Clinical Pharmacology
Mechanism of Action
Acetaminophen, also known as paracetamol, is a synthetic derivative of p-aminophenol. It is also an active metabolite of two other p-aminophenol derivatives, phenacetin and acetanilid, which were withdrawn from the market because of unacceptable nephrotoxicity.
Acetaminophen is an analgesic and antipyretic agent, similar in potency and efficacy to salicylates. Acetaminophen does not share the anti-inflammatory or uricosuric effects of ASA and does not cause gastrointestinal ulceration or inhibit platelet aggregation.
The mechanism of acetaminophen’s antipyretic action may involve a direct effect on the heat-regulating centres in the hypothalamus, leading to increased heat dissipation through vasodilation and sweating.
The proposed mechanism of acetaminophen’s analgesic action is through inhibition of prostaglandin synthetase in the CNS. Acetaminophen has minimal effect on peripheral prostaglandin synthesis, which may explain its relative lack of anti-inflammatory effect compared to ASA.
Indications and Clinical Use
- Treatment of mild-moderate pain. Although it is not the most effective analgesic, due to its low risk of adverse effects, acetaminophen is the drug of first choice for several conditions and patient populations including osteoarthritis, pain and fever in children, women who are pregnant or breastfeeding, patients at risk of GI bleeding, patients on anticoagulants and patients with renal disease. Acetaminophen is likely not effective for centralized pain disorders (e.g., fibromyalgia), nor pain primarily due to inflammation (e.g., rheumatoid arthritis, dysmenorrhea).
- Reduction of fever
Pharmacokinetics
Adults
Absorption
Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. A mean peak plasma concentration of 100 µmol/L is reached approximately 0.8 hours following a 1000 mg oral dose of immediate-release acetaminophen tablets. Rectal absorption is slower and less complete, with peak plasma concentrations occurring in roughly 2–5 hours in children. Extended-release bilayer tablets contain a total of 650 mg acetaminophen, with 325 mg in an immediate-release layer and 325 mg in a slow-release matrix. Following a 1300 mg oral dose, a mean peak concentration of 60 µmol/L is reached in approximately 1.5 hours.
Distribution
The volume of distribution ranges from 0.8–1.0 L/kg. Plasma protein binding is low: 10–25%.
Metabolism
Up to 95% of a dose of acetaminophen is conjugated in the liver, mainly with glucuronic acid and to a lesser extent sulfuric acid, then excreted renally. A small percentage is either excreted in the urine unchanged or oxidized by hepatic CYP2E1 yielding N-acetyl-p-benzoquinoneimine (NAPQI), a toxic metabolite that is subsequently conjugated with glutathione and excreted by the kidney. However, when glutathione is depleted following a high dose of acetaminophen, NAPQI accumulates and is believed to be the cause of acetaminophen-induced liver necrosis (see Overdosage).
Excretion
The plasma half life is short and ranges depending on the patient population:
- Neonates: 7 h
- Infants: 4 h
- Children and adolescents: 3 h
- Adults: 2–3 h
- Renal insufficiency: 2–5 h
The half-life may be prolonged during acute overdose. Pregnant women may demonstrate a higher rate of clearance. Only 5% of acetaminophen is excreted in the urine unchanged.