TOXICOLOGY QUESTION OF THE WEEK
September 9, 2022
What is the value in knowing the half-life of a drug taken in a large overdose?
There is no value because toxicologists don’t know the half-life in that situation, and usually, neither does anyone else.
The assumption is that half-life is the time it takes for a serum drug level of the xenobiotic to drop by half due to elimination either by biotransformation and/or excretion. In the setting of therapeutic levels of a xenobiotic, the kinetics typically follow first-order elimination. In first-order elimination, a proportion (e.g. 20% of the drug is cleared) of the xenobiotic is eliminated and the half-life stays the same regardless of the concentration of the xenobiotic. This is the “half-life” that is reported in most references.
The problem with determining the half-life of a xenobiotic in an overdose is severalfold. First, if this was oral ingestion, there may be delayed absorption of the xenobiotic from the gastrointestinal tract. This delays the distribution of the xenobiotic, which further delays the elimination. Elimination can’t occur when the drug hasn’t even been fully absorbed and distributed. The other issue is that most xenobiotics are predominantly biotransformed (metabolized) via enzymes. Most enzymes that metabolize xenobiotics are saturable when the drug concentrations are high. When the enzymes are saturated, the clearance becomes fixed. The elimination transitions to zero order kinetics which means a set amount of xenobiotic is cleared for a time period (e.g. 20 mg/dl/hour). When a xenobiotic has zero order kinetics, the half-life becomes variable because the half-life is now dependent on the (high) concentration of the xenobiotic. The properties of transitioning between first-order and zero-order kinetics are explained by the Michaelis-Menten model of pharmacokinetics.
Oh, by the way, some drugs continue to exhibit clinical effects long after they are cleared. Good examples include some MAO inhibitors because they permanently disable the enzyme. Another example is the antiplatelet effect of salicylates. There are also some xenobiotics that never exhibit first-order kinetics and are always zero-order kinetics. Ethanol is a nice example of this.
Take home point: The pharmacokinetic values given in most references do not apply to the drugs that most patients ingest in overdose. Even if we knew the toxicokinetic half-life of a drug, that still does not correspond with the time to medical clearance.
Question by Saralyn Williams, MD, Professor of Emergency Medicine, Medicine, and Pediatrics VUMC
Dr. Williams makes an excellent point. Many health care providers assume that if you know the half-life you can then determine the time that the clinical effects will last (as evidenced by the number of calls the Poison Center receives asking for the half-life of a drug ingested by a patient with an overdose). Just not so. The Poison Information Specialists (certified nurses, pharmacists, and physicians) are there to discuss any aspect of treatment of an overdose patient and answer any questions you have regarding pharmacokinetic (or toxicokinetic) parameters. ds
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