Toxicokinetics, Toxicodynamics, and Laboratory Testing
ADME and why it matters clinically
Absorption determines the decontamination window; activated charcoal is most useful within one to two hours. Volume of distribution (Vd) predicts extracorporeal removal: a large Vd (>1 L/kg, lipophilic drugs such as tricyclics, digoxin, chloroquine) means dialysis will not help. Half-life relates as t½ = 0.693 × Vd/clearance. Most drugs follow first-order kinetics, but ethanol, salicylate, and phenytoin saturate and become zero-order, so small increments in dose produce disproportionate rises in level.
Metabolism is phase I (CYP450 oxidation, reduction, hydrolysis) then phase II (glucuronidation, sulfation, glutathione conjugation). Key concepts: prodrugs requiring activation (paracetamol to NAPQI via CYP2E1; methanol and ethylene glycol to toxic acids; codeine to morphine via CYP2D6), enzyme induction and inhibition, and genetic polymorphisms.
Toxicodynamics
Toxicity arises through receptor agonism/antagonism, enzyme inhibition (cholinesterase, cytochrome oxidase), and ion-channel blockade (sodium channels in tricyclics, potassium channels in antipsychotics). Potency and efficacy are distinct.
Interpreting the laboratory
- Anion gap = Na − (Cl + HCO3); normal 8–12. A delta-delta ratio helps separate mixed disorders.
- Osmolar gap is useful only early; it normalizes as parent alcohol is metabolized.
- Co-oximetry is required for carboxyhemoglobin and methemoglobin; calculated oxygen saturation from a standard blood gas will be misleadingly normal.
- Drug levels guide care for acetaminophen, salicylate, lithium, iron, theophylline, and digoxin; they are largely qualitative or unhelpful for tricyclics and most stimulants.
- Urine immunoassays produce false positives (bupropion, diphenhydramine, ranitidine for amphetamine) and miss synthetic agents.
Rule of thumb: consider hemodialysis when the toxin is small, water-soluble, minimally protein-bound, has a small Vd, and the patient is deteriorating despite supportive care.