TOXICOLOGY QUESTION OF THE WEEK
September 23, 2022
Why do therapeutic pharmacokinetics not apply to drugs in overdose? What determines observation time?
The last Question of the Week generated some great reader's comments, which we appreciate. Thus the current topics.
Regarding Pharmacokinetics Following OD:
Dr. Ariel Deutch, Professor Emeritus, Dept of Psychiatry and Behavioral Sciences, VUMC commented: “One more reason that PK data are not generally very useful in determining best therapeutic approaches for ODs: the biotransformation into a more active “metabolite”. A classic example would be the renin-angiotensin system, with differences in affinity of the successive metabolites of ANG I for receptors. Other examples include certain antipsychotic drugs.”
Dr. Deutch makes a good point. Sometimes the metabolite exhibits the toxicodynamic effects of the drug-so onset of target organ toxicity may occur later than the typical pharmacodynamic effects. One of the toxicities that occurs after an overdose of bupropion is convulsions. However, this may not manifest until about 18 hours post-ingestion since the convulsions are mainly caused by bupropion's active metabolites. A patient may be fairly asymptomatic unit the convulsions occur. Another example is meperidine whose metabolite, normeperidine, is far more neurotoxic than its parent compound. Ethylene glycol causes initial intoxication; its metabolites cause the anion gap acidosis and renal failure.
There are other considerations. Some xenobiotics have delayed onset of pharmacodynamic or toxicodynamic effects even if the xenobiotic is absorbed within the “typical” 4-6 hours. Sulfonylureas are examples of this as markedly delayed onset (>12 hours after ingestion) of hypoglycemia is quite common.
Some xenobiotics are actually pro-drugs e.g. codeine, that have to be absorbed, distributed, and then metabolized to have clinical effects. These ingestions may need a prolonged observation period before the patient can be medically cleared.
And there is the issue of drugs that increase synaptic neurotransmitters (many psych drugs and recreational drugs). The increased concentration of synaptic neurotransmitters (such as serotonin and dopamine) cause the clinical effects but have no relationship to serum drug concentration. The increased synaptic concentration of neurotransmitters can be present long after the serum drug concentration is below the limits of detection.
Regarding Observation times following OD:
The Poison Center will initially recommend a time frame of observation after a suspected exposure/overdose in an asymptomatic patient. This recommendation is based on when a patient should start manifesting systemic signs or symptoms of the overdose. The premise is that the drug is going to be absorbed AND distributed to the target organs AND exhibit some clinical effect within that recommended observation period. The recommended observation is not necessarily when peak effects are predicted.
Absorption in OD: Absorption can be markedly delayed in overdose. Any drug with anticholinergic properties delays absorption (can do so for days). If the drug in overdose causes CNS depression requiring endotracheal intubation, an ileus usually develops which further delays absorption.
SR drugs have external coatings that can prevent the absorption for up to 16 hours so clinical effects may not occur for that number of hours. Patients who have ingested SR drugs are usually admitted because the patient requires prolonged observation to determine if they are medically cleared.
Then there is the question of the length of the observation time in a patient who has manifested signs and symptoms of the toxicodynamic effects (symptomatic patient). This can be difficult to predict at times due to issues such as changes in the kinetics from first order to zero order, metabolism to active metabolites that prolong clinical effects, a mechanism of action that includes permanent disabling of an enzyme, etc.
In the end, the poison center is a valuable resource to provide recommendations for observation time for medical clearance and for anticipatory guidance on the duration of the toxicodynamic effects.
Question prepared by Saralyn Williams, MD, Professor of Emergency Medicine, Medicine, and Pediatrics VUMC, and Donna Seger, MD Professor Emerita, Dept of Medicine VUMC
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DONNA SEGER, MD
Department of Medicine
Tennessee Poison Center
24/7 toll-free Poison Help Medical Hotline