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药品详细

Acetaminophen(对乙酰氨基酚)

化学结构式图
中文名
对乙酰氨基酚
英文名
Acetaminophen
分子式
C8H9NO2
化学名
N-(4-hydroxyphenyl)acetamide
分子量
Average: 151.1626
Monoisotopic: 151.063328537
CAS号
103-90-2
ATC分类
N02B Other Analgesics and Antipyretics
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Acetaminophen, also known as paracetamol, is commonly used for its analgesic and antipyretic effects. Its therapeutic effects are similar to salicylates, but it lacks anti-inflammatory, antiplatelet, and gastric ulcerative effects.

生产厂家
  • Able laboratories inc
  • Actavis mid atlantic llc
  • G and w laboratories inc
  • L perrigo co
  • Mcneil consumer healthcare
  • Ohm laboratories inc
  • Ortho mcneil pharmaceutical inc
  • Perrigo new york inc
  • Polymedica industries inc
  • Ranbaxy inc
  • Roxane laboratories inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Kis B, Snipes JA, Busija DW: Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. J Pharmacol Exp Ther. 2005 Oct;315(1):1-7. Epub 2005 May 6. Pubmed
  2. Aronoff DM, Oates JA, Boutaud O: New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther. 2006 Jan;79(1):9-19. Pubmed
  3. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S: Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006 Fall-Winter;12(3-4):250-75. Pubmed
  4. Graham GG, Scott KF: Mechanism of action of paracetamol. Am J Ther. 2005 Jan-Feb;12(1):46-55. Pubmed
  5. Ohki S, Ogino N, Yamamoto S, Hayaishi O: Prostaglandin hydroperoxidase, an integral part of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. J Biol Chem. 1979 Feb 10;254(3):829-36. Pubmed
  6. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S: Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006 Fall-Winter;12(3-4):250-75. Pubmed
  7. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13926-31. Epub 2002 Sep 19. Pubmed
  8. Adjei AA, Gaedigk A, Simon SD, Weinshilboum RM, Leeder JS: Interindividual variability in acetaminophen sulfation by human fetal liver: implications for pharmacogenetic investigations of drug-induced birth defects. Birth Defects Res A Clin Mol Teratol. 2008 Mar;82(3):155-65. doi: 10.1002/bdra.20535. Pubmed
  9. Hazai E, Vereczkey L, Monostory K: Reduction of toxic metabolite formation of acetaminophen. Biochem Biophys Res Commun. 2002 Mar 8;291(4):1089-94. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Acetanilides
Substructures
  • Phenols and Derivatives
  • Amino Ketones
  • Benzene and Derivatives
  • Acetanilides
  • Carboxylic Acids and Derivatives
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Phenyl Esters
  • Anilines
适应症
药理
Indication For temporary relief of fever, minor aches, and pains.
Pharmacodynamics Acetaminophen (USAN) or Paracetamol (INN) is a widely used analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. It is a major ingredient in numerous cold and flu medications and many prescription analgesics. It is extremely safe in standard doses, but because of its wide availability, deliberate or accidental overdoses are not uncommon. Acetaminophen, unlike other common analgesics such as aspirin and ibuprofen, has no anti-inflammatory properties or effects on platelet function, and it is not a member of the class of drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. At therapeutic doses acetaminophen does not irritate the lining of the stomach nor affect blood coagulation, kidney function, or the fetal ductus arteriosus (as NSAIDs can). Like NSAIDs and unlike opioid analgesics, acetaminophen does not cause euphoria or alter mood in any way. Acetaminophen and NSAIDs have the benefit of being completely free of problems with addiction, dependence, tolerance and withdrawal. Acetaminophen is used on its own or in combination with pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, doxylamine, codeine, hydrocodone, or oxycodone.
Mechanism of action Acetaminophen is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) synthesis. Unlike NSAIDs, acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects. While aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme's active site, studies have found that acetaminophen indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why acetaminophen is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides. Studies also report data suggesting that acetaminophen selectively blocks a variant of the COX enzyme that is different from the known variants COX-1 and COX-2. This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works. The antipyretic properties of acetaminophen are likely due to direct effects on the heat-regulating centres of the hypothalamus resulting in peripheral vasodilation, sweating and hence heat dissipation.
Absorption Rapid and almost complete
Volume of distribution Not Available
Protein binding 25%
Metabolism
Acetaminophen primarily undergoes glucuronidation (45-55% of the dose) in which this process is facilitated by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver or UGT1A10 in the gut. 30-35% of the dose undergoes sulfation. This biotransformation is facilitated by SULT1A1, SULT1A3, SULT1A4, SULT1E1 and SULT2A1. A small percentage of acetaminophen is oxidized by CYP2E1 to form N-acetyl-p-benzo-quinone imine (NAPQI), a toxic metabolite which is then conjugated to glutathione and excreted renally. Studies suggest that CYP3A4 and CYP2E1 are the primary cytochrome P450 isozymes responsible for the generation of toxic metabolites. Accumulation of NAPQI may occur if primary metabolic pathways are saturated.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Acetaminophen
NAPQI Details
Acetaminophen
    		Acetaminophen glucuronide Details
    Acetaminophen
      		Acetaminophen sulfate Details
      Acetaminophen
        		Acetaminophen cystein Details
        Route of elimination Approximately 80% of acetaminophen is excreted in the urine after conjugation and about 3% is excreted unchanged.
        Half life 1 to 4 hours
        Clearance Not Available
        Toxicity Oral, mouse: LD50 = 338 mg/kg; Oral, rat: LD50 = 1944 mg/kg. Acetaminophen is metabolized primarily in the liver, where most of it is converted to inactive compounds by conjugation with glucuronic acid and, to a lesser extent, sulfuric acid. Conjugates are then excreted by the kidneys. Only a small portion is excreted in unchanged in urine or oxidized via the hepatic cytochrome P450 enzyme system (CYP2E1). Metabolism via CYP2E1 produces a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). The toxic effects of acetaminophen are due to NAPQI, not acetaminophen itself nor any of the major metabolites. At therapeutic doses, NAPQI reacts with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is excreted by the kidneys. High doses of acetaminophen may cause glutathione depletion, accumulation of NAPQI and hepatic necrosis. The maximum daily dose of acetaminophen is 4 g. Liver failure has been observed at doses as low as 6 g per day. As such, the maximum daily and single dose of acetaminophen is currently being reviewed in some countries. N-acetyl-cysteine, a precursor of glutathione, may be administered in the event of acetaminophen toxicity.
        Affected organisms
        • Humans and other mammals
        Pathways Not Available
        理化性质
        Properties
        State solid
        Experimental Properties
        Property Value Source
        melting point 170 °C PhysProp
        water solubility 1.4E+004 mg/L (at 25 °C) YALKOWSKY,SH & DANNENFELSER,RM (1992)
        logP 0.46 SANGSTER (1994)
        logS -1.03 ADME Research, USCD
        pKa 9.38 DASTMALCHI,S ET AL. (1995)
        Predicted Properties
        Property Value Source
        water solubility 4.15e+00 g/l ALOGPS
        logP 0.51 ALOGPS
        logP 0.91 ChemAxon
        logS -1.6 ALOGPS
        pKa (strongest acidic) 9.46 ChemAxon
        pKa (strongest basic) -4.4 ChemAxon
        physiological charge 0 ChemAxon
        hydrogen acceptor count 2 ChemAxon
        hydrogen donor count 2 ChemAxon
        polar surface area 49.33 ChemAxon
        rotatable bond count 1 ChemAxon
        refractivity 42.9 ChemAxon
        polarizability 15.52 ChemAxon
        药物相互作用
        Drug Interaction
        Acenocoumarol Acetaminophen may increase the anticoagulant effect of acenocoumarol. Monitor for changes in the therapeutic and adverse effects of acenocoumarol if acetaminophen is initiated, discontinued or dose changed.
        Anisindione Acetaminophen increases the anticoagulant effect of anisindione. Monitor for changes in the therapeutic and adverse effects of anisindione if acetaminophen is initiated, discontinued or dose changed.
        Dicumarol Acetaminophen may increase the anticoagulant effect of dicumarol. Monitor for changes in the therapeutic and adverse effects of dicumarol if acetaminophen is initiated, discontinued or dose changed.
        Eltrombopag Eltrombopag increases acetaminophen levels via decreasing metabolism. UDP-glucuronosyltransferase inhibition with unclear significance.
        Imatinib Increased hepatic toxicity of both agents
        Isoniazid Risk of hepatotoxicity
        Warfarin Acetaminophen increases the anticoagulant effect of warfarin. Monitor for changes in the therapeutic and adverse effects of warfarin if acetaminophen is initiated, discontinued or dose changed.
        食物相互作用
        • Avoid alcohol (may increase risk of hepatotoxicity).
        • Take without regard to meals.

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