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Intoxication is exposure to an exogenous chemical substance (drug, drug of abuse, industrial toxin, poison) in an amount that exceeds normal elimination mechanisms. The one-compartment pharmacokinetic model describes the temporal evolution of the plasma concentration C(t): the absorption phase (k_a) raises C to a peak (C_max); the elimination phase (k_e) reduces C exponentially. In massive overdose, the kinetics can change qualitatively.

Saturation of hepatic metabolism in overdose is the most clinically dangerous phenomenon. Under normal conditions, paracetamol follows first-order kinetics (C << K_m): the liver metabolizes it proportionally to C. In overdose (C >> K_m, generally > 150 mg/kg), the metabolism goes to zero order (constant speed = V_max): the concentration decreases linearly and elimination is much slower than expected, allowing greater accumulation of the toxic metabolite NAPQI.

NAPQI (N-acetyl-p-benzoquinone-imine) is the hepatotoxic metabolite of paracetamol: it reacts with glutathione (GSH) to detoxify. When the dose exceeds the capacity of GSH (GSH < 30% of normal), free NAPQI covalently binds to hepatocellular proteins centrilobular necrosis. The antidote N-acetylcysteine replenishes GSH: it should be administered within 8 hours for maximum effectiveness.

The volume of distribution Vd determines the distribution of the toxicant in the body: a high Vd (amiodarone: 60 L/kg; tricyclics: 1020 L/kg) indicates accumulation in tissues and makes extracorporeal elimination difficult (ineffective dialysis for Vd > 1 L/kg). Toxicants with low Vd (lithium: 0.7 L/kg; methanol: 0.6 L/kg) are good candidates for hemodialysis, which can multiply total clearance by 310×.

The concentration-effect relationship of the toxicant follows the Hill curve: the EC varies enormously between individuals (pharmacogenomics: variants of CYP enzymes) and with the level of tolerance (tolerant opioid can have EC 10× higher). In emergencies, the Rumack-Matthew nomogram (paracetamol) and the Done nomogram (salicylates) use C measured at known time to estimate risk and guide the indication of antidote or dialysis.

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