of radiolabelled cocaine to rats, the highest concentrations were found in the brain, spleen, kidney, and lung after 15 min, with the lowest concentrations in the blood, heart and muscle.10 Plasma protein binding in humans is approximately 91% at low concentrations.10 Cocaine binds to the plasma protein, albumin, and also to a1-acid glycoprotein. The steady state volume of distribution is large (1.6 to 2.7 L/kg), reflecting extensive extravascular distribution.11

A two-compartment open linear model has been described for the pharmacokinetic profile of cocaine after intravenous administration.12 The distribution phase after cocaine administration is rapid and the elimination half-life estimated as 31 to 82 min.12 Cone9 fitted data to a two-compartment model with bolus input and first order elimination for the intravenous and smoked routes. For the intranasal route, data were fitted to a 2-compartment model with first order absorption and first order elimination. The average elimination half-life (tj/26) was 244 min after intravenous administration, 272 min after smoked administration, and 299 min after intranasal administration.

3.6.9.4 Metabolism

In humans, the principle route of metabolism of cocaine is by hydrolysis of the ester linkages. Plasma and liver cholinesterases produce the inactive metabolite, ecgonine methyl ester (EME) (Figure 3.6.9). The second major metabolite, benzoylecgonine (BE), is formed spontaneously at physiological pH. N-demethylation of benzoylecgonine produces benzoylnorecgonine.

Further metabolism of EME and BE produces ecgonine. Further hydrolysis of cocaine and BE produce minor metabolites, meta- and para- hydroxy- cocaine and -BE. The proportion produced and activity of these metabolites have yet to be completely described.

Cocaine may be N-demethylated by the cytochrome P-450 system to produce an active metabolite, norcocaine. Further breakdown produces N-hydroxynorcocaine and norcocaine nitroxide. Further metabolism produces a highly reactive free radical which is thought to be responsible for the hepatotoxicity observed in cocaine users.1

When cocaine is coadministered with ethanol, cocaethylene is formed in the liver by transesterification. This lipophilic compound crosses the blood-brain barrier and is known to contribute to the psychological effects produced by cocaine.1 When cocaine is smoked, a pyrolysis product, anhydroecgonine methyl ester (AEME), is formed. Therefore, the presence of this compound indicates exposure to smoked cocaine. The pharmacological and toxicologi-cal properties of this compound have not been studied.

3.6.9.5 Elimination

Approximately 85 to 90% of a cocaine dose is recovered in the 24-h urine.13 Unchanged drug accounts for 1 to 9% of the dose depending on urine pH, BE, 35 to 54%, and EME, 32 to 49%. In one study, excretion data was obtained from subjects administered a bolus intravenous injection of cocaine followed by an intravenous infusion, supplying total doses of 253, 444, and 700 mg cocaine.14 Elimination half-lives averaged 0.8 h, 4.5 h, and 3.1 h, for cocaine, BE, and EME, respectively. After intranasal application of 1.5 mg/kg, urine cocaine concentrations averaged 6.7 mg/L during the first hour, and BE concentrations peaked between 4 to 8 hours at 35 mg/L.11 Oral ingestion of 25 mg cocaine by a single individual resulted in a peak urine BE concentration of 7.9 mg/L in the 6- to 12-h collection period, with a decline to 0.4 mg/ L by 48 h.15 The minor metabolites, including the p- and m-hydroxy metabolites, and also the pyrolysis product, AEME, have been detected in urine after cocaine administration.16,17

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