TOXCards: Elimination Toxicokinetics

Authors: Alexander M Mozeika, PharmD (MS3, Rutgers New Jersey Medical School), Cynthia Santos, MD (Assistant Professor Emergency Medicine, Medical Toxicology, Rutgers New Jersey Medical School) // Reviewed by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case:

A 14-year-old female with a history of asthma on an unknown oral medication presents with vomiting and diarrhea. She was admitted and subsequently developed seizures in the setting of hyperglycemia and hypokalemia. Further work-up revealed a combined respiratory alkalosis and metabolic acidosis. She endorses that she has “been forgetful” and took double her dose for the last two days.

Questions:

• What are the pharmacokinetic factors of elimination?
• How are these factors altered in the setting of toxicology (i.e. toxicokinetics)?
• What are treatment options for gastric decontamination?

Background:^1,2

• Elimination is a multi-organ process to rid the body of xenobiotics and their metabolites.
  • Most of elimination occurs by the kidneys and liver.
• Clearance is the volume of blood that an organ can clear substance from per unit time.
  • The summation of organ-specific clearances equals the total body clearance.
• Half-life is the amount of time it takes for plasma concentrations of a xenobiotic to reduce by half.
  • It may be constant (first-order kinetics) or vary by concentration (zero-order kinetics).
• Elimination kinetics can be classified by zero-order, first-order, or Michaelis-Menten kinetics.

Elimination Kinetics:^1,2

• See “TOXCards: General Principles of Toxicokinetics” for more information.
• Zero-order kinetics:
  • Fixed amount of xenobiotic is eliminated per unit time.
  • Examples: ethanol, phenytoin, salicylates, omeprazole, fluoxetine, cisplatin

• First-order kinetics:
  • Fixed proportion of xenobiotic is eliminated per unit time.
  • A large majority (~95%) substances exhibit first-order kinetics.

• Michaelis-Menten kinetics:
  • A non-linear kinetic state with both zero- and first-order kinetics.
  • Kinetics are dependent on concentration:
    • Low concentrations ([C] <<< k_m) = first-order kinetics
    • High concentrations ([C] >>> k_m) = zero-order kinetics

Case (continued):

The patient’s parents arrive to the emergency department and endorse that she is on theophylline for chronic asthma control. Her labs resulted a theophylline level of 83 mg/dL. Multi-dose activated charcoal and intermittent hemodialysis are initiated to enhance the elimination of theophylline.

Enhance Elimination Treatments:

Main Point:

• Elimination is a multi-organ process in order to eliminate xenobiotics from the body.
• The elimination kinetics enable us to predict how the plasma concentrations change with respect to ingestion quantity and time.
  • However, they can be significantly altered in the setting of toxicological ingestions.
• Substances with zero-order kinetics can show large fluctuations in concentration with small increments in dose.

References/Further Reading:

1. Howland MA. Pharmacokinetic and Toxicokinetic Principles. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank’s Toxicologic Emergencies, 10e. New York, NY: McGraw-Hill Education; 2015.
2. Ducharme MP. Drug Elimination, Clearance, and Renal Clearance. In: Shargel L, Yu ABC, eds. Applied Biopharmaceutics &amp; Pharmacokinetics, 7e. New York, NY: McGraw-Hill Education; 2016.
3. Goldfarb DS, Ghannoum M. Principles and Techniques Applied to Enhance Elimination. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank’s Toxicologic Emergencies, 10e. New York, NY: McGraw-Hill Education; 2015.
4. American Academy of Clinical Toxicology EAoPC, Toxicologists C. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. Journal of Toxicology: Clinical Toxicology. 1999;37(6):731-751.
5. Thanacoody R, Caravati EM, Troutman B, et al. Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients. Clinical Toxicology. 2015;53(1):5-12.
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