Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration

Interpretation of analgesic and antipyretic responses documented after paracetamol administration is confused because response is not directly related to concentration in the blood, but rather to an effect compartment. The effect compartment does not have real measurable concentrations, but concentrations equate approximately to those observed in the cerebrospinal fluid. A time delay exists before drug reaches the effect compartment, and the equilibration half-time between the central and effect compartment is described by a single first-order parameter (Teq or T(1/2)keo), reported to be approximately 1 h for paracetamol. Paediatric analgesic studies are limited because they have only explored postoperative pain after tonsillectomy or day-stay surgery. Other pain types and pain confounders have not been investigated. Adult studies are also similarly limited. Studies investigating antipyresis have not explored the maximum response, limiting the precision of any EC(50) estimate. The influence of the cyclical nature of fever or initial temperature is seldom accounted for in antipyretic studies. Target effect compartment concentrations of 5 mg/l for fever and 10 mg/l for pain do not seem unreasonable on the basis of current literature. Speed of onset may be shortened by giving a larger initial dose or improving absorption characteristics. Consequent plasma concentration achieved, differences in effect compartment equilibration times, and the shape of the effect compartment concentration-response curve help to explain differences between common analgesic/antipyretic drugs.