book review

Toxicology Cases for the Clinical and Forensic Laboratory

by Hemamalini Ketha and Uttam Garg, eds.
Academic Press, 2020, 518 pages

Reviewed by T. Nelson

When you take a prescription drug you often find yourself needing a second drug to treat the side effects of the first one, then a third drug to treat the new side effects, and so on. The doctors’ primary goal is to make sure you don’t die from the disease they’re treating you for. As a patient, your goal is to avoid dying from the treatment instead of the disease.

That happens more than you might think. In this book you will learn surprising and unexpected fatal drug interac­tions that everyone should know about. For instance, ibuprofen, a common pain reliever, can cause CNS depres­sion and rhabdo­myolysis (destruction of muscle tissue), leading to amputation. Cancer treatment causes cardiac symptoms so often there’s an entire field for it: cardio-oncology. This is when your oncologist denies that the drug he’s giving you is causing your cardiac problems and your cardiologist blames the drug but puts you on statins and beta-blockers anyway “just to be safe.”

Taking cocaine and alcohol at the same time causes the formation of cocaethylene by liver carboxyl­ester­ase. Cocaethylene has effects similar to cocaine but is metabolized five times slower, so it makes an overdose virtually certain: the risk of sudden death is 18 to 25 times higher than for cocaine alone. Even without alcohol, twenty percent of cocaine users get rhabdo­myolysis.

Many of the case studies involve people making dumb mistakes. One 20 year old student missed a decimal point and ingested 30 grams of caffeine instead of 30 milligrams. His blood pressure shot up to 171/70. He lived, but they had to give him ondansetron i.v. to stop the vomiting.

Other problems are caused by injecting amphetamine into an artery instead of a vein. Bad move: the patient got rhabdo and a terrible rash. Another time a baby somehow ingested olanzapine (Zyprexa), an anti­psychotic used to treat schizo­phrenia and bipolar manic disorders. The baby had pinpoint pupils and became extremely drowsy but survived.

Deadly effects on cytochrome P450 2D6

Perhaps the most common lethal drug interaction happens when one drug inhibits liver enzymes including CYP2D6 (cytochrome P450 2D6), which metabolizes 25% of all pharmacologicals. When this happens the second drug easily reaches toxic levels. One 57 year old guy had a mutation in CYP2D6, which prevented him from detoxifying his clozapine and olanzapine. When he was put on bupropion (Wellbutrin, an antidepres­sant) the drug inhibited the P450 even further, leading to death by falling and a broken neck. This was only discovered in the tox report when they found O-desmethylolanzapine, a metabolite of olanzapine, was extremely low. CYP2D6 mutations are far from rare: seven percent of Caucasians lack the enzyme and sky-high drug levels are often found. In one case it reached 56 times the normal level, well above the fatal threshold. It points to an urgent need for genetic screening.

Duloxetine (Cymbalta, a SNRI), escitalopram (Lexapro, a SSRI), and celecoxib (a COX-2 inhibitor) also inhibit CYP2D6, so patients who take codeine or hydrocodone afterwards will have 40% higher blood levels, putting them at risk of dying. Conversely, modafinil (a dopamine reuptake inhibitor) and topiramate (an anti-seizure drug) induce CYP3A4, which metabolizes benzodiazepines.

Monitoring deadly opioids

This is why the authors make a strong case for therapeutic drug monitoring (TDM), where the doctor measures the blood levels of your drug instead of giving the same dose to everybody. This is something many biochemists (myself included) as well as the authors say is essential, especially if the drug has a narrow therap­eutic index (TI, the ratio of toxic to therap­eutic concentra­tion) or if there’s a wide inter­patient variability.

One reason TDM isn’t universal might be the lab’s requirement for FDA approval known as CLIA certification. Becoming certified is an arduous and expensive process.

Another is the expense and expertise needed to run a mass spectrometer, which the authors say is essential for accurate results. Opioid users, who are are almost always on TDM, sometimes spike their urine samples with naloxone and even oxycodone. This is only detectable when urine is analyzed by mass spec because the expected metabolites are absent. Many authors point out with apparent frustration how inaccurate the quick clinical tests are and advocate strongly for GCMS or LC-MS/MS. Even then, urine samples can give weird results, as some drugs are metabolized amazingly fast. Heroin is the classic example. Its half-life is only 2 to 8 minutes, so it’s impossible to detect in blood. The lab must look for its metabolite morphine instead.

And then there are the really sad cases where a patient commits suicide using a prescribed drug. One patient deliberately OD’d on antihistamines (diphen­hydra­mine), which screws up your thermal regulation and also causes psychosis. Often such patients are found naked, having thrown off all their clothes in an attempt to cool down.

In another case, a worker accidently got splashed with anhydrous ammonia and died of ammonia toxicity six days later. But the cause of death was not the ammonia. It was an overdose of acetaminophen, which the patient took to reduce the pain of the injury. It caused liver failure and hepatic encephalopathy due to hyperammonemia.

Deadly carbon monoxide and nitrate

Later sections of the book discuss chemical toxins such as carbon monoxide (CO), a gas that is formed naturally in small amounts in the body. Despite the ubiquity of catalytic converters, CO still causes many deaths. Though not mentioned in the book, death from CO is often delayed. About 12–13% of patients who survive and appear to recover die after two weeks of a symptom-free period due to delayed cell loss in the globus pallidus and to a lesser extent in thalamus, caudate / putamen, and corpus callosum.

Evidently there’s now debate as to whether neuronal cell death is caused by anoxia or by CO displacing NO (nitric oxide) from platelets. It’s likely both contribute. Babies are more vulnerable to CO than adults.

Nitrate and nitrite cause methemo­globin­emia (oxidation of Fe²⁺ iron in heme to Fe³⁺), which makes blood unable to carry oxygen. The treatment is methylene blue, a blue dye that gets reduced to the leuco form by NADPH-met­hemo­globin reductase. The leuco form then reacts with methemo­globin, reducing it back to hemo­globin. But in one of the great ironies of nature, nitrite is an antidote to cyanide poisoning. Cyanide acts by binding to the ferric (Fe³⁺) atom in cytochrome oxidase A3, a mitochondrial enzyme essential for cellular respiration. But it binds even more avidly to the Fe³⁺ in methemoglobin. So nitrite (along with amyl nitrite and sodium thiosulfate) are used to produce methemoglobin, which sucks up all the cyanide, rescuing the mitochondria. Of course there are safer antidotes. Most, such as hydroxy­cobal­amin, contain cobalt, which binds strongly to cyanide ions. This converts hydroxy­cobal­amin to vitamin B12 (cyano­cobal­amin).

Deadly herbal medicines

There are also significant dangers from herbal medicines such as Monkshood, which contains aconite (unlike what they say in the movies, they’re not identical!). Many other flowers including lily, oleander, and foxglove contain alkaloids that are highly toxic. Germander extracts (Larrea chaparral herb) can induce liver failure, requiring a transplant. Kombucha, kava, ma huang, and wintergreen oil can all be deadly. Kratom is toxic when consumed with alcohol or antidepressants.

Each section of this fascinating multi-author book starts with a brief review of the topic, followed by short case studies. The writing isn’t Shakespeare. Occasionally an author produces a sentence that means the opposite of what is intended. But in our drug-saturated medical world, any patient who doesn’t know the information in this book is taking a big risk.

jun 06 2026