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Toxicology Rounds: Will This Dog(ma) Hunt? Beta Blockers for Cocaine Toxicity

Gussow, Leon MD

doi: 10.1097/01.EEM.0000520587.65965.0b
Toxicology Rounds

Dr. Gussowis a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Read his blog, follow him on Twitter @poisonreview, and read his past columns at



Nearly 30 years ago, volunteers undergoing routine cardiac catheterization for chest pain were given intranasal cocaine followed by intracoronary (!) propranolol during the procedure. Needless to say, that paper continues to spark controversy today, but its conclusions — that propranolol seemed to increase coronary vasospasm — led its authors to suggest that beta blockers “probably should be avoided in patients with cocaine-associated myocardial ischemia or infarction.” (Ann Intern Med 1990;112[12]:897.)

The belief that beta blockers were contraindicated after cocaine use was passed down from generations of emergency physicians to generations of trainees. Some experts now claim that this dogma just won't hunt. They point out that control of coronary artery diameter is complex, depending not only on a balance between the alpha- and beta-adrenergic systems but also processes mediated by nitric oxide, adenosine, and ATP, among other bioactive molecules.

So how exactly did we get here?

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Smoking during Cath?

A series of remarkable papers, including the one above that gave intranasal cocaine and intracoronary propranolol, were published about a quarter of a century ago by Richard Lange, MD, and his colleagues at Parkland Hospital in Dallas, and went a long way toward eliciting the effect of cocaine on the heart. One of the first studies gave patients in the cath lab intranasal cocaine (2 mg/kg) or an intranasal saline solution. The investigators demonstrated that cocaine caused vasoconstriction of the coronary arteries, with a greater effect on atherosclerotic ones than normal vessels. Additional work found that this cocaine-induced vasoconstriction was reversed by sublingual nitroglycerin.

Another interesting study gave chest pain patients who were smokers intranasal cocaine, had them smoke one cigarette during their catheterization procedure, or both. Results showed that the combination of cocaine and cigarette smoking decreased the diameter of diseased coronary artery segments to a greater degree than either did alone. (N Eng J Med 1994;330[7]:454.)

The idea that beta blockers were contraindicated in cocaine toxicity based on the concept of unopposed alpha stimulation. The reasoning went like this: Arterial vessel resistance is controlled by two competing mechanisms. Alpha adrenergic stimulation causes vasoconstriction, increasing vascular resistance and blood pressure. A competing factor involves beta-2 stimulation, which produces vasodilation. Precise control of blood pressure depends on these systems being balanced and unimpaired. Blocking beta stimulation would exacerbate the effects of alpha-induced vasoconstriction, potentially causing severe hypertension with complications such as aortic dissection. As we shall see, this model is somewhat simplistic.

A recent review by Richards, et al., identified 1744 cases reported in the medical literature in which patients were treated with beta blockers for cocaine-associated cardiovascular toxicity. Seven patients experienced adverse events after receiving propranolol, esmolol, and metoprolol. No adverse events associated with administration of mixed alpha/beta blockers such as labetalol were reported. (Clin Toxicol 2016;54[5]:345.) It is interesting that an author of this review is Dr. Lange, the cardiologist whose original 1990 study fueled the “unopposed alpha stimulation” dogma. In fact, Dr. Lange has been an author on a number of recent papers and letters suggesting that those who think cocaine use is an absolute contraindication to administering a mixed alpha/beta blocker, if needed, to control hypertension and tachycardia are mistaken.

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CNS and Toxicity

Equally prominent and strong voices on the other side of this debate argue that treating cocaine toxicity with adequate doses of a benzodiazepine is a crucial intervention because the central nervous system seems to play a key role in this poisoning. They maintain that hypertension can be treated with a specific alpha-1 blocker such as phentolamine, and that using a beta blocker (or even a mixed alpha/beta blocker) is risky, despite the scant existing evidence.

The current edition of Goldfrank's Toxicologic Emergencies states unequivocally that “β-adrenergic antagonism is absolutely contraindicated” in patients with cocaine use. This absolute prohibition seems to be based on theoretical concerns and a handful of adverse clinical events — reported nearly 30 years ago — occurring after a handful of patients with cocaine cardiotoxicity were treated with esmolol. (Goldfrank's Toxicologic Emergencies, 10th Edition, New York: McGraw-Hill Education/Medical, 2014.)

To support its position, Goldfrank's cites a 2008 American Heart Association statement advising that “use of β-adrenergic antagonists should be avoided” when treating acute cocaine toxicity. (Circulation 2008;117[14]:1897.) The AHA statement goes on: “Although theoretically more attractive than propranolol, labetalol does not appear to offer any advantages [in treating acute cocaine toxicity]. ... Labetalol increases the risk of seizure and death in animal models of cocaine toxicity and does not reverse coronary artery vasoconstriction in humans.”

Let's take those two claims one at a time. There are not actually animal “models.” The statement cites only one paper in which rats were rapidly infused with an LD50 dose of intravenous cocaine and then given 3 mg per 100 g labetalol. (Ann Emerg Med 1991;20[7]:768.) For those doing the math, that's the equivalent of 2100 mg labetalol in a 70 kg human. It does not seem reasonable to extrapolate from this model to make any clinical decisions.

The second claim is apparently based on one of Dr. Lange's studies in which cardiac catheterization patients were given intranasal cocaine followed by saline or 0.25 mg/kg IV labetalol. (Am J Med 1993;94[6]:608.) Labetalol in that trial did not alleviate cocaine-induced coronary vasoconstriction, but — and this is important — labetalol is not given in this setting to alleviate cocaine-induced vasoconstriction. Rather, the goal is to control tachycardia or hypertension. It is also misleading to say that labetalol “does not appear to offer any advantages.” The same Lange paper showed that labetalol reduces mean arterial pressure and pulse rate without increasing coronary vasoconstriction — exactly the outcomes one wants.

The bottom line: Better primary options than beta blockers to treat chest pain, hypertension, or tachycardia associated with acute exposure to cocaine probably exist. These include benzodiazepines, nitroglycerine, and the alpha blocker phentolamine (if available.) But if these fail or are not at hand, cautiously using a mixed alpha/beta blocker such as labetalol should not be ruled out.

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