How is cocaine metabolized during the development of cocaine toxicity?

Updated: Sep 01, 2018
  • Author: Lynn Barkley Burnett, MD, EdD, LLB(c); Chief Editor: Sage W Wiener, MD  more...
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Answer

Approximately 30-50% of cocaine is metabolized by hepatic esterases and plasma pseudocholinesterase, resulting in the formation of ecgonine methyl ester. Spontaneous nonenzymatic hydrolysis of another 30-40% results in benzoylecgonine. Both products are water-soluble, metabolically active, and capable of increasing blood pressure (BP). Benzoylecgonine, which has a half-life of 7.5 hours, can induce seizures, perhaps even hours to days after the last use.

Approximately 80-90% of injected cocaine is rapidly metabolized. Decreased hepatic perfusion, secondary to conditions such as hypotension or low-output congestive heart failure (CHF), results in prolonged elevation of cocaine levels. A similar result may be observed in pregnant women, fetuses, infants, patients with liver disease, and elderly men, because their plasma cholinesterase activity is decreased. In addition, some people have a genetic deficiency of plasma pseudocholinesterase or a nutritional predisposition to abnormally low pseudocholinesterase levels. Some have postulated that these patients may metabolize cocaine slowly and have increased sensitivity to small doses of cocaine, which places them at risk for increased toxicity and sudden death. Evidence supporting this postulate is scant.

Most of the remaining amount of cocaine is metabolized by hepatic N-demethylation into norcocaine, which is metabolically active. Pregnancy, during which circulating progesterone levels are high, or the exogenous administration of progesterone increase the activity of hepatic N -demethylation. This increased formation of norcocaine, which is more vasoconstrictive than cocaine, may result in women being more sensitive to the cardiotoxic effects of cocaine than men as a result of hormonal potentiation.

Approximately 1-5% of cocaine is excreted, unaltered, through the kidneys within 6 hours of use.

With the multiplicity of physiologic and pharmacologic modifiers cited above, the literature reflects tremendous variability in the reported lethal dose of cocaine in humans. The range is as little as 20 mg IV, to a mean of 500 mg ingested orally, to 1.4 g.


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