Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration

Abstract

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.

Population pharmacokinetics of intravenous acetaminophen in Japanese patients undergoing elective surgery

“…In analyzing the drug effects using a compartmental PK model, the transition of the drug from the central compartment to the effect site should be taken into account as the drug concentration would enhance the drug effect. The cerebrospinal fluid (CSF) concentrations can be equated to be the effect site concentrations [14] because the time course of acetaminophen concentration in CSF correlates with the analgesic and antifebrile effect of the drug [15]. Because acetaminophen is thought to penetrate the blood−brain barrier by passive diffusion due to a concentration gradient, larger peak concentrations after i.v.…”

Randomised placebo-controlled study of the effect of paracetamol on asthma severity in adults

“…Following a 1 g dose, participant blood levels may fall below this laboratory cut-off level in as little as 3 h (given a paracetamol half-life of 2 h and a peak plasma concentration 1 h after administration of 80 μmol/L38). The use of this laboratory cut-off for paracetamol levels meant that it was not possible to investigate medication compliance through this method.…”

Analgosedation in neonates: do we still need additional tools after 30 years of clinical research?

“…Consequently, a loading dose of 20 mg/kg to adapt for the higher distribution volume, followed by a 6-hourly 10 mg/kg dose to adapt for the lower clearance in neonates was suggested 33. In contrast to these pharmacokinetic estimates, there are still no robust data to disentangle paracetamol pharmacokinetics and pharmacodynamics in newborns 34. Data are limited to haemodynamics, hepatic tolerance and body temperature dynamics 35–37.…”