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Paracetamol
Paracetamol is a non-opioid analgesic and antipyretic1 of the phenol class2, used to relieve mild to moderate pain1 and reduce fever.3 It was synthesized by Harmon Northrop Morse in 1878,4 although Charles Frédéric Gerhardt may have made it in 1852.5 It is reported to have no recreational value and is commonly combined with opioids and other medicines. Excessive doses can cause liver damage, liver failure, and fatal poisoning.6
Dosage & Duration
Dosage
Doses are population estimates that vary widely between individuals.
Moderate200-500 mg
The maximum recommended daily intake is 4 grams. Exceeding this limit significantly increases the risk of hepatotoxicity.
Duration
Onset60 minutes
After Effects1-2 hours
Total4-6 hours
Subjective Effects
Subjective Effects not written up yet
Pharmacology
Pharmacodynamics
The mechanism of paracetamol's analgesic and antipyretic effects is not established.6 Paracetamol inhibits COX-1 and COX-2 indirectly by reducing their active forms. This inhibition occurs when arachidonic acid and peroxide concentrations are low, conditions under which COX-2 predominates; higher peroxide concentrations during inflammation counteract this action and limit its anti-inflammatory effects. Its fever-reducing action is thought to involve the brain's temperature-regulating centers.7 Its active metabolite also activates TRPV1, weakly stimulates cannabinoid receptors, inhibits endocannabinoid transport, and blocks pain-sensing sodium channels, mechanisms that may contribute to analgesia. In mice, paracetamol has shown dose-dependent anticonvulsant activity associated with TRPV1 activation and reduced neuronal excitability, although the precise mechanism remains uncertain.
Pharmacokinetics
Oral paracetamol is absorbed rapidly from the small intestine, with the rate governed by stomach emptying and formulation. Reported oral bioavailability is 88%, while dose-dependent measurements range from 63% at 500 mg to 89% at 1000 mg. Rectal absorption is variable.9 Paracetamol distributes widely through most tissues except fat, with reported distribution volumes of about 0.9 L/kg or 50 L; 10-20% binds to red blood cells. Plasma protein binding is described as negligible in one excerpt and 10-25% at therapeutic doses in another. Liver metabolism follows first-order kinetics,6 primarily through glucuronidation by UGT1A1 and UGT1A6 (50-70%) and sulfation by SULT1A1, SULT1A3, and SULT1E1 (25-35%). A smaller fraction undergoes oxidation, mainly through CYP2E1 (5-15%), followed at usual doses by rapid glutathione conjugation, biliary transfer, and further processing into urinary conjugates. Deacetylation accounts for 1-2%, and its product can undergo further conversion by fatty acid amide hydrolase in the brain; the resulting active metabolite has been detected in animal brains and human cerebrospinal fluid and is also produced by peripheral sensory neurons in vitro. Metabolites are eliminated mainly in urine, with 2-5% excreted unchanged and at least 90% of the administered dose excreted within 24 hours. The reported terminal elimination half-life is 1.9-2.5 hours, increasing to 4-8 hours after overdose depending on liver impairment. Following intravenous administration at 15 mg/kg, clearance is 0.27 L/h/kg in adults and 0.34 L/h/kg in children. Paracetamol also passes into breast milk, with a reported milk-to-plasma concentration ratio of approximately 1.10
Interactions
Interactions not written up yet
An unlisted combination is an unknown one, not a safe one. Check a dedicated combination chart before mixing.
Tolerance
Tolerance not written up yet
Harm Potential
Toxicity
Paracetamol overdose can cause fatal liver damage; acetaminophen-associated overdoses were linked to an estimated 458 deaths annually in the United States during the 1990s.11 In cats, toxicity can cause fatal impairment of blood oxygen transport, while liver damage is rarely the cause of death. Paracetamol is also lethal to snakes.
LD50 Data
| Species | Route | Value |
|---|---|---|
| Mouse | Oral | 338 mg/kg |
| Rat | Oral | 1944 mg/kg |
Paracetamol overdose can cause hepatic necrosis and acute liver failure, potentially requiring transplantation or causing death.6 Prolonged daily use may also damage the liver, and abnormal liver function tests were almost four times more likely among paracetamol users in the reported comparison. Liver damage is the principal toxic effect reported in dogs.
Paracetamol overdose can cause renal tubular necrosis and kidney failure, and prolonged daily use may cause kidney damage. Meta-analyses suggest a 23% increase in the risk of kidney impairment.
Paracetamol use is associated with peptic ulcers and gastrointestinal bleeding, with greater bleeding risk during regular use above 2–3 g daily. Gastrointestinal ulceration has also been reported in dogs.
Paracetamol slightly but significantly increases blood pressure and heart rate. Increasing doses have been associated with cardiovascular adverse outcomes, including stroke and myocardial infarction.
Paracetamol can cause rare, potentially fatal skin reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis.6
Paracetamol overdose can cause thrombocytopenia in humans.6 In cats, paracetamol toxicity causes methemoglobinemia and hemolytic anemia that impair oxygen transport and can cause fatal asphyxiation.
Paracetamol overdose can cause hypoglycemic coma.6
Some observational studies suggest a possible association between prenatal paracetamol exposure and neurodevelopmental disorders, including ADHD and autism.14
Possible
Female rats had an increased incidence of mononuclear cell leukemia at doses reported as 0.8 times the maximum human daily dose, and rats showed chromosome damage at 1,500 mg/kg/day, reported as 3.6 times that maximum. Paracetamol tested positive in mouse lymphoma and human lymphocyte chromosomal aberration assays.6 Human meta-analyses suggest a 28% increase in kidney cancer risk.
Evidence Basis
Human EpidemiologicalLimited
Animal Models
Positive
(Rat)
In Vitro
Positive mutagenicity and chromosomal aberration findings[cite:dailymed-nlm-nih-gov-otc-monograph-m013-internal-analgesic-antipyretic-and-antirheumatic-drug-products-for-over-the-counter-human-use-federal-food-drug-and-cosmetic-act-503-b-21-u-s-c-353-b-and-current-fda-structured-product-labels-3b84a6]
Mouse lymphoma assay; human lymphocyte chromosomal aberration assay[cite:dailymed-nlm-nih-gov-otc-monograph-m013-internal-analgesic-antipyretic-and-antirheumatic-drug-products-for-over-the-counter-human-use-federal-food-drug-and-cosmetic-act-503-b-21-u-s-c-353-b-and-current-fda-structured-product-labels-3b84a6]
History & Culture
Early synthesis and clinical investigation
Some reports attributed the first synthesis of paracetamol to Charles Gerhardt or Cahn and Hepp in 1852. Harmon Northrop Morse synthesized it at Johns Hopkins University in 1877. Joseph von Mering first tested it in humans in 1887 and published clinical findings comparing it with phenacetin in 1893.…
Legality
International
Paracetamol has approved and investigational status and is commonly available over the counter.
By Country
Legal / decriminalized1
United StatesLegal (regulated)OTC Monograph M013—Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Federal Food, Drug, and Cosmetic Act § 503(b) (21 U.S.C. § 353(b)); and current FDA Structured Product Labels3212223624
In the United States, acetaminophen is the name used for paracetamol, and its federal marketing status depends on the product and dosage form. Oral acetaminophen products, including Tylenol Extra Strength 500 mg tablets, are marketed over the counter under FDA OTC Monograph M013. Acetaminophen injection is marketed as a prescription product; under 21 U.S.C. § 353(b), a drug limited by its approved application to professional supervision may be dispensed only by prescription. Federal classification is product- and dosage-form-specific and does not determine state, district, territorial, tribal, or local requirements.
References
Citations
Article Status
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