New Thoughts
About What Causes
Cocaine Toxicity

CITATION:
[I don't have the AUTHORS' names yet! I'm working on getting them!]
New thoughts about what causes cocaine toxicity. Forensic Drug Abuse Advisor (April) 2002;14(4):17-8.

"Forensic Drug Abuse Advisor (FDAA) is the only monthly newsletter written
with the specific intent of keeping the reader up-to-date on the latest breaking
scientific issues relating to drug testing and drug abuse. Steven B. Karch, M.D.
is the founder and editor of FDAA, which began publication in 1989."

New Thoughts About What Causes Cocaine Toxicity

It is almost a ritual that research papers dealing with cocaine cardiovascular toxicity begin with the observation that cocaine is toxic because it blocks the reuptake of norepinephrine (NE) in the nerve endings of the peripheral sympathetic nervous system. Authors then go on to explain that, as a consequence, blood concentrations of NE increase, raising blood pressure, and damaging the heart and blood vessels.

While it is certainly true that cocaine raises blood concentrations of NE, it turns out that all the evidence relating NE to dangerous blood pressure increases has actually come from animal studies. Researchers from Texas Southwestern have finally studied humans, and it turns out that previous beliefs may not be accurate.(M. Tuncel, et al, "Mechanism of the blood pressure-raising effect of cocaine in humans." Circulation, 2002; 105:1054-1059)

Fifteen healthy subjects were enrolled in a study measuring blood pressure, blood flow, and venous NE concentration in the forearm after
(1) a 2 mg/kg dose of insufflated cocaine, or
(2) injection of .15 mg (low dose) or 15 mg (high dose) of cocaine directly into a catheter that had been inserted into the brachial artery.
This may sound like an " extreme" type of experiment, but measurement of forearm blood flow, with catheters inserted into the brachial artery, with inflatable tourniquets placed at the wrist and above the elbow to temporarily isolate the blood vessels in the forearm, is a fairly standard vascular research technique, approved by the university independent review board (IRB). At the same time, measurements were made of sympathetic nerve activity by placement of tiny electrodes inserted into leg muscles.

When the low dose of cocaine was injected into the forearm, the venous blood cocaine concentration was 102 : 30 ng/mL, concentrations of NE increased by 82 percent, and vascular resistance by 71 percent (cocaine makes the blood vessels contract, which increases vascular resistance), but there was no increase in systemic blood pressure because the cocaine was already partly metabolized before it was released into the circulation. When the high dose was injected, venous cocaine concentrations reached nearly 4000 ng/mL, and there was a very small additional increase in blood NE levels, but no additional increase in blood vessel constriction.

When the cocaine was given nasally, the cocaine systemic venous blood concentration was 100 ng, but there was no increase in venous blood NE concentration. The reason the cocaine did not cause a sustained increase was that, when the blood pressure started to increase, it set off a protective mechanism called a baroreflex, which lowers blood pressure, mainly by switching off sympathetic nerves and preventing them from releasing NE. Cocaine cannot prevent the reuptake of NE that was never released in the first place!

What this all amounts to is quite simple: people who do not use cocaine regularly have normal baroreceptor reflexes, and these reflexes counteract any effect cocaine has on elevating NE levels. If it were not for the presence of this reflex there would be very great elevations in blood pressure. Thus, the authors of the paper speculate that "the risk of hypertensive crisis, and other catastrophic cardiovascular complications from cocaine, is excessive in patients with long-standing hypertension, heart failure, or other pathophysiological conditions accompanied by impaired baroreceptor reflexes."

COMMENT: Much of the literature on cocaine cardiotoxicity consists of anecdotal data and case reports, which then get incorporated into peer reviewed papers, which then get cited as proven data. It is refreshing to see someone actually do the science, and even more exciting when something that "everyone knows is true", turns out to be wrong. The authors' conclusion confirms what pathologists have known for sometime: most cocaine-related deaths occur in chronic cocaine users, not in naive experiments.

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