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Toxicology Rounds: The Best Toxicology Articles of 2011

Gussow, Leon MD

doi: 10.1097/01.EEM.0000410882.41622.56
Toxicology Rounds
Chemical structure

Chemical structure

Several toxicology papers published in 2011 are well worth reading, including one I would nominate for toxicology paper of the year if such a distinction existed. From a surprising finding about IV calcium in digoxin toxicity to the black (box) hole of FDA warnings, toxicologists reported some important results this year.

Although the use of hemodialysis to treat poisoning goes back to 1948, considerable confusion still exists about exactly when it is indicated. This superb article — my nomination for toxicology paper of the year — states unequivocally that “the science of blood purification in toxicology remains desperately stagnant today.”

The authors explain that the clinically significant purpose of hemodialysis is to remove toxins, not from the blood but from target organs. This is difficult to measure. Much of the clinical literature on hemodialysis is based on outdated technology, they note, and may not apply to currently available high-flow and high-flux dialysis membranes, not to mention that virtually no randomized controlled trials have evaluated specific indications for hemodialysis.

For ethical and logistical reasons, we will never have good randomized controlled trials evaluating these issues, and the best available evidence will continue to be frustratingly incomplete. One approach to this problem would be to establish guidelines developed by experts from many of the subspecialties involved: emergency medicine, medical toxicology, nephrology, pediatrics, critical care, and pharmacology. The authors are members of the EXTRIP work group (Extracorporeal Treatments in Poisoning) that has undertaken just such a project. While their recommendations won't appear until later in 2012, this must-read article is the clearest discussion I've seen about why many issues concerning the use of hemodialysis in toxicology cases remain unsettled.

Although this is not primarily a clinical article, it will be catnip to molecular structure nerds like me who enjoy getting granular about the pharmacology of new designer drugs such as Bromo-DragonFLY and foxy-methoxy. The article's 169 references are also a valuable resource for anyone interested in the topic.

The authors define designer drugs as chemicals synthesized for recreational use, often by slight modification to the structures of illegal drugs. This structural alteration may modify or enhance specific psychogenic and clinical effects or produce a drug that is temporarily “legal” because the specific molecule has not yet been regulated.

The authors searched PubMed.gov and Medline for relevant medical literature published since 1950. They classified designer drugs into four categories.

Piperazines are synthetic chemicals that do not exist in nature. Included in this group is BZP, a sympathomimetic stimulant with effects similar to amphetamine. BZP inhibits reuptake of dopamine and norepinephrine, and clinical effects of piperazine toxicity include seizures, ventricular repolarization abnormalities, paranoid psychosis, and possibly hyponatremia.

Phenethylamines include many new designer drugs as well as amphetamine, methamphetamine, and MDMA (ecstasy). These drugs are primarily stimulants, but also often have psychogenic or hallucinogenic properties related to effects on serotonin. Examples of some newer phenethylamines include such dangerous drugs as MDPV (bath salts), 2C-E (Europa), Bromo-DragonFLY, and mephedrone.

Tryptamines are structurally similar to the amino acid tryptophan. Examples include LSD, psilocybin, DMT (Dimitri), and 5-MeO-DIPT (foxy methoxy). These are serotonin agonists, and have strong hallucinogenic properties.

Piperidines can produce prolonged agitation and psychosis. Some samples of Ivory Wave bath salts seized in the United Kingdom have recently been found to contain the piperidine desoxypipradrol.

I find this scheme helpful when thinking about the various designer recreational drugs, but its clinical usefulness is limited because one is never completely certain exactly what drug a patient has taken. The authors' treatment recommendations are limited to one sentence: “The management of users with acute toxic manifestations is pragmatic, and in general, as for poisoning with longer established stimulant or hallucinogenic drugs such as amphetamines and MDMA.”

This caveat has been conventional wisdom since time immemorial: Do not use calcium to treat hyperkalemia associated with digoxin toxicity; it may worsen ventricular arrhythmias. (Poisoning & Drug Overdose. McGraw-Hill; 2007.) The concern is that in a digoxin-toxic patient, intravenous calcium will, aside from precipitating life-threatening cardiac dysrhythmia, impair diastolic function, preventing myocardial relaxation and producing a heart frozen in systole — the dreaded stone heart.

But does this actually occur in clinical situations? The authors retrospectively reviewed charts of all adults diagnosed with digoxin toxicity at their hospital for nearly 17 years. They identified 23 patients who had been treated with IV calcium. No significant arrhythmias occurred within one hour (or even four hours) of calcium administration, and there was no significant difference between the mortality rates of those who did or did not receive calcium. The authors' conclusion: “We question the ‘stone heart’ theory, and suggest that intravenous calcium may not be harmful in digoxin-intoxicated patients.”

It is important to note only one case of single acute digoxin ingestion was reported among these patients; the other cases involved chronic or subacute ingestions. The results may not be able to be generalized to all cases of digoxin toxicity.

Food & Drug Administration black box warnings on widely used drugs with long records of safety continue to be problematic and confusing. Several years ago, droperidol, a drug that until then had been commonly administered in the emergency department as an antiemetic and sedating antipsychotic, was black-boxed. This past September, the FDA issued a safety alert for ondansetron, suggesting that even an effective, safe antiemetic might receive a black box warning in the near future. Like a crazed bureaucratic version of J. Edgar Hoover, the FDA seems to be seeing not communists but prolonged QTc intervals behind every door.

This important commentary points out that black box warnings generally give no information about the incidence or prevalence about adverse events. Because of this, they do not provide the physician with any data with which he can estimate the risk-benefit ratio of using the drug or meaningfully discuss it with a patient. As the authors rightly note, “[T]he boxed warning can become a ‘black hole,’ creating clinician anxiety for using drugs they may have comfortably been using for years.”

Dr. Gussow

Dr. Gussow

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