NationMaster - Encyclopedia: Paracetamol

Paracetamol (INN) (IPA: /ˌpærəˈsiːtəmɒl, -ˈsɛtə-/) or acetaminophen (USAN) is a widely-used analgesic and antipyretic. Derived from coal tar, it is the active metabolite of phenacetin, but unlike phenacetin, paracetamol has not been shown to be carcinogenic in any way. Unlike aspirin, it is not a very effective anti-inflammatory agent. It is well tolerated, lacks many of the side-effects of aspirin, and is available over-the-counter, so it is commonly used for the relief of fever, headaches, and other minor aches and pains. Paracetamol is also useful in the management of more severe pain, where it allows lower dosages of additional non-steroidal anti-inflammatory drugs (NSAIDs) to be used, thereby minimizing overall side-effects. It is also used in combination with opioid analgesics.^[1] It is a major ingredient in numerous cold and flu medications. It is considered safe for human use at recommended doses; however, acute overdose can cause potentially fatal liver damage. The risk is heightened by the use of alcohol. The number of accidental self-poisonings and suicides from paracetamol has grown in recent years^{[citation needed]}. In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body. ... The posterior aspect of the rectum exposed by removing the lower part of the sacrum and the coccyx. ... Intravenous therapy or IV therapy is the giving of liquid substances directly into a vein. ... An International Nonproprietary Name (INN) is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization. ... United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. ... An analgesic (colloquially known as a painkiller) is any member of the diverse group of drugs used to relieve pain (achieve analgesia). ... Antipyretics are drugs that prevent or reduce fever by lowering the body temperature from a raised state. ... Phenacetin, introduced in 1887, was used principally as an analgesic, and was the first fever reducer to go on the market. ... In pathology, a carcinogen is any substance or agent that promotes cancer. ... This article is about the drug. ... Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. ... This article is about the drug. ... Over-the-counter (OTC) drugs are medicines that may be sold without a prescription, in contrast to prescription drugs. ... An analogue medical thermometer showing the temperature of 38. ... A headache (cephalgia in medical terminology) is a condition of pain in the head; sometimes neck or upper back pain may also be interpreted as a headache. ... Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. ... An opioid is a chemical substance that has a morphine-like action in the body. ... Acute viral nasopharyngitis, or acute coryza, usually known as the common cold, is a highly contagious, viral infectious disease of the upper respiratory system, primarily caused by picornaviruses or coronaviruses. ... Flu redirects here. ... Categories: | | | ... A drug overdose occurs when a chemical substance (i. ... Hepatotoxicity (from hepatic toxicity) implies chemical-driven liver damage. ... For other uses, see Suicide (disambiguation). ...

The words acetaminophen and paracetamol come from the chemical names for the compound: para-acetylaminophenol and para-acetylaminophenol. (The brand name Tylenol also derives from this name: para-acetylaminophenol.) In some contexts, it is shortened to APAP, for N-acetyl-para-aminophenol. Each caplet in this bottle of Extra Strength Tylenol contains a 500 mg dose of acetaminophen (paracetamol). ...

History

In ancient and medieval times, known antipyretic agents were compounds contained in white willow bark (a family of chemicals known as salicins, which led to the development of aspirin), and compounds contained in cinchona bark.^[2] Cinchona bark was also used to create the anti-malaria drug quinine. Quinine itself also has antipyretic effects. Efforts to refine and isolate salicin and salicylic acid took place throughout the middle- and late-19th century, and was accomplished by Bayer chemist Felix Hoffmann (this was also done by French chemist Charles Frédéric Gerhardt 40 years earlier, but he abandoned the work after deciding it was impractical).^[3] Antipyretics are drugs that prevent or reduce fever by lowering the body temperature from a raised state. ... Species About 350, including: Salix acutifolia - Violet Willow Salix alaxensis - Alaska Willow Salix alba - White Willow Salix alpina - Alpine Willow Salix amygdaloides - Peachleaf Willow Salix arbuscula - Mountain Willow Salix arbusculoides - Littletree Willow Salix arctica - Arctic Willow Salix atrocinerea Salix aurita - Eared Willow Salix babylonica - Peking Willow Salix bakko Salix barrattiana... Salicylic acid is a colorless, crystalline organic carboxylic acid. ... This article is about the drug. ... Species See text Cinchona L., is the name of a genus in Rubiaceae family, large evergreens that can grow over 10 metres tall. ... Malaria is a vector-borne infectious disease caused by protozoan parasites. ... Quinine (IPA: ) is a natural white crystalline alkaloid having antipyretic (fever-reducing), anti-smallpox, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. ... Salicylic acid is a colorless, crystalline organic carboxylic acid. ... Salicylic acid (from the Latin word for the willow tree, Salix, from whose bark it can be obtained) is a beta hydroxy acid (BHA) with the formula C6H4(OH)CO2H, where the OH group is adjacent to the carboxyl group. ... Bayer AG (IPA pronunciation //) (ISIN: DE0005752000, NYSE: BAY, TYO: 4863 ) is a German chemical and pharmaceutical company founded in Barmen, Germany in 1863. ... Felix Hoffmann (January 21, 1868 â€“ February 8, 1946) was a German chemist, who first synthesized medically useful forms of Heroin and Aspirin. ... Charles FrÃ©dÃ©ric Gerhardt (August 21, 1816 - August 19, 1856) was a French chemist. ...

When the cinchona tree became scarce in the 1880s, people began to look for alternatives. Two alternative antipyretic agents were developed in the 1880s: acetanilide in 1886 and phenacetin in 1887. Harmon Northrop Morse first synthesized paracetamol via the reduction of p-nitrophenol with tin in glacial acetic acid in 1878;^[4] however, paracetamol was not used in medical treatment for another 15 years. In 1893, paracetamol was discovered in the urine of individuals that had taken phenacetin, and was concentrated into a white, crystalline compound with a bitter taste. In 1899, paracetamol was found to be a metabolite of acetanilide. This discovery was largely ignored at the time. | Water solubility | 0. ... Phenacetin, introduced in 1887, was used principally as an analgesic, and was the first fever reducer to go on the market. ... 4-Nitrophenol is a phenolic compound that has a nitro group at the opposite position of hydroxy group on the benzene ring. ... This article is about the metallic chemical element. ... R-phrases , S-phrases , , , Flash point 43 Â°C Related Compounds Related carboxylic; acids Formic acid; Propionic acid; Butyric acid Related compounds acetamide; ethyl acetate; acetyl chloride; acetic anhydride; acetonitrile; acetaldehyde; ethanol; thioacetic acid; acetylcholine; acetylcholinesterase Supplementary data page Structure and properties n, Îµr, etc. ... Phenacetin, introduced in 1887, was used principally as an analgesic, and was the first fever reducer to go on the market. ...

In 1946, the Institute for the Study of Analgesic and Sedative Drugs awarded a grant to the New York City Department of Health to study the problems associated with analgesic agents. Bernard Brodie and Julius Axelrod were assigned to investigate why non-aspirin agents were associated with the development of methemoglobinemia, a condition that decreases the oxygen-carrying capacity of blood and is potentially lethal. In 1948, Brodie and Axelrod linked the use of acetanilide with methemoglobinemia and determined that the analgesic effect of acetanilide was due to its active metabolite paracetamol. They advocated the use of paracetamol, since it did not have the toxic effects of acetanilide.^[5] Julius Axelrod won a Nobel Prize in 1970 Julius Axelrod (May 30, 1912 – December 29, 2004) was an influential American biochemist. ... Methemoglobinemia, also known as met-Hb, is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood. ...

The product was first sold in 1955 by McNeil Laboratories as a pain and fever reliever for children, under the brand name Tylenol Children's Elixir.^[6] Each caplet in this bottle of Extra Strength Tylenol contains a 500 mg dose of acetaminophen (paracetamol). ...

In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a known stomach irritant. In June 1958, a children's formulation, Panadol Elixir, was released. The milligram (symbol mg) is an SI unit of mass. ... Sterling Drug was a global pharmaceutical company based in the United States, later known as Sterling-Winthrop, Inc, whose primary product lines included diagnostic imaging agents, hormonal products, cardiovascular products, analgesics, antihistamines and muscle relaxants. ...

In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents. The British Pharmacopoeia is the authoritative collection of standards for UK medicinal substances. ...

The U.S. patent on paracetamol has long expired, and generic versions of the drug are widely available under the Drug Price Competition and Patent Term Restoration Act of 1984, although certain Tylenol preparations were protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles." For other uses, see Patent (disambiguation). ... The Drug Price Competition and Patent Term Restoration Act, informally known as the Hatch-Waxman Act [Public Law 98-417], is a 1984 United States federal law which established the modern system of generic drugs. ... is the 246th day of the year (247th in leap years) in the Gregorian calendar. ... Year 1998 (MCMXCVIII) was a common year starting on Thursday (link will display full 1998 Gregorian calendar). ...

Chemistry

Structure and reactivity

Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern. The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are ortho,para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion. Benzene, or Benzol (see also Benzine), is an organic chemical compound and a known carcinogen with the molecular formula C6H6. ... In organic chemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon. ... // Hydroxyl group The term hydroxyl group is used to describe the functional group -OH when it is a substituent in an organic compound. ... General Name, symbol, number nitrogen, N, 7 Chemical series nonmetals Group, period, block 15, 2, p Appearance colorless gas Standard atomic weight 14. ... Amide functional group Amides possess a conjugated system spread over the O, C and N atoms, consisting of molecular orbitals occupied by delocalized electrons. ... Arene substitution patterns are part of organic chemistry IUPAC nomenclature and pinpoint the position of substituents other than hydrogen in relation to each other on an aromatic hydrocarbon. ... acetamide Acetamide (or Acetic acid amide or ÐÑ†ÐµÑ‚Ð°Ð¼Ð¸Ð´) CH3CONH2, the amide of acetic acid, is a white crystalline solid in pure form. ... A chemically conjugated system, is a system of atoms covalently bonded with alternating single and double bonds (e. ... A lone pair is an electron pair without bonding or sharing with other atoms. ... In chemistry, an atomic orbital is the region in which an electron may be found around a single atom. ... Carbonyl group In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom : C=O. The term carbonyl can also refer to carbon monoxide as a ligand in an inorganic or organometallic complex (a metal carbonyl, e. ... In chemistry, an electrophile (literally electron-lover) is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. ... Acids and bases: Acid-base extraction Acid-base reaction Acid dissociation constant Acidity function Buffer solutions pH Proton affinity Self-ionization of water Acids: Lewis acids Mineral acids Organic acids Strong acids Superacids Weak acids Bases: Lewis bases Organic bases Strong bases Superbases Non-nucleophilic bases Weak bases edit In... Phenol, also known under an older name of carbolic acid, is a colourless crystalline solid with a typical sweet tarry odor. ... This article is about the electrically charged particle. ...

Synthesis

From the starting material phenol, paracetamol can be made in the following manner:

Notice that the synthesis of paracetamol lacks one very significant difficulty inherent in almost all drug syntheses: Lack of stereocenters means there is no need to design a stereo-selective synthesis. More efficient, industrial syntheses are also available. Made of Porn and sex things Inhalation respiratory irritation Skin May cause irritation. ... Sodium borohydride, also known as sodium tetrahydroborate, has the chemical formula NaBH4. ... Acetic anhydride, also known as ethanoic anhydride, is one of the simplest of acid anhydrides. ...

Available forms

Panadol, which is marketed in Europe, Africa, Asia, Central America, and Australasia, is the most widely available brand, sold in over 80 countries. In North America, paracetamol is sold in generic form (usually labeled as acetaminophen) or under a number of trade names, for instance, Tylenol (McNeil-PPC, Inc), Anacin-3, Tempra, and Datril. While there is brand named paracetamol available in the UK (e.g. Panadol), unbranded or generic paracetamol is more commonly sold. Acetaminophen http://geekphilosopher. ... Acetaminophen http://geekphilosopher. ... four 500mg panadol (acetaminophen/paracetamol) suppositories This image has been released into the public domain by the copyright holder, its copyright has expired, or it is ineligible for copyright. ... four 500mg panadol (acetaminophen/paracetamol) suppositories This image has been released into the public domain by the copyright holder, its copyright has expired, or it is ineligible for copyright. ... Australasia Australasia is a term variably used to describe a region of Oceania: Australia, New Zealand, and neighbouring islands in the Pacific Ocean. ...

In some formulations, paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4, which contain approximately 1/8 grain, approximately 1/4 grain, approximately 1/2 grain, and approximately 1 grain of codeine, respectively. A US grain is 64.78971 milligrams - this is usually rounded in manufacture down to a multiple of 5 mg (so that a #3 contains 30 mg, and a #4 contains 60 mg, while a #1 may be 8 mg or 10 mg depending on manufacturer. In the U.S., this combination is available only by prescription, while the lowest-strength preparation is over-the-counter in Canada, and, in other countries, other strengths may be available over the counter. There are generics as well. In the UK and in many other countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone, marketed in the U.S. as Percocet and Vicodin, respectively. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate, sold under the brand name Darvocet. A combination of paracetamol, codeine, and the calmative doxylamine succinate is marketed as Syndol or Mersyndol. An opioid is a chemical substance that has a morphine-like action in the body. ... For the band, see Codeine (band). ... Co-codamol (BAN) is a non-proprietary name used to denote a combination of codeine phosphate and paracetamol (acetaminophen). ... A British Approved Name (BAN) is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia (BP). ... A grain is a unit of mass equal to 0. ... A grain is a unit of mass equal to 0. ... A grain is a unit of mass equal to 0. ... A grain is a unit of mass equal to 0. ... For the band, see Codeine (band). ... A grain is a unit of mass equal to 0. ... Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and by the brand names of Synalgos DC, Panlor DC, Panlor SS, SS Bron, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine, Didrate, Dihydrin, Hydrocodin, Nadeine, Novicodin, Rapacodin, Fortuss, Dico, and DF-118 amongst others, is a semi-synthetic opioid... Co-dydramol (BAN) is a non-proprietary name used to denote a combination of dihydrocodeine tartrate and paracetamol. ... A British Approved Name (BAN) is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia (BP). ... Not to be confused with oxytocin. ... Hydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from two of the naturally occurring opiates, codeine and thebaine. ... Oxycodone is a very powerful and potentially addictive opioid analgesic medication synthesized from thebaine. ... Hydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from two of the naturally occurring opiates, codeine and thebaine. ... Dextropropoxyphene is an analgesic in the opioid category. ... Manufactured and distributed by Eli Lilly and Company, Darvocet is a brand name for mild narcotic analgesic drug which combines Acetaminophen and Propoxy or Propoxyphene, prescribed for the relief of mild to moderate pain, with or without fever. ... This article or section may be confusing or unclear for some readers, and should be edited to rectify this. ...

Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine. Butalbital, 5-allyl-5-isobutylbarbituric acid, is a barbiturate with an intermediate duration of action. ... For other uses, see Caffeine (disambiguation). ...

It is commonly administered in tablet, liquid suspension, suppository, intravenous, or intramuscular form. The common adult dose is 500 mg to 1000 mg. The recommended maximum daily dose, for adults, is 4 grams. In recommended doses, paracetamol is safe for children and infants, as well as for adults. This article does not cite any references or sources. ... Suppository casting mould A suppository is a drug delivery system that is inserted either into the rectum (rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository) where it dissolves. ... An intravenous drip in a hospital Intravenous therapy or IV therapy is the administration of liquid substances directly into a vein. ... Intramuscular injection is an injection of a substance directly into a muscle. ... The milligram (symbol mg) is an SI unit of mass. ...

Mechanism of action

The mechanism by which paracetamol reduces fever and pain is still a source of debate.^[8] The reason for this confusion has largely been due to the fact that paracetamol reduces the production of prostaglandins—pro-inflammatory chemicals. Aspirin also inhibits the production of prostaglandins, but, unlike aspirin, paracetamol does not have much anti-inflammatory action. Likewise, whereas aspirin inhibits the production of the pro-clotting chemicals thromboxanes, paracetamol does not. Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes, and, because of paracetamol's partial similarity of aspirin's action, much research has focused on whether paracetamol also inhibits COX. It is now clear, however, that paracetamol acts via (at least) two pathways.^[9]^[10]^[11]^[12] A prostaglandin is any member of a group of lipid compounds that are derived from fatty acids and have important functions in the animal body. ... This article is about the drug. ... Thromboxane A2 Thromboxane B2 Thromboxane is a member of the family of lipids known as eicosanoids. ... Cyclooxygenase (COX) is an enzyme (EC 1. ...

The COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H₂, an unstable molecule, which is, in turn, converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories, such as the NSAIDs, block this step. The activity of the COX enzyme relies on its being in the oxidized form to be specific, tyrosine 385 must be oxidized to a radical.^[13]^[14] It has been shown that paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.^[10]^[15] Arachidonic acid (AA) is an omega-6 fatty acid 20:4(Ï‰-6). ... Prostaglandin H2 is a type of Prostaglandin which is derived from arachidonic acid and is a precursor for many other biologically signficant molecules: Eicosanoid synthesis. ... Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. ...

Further research has shown that paracetamol also modulates the endogenous cannabinoid system.^[16] Paracetamol is metabolized to AM404, a compound with several actions; most important, it inhibits the uptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide uptake would result in the activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). Furthermore, AM404 inhibits sodium channels, similarly to the anesthetics lidocaine and procaine.^[17] Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol, though it has been demonstrated that, after blocking cannabinoid receptors and hence making any action of cannabinoid reuptake irrelevant, paracetamol no longer has any analgesic effect, suggesting its pain-relieving action is indeed mediated by the endogenous cannabinoid system.^[18] The endocannabinoid system (also endogenous cannabinoid system) consists of two transmembrane cannabinoid receptors, endogenous cannabinoids, a transporter protein (anandamide transporter), and the metabolic enzymes inactivating the endocannabinoids (MGL and FAAH). ... AM404 AM404 also known as N-arachidonoylphenolamine is an active metabolite of Paracetamol (Acetaminophen) responsible for all or part of its analgesic action. ... Anandamide, also known as arachidonoylethanolamine or AEA, is a naturally occurring endogenous cannabinoid neurotransmitter found in the brain of animals, as well as other organs. ... The vanilloid receptor subtype 1 (TRPV1) is a nonselective ligand-gated cation channel that may be activated by a wide variety of exogenous and endogenous stimuli, including heat greater than 43Â°C, low pH, anandamide, and capsaicin. ...

A theory that held some sway, but has now largely been discarded, is that paracetamol inhibits the COX-3 isoform of the cyclooxygenase family of enzymes.^[9]^[19] This enzyme, when expressed in dogs, shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol. However, in humans and mice, the COX-3 enzyme is without inflammatory action, and is not modulated by paracetamol.^[9] A more likely possibility is that paracetamol is able to block cycloxygenase as in aspirin, but in an inflammatory environment, where the concentration of peroxides is high, the oxidation state of paracetamol is high which prevents its actions. Thus paracetamol has no direct effect at the site of inflammation but instead acts in the CNS to reduce temperature etc where the environment is not oxidative.

Metabolism

Paracetamol is metabolised primarily in the liver, where its major metabolites include inactive sulfate and glucuronide conjugates, which are excreted by the kidneys. Only a small, yet significant amount is metabolised via the hepatic cytochrome P450 enzyme system (its CYP2E1 and CYP1A2 isoenzymes), which is responsible for the toxic effects of paracetamol due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine, abbreviated as NAPQI).^[20] There is a great deal of polymorphism in the P450 gene, and genetic polymorphisms in CYP2D6 have been studied extensively. The population can be divided into "extensive," "ultrarapid," and "poor metabolizers" depending on their levels of CYP2D6 expression. CYP2D6 may also contribute to the formation of NAPQI, albeit to a lesser extent than other P450 isozymes, and its activity may contribute to paracetamol toxicity, in particular, in extensive and ultrarapid metabolizers and when paracetamol is taken at very large doses.^[21] Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ... The liver is the largest internal organ in the human body, and is an organ present in vertebrates and some other animals. ... Glucuronide is a substance produced by attaching glucuronic acid to another substance with glycosidic bonds. ... Cytochrome P450 Oxidase (CYP2E1) Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1. ... Cytochrome P450 2E1 (abbreviated CYP2E1) (EC 1. ... This page is a candidate for speedy deletion. ... NAPQI is an acronym for the chemical N-acetyl-p-benzo-quinone imine. ... In biology, polymorphism can be defined as the occurrence in the same habitat of two or more forms of a trait in such frequencies that the rarer cannot be maintained by recurrent mutation alone. ... Cytochrome P450 2D6 (CYP2D6), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. ... Cytochrome P450 2D6 (CYP2D6), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. ...

The metabolism of paracetamol is an excellent example of toxication, because the metabolite NAPQI is primarily responsible for toxicity rather than paracetamol itself. Toxication is the process of drug metabolism in which the metabolite of a compound is more toxic than the parent drug or chemical. ...

Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance, accounting for more than 100,000 calls, as well as 56,000 emergency room visits, 2,600 hospitalizations, and 458 deaths due to acute liver failure per year.^[22] A recent study of cases of acute liver failure between November 2000 and October 2004 by the Centers for Disease Control and Prevention (US) found that paracetamol was the cause of 41% of all cases in adults, and 25% of cases in children.^[23] The Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, is recognized as the leading United States agency for protecting the public health and safety of people. ...

At usual doses, the toxic metabolite NAPQI is quickly detoxified by combining irreversibly with the sulfhydryl groups of glutathione or administration of a sulfhydryl compound such as N-acetylcysteine, to produce a non-toxic conjugate that is eventually excreted by the kidneys.^[20] Also, methionine has been recommended in some cases,^[24] although recent studies show that N-acetylcysteine is a more effective antidote to paracetamol overdose.^[25] Sulphydryl // In organic chemistry, a thiol is a compound that contains the functional group composed of a sulfur atom and a hydrogen atom (-SH). ... Glutathione (GSH) is a tripeptide. ... N-acetylcysteine is a chemical, commonly called NAC, produced by the body that enhances the production of the co-enzyme glutathione, a powerful antioxidant. ... The kidneys are the organs that filter wastes (such as urea) from the blood and excrete them, along with water, as urine. ... Methionine is an Î±-amino acid with the chemical formula HO2CCH(NH2)CH2CH2SCH3. ...

Comparison with NSAIDs

Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has relatively little anti-inflammatory activity, and so it is not considered to be a non-steroidal anti-inflammatory drug (NSAID). This article is about the drug. ... Coated 200 mg ibuprofen tablets Ibuprofen (INN) (IPA: ) (from the earlier and no longer correct nomenclature iso-butyl-propanoic-phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally marketed as Brufen, and since then under various other trademarks (see tradenames section), most notably Advil. ... Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. ... Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. ...

Efficacy

Regarding comparative efficacy, studies show conflicting results when compared to NSAIDs. A randomized controlled trial of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and ibuprofen.^[26] However, a randomized controlled trial of acute musculoskeletal pain in children found that the standard OTC dose of ibuprofen (400 mg) gives greater relief of pain than the standard dose of paracetamol (1000 mg).^[27] Efficacy is the ability to produce a desired amount of a desired effect. ... Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. ... A randomized controlled trial (RCT) is a form of clinical trial, or scientific procedure used in the testing of the efficacy of medicines or medical procedures. ... Coated 200 mg ibuprofen tablets Ibuprofen (INN) (IPA: ) (from the earlier and no longer correct nomenclature iso-butyl-propanoic-phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally marketed as Brufen, and since then under various other trademarks (see tradenames section), most notably Advil. ... A randomized controlled trial (RCT) is a form of clinical trial, or scientific procedure used in the testing of the efficacy of medicines or medical procedures. ... Coated 200 mg ibuprofen tablets Ibuprofen (INN) (IPA: ) (from the earlier and no longer correct nomenclature iso-butyl-propanoic-phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally marketed as Brufen, and since then under various other trademarks (see tradenames section), most notably Advil. ...

Adverse effects

In recommended doses, paracetamol does not irritate the lining of the stomach, affect blood coagulation as much as NSAIDs, or affect function of the kidneys. However, some studies have shown that high dose-usage (greater than 2000 mg per day) does increase the risk of upper gastrointestinal complications.^[28] This article is about the clotting of blood. ... The kidneys are the organs that filter wastes (such as urea) from the blood and excrete them, along with water, as urine. ...

Paracetamol is safe in pregnancy, and does not affect the closure of the fetal ductus arteriosus as NSAIDs can. Unlike aspirin, it is safe in children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses. In the developing fetus, the ductus arteriosus (DA) is a shunt connecting the pulmonary artery to the aortic arch that allows much of the blood from the right ventricle to bypass the fetus fluid-filled lungs. ... Reyes syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver. ...

Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood in any way. Paracetamol and NSAIDs have the benefit of bearing a low risk of addiction, dependence, tolerance, and withdrawal, but, unlike opioid medications, may damage the liver; however, this is, in general, taken into account when compared to the danger of addiction. An opioid is a chemical substance that has a morphine-like action in the body. ... This article is about the concept of addiction. ... A chemical dependency is such a strong dependency on a substance that it becomes necessary to have this substance just to function properly; The need of a substance developed from abusing the substance, requiring the substance for survival, like the need for food, or water See also: addiction drug tolerance... In physiology, tolerance occurs when an organism builds up a resistance to the effects of a substance after repeated exposure. ... Withdrawal, also known as withdrawal syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes physical dependence is regularly used for a long time and then suddenly discontinued or decreased in dosage. ...

Paracetamol, particularly in combination with weak opioids, is more likely than NSAIDs to cause rebound headache (medication overuse headache), although less of a risk than ergotamine or triptans used for migraines.^[29] An opioid is a chemical substance that has a morphine-like action in the body. ... Rebound headaches, also known as medication overuse headaches, occur when pain medications (analgesics) are taken too frequently to relieve headache. ... Ergotamine is a vasoconstrictor used for migraine prevention and is sometimes mixed with caffeine. ... Triptans are a family of tryptamine drugs used as abortive medication in the treatment of migraine and cluster headaches. ...

Toxicity

Paracetamol is contained in many preparations (both over-the-counter and prescription-only medications). In some animals—for example, cats—small doses are toxic. Because of the wide availability of paracetamol, there is a large potential for overdose and toxicity.^[30] Without timely treatment, overdose can lead to liver failure and death within days; paracetamol toxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom.^[31]^[32] It is sometimes used in suicide attempts by those unaware of the prolonged timecourse and high morbidity (likelihood of significant illness) associated with paracetamol-induced toxicity in survivors. Over-the-counter (OTC) drugs are medicines that may be sold without a prescription, in contrast to prescription drugs. ... Zoloft, an antidepressant and antianxiety medication A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained. ... Liver failure is the final stage of liver disease. ... For other uses, see Suicide (disambiguation). ...

In the UK, sales of over-the-counter paracetamol are restricted to packs of 32 tablets in pharmacies, and 16 tablets in non-pharmacy outlets.^[33] Up to 100 tablets may be sold in a single transaction, however in pharmacies, 32 may only be sold, with more being sold at a pharmacists discretion. In Ireland, the limits are 24 and 12 tablets, respectively. In Australia, paracetamol tablets are available at supermarkets in small-pack sizes, whereas, with children's formulations, pack sizes greater than 48 tablets and suppositories are restricted to pharmacies.

Mechanism

Paracetamol is mostly converted to inactive compounds via Phase II metabolism by conjugation with sulfate and glucuronide, with a small portion being oxidized via the cytochrome P450 enzyme system. Cytochromes P450 2E1 (CYP2E1) and 3A4 (CYP3A4) convert paracetamol to a highly-reactive intermediary metabolite, N-acetyl-p-benzo-quinone imine (NAPQI).^[34]^[35]^[36] Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ... The sulfate anion, SO42âˆ’ The structure and bonding of the sulfate ion In inorganic chemistry, a sulfate (IUPAC-recommended spelling; also sulphate in British English) is a salt of sulfuric acid. ... Glucuronide is a substance produced by attaching glucuronic acid to another substance with glycosidic bonds. ... Cytochrome P450 Oxidase (CYP2E1) Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1. ... Cytochrome P450 2E1 (abbreviated CYP2E1) (EC 1. ... Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. ... NAPQI is an acronym for the chemical N-acetyl-p-benzo-quinone imine. ...

Under normal conditions, NAPQI is detoxified by conjugation with glutathione. In cases of paracetamol toxicity, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become exhausted and NAPQI is free to react with cellular membrane molecules, resulting in widespread hepatocyte damage and death, leading to acute hepatic necrosis. In animal studies, hepatic glutathione must be depleted to less than 70% of normal levels before hepatotoxicity occurs.^[34] Glutathione (GSH) is a tripeptide. ... Sinusoid of a rat liver with fenestrated endothelial cells. ...

Toxic dose

The toxic dose of paracetamol is highly variable. In individuals over 6 years of age, single doses above 200 mg/kg consumed over a single 24-hour period have a reasonable likelihood of causing toxicity. If an individual has consumed large quantities of paracetamol over a 48 hour period, a dose of above 6 grams or 150 mg/kg in the subsequent 24 hour period may cause toxicity.^[37] Toxicity can also occur when multiple smaller doses within 24 hours exceeds these levels, or even with chronic ingestion of doses as low as 4 g/day, and death with as little as 6 g/day. Consumption of alcohol has been tied to a smaller dose toxicity. For other meanings of gram, see gram (disambiguation). ...

In children of 6 and under, acute doses above 10 grams or 200 mg/kg could potentially cause toxicity. This higher threshold is largely due to larger kidneys and livers relative to body size in children versus adults, and hence greater tolerance per body mass of paracetamol overdose than adults.^[38] Acute paracetamol overdose in children rarely causes illness or death with chronic, supratherapeutic doses being the major cause of toxicity in children. For other meanings of gram, see gram (disambiguation). ...

In a normal dose of 1 gram of paracetamol four times a day, one-third of patients may have an increase in their liver function tests to three times the normal value.^[39] However, it is unclear as to whether this leads to liver failure.^[40] Liver function tests (LFTs or LFs), which include liver enzymes, are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patients liver. ... Liver failure is the final stage of liver disease. ...

Since paracetamol is often included in combination with other drugs, it is important to include all sources of paracetamol when checking a person's dose for toxicity. In addition to being sold by itself, paracetamol may be included in the formulations of various analgesics and cold/flu remedies as a way to increase the pain-relieving properties of the medication, and sometimes in combination with opioids such as hydrocodone to deter people from using it recreationally or becoming addicted to the opioid substance. In fact, the human toll of paracetamol, in terms of both fatal overdoses and chronic liver toxicity, likely far exceeds the damage caused by the opioids themselves.^[41]^{[page # needed]} An opioid is any agent that binds to opioid receptors found principally in the central nervous system and gastrointestinal tract. ... Hydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from two of the naturally occurring opiates, codeine and thebaine. ...

Risk factors

Chronic excessive alcohol consumption can induce CYP2E1, thus increasing the potential toxicity of paracetamol.^[42] For this reason, analgesics such as aspirin or ibuprofen are often recommended over paracetamol for relief of hangovers when other factors, such as gastric irritation, are not involved. The relationship between alcohol consumption and health has been the subject of formal scientific research since at least 1926, when Dr. Raymond Pearl published his book, Alcohol and Longevity, in which he reported his finding that drinking alcohol in moderation was associated with greater longevity than either abstaining or drinking... Enzyme induction is a process in which a molecule ( a drug) induces ( initiates or enhances) the expression of an enzyme. ... Cytochrome P450 2E1 (abbreviated CYP2E1) (EC 1. ... An analgesic (colloquially known as a painkiller) is any member of the diverse group of drugs used to relieve pain (achieve analgesia). ... This article is about the drug. ... Coated 200 mg ibuprofen tablets Ibuprofen (INN) (IPA: ) (from the earlier and no longer correct nomenclature iso-butyl-propanoic-phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally marketed as Brufen, and since then under various other trademarks (see tradenames section), most notably Advil. ... For other uses, see Hangover (disambiguation). ...

Fasting is a risk factor, possibly because of depletion of hepatic glutathione reserves. Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. ...

It is well documented that concomitant use of the CYP2E1 inducer isoniazid increases the risk of hepatotoxicity, though whether 2E1 induction is related to the hepatotoxicity in this case is unclear.^[43]^[44] Concomitant use of other drugs that induce CYP enzymes such as antiepileptics (including carbamazepine, phenytoin, and barbiturates) have also been reported as risk factors. Isoniazid (also called isonicotinyl hydrazine or isonicotinic acid hydrazide); abbreviated INH or just H. Isoniazid is a first-line antituberculous medication used in the prevention and treatment of tuberculosis. ... Carbamazepine (CBZ) is an benzodiazepiene and mood stabilizing drug, used primarily in the treatment of epilepsy and bipolar disorder. ... Phenytoin sodium (marketed as DilantinÂ® in the USA and as EpanutinÂ® in the UK, by Parke-Davis, now part of Pfizer) is a commonly used antiepileptic. ... Barbituric acid, the basic structure of all barbiturates Barbiturates are drugs that act as central nervous system depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. ...

Natural history

Individuals that have overdosed on paracetamol, in general, have no specific symptoms for the first 24 hours. Although nausea, vomiting, and diaphoresis may occur initially, these symptoms, in general, resolve after several hours. After resolution of these symptoms, individuals tend to feel better, and may believe that the worst is over. If a toxic dose was absorbed, after this brief feeling of relative wellness, the individual develops overt liver failure. In massive overdoses, coma and metabolic acidosis may occur prior to hepatic failure. For other uses, see Nausea (disambiguation). ... Heaving redirects here. ... Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions. ... Toxic redirects here, but this is also the name of a song by Britney Spears; see Toxic (song) Look up toxic and toxicity in Wiktionary, the free dictionary. ... For other uses, see Health (disambiguation). ... Liver failure is the final stage of liver disease. ... For other uses, see Coma (disambiguation). ... In medicine, metabolic acidosis is a state in which the blood pH is low (under 7. ...

In general, damage occurs in hepatocytes as they metabolize the paracetamol. Rarely, acute renal failure also may occur. This is usually caused by either hepatorenal syndrome or Multiple organ dysfunction syndrome. Acute renal failure may also be the primary clinical manifestation of toxicity. In these cases, it has been suggested that the toxic metabolite is produced more in the kidneys than in the liver.^[45] Hepatorenal syndrome (HRS), also called hepatorenal failure, refers to acute renal failure that occurs in the setting of cirrhosis or fulminant liver failure associated with portal hypertension, usually in the absence of other disease of the kidney. ... Multiple organ dysfunction syndrome MODS; previously known as multiple organ failure (MOF) is altered organ function in an acutely ill patient requiring medical intervention to maintain homeostasis. ...

The prognosis of paracetamol toxicity varies depending on the dose and the appropriate treatment. In some cases, massive hepatic necrosis leads to fulminant hepatic failure with complications of bleeding, hypoglycemia, renal failure, hepatic encephalopathy, cerebral edema, sepsis, multiple organ failure, and death within days. In many cases, the hepatic necrosis may run its course, hepatic function may return, and the patient may survive with liver function returning to normal in a few weeks. Necrosis (in Greek ÎÎµÎºÏÏŒÏ‚ = Dead) is the name given to accidental death of cells and living tissue. ... Hypoglycemia (hypoglycaemia in British English) is a medical term referring to a pathologic state produced by a lower than normal level of glucose (sugar) in the blood. ... Renal failure or kidney failure is a situation in which the kidneys fail to function adequately. ... Hepatic encephalopathy is a potentially reversible neuropsychiatic abnormality in the setting of liver failure, whether chronic (as in cirrhosis), or acutely. ... Cerebral edema (cerebral oedema in British English) is an excess accumulation of water in the intra- and/or extracellular spaces of the brain. ... Sepsis (in Greek Î£Î®ÏˆÎ¹Ï‚, putrefaction) is a serious medical condition, resulting from the immune response to a severe infection. ...

Diagnosis

Evidence of liver toxicity may develop in one to four days, although, in severe cases, it may be evident in 12 hours. Right-upper-quadrant tenderness may be present. Laboratory studies may show evidence of massive hepatic necrosis with elevated AST, ALT, bilirubin, and prolonged coagulation times (in particular, elevated prothrombin time). After paracetamol overdose, when AST and ALT exceed 1000 IU/L, paracetamol-induced hepatotoxicity can be diagnosed. However, the AST and ALT levels can exceed 10,000 IU/L. In general, the AST is somewhat higher than the ALT in paracetamol-induced hepatotoxicity. Aspartate transaminase (AST) also called Serum Glutamic Oxaloacetic Transaminase (SGOT) or aspartate aminotransferase (ASAT) (EC 2. ... Alanine transaminase or ALT is an enzyme (EC 2. ... Bilirubin is a yellow breakdown product of normal heme catabolism. ... The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ...

A drug nomogram was developed in 1975, which estimated the risk of toxicity based on the serum concentration of paracetamol at a given number of hours after ingestion.^[46] To determine the risk of potential hepatotoxicity, the paracetamol level is traced along the standard nomogram. A paracetamol level drawn in the first four hours after ingestion may underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the gastrointestinal tract. Delay of the initial draw for the paracetamol level to account for this is not recommended, since the history in these cases is often poor and a toxic level at any time is a reason to give the antidote. Smith chart which shows how the complex impedance of a transmission line varies along its length This article is about the graphical devices called nomograms. ...

Treatment

Initial measures

The initial treatment for uncomplicated paracetamol overdose, similar to most other overdoses, is gastrointestinal decontamination. In addition, the antidote, acetylcysteine plays an important role. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this time. Absorption may be somewhat slowed when it is ingested with food. There is considerable room for physician judgement regarding gastrointestinal decontamination; activated carbon administration is the most commonly-used procedure; however, gastric lavage may also be considered if the amount ingested is potentially life threatening and the procedure can be performed within 60 minutes of ingestion.^[47] Syrup of ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated carbon and oral acetylcysteine. A drug overdose occurs when a chemical substance (i. ... An antidote is a substance which can counteract a form of poisoning. ... Acetylcysteine (rINN) (IPA: ), also known as N-acetylcysteine (abbreviated NAC), is a pharmacological agent used mainly as a mucolytic and in the management of paracetamol overdose. ... Activated carbon Activated carbon, also called activated charcoal or activated coal, is a general term which covers carbon material mostly derived from charcoal. ... Gastric lavage, also commonly called a stomach pump, is the process of cleaning out the contents of the stomach. ... Syrup of Ipecac (derived from the dried rhizome and roots of the Ipecacuanha plant), is an emeticâ€”a substance used to induce vomiting. ...

Activated carbon adsorbs paracetamol, reducing its gastrointestinal absorption. Administering activated carbon also poses less risk of aspiration than gastric lavage. Previous to this method, there was reluctance to give activated carbon in paracetamol overdose, because of concern that it may also absorb acetylcysteine. Studies have shown that no more than 39% of an oral acetylcysteine is absorbed when they are administered together.^[48] Other studies have shown that activated carbon seems to be beneficial to the clinical outcome. It appears that the most benefit from activated carbon is gained if it is given within two hours of ingestion.^[49] However, administering activated carbon later than this can be considered in patients that may have delayed gastric emptying due to co-ingested drugs or following ingestion of sustained- or delayed-release paracetamol preparations. Activated carbon should also be administered if co-ingested drugs warrant decontamination. There are conflicting recommendations^[48]^[50] regarding whether to change the dosing of oral acetylcysteine after the administration of activated carbon, and even whether the dosing of acetylcysteine needs to be altered at all. Adsorption is a process that occurs when a liquid or gas (called adsorbate) accumulates on the surface of a solid or liquid (adsorbent), forming a molecular or atomic film (adsorbate). ... Aspiration pneumonia is a specific form of lung infection (pneumonia) that develops when oral or gastric contents (including food, saliva, or nasal secretions) enter the bronchial tree. ...

Acetylcysteine

Acetylcysteine (also called N-Acetylcysteine or NAC) works to reduce paracetamol toxicity by supplying sulfhydryl groups (mainly in the form of glutathione, of which it is a precursor) to react with the toxic NAPQI metabolite so that it does not damage cells and can be safely excreted. (NAC can be bought as a dietary supplement in the United States.) Acetylcysteine (rINN) (IPA: ), also known as N-acetylcysteine (abbreviated NAC), is a pharmacological agent used mainly as a mucolytic and in the management of paracetamol overdose. ... Glutathione (GSH) is a tripeptide. ... A protein precursor is an inactive protein (or peptide) that can be turned into an active form by posttranslational modification. ...

If the patient presents less than eight hours after paracetamol overdose, then acetylcysteine significantly reduces the risk of serious hepatotoxicity. If NAC is started more than 8 hours after ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver has already begun, and the risk of acute hepatic necrosis and death increases dramatically. Although acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48 hours after ingestion.^[51] In clinical practice, if the patient presents more than eight hours after the paracetamol overdose, then activated carbon is probably not useful, and acetylcysteine is started immediately. In earlier presentations, the doctor can give carbon as soon as the patient arrives, start giving acetylcysteine, and wait for the paracetamol level from the laboratory.

In United States practice, intravenous (IV) and oral administration are considered to be equally effective. However, IV is the only recommended route in Australasian and British practice. An intravenous drip in a hospital Intravenous therapy or IV therapy is the administration of liquid substances directly into a vein. ...

Oral acetylcysteine is given as a 140mg/kg loading dose followed by 70 mg/kg every four hours for 17 more doses. Oral acetylcysteine may be poorly tolerated due to its unpleasant taste, odor, and its tendency to cause nausea and vomiting. It can be diluted to a 5% solution, from its marketed 10% or 20% solutions, to improve palatability. Where oral acetylcysteine is required, the inhalation formulation of acetylcysteine (Mucomyst) is often given orally. The respiratory formulation can also be diluted and filter sterilized by a hospital pharmacist for IV use; however this is an uncommon practice. If repeat doses of carbon are indicated because of another ingested drug, then subsequent doses of carbon and acetylcysteine should be staggered every two hours.

Intravenous acetylcysteine (Parvolex/Acetadote) is used as a continuous intravenous infusion over 20 hours (total dose 300 mg/kg). Recommended administration involves infusion of a 150mg/kg loading dose over 15 minutes, followed by a 50mg/kg infusion over four hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol. Intravenous acetylcysteine has the advantage of shortening hospital stay, increasing both doctor and patient convenience, and it allows administration of activated carbon to reduce absorption of both the paracetamol and any co-ingested drugs without concerns about interference with oral acetylcysteine.^[52]

Baseline laboratory studies include bilirubin, AST, ALT, and prothrombin time (with INR). Studies are repeated at least daily. Once it has been determined that a potentially-toxic overdose has occurred, acetylcysteine is continued for the entire regimen, even after the paracetamol level becomes undetectable in the blood. If hepatic failure develops, acetylcysteine should be continued beyond the standard doses until hepatic function improves or until the patient has a liver transplant. Bilirubin is a yellow breakdown product of normal heme catabolism. ... Aspartate transaminase (AST) also called Serum Glutamic Oxaloacetic Transaminase (SGOT) or aspartate aminotransferase (ASAT) (EC 2. ... Alanine transaminase or ALT is an enzyme (EC 2. ... The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ...

Prognosis

The mortality rate from paracetamol overdose increases two days after the ingestion, reaches a maximum on day four, and then gradually decreases. Patients with a poor prognosis are usually identified for likely liver transplantation. Acidemia is the most important single indicator of probable mortality and the need for transplantation. A mortality rate of 95% without transplant was reported in patients who had a documented pH less than 7.30. Other indicators of poor prognosis include renal insufficiency, grade 3 or worse hepatic encephalopathy, a markedly elevated prothrombin time, or a rise in prothrombin time from day three to day four. One study has shown that a factor V level less than 10% of normal indicated a poor prognosis (91% mortality), whereas a ratio of factor VIII to factor V of less than 30 indicated a good prognosis (100% survival).^[53] Acidosis is an increased acidity (i. ... For other uses, see PH (disambiguation). ... Renal failure is when the kidneys fail to function properly. ... Hepatic encephalopathy is a potentially reversible neuropsychiatic abnormality in the setting of liver failure, whether chronic (as in cirrhosis), or acutely. ... Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. ... Factor VIII (FVIII) is an essential clotting factor. ...

Prevention

Besides preventing an overdose, one way to prevent liver damage may be the use of Paradote. Paradote is a combination tablet containing 100 mg methionine and 500 mg paracetamol. Methionine is included in order to ensure that sufficient levels of glutathione in the liver are maintained in order to minimize the liver damage caused if a paracetamol overdose is taken. Methionine is an Î±-amino acid with the chemical formula HO2CCH(NH2)CH2CH2SCH3. ... Glutathione (GSH) is a tripeptide. ... The liver is the largest internal organ in the human body, and is an organ present in vertebrates and some other animals. ...

Effects on animals

Paracetamol is extremely toxic to cats, and should not be given to them under any circumstances. Cats lack the necessary glucuronyl transferase enzymes to safely break paracetamol down and minute portions of a normal tablet for humans may prove fatal.^[54] Initial symptoms include vomiting, salivation and discolouration of the tongue and gums. After around two days, liver damage is evident, typically giving rise to jaundice. Unlike an overdose in humans, it is rarely liver damage that is the cause of death, instead methaemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation. Effective treatment is occasionally possible for small doses, but must be extremely rapid. Binomial name Felis catus Linnaeus, 1758 Synonyms Felis lybica invalid junior synonym The cat (or domestic cat, house cat) is a small carnivorous mammal. ... Look up jaundice in Wiktionary, the free dictionary. ... Methemoglobin (pronounced MET-hemoglobin) is a form of the oxygen-carrying protein hemoglobin (British English: haemoglobin), in which the iron in the heme group is in the Fe3+ state, not the Fe2+ of normal hemoglobin. ... Heinz bodies (also referred to as Heinz-Erhlich bodies) are inclusions within red blood cells composed of denatured hemoglobin. ... Asphyxia is a condition of severely deficient supply of oxygen to the body. ...

In dogs, paracetamol is a useful anti-inflammatory with a good safety record, causing a lower incidence of gastric ulceration than NSAIDs. It should be administered only on veterinary advice. A paracetamol-codeine product (trade name Pardale-V)^[55] licensed for use in dogs is available on veterinary prescription in the UK.^[56]

Any cases of suspected ingestion in cats or overdose in dogs should be taken to a veterinarian immediately for detoxification.^[57] The effects of toxicity can include liver damage, haemolytic anaemia, oxidative damage to the red blood cells and bleeding tendencies. There are no home remedies, and the amount of irreversible liver failure is dependent on how quickly veterinary intervention begins. Treatment of paracetamol overdose by a veterinarian may involve the use of supportive fluid therapy, acetylcysteine (trade name Mucomyst), methionine, or S-adenosyl-L-methionine (SAMe) to slow liver damage and cimetidine (trade name Tagamet) to protect against gastric ulceration. Once liver damage has occurred, it cannot be reversed. ^[58] Vitamin C can be used to aid in the conversion of methemoglobine back to hemoglobine (6 x 30mg/kg every 6 hours) Look up veterinarian in Wiktionary, the free dictionary. ... Hemolytic anemia is anemia due to hemolysis, the abnormal breakdown of red blood cells either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). ... Acetylcysteine (rINN) (IPA: ), also known as N-acetylcysteine (abbreviated NAC), is a pharmacological agent used mainly as a mucolytic and in the management of paracetamol overdose. ... Methionine is an Î±-amino acid with the chemical formula HO2CCH(NH2)CH2CH2SCH3. ... This article does not cite its references or sources. ... Cimetidine (INN) (IPA: ) is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. ...

Paracetamol is lethal to snakes, also, and has been used in attempts to control the brown tree snake (Boiga irregularis) in Guam.^[59] Binomial name Boiga irregularis (Merrem, 1802) The brown tree snake (Boiga irregularis) is an arboreal colubrid snake native to eastern and northern coastal Australia, Papua New Guinea, and a large number of islands in northwestern Melanesia. ...

See also

The Tylenol scare occurred in the autumn of 1982, after seven people in the Chicago, Illinois area died after ingesting Extra Strength Tylenol medicine capsules which had been laced with cyanide poison. ... Categories: | | | ...

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is the 229th day of the year (230th in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... Year 2006 (MMVI) was a common year starting on Sunday of the Gregorian calendar. ... is the 363rd day of the year (364th in leap years) in the Gregorian calendar. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... is the 229th day of the year (230th in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... is the 181st day of the year (182nd in leap years) in the Gregorian calendar. ... Year 2004 (MMIV) was a leap year starting on Thursday of the Gregorian calendar. ... is the 229th day of the year (230th in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 180th day of the year (181st in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 229th day of the year (230th in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 209th day of the year (210th in leap years) in the Gregorian calendar. ... This article is about the year. ... is the 229th day of the year (230th in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 229th day of the year (230th in leap years) in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... is the 349th day of the year (350th in leap years) in the Gregorian calendar. ... Year 2000 (MM) was a leap year starting on Saturday. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... Year 2006 (MMVI) was a common year starting on Sunday of the Gregorian calendar. ... is the 363rd day of the year (364th in leap years) in the Gregorian calendar. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... PubMed Central grew from the online Entrez PubMed biomedical literature search system. ... is the 271st day of the year (272nd in leap years) in the Gregorian calendar. ... Year 2006 (MMVI) was a common year starting on Sunday of the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 3rd day of the year in the Gregorian calendar. ... is the 319th day of the year (320th in leap years) in the Gregorian calendar. ... Year 2005 (MMV) was a common year starting on Saturday (link displays full calendar) of the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 3rd day of the year in the Gregorian calendar. ... Year 2007 (MMVII) was a common year starting on Monday of the Gregorian calendar in the 21st century. ... is the 3rd day of the year in the Gregorian calendar. ...

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Clonidine is a direct-acting adrenergic agonist prescribed historically as an anti-hypertensive agent. ... Cyclobenzaprine is a skeletal muscle relaxant and a central nervous system (CNS) depressant. ... Duloxetine (brand names Cymbalta, Yentreve, and in parts of Europe, Xeristar or Ariclaim) is a drug which primarily targets major depressive disorder (MDD), generalized anxiety disorder (GAD), pain related to diabetic peripheral neuropathy and in some countries stress urinary incontinence (SUI). ... Gabapentin (brand name Neurontin) is a medication originally developed for the treatment of epilepsy. ... Categories: Possible copyright violations ... Orphenadrine (NorflexÂ®, DisipalÂ®, BanflexÂ®, FlexonÂ® and others) is an anticholinergic and NMDA receptor antagonist [1]drug belonging to the ethanolamine class of antihistamines. ... Trazodone (DesyrelÂ®, TritticoÂ®, ThombranÂ®, TrialodineÂ®) is a psychoactive compound with sedative, anxiolytic, and antidepressant properties. ... Ziconotide is a non-opioid, non local anesthetic used for the amelioration of chronic pain. ...

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