Collated from TripSit, Pharmacology, DrugCentral. Where sources differ (e.g. dosing), Compare shows them side by side.
Also known as acetaminophen, paracetamol, tylenolTS
A common, over the counter, fever reducer and painkiller. It is mixed with many common opiates. Can cause liver damage and failure in higher doses. No recreational value.TS
Oral
Route dataTripSit
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| — | — | 200–500 mg | — | —+ |
| Onset | 60–60 minutes |
|---|---|
| Total | 4–6 hours |
| After-effects | 1–2 hours |
🧬 Receptor activityPHDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Xaa-Pro dipeptidase | — | Ki 9730 nM | CHEMBL | TargetXaa-Pro dipeptidase Action— AffinityKi 9730 nM SourceCHEMBL |
| Cannabinoid receptor 1 (CNR1) | Agonist | — | DRUGCENTRAL | TargetCannabinoid receptor 1 (CNR1) ActionAgonist Affinity— SourceDRUGCENTRAL |
| Prostaglandin G/H synthase 2 (PTGS2) | Inhibitor | 4.31 IC50 | DRUGCENTRAL | TargetProstaglandin G/H synthase 2 (PTGS2) ActionInhibitor Affinity4.31 IC50 SourceDRUGCENTRAL |
| Transient receptor potential cation channel subfamily V member 1 (TRPV1) | Opener | — | DRUGCENTRAL | TargetTransient receptor potential cation channel subfamily V member 1 (TRPV1) ActionOpener Affinity— SourceDRUGCENTRAL |
| Arachidonate 15-lipoxygenase (ALOX15) | — | 4.547 IC50 | DRUGCENTRAL | TargetArachidonate 15-lipoxygenase (ALOX15) Action— Affinity4.547 IC50 SourceDRUGCENTRAL |
| Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) | — | 4.36 IC50 | DRUGCENTRAL | TargetArachidonate 5-lipoxygenase-activating protein (ALOX5AP) Action— Affinity4.36 IC50 SourceDRUGCENTRAL |
| Carbonic anhydrase 1 (CA1) | — | 5 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 1 (CA1) Action— Affinity5 Ki SourceDRUGCENTRAL |
| Carbonic anhydrase 12 (CA12) | — | 5.39 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 12 (CA12) Action— Affinity5.39 Ki SourceDRUGCENTRAL |
| Carbonic anhydrase 13 (Ca13) | — | 4.52 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 13 (Ca13) Action— Affinity4.52 Ki SourceDRUGCENTRAL |
| Carbonic anhydrase 14 (CA14) | — | 4.97 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 14 (CA14) Action— Affinity4.97 Ki SourceDRUGCENTRAL |
| Carbonic anhydrase 15 (Ca15) | — | 5.03 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 15 (Ca15) Action— Affinity5.03 Ki SourceDRUGCENTRAL |
| Carbonic anhydrase 2 (CA2) | — | 5.21 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 2 (CA2) Action— Affinity5.21 Ki SourceDRUGCENTRAL |
| Carbonic anhydrase 3 (CA3) | — | 5.15 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 3 (CA3) Action— Affinity5.15 Ki SourceDRUGCENTRAL |
| Carbonic anhydrase 4 (CA4) | — | 4.94 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 4 (CA4) Action— Affinity4.94 Ki SourceDRUGCENTRAL |
| Carbonic anhydrase 7 (CA7) | — | 5.04 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 7 (CA7) Action— Affinity5.04 Ki SourceDRUGCENTRAL |
| Carbonic anhydrase 9 (CA9) | — | 4.15 Ki | DRUGCENTRAL | TargetCarbonic anhydrase 9 (CA9) Action— Affinity4.15 Ki SourceDRUGCENTRAL |
| Myoglobin (MB) | — | 5.64 IC50 | DRUGCENTRAL | TargetMyoglobin (MB) Action— Affinity5.64 IC50 SourceDRUGCENTRAL |
| Nuclear receptor subfamily 1 group I member 3 (NR1I3) | — | — | DRUGCENTRAL | TargetNuclear receptor subfamily 1 group I member 3 (NR1I3) Action— Affinity— SourceDRUGCENTRAL |
Mechanism of actionPH
According to its FDA labeling, acetaminophen's exact mechanism of action has not been fully established - despite this, it is often categorized alongside NSAIDs (non-steroidal anti-inflammatory drugs) due to its ability to inhibit the cyclo-oxygenase (COX) pathways. It is thought to exert central actions which ultimately lead to the alleviation of pain symptoms. One theory is that acetaminophen increases the pain threshold by inhibiting two isoforms of cyclo-oxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis. Prostaglandins are responsible for eliciting pain sensations. Acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, therefore, has no peripheral anti-inflammatory effects. Though acetylsalicylic acid (aspirin) is an irreversible inhibitor of COX and directly blocks the active site of this enzyme, studies have shown that acetaminophen (paracetamol) blocks COX indirectly. Studies also suggest that acetaminophen selectively blocks a variant type of the COX enzyme that is unique from the known variants COX-1 and COX-2. This enzyme has been referred to as _COX-3_. The antipyretic actions of acetaminophen are likely attributed to direct action on heat-regulating centers in the brain, resulting in peripheral vasodilation, sweating, and loss of body heat. The exact mechanism of action of this drug is not fully understood at this time, but future research may contribute to deeper knowledge. Although further investigation is warranted, the active metabolite of acetaminophen (AM404) was shown to interact with several molecular targets, including the Ca<sub>v</sub>3.2 calcium channel, the cannabinoid CB1 receptors, TRPV1 receptors, and Na<sub>v</sub>1.8 and Na<sub>v</sub>1.7 channels.
Acetaminophen produces analgesia and antipyresis by a mechanism similar to that of salicylates. Unlike salicylates, however, acetaminophen does not have uricosuric activity. There is some evidence that acetaminophen has weak anti-inflammatory activity in some nonrheumatoid conditions (e.g., in patients who have had oral surgery). ... Acetaminophen lowers body temperature in patients with fever but rarely lowers normal body temperature. The drug acts on the hypothalamus to produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow.
The effects of acetaminophen on cyclooxygenase activity have not been fully determined. Acetaminophen is a weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily. The inhibitory effect of acetaminophen on cyclooxygenase-1 is limited, and the drug does not inhibit platelet function. Therapeutic doses of acetaminophen appear to have little effect on cardiovascular and respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.
Acetaminophen (N-acetyl-p-aminophenol (APAP)) is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, /the researchers/ hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase activity, and cytokine and chemokine levels in the airways or skin. Inflammatory responses evoked by NAPQI and APAP are abated by TRPA1 antagonism or are absent in TRPA1-deficient mice. This novel pathway, distinguished from the tissue-damaging effect of NAPQI, may contribute to the risk of COPD and asthma associated with therapeutic APAP use.
Acetaminophen is at present one of the most commonly used analgesics and antipyretics. Recent evidence has suggested that oxidative stress is involved in the mechanism of acetaminophen intoxication. Paraoxonase-1 (PON1) plays an important role as an endogenous free-radical scavenging molecule. The aim of this study was to evaluate the influence of serum PON1 activity and oxidative stress in patients with acetaminophen intoxication. A total of 20 patients with acetaminophen intoxication and 25 healthy controls were enrolled. Serum total antioxidant capacity (TAC), lipid hydroperoxide (LOOH) levels, and paraoxonase and arylesterase activities were measured spectrophotometrically. The serum TAC levels and the paraoxonase and arylesterase activities were significantly lower in patients with acetaminophen intoxication compared with controls (all, p < 0.001), while the serum LOOH levels were significantly higher (p < 0.001). Results suggest that decreased PON1 activity seems to be associated with increased oxidative stress in patients with acetaminophen intoxication. Measuring serum PON1 activity may be useful in assessing the development of toxicity risk in acetaminophen toxicity. It would be useful to recommend vitamins with antioxidant effects such as vitamins C and E along with medical treatments.
For more Mechanism of Action (Complete) data for ACETAMINOPHEN (9 total), please visit the HSDB record page.
PharmacodynamicsPH
Animal and clinical studies have determined that acetaminophen has both antipyretic and analgesic effects. This drug has been shown to lack anti-inflammatory effects. As opposed to the _salicylate_ drug class, acetaminophen does not disrupt tubular secretion of uric acid and does not affect acid-base balance if taken at the recommended doses. Acetaminophen does not disrupt hemostasis and does not have inhibitory activities against platelet aggregation. Allergic reactions are rare occurrences following acetaminophen use.
Pharmacokinetics
Half-lifePH
The half-life for adults is 2.5 h after an intravenous dose of 15 mg/kg. After an overdose, the half-life can range from 4 to 8 hours depending on the severity of injury to the liver, as it heavily metabolizes acetaminophen.
The elimination half life is 1-3 hours after a therapeutic dose but may be greater than 12 hours after an overdose.
AbsorptionPH
Acetaminophen has 88% oral bioavailability and reaches its highest plasma concentration 90 minutes after ingestion. Peak blood levels of free acetaminophen are not reached until 3 hours after rectal administration of the suppository form of acetaminophen and the peak blood concentration is approximately 50% of the observed concentration after the ingestion of an equivalent oral dose (10-20 mcg/mL). The percentage of a systemically absorbed rectal dose of acetaminophen is inconsistent, demonstrated by major differences in the bioavailability of acetaminophen after a dose administered rectally. Higher rectal doses or an increased frequency of administration may be used to attain blood concentrations of acetaminophen similar to those attained after oral acetaminophen administration.
Acetaminophen metabolites are mainly excreted in the urine. Less than 5% is excreted in the urine as free (unconjugated) acetaminophen and at least 90% of the administered dose is excreted within 24 hours.
Volume of distribution is about 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Acetaminophen appears to be widely distributed throughout most body tissues except in fat.
Adults: 0.27 L/h/kg following a 15 mg/kg intravenous (IV) dose. Children: 0.34 L/h/kg following a 15 mg/kg intravenous (IV dose).
Acetaminophen is rapidly and almost completely absorbed from the GI tract following oral administration. In healthy men, steady-state oral bioavailability of 1.3-g doses of extended-release tablets of acetaminophen administered every 8 hours for a total of 7 doses was equal to 1-g doses of conventional tablets of acetaminophen given every 6 hours for a total of 7 doses. Food may delay slightly absorption of extended-release tablets of acetaminophen. Following oral administration of immediate- or extended-release acetaminophen preparations, peak plasma concentrations are attained within 10-60 or 60-120 minutes, respectively. Following oral administration of a single 500-mg conventional tablet or a single 650-mg extended-release tablet, average plasma acetaminophen concentrations of 2.1 or 1.8 ug/mL, respectively, occur at 6 or 8 hours, respectively. In addition, dissolution of the extended-release tablets may depend slightly on the gastric or intestinal pH. Dissolution appears to be slightly faster in the alkaline pH of the intestines compared with the acidic pH of the stomach; however, this is of no clinical importance. Following administration of conventional preparations of acetaminophen, only small amounts of the drug are detectable in plasma after 8 hours. The extended-release tablets of acetaminophen release the drug for up to 8 hours, but in vitro data indicate that at least 95% of the dose is released within 5 hours.
Following rectal administration of acetaminophen, there is considerable variation in peak plasma concentrations attained, and time to reach peak plasma concentrations is substantially longer than after oral administration.
MetabolismPH
Acetaminophen is the major metabolite of _phenacetin_ and _acetanilid_. Acetaminophen is mainly metabolized in the liver by first-order kinetics and its metabolism of comprised of 3 pathways: conjugation with glucuronide, conjugation with sulfate, and oxidation through the cytochrome P450 enzyme pathway, mainly CYP2E1, to produce a reactive metabolite (N-acetyl-p-benzoquinone imine or NAPQI). At normal therapeutic doses, NAPQI undergoes fast conjugation with glutathione and is subsequently metabolized to produce both cysteine and mercapturic acid conjugates. High doses of acetaminophen (overdoses) can lead to hepatic necrosis due to the depletion of glutathione and of binding of high levels of reactive metabolite (NAPQI) to important parts of liver cells. The abovementioned damage to the liver can be prevented by the early administration of sulfhydryl compounds, for example, methionine and N-acetylcysteine.
About 80-85% of the acetaminophen in the body undergoes conjugation principally with glucuronic acid and to a lesser extent with sulfuric acid. Acetaminophen also is metabolized by microsomal enzyme systems in the liver.
In vitro and animal data indicate that small quantities of acetaminophen are metabolized by a cytochrome P-450 microsomal enzyme to a reactive intermediate metabolite (N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI) which is further metabolized via conjugation with glutathione and ultimately excreted in urine as a mercapturic acid. It has been suggested that this intermediate metabolite is responsible for acetaminophen-induced liver necrosis and that high doses of acetaminophen may deplete glutathione so that inactivation of this toxic metabolite is decreased. At high doses, the capacity of metabolic pathways for conjugation with glucuronic acid and sulfuric acid may be exceeded, resulting in increased metabolism of acetaminophen by alternative pathways. In addition, it also has been suggested that in fasting individuals conjugation of high doses of acetaminophen with glucuronic acid may be reduced, secondary to decreased hepatic carbohydrate reserves and microsomal oxidation may be increased, resulting in increased risk of hepatotoxicity.
Yields 4-acetamidocatechol in rat; yields s-(5-acetamido-2-hydroxyphenyl)-l-cysteine probably in man. Yields p-acetamidophenyl-beta-d-glucuronide in rabbit; yields p-acetamidophenyl-beta-d-glucuronide in rat, in guinea pig, & in ferret; yields p-acetamidophenyl-beta-d-glucuronide in man & in dog; yields p-acetamidophenyl sulfate in rabbit, guinea pig, & ferret; yields p-acetamidophenyl sulfate in rat & in man; yields p-methoxyacetanilide in guinea pig; yields quinol probably in rat. /From table/
Children have less capacity for glucuronidation of the drug than do adults. A small proportion of acetaminophen undgoes n-hydroxylation to form n-acetyl-benzoquinoneimine, a highly reactive intermediate. This metabolite normally reacts with sulfhydryl groups in glutathione. However, after large doses of acetaminophen the metabolite is formed in amounts sufficient to deplete hepatic glutathione; under these circumstances reaction with sulfhydryl groups in hepatic proteins is increased and hepatic necrosis can result.
For more Metabolism/Metabolites (Complete) data for ACETAMINOPHEN (7 total), please visit the HSDB record page.
Protein bindingPH
The binding of acetaminophen to plasma proteins is low (ranging from 10% to 25%), when given at therapeutic doses.
Plan a dose of Paracetamol
Loading the fact-sheet…
Logging a dose needs somewhere to keep it. Start a free session — no signup; it and everything in it expire in 7 days.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.