Chemistry:Paracetamol
![]() | |
![]() | |
Clinical data | |
---|---|
Pronunciation | Paracetamol: /ˌpærəˈsiːtəmɒl/ Acetaminophen: /əˌsiːtəˈmɪnəfɪn/ ( ![]() |
Trade names | Tylenol, Panadol, others[1] |
Other names | N-acetyl-para-aminophenol (APAP), acetaminophen (USAN US) |
AHFS/Drugs.com | Monograph |
MedlinePlus | a681004 |
License data |
|
Pregnancy category |
|
Routes of administration | Oral (by mouth), rectal, intravenous (IV) |
Drug class | Analgesics and antipyretics |
ATC code | |
Legal status | |
Legal status |
|
Pharmacokinetic data | |
Bioavailability | 63–89%[4]:73 |
Protein binding | negligible to 10–25% in overdose[5] |
Metabolism | Predominantly in the liver[8] |
Metabolites | APAP gluc, APAP sulfate, APAP GSH, APAP cys, AM404, NAPQI[6] |
Onset of action | Pain relief onset by route: oral – 37 minutes[7] Intravenous – 8 minutes[7] |
Elimination half-life | 1.9–2.5 hours[5] |
Excretion | Urine[5] |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
PubChem SID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
PDB ligand | |
Chemical and physical data | |
Formula | C8H9NO2 |
Molar mass | 151.165 g·mol−1 |
3D model (JSmol) | |
Density | 1.263 g/cm3 |
Melting point | 169 °C (336 °F) [9][10] |
Solubility in water | |
| |
| |
(verify) |
Paracetamol (acetaminophen[lower-alpha 1] or para-hydroxyacetanilide) is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain.[12][13][14] It is a widely used over the counter medication. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature;[13][15][16] it is inferior to ibuprofen in that respect,[17] and the benefits of its use for fever are unclear, particularly in the context of fever of viral origins.[13][18][19] Paracetamol may relieve pain in acute mild migraine but only slightly in episodic tension headache.[20][21] However, the aspirin/paracetamol/caffeine combination helps with both conditions where the pain is mild and is recommended as a first-line treatment for them.[22][23] Paracetamol is effective for post-surgical pain, but it is inferior to ibuprofen.[24] The paracetamol/ibuprofen combination provides further increase in potency and is superior to either drug alone.[24][25] The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant.[14][26][27] The evidence in its favor for the use in low back pain, cancer pain, and neuropathic pain is insufficient.[14][28][26][29][30][31]
In the short term, paracetamol is safe and effective when used as directed.[32] Short term adverse effects are uncommon and similar to ibuprofen,[33] but paracetamol is typically safer than non-steroidal anti-inflammatory drugs (NSAID) for long term use.[34] Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen.[35][36] Chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding,[37] and abnormal liver function tests. Some epidemiological studies have linked paracetamol to cardiovascular, renal, and gastrointestinal diseases, but are largely due to confounding biases and of insignificant relevance with short-term use of paracetamol.[38][39][37][36][40] Paracetamol may slightly increase systolic blood pressure in hypertensive patients at a dose of 4 grams a day.[41][42] Elevated frequency of asthma and developmental and reproductive disorders is observed in the offspring of women with prolonged use of paracetamol during pregnancy, although whether paracetamol is the true cause of this increase is unclear.[41] Some studies suggest that there is evidence for an association between paracetamol during pregnancy and autism spectrum disorder and attention deficit hyperactivity disorder, while making clear further research is required to establish any causal link,[43][44] which has prompted some calls to limit its use in pregnancy to the lowest effective dosage for the shortest possible time.[41][45][46]
The recommended maximum daily dose for an adult is three to four grams.[47][48][26] Higher doses may lead to toxicity, including liver failure.[49] Paracetamol poisoning is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.[50][51][52]
Paracetamol was first made in 1878 by Harmon Northrop Morse or possibly 1852 by Charles Frédéric Gerhardt.[53][54][55] It is the most commonly used medication for pain and fever in both the United States and Europe.[56] It is on the World Health Organization's List of Essential Medicines.[57] Paracetamol is available as a generic medication, with brand names including Tylenol and Panadol among others.[58] In 2020, it was the 118th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[59][60]
Etymology
The word "acetaminophen" is a shortened form of N-acetyl aminophenol, and was coined and first marketed by McNeil Laboratories in 1955.[61]
The word "paracetamol" is a shortened form of para-acetyl-amino-phenol,[62] and was coined by Frederick Stearns & Co in 1956.[63]
Medical uses
Fever
Paracetamol is a drug of choice for reducing fever. However, there has been a lack of research on its antipyretic properties, particularly in adults.[13] The most recent review on paracetamol and management of fever in the general practice (2008) argued that its benefits are unclear.[13] In addition, when used for the common cold, paracetamol may relieve a stuffed or runny nose, but not other cold symptoms such as a sore throat, malaise, sneezing, or cough; however, these data are of poor quality.[64]
For patients in critical care, paracetamol decreased body temperature by only 0.2–0.3 °C more than control interventions; there was no difference in mortality.[15] It did not change the outcome in febrile patients with stroke.[65] The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported.[15] Paracetamol offered no benefit in the treatment of dengue fever and was accompanied by a higher rate of liver enzyme elevation: a sign of a potential liver damage.[66] Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection.[19]
The efficacy of paracetamol in children with fever is unclear.[67] Paracetamol should not be used solely with the aim of reducing body temperature; however, it may be considered for children with fever who appear distressed.[68] It does not prevent febrile seizures and should not be used for that purpose.[68][69] It appears that 0.2 °C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergency situations.[13] Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7 °C.[16] Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis[70]), including children younger than 2 years old,[71] with equivalent safety.[17] Exacerbation of asthma occurs with similar frequency for both medications.[72] Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended, however doses may be alternated if required.[68]
Pain
Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, toothache as well as pain caused by cold, flu, sprains, and dysmenorrhea.[73] It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.[14]
Musculoskeletal pain
The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.[14]
It appears to provide only small and not clinically important benefits in osteoarthritis.[14][26] American College of Rheumatology and Arthritis Foundation guideline for the management of osteoarthritis notes that the effect size in clinical trials of paracetamol has been very small, which suggests that for most individuals it is ineffective.[27] The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate nonsteroidal anti-inflammatory drugs. For people taking it regularly, monitoring for liver toxicity is required.[27] Essentially the same recommendation was issued by EULAR for hand osteoarthritis.[74] Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only.[75]
Paracetamol is ineffective for acute low back pain.[14][28] No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol is lacking.[26][29][28]
Headaches
Paracetamol is effective for acute migraine:[20] 39% of people experience pain relief at one hour compared with 20% in the control group.[76] The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine".[22] Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently.[21] However, the aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: 2 hours after administering the medication, 29% of those who took the combination were pain-free as compared with 21% on paracetamol and 18% on placebo.[77] The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as a "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice".[23]
Dental and other post-surgical pain
Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain.[78] For the relief of such pain, paracetamol is inferior to ibuprofen.[24] Full therapeutic doses of non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen or diclofenac are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain.[79] The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone.[24][25][80][81] Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations.[25]
A meta-analysis of general post-surgical pain, which included dental and other surgery, showed the paracetamol/codeine combination to be more effective than paracetamol alone: it provided significant pain relief to as much as 53% of the participants, while the placebo helped only 7%.[82]
Other pain
Paracetamol fails to relieve procedural pain in newborn babies.[83][84] For perineal pain postpartum paracetamol appears to be less effective than non-steroidal anti-inflammatory drugs (NSAIDs).[85]
The studies to support or refute the use of paracetamol for cancer pain and for neuropathic pain are lacking.[30][31] There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department.[86] The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.[87]
Patent ductus arteriosus
Paracetamol helps ductal closure in patent ductus arteriosus. It is as effective for this purpose as ibuprofen or indomethacin, but results in less frequent gastrointestinal bleeding than ibuprofen.[88] Its use for extremely low birth weight and gestational age infants however requires further study.[88]
Adverse effects
Gastrointestinal adverse effects such as nausea and abdominal pain are common, and their frequency is similar to that of ibuprofen.[36] Increase in risk-taking behavior is possible.[89] According to the US Food and Drug Administration, the drug may cause rare and possibly fatal skin reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis,[90] Rechallenge tests and an analysis of American but not French pharmacovigilance databases indicated a risk of these reactions.[90][91]
In clinical trials for osteoarthritis, the number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain.[39] After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating gastrointestinal bleeding was observed in 20% of participants, this rate being similar to ibuprofen group.[37]
Due to the absence of controlled studies, most of the information about the long-term safety of paracetamol comes from observational studies.[36] These indicate a consistent pattern of increased mortality as well as cardiovascular (stroke, myocardial infarction), gastrointestinal (ulcers, bleeding) and renal adverse effects with increased dose of paracetamol.[37][36][40] Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer.[36] Those who take it regularly at a higher dose (more than 2–3 g daily) are at much higher risk (3.6–3.7 times) of gastrointestinal bleeding and other bleeding events.[41] Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23%[92] and kidney cancer by 28%.[40] Paracetamol is particularly dangerous to the liver in overdose, but even without overdose those who take this drug may develop acute liver failure requiring liver transplantation more frequently than the users of nonsteroidal anti-inflammatory drugs.[35] Paracetamol slightly but significantly increases blood pressure and heart rate.[36] The majority of observational studies suggests that, used chronically, it may increase the risk of developing hypertension, as confirmed in a prospective randomized confirmed trial.[42] The risk is higher with the higher dose.[41]
The association between paracetamol use and asthma in children has been a matter of controversy.[93] However, the most recent research suggests that there is no association,[94] and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer ibuprofen.[72]
Use in pregnancy
Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or birth defects. However, indications exist of a possible increase of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy.[41]
Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma,[95][96] but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult.[41] Paracetamol, in a small scale meta-analysis was also associated with 20–30% increase in autism spectrum disorder, attention deficit hyperactivity disorder, hyperactivity symptoms, and conduct disorder, with the association being lower in a meta-analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and there was potential bias in the findings.[41][97][98] There is also an argument that the large number, consistency, and the robust designs of the studies provide a strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders.[43][44] In animal experiments, paracetamol disrupts fetal testosterone production, and several epidemiological studies linked cryptorchidism with mother's paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association.[41]
The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage and for the shortest time.[41][45][46]
Overdose
Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams),[47][48] and can cause potentially fatal liver damage.[99][100] A single dose should not exceed 1000 mg, and doses should be taken no sooner than four hours apart.[47] While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period.[101]
Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.[50][102][51][52] Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.[103] According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25% of the emergency department visits, 10% of the hospitalizations, and 25% of the deaths."[104]
Overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with paracetamol.[105] The overdose risk may be heightened by frequent consumption of alcohol.[106]
Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure starts.[107] People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by the drug.[108][109]
Treatment is aimed at removing the paracetamol from the body and replenishing glutathione.[109] Activated charcoal can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote, acetylcysteine (also called N-acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease the possible damage to the liver; a liver transplant is often required if damage to the liver becomes severe.[50][110]
NAC was usually given following a treatment nomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice.[111][112] Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it.[109] Kidney failure is also a possible side effect.[106]
Interactions
Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (tmax) to paracetamol peak blood plasma concentration (Cmax), and increase Cmax. Medications slowing gastric emptying such as propantheline and morphine lengthen tmax and decrease Cmax.[113][114] The interaction with morphine may result in patients failing to achieve the therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear.[114]
There have been suspicions that cytochrome inducers may enhance the toxic pathway of paracetamol metabolism to NAPQI (see Paracetamol). By and large, these suspicions have not been confirmed.[114] Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for phenobarbital, primidone, isoniazid, and possibly St John's wort.[115] On the other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%.[114]
Ranitidine increased paracetamol area under the curve (AUC) 1.6-fold. AUC increases are also observed with nizatidine and cisapride. The effect is explained by these drugs inhibiting glucuronidation of paracetamol.[114]
Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation.[114] Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week.[116][117][118]
Pharmacology
Pharmacodynamics
Paracetamol appears to exert its effects through two mechanisms: the inhibition of cyclooxygenase and actions of its metabolite N-arachidonoylphenolamine (AM404).[119]
Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors.[120] Paracetamol inhibits prostaglandin synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight.[119][120] The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding.
The second mechanism centers on the paracetamol metabolite AM404. This metabolite has been detected in the brains of animals and cerebrospinal fluid of humans taking paracetamol.[119][121] It is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase.[119] AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor.[119] This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.[119][122]
In 2018, Suemaru et al. found that, in mice, paracetamol exerts anticonvulsant effect by activation of TRPV1 receptors[123] and decrease in neuronal excitability by hyperpolarization of neurons.[124] The exact mechanism of the anticonvulsant effect of acetaminophen is not clear. According to Suemaru et al., acetaminophen and its active metabolite AM404 show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice.[123]
Pharmacokinetics
After being taken by mouth, paracetamol is rapidly absorbed from the small intestine, while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach emptying and absorption, but the total amount absorbed stays the same.[125] In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.[5]
Paracetamol's bioavailability is dose-dependent: it increases from 63% for 500 mg dose to 89% for 1000 mg dose.[5] Its plasma terminal elimination half-life is 1.9–2.5 hours,[5] and volume of distribution is roughly 50 L.[126] Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21%.[5] The concentration in serum after a typical dose of paracetamol usually peaks below 30 μg/mL (200 μmol/L).[127] After 4 hours, the concentration is usually less than 10 μg/mL (66 μmol/L).[127]
Paracetamol is metabolized primarily in the liver, mainly by glucuronidation and sulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 2–5% of the drug is excreted unchanged in the urine.[5] Glucuronidation by UGT1A1 and UGT1A6 accounts for 50–70% of the drug metabolism. Additional 25–35% of paracetamol is converted to sulfate by sulfation enzymes SULT1A1, SULT1A3, and SULT1E1.[128]
A minor metabolic pathway (5–15%) of oxidation by cytochrome P450 enzymes, mainly by CYP2E1, forms a toxic metabolite known as NAPQI (N-acetyl-p-benzoquinone imine).[128] NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with glutathione. The non-toxic conjugate APAP-GSH is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by the large amount of formed NAPQI, and NAPQI binds to mitochondria proteins of the liver cells causing oxidative stress and toxicity.[128]
Yet another minor but important direction of metabolism is deacetylation of 1–2% of paracetamol to form p-aminophenol. p-Aminophenol is then converted in the brain by fatty acid amide hydrolase into AM404, a compound that may be partially responsible for the analgesic action of paracetamol.[126]
Chemistry
Synthesis
Classical methods
The classical methods for the production of paracetamol involve the acetylation of 4-aminophenol with acetic anhydride as the last step. They differ in how 4-aminophenol is prepared. In one method, nitration of phenol with nitric acid affords 4-nitrophenol, which is reduced to 4-aminophenol by hydrogenation over Raney nickel. In another method, nitrobenzene is reduced electrolytically giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by Tin(II) Chloride in absolute ethanol or ethyl acetate to produce a 91% yield of 4-aminophenol.[129][130][131]
Celanese synthesis
An alternative industrial synthesis developed at Celanese involves firstly direct acylation of phenol with acetic anhydride in the presence of hydrogen fluoride to a ketone, then the conversion of the ketone with hydroxylamine to a ketoxime, and finally the acid-catalyzed Beckmann rearrangement of the cetoxime to the para-acetylaminophenol product.[129][132]
Reactions
4-Aminophenol may be obtained by the amide hydrolysis of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, 4-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air.[133]
History
Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by Cahn & Hepp in 1886.[134] But its unacceptable toxic effects—the most alarming being cyanosis due to methemoglobinemia, an increase of hemoglobin in its ferric [Fe3+] state, called methemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives.[135] Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.[54][55]
Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,[136][137] but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans.[135] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.[138] Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company.[139]
Von Mering's claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin.[139] In 1947, David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.[140] In 1948, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor.[141][142][143] They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.[144] This led to a "rediscovery" of paracetamol.[135]
Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol, aspirin, and caffeine.[137] Reports in 1951 of three users stricken with the blood disease agranulocytosis led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected.[137] The following year, 1952, paracetamol returned to the US market as a prescription drug.[145] In the United Kingdom, marketing of paracetamol began in 1956 by Sterling-Winthrop Co. as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers.[146][147] 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.[146][137]
Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy and hematological toxicity.[135] Available in the US without a prescription since 1955[145] (1960, according to another source[148]) paracetamol has become a common household drug.[149] In 1988, Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994.[150]
In June 2009, an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects. The maximum single adult dosage would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and other products would be prohibited. Committee members were particularly concerned by the fact that the then-present maximum dosages of paracetamol had been shown to produce alterations in liver function.[151]
In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage.[152][153][154][155][156] Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.[153][155]
In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.[157]
In September 2013, "Use Only as Directed", an episode of the radio program This American Life[158] highlighted deaths from paracetamol overdose. This report was followed by two reports by ProPublica alleging that the "FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of Johnson & Johnson"[159] and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."[160]
During the COVID-19 pandemic it was considered by some in the scientific community that it was an effective analgesic medication to treat symptoms of COVID-19, but this was found to be unsubstantiated.[161][162][163][164]
Society and culture
Naming
Paracetamol is the Australian Approved Name[165] and British Approved Name[166] as well as the international nonproprietary name used by the WHO and in many other countries; acetaminophen is the United States Adopted Name[166] and Japanese Accepted Name and also the name generally used in Canada,[166] Venezuela, Colombia, and Iran.[166][167] Both paracetamol and acetaminophen are contractions of para-acetylaminophenol, a chemical name for the compound. The initialism APAP used by dispensing pharmacists in the United States comes from the alternative chemical name [N-]acetyl-para-aminophenol.[168]
Available forms
Paracetamol is available in oral, suppository, and intravenous forms.[169] Intravenous paracetamol is sold under the brand name Ofirmev in the United States.[170]
In some formulations, paracetamol is combined with the opiate codeine, sometimes referred to as co-codamol (BAN) and Panadeine in Australia. In the US, this combination is available only by prescription.[171] As of 1 February 2018, medications containing codeine also became prescription-only in Australia.[172] Paracetamol is also combined with other opioids such as dihydrocodeine,[173] referred to as co-dydramol (British Approved Name (BAN)), oxycodone[174] or hydrocodone.[175] Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate.[176] A combination of paracetamol, codeine, and the doxylamine succinate is also available.[177]
Paracetamol is sometimes combined with phenylephrine hydrochloride.[178] Sometimes a third active ingredient, such as ascorbic acid,[178][179] caffeine,[180][181] chlorpheniramine maleate,[182] or guaifenesin[183][184][185] is added to this combination.
Veterinary use
Cats
Paracetamol is extremely toxic to cats, which lack the necessary UGT1A6 enzyme to detoxify it. Initial symptoms include vomiting, salivation, and discoloration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, methemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation (methemoglobinemia and hemolytic anemia).[186] Treatment of the toxicosis with N-acetylcysteine is recommended.[187]
Dogs
Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.[188] A paracetamol–codeine product (brand name Pardale-V)[189] licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person.[189] It should be administered to dogs only on veterinary advice and with extreme caution.[189]
The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.[187][190][191][192] N-acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.[187][188]
Snakes
Paracetamol is lethal to snakes[193] and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam.[194][195] Doses of 80 mg are inserted into dead mice that are scattered by helicopter[196] as lethal bait to be consumed by the snakes.
Notes
- ↑ Commonly called "acetaminophen" in the US, Canada, Japan, and South Korea.
References
- ↑ International Drug Names
- ↑ "Acetaminophen Use During Pregnancy". 14 June 2019. https://www.drugs.com/pregnancy/acetaminophen.html.
- ↑ "Regulatory Decision Summary – Acetaminophen Injection". 23 October 2014. https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00565.
- ↑ (PDF) Acute Pain Management: Scientific Evidence (4th ed.). Melbourne: Australian and New Zealand College of Anaesthetists (ANZCA), Faculty of Pain Medicine (FPM). 2015. ISBN 978-0-9873236-7-5. http://fpm.anzca.edu.au/documents/apmse4_2015_final. Retrieved 28 October 2019.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 "Clinical pharmacokinetics of paracetamol". Clin Pharmacokinet 7 (2): 93–107. 1982. doi:10.2165/00003088-198207020-00001. PMID 7039926.
- ↑ "Acetaminophen Pathway (therapeutic doses), Pharmacokinetics". https://www.pharmgkb.org/pathway/PA165986279.
- ↑ 7.0 7.1 "Buccal acetaminophen provides fast analgesia: two randomized clinical trials in healthy volunteers". Drug Design, Development and Therapy 8: 1621–1627. September 2014. doi:10.2147/DDDT.S63476. PMID 25302017. "In postoperative conditions for acute pain of mild to moderate intensity, the quickest reported time to onset of analgesia with APAP is 8 minutes9 for the iv route and 37 minutes6 for the oral route.".
- ↑ "Codapane Forte Paracetamol and codeine phosphate product information" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 29 April 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05623-3.
- ↑ "General Melting Point Prediction Based on a Diverse Compound Data Set and Artificial Neural Networks". Journal of Chemical Information and Modeling 45 (3): 581–590. 2005. doi:10.1021/ci0500132. PMID 15921448.
- ↑ "melting point data for paracetamol". Lxsrv7.oru.edu. http://lxsrv7.oru.edu/~alang/meltingpoints/meltingpointof.php?csid=1906.
- ↑ 11.0 11.1 11.2 11.3 11.4 "Solubility of paracetamol in pure solvents". Journal of Chemical & Engineering Data 44 (6): 1391–95. 1999. doi:10.1021/je990124v.
- ↑ "Paracetamol: past, present, and future". American Journal of Therapeutics 7 (2): 143–147. March 2000. doi:10.1097/00045391-200007020-00011. PMID 11319582.
- ↑ 13.0 13.1 13.2 13.3 13.4 13.5 "Paracetamol and fever management". J R Soc Promot Health 128 (6): 320–323. November 2008. doi:10.1177/1466424008092794. PMID 19058473.
- ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 "Paracetamol for pain in adults". BMJ 367: l6693. December 2019. doi:10.1136/bmj.l6693. PMID 31892511.
- ↑ 15.0 15.1 15.2 "Paracetamol in fever in critically ill patients-an update". J Crit Care 38: 245–252. April 2017. doi:10.1016/j.jcrc.2016.10.021. PMID 27992852.
- ↑ 16.0 16.1 "Recent Advances in Pediatric Use of Oral Paracetamol in Fever and Pain Management". Pain Ther 4 (2): 149–68. December 2015. doi:10.1007/s40122-015-0040-z. PMID 26518691.
- ↑ 17.0 17.1 "Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review". Ann Pharmacother 44 (3): 489–506. March 2010. doi:10.1345/aph.1M332. PMID 20150507.
- ↑ "Paracetamol for treating fever in children". Cochrane Database Syst Rev 2002 (2): CD003676. 2002. doi:10.1002/14651858.CD003676. PMID 12076499.
- ↑ 19.0 19.1 "Antipyretic drugs in patients with fever and infection: literature review". Br J Nurs 28 (10): 610–618. May 2019. doi:10.12968/bjon.2019.28.10.610. PMID 31116598.
- ↑ 20.0 20.1 "The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies". Headache 55 (1): 3–20. January 2015. doi:10.1111/head.12499. PMID 25600718.
- ↑ 21.0 21.1 "Paracetamol (acetaminophen) for acute treatment of episodic tension-type headache in adults". Cochrane Database Syst Rev 2019 (6): CD011889. June 2016. doi:10.1002/14651858.CD011889.pub2. PMID 27306653.
- ↑ 22.0 22.1 "Acute Migraine Headache: Treatment Strategies". Am Fam Physician 97 (4): 243–251. February 2018. PMID 29671521.
- ↑ 23.0 23.1 "Self-medication of migraine and tension-type headache: summary of the evidence-based recommendations of the Deutsche Migräne und Kopfschmerzgesellschaft (DMKG), the Deutsche Gesellschaft für Neurologie (DGN), the Österreichische Kopfschmerzgesellschaft (ÖKSG) and the Schweizerische Kopfwehgesellschaft (SKG)". J Headache Pain 12 (2): 201–217. April 2011. doi:10.1007/s10194-010-0266-4. PMID 21181425.
- ↑ 24.0 24.1 24.2 24.3 "Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth". Cochrane Database Syst Rev (12): CD004624. December 2013. doi:10.1002/14651858.CD004624.pub2. PMID 24338830.
- ↑ 25.0 25.1 25.2 "Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: translating clinical research to dental practice". J Am Dent Assoc 144 (8): 898–908. August 2013. doi:10.14219/jada.archive.2013.0207. PMID 23904576.
- ↑ 26.0 26.1 26.2 26.3 26.4 "Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo-controlled trials.". BMJ 350: h1225. March 2015. doi:10.1136/bmj.h1225. PMID 25828856.
- ↑ 27.0 27.1 27.2 "2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee". Arthritis Care & Research 72 (2): 149–162. February 2020. doi:10.1002/acr.24131. PMID 31908149.
- ↑ 28.0 28.1 28.2 "Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians". Ann Intern Med 166 (7): 514–530. April 2017. doi:10.7326/M16-2367. PMID 28192789.
- ↑ 29.0 29.1 "Paracetamol for low back pain". Cochrane Database Syst Rev 6 (6): CD012230. June 2016. doi:10.1002/14651858.CD012230. PMID 27271789.
- ↑ 30.0 30.1 "Oral paracetamol (acetaminophen) for cancer pain". Cochrane Database Syst Rev 7 (2): CD012637. July 2017. doi:10.1002/14651858.CD012637.pub2. PMID 28700092.
- ↑ 31.0 31.1 "Paracetamol (acetaminophen) with or without codeine or dihydrocodeine for neuropathic pain in adults". Cochrane Database Syst Rev 12 (5): CD012227. December 2016. doi:10.1002/14651858.CD012227.pub2. PMID 28027389.
- ↑ "Acetaminophen". 11 October 2012. https://www.canada.ca/en/health-canada/services/drugs-medical-devices/acetaminophen.html.
- ↑ "Systematic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever". Current Medical Research and Opinion 25 (9): 2207–2222. September 2009. doi:10.1185/03007990903116255. PMID 19606950. https://figshare.com/articles/journal_contribution/11815293. Retrieved 2 December 2022.
- ↑ "Acetaminophen vs Ibuprofen: Which is better?". https://www.drugs.com/medical-answers/difference-between-ibuprofen-acetaminophen-3016163/.
- ↑ 35.0 35.1 "Paracetamol and pain: the kiloton problem". European Journal of Hospital Pharmacy 23 (4): 187–188. July 2016. doi:10.1136/ejhpharm-2016-000952. PMID 31156845.
- ↑ 36.0 36.1 36.2 36.3 36.4 36.5 36.6 "Safety of Paracetamol in Osteoarthritis: What Does the Literature Say?". Drugs Aging 36 (Suppl 1): 7–14. April 2019. doi:10.1007/s40266-019-00658-9. PMID 31073920.
- ↑ 37.0 37.1 37.2 37.3 "Paracetamol: not as safe as we thought? A systematic literature review of observational studies". Ann Rheum Dis 75 (3): 552–9. March 2016. doi:10.1136/annrheumdis-2014-206914. PMID 25732175.
- ↑ "Why paracetamol (acetaminophen) is a suitable first choice for treating mild to moderate acute pain in adults with liver, kidney or cardiovascular disease, gastrointestinal disorders, asthma, or who are older". Current Medical Research and Opinion 38 (5): 811–825. May 2022. doi:10.1080/03007995.2022.2049551. PMID 35253560.
- ↑ 39.0 39.1 "Paracetamol versus placebo for knee and hip osteoarthritis". Cochrane Database Syst Rev 2 (8): CD013273. February 2019. doi:10.1002/14651858.CD013273. PMID 30801133.
- ↑ 40.0 40.1 40.2 "Analgesic use and the risk of kidney cancer: a meta-analysis of epidemiologic studies". Int J Cancer 134 (2): 384–96. January 2014. doi:10.1002/ijc.28093. PMID 23400756.
- ↑ 41.0 41.1 41.2 41.3 41.4 41.5 41.6 41.7 41.8 41.9 "Long-term adverse effects of paracetamol – a review". Br J Clin Pharmacol 84 (10): 2218–2230. October 2018. doi:10.1111/bcp.13656. PMID 29863746.
- ↑ 42.0 42.1 "Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial". Circulation 145 (6): 416–423. February 2022. doi:10.1161/CIRCULATIONAHA.121.056015. PMID 35130054.
- ↑ 43.0 43.1 "Prenatal paracetamol exposure and child neurodevelopment: A review". Horm Behav 101: 125–147. May 2018. doi:10.1016/j.yhbeh.2018.01.003. PMID 29341895.
- ↑ 44.0 44.1 "Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis". Aust N Z J Psychiatry 53 (3): 195–206. March 2019. doi:10.1177/0004867418823276. PMID 30654621.
- ↑ 45.0 45.1 "Is acetaminophen safe in pregnancy?". Scand J Pain 17: 445–446. October 2017. doi:10.1016/j.sjpain.2017.09.007. PMID 28986045.
- ↑ 46.0 46.1 "Medication Use and Pain Management in Pregnancy: A Critical Review". Pain Pract 19 (8): 875–899. November 2019. doi:10.1111/papr.12814. PMID 31242344.
- ↑ 47.0 47.1 47.2 "Paracetamol for adults: painkiller to treat aches, pains and fever". https://www.nhs.uk/medicines/paracetamol-for-adults/.
- ↑ 48.0 48.1 "What are the recommended maximum daily dosages of acetaminophen in adults and children?". https://www.medscape.com/answers/820200-27207/what-are-the-recommended-maximum-daily-dosages-of-acetaminophen-in-adults-and-children.
- ↑ "Acetaminophen". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/acetaminophen.html.
- ↑ 50.0 50.1 50.2 "Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres". The Medical Journal of Australia 188 (5): 296–301. March 2008. doi:10.5694/j.1326-5377.2008.tb01625.x. PMID 18312195.
- ↑ 51.0 51.1 "Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature". Drug Saf 30 (6): 465–79. 2007. doi:10.2165/00002018-200730060-00002. PMID 17536874.
- ↑ 52.0 52.1 "Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study". Hepatology 42 (6): 1364–72. 2005. doi:10.1002/hep.20948. PMID 16317692.
- ↑ Pharmacology application in athletic training. Philadelphia, Pennsylvania: F.A. Davis. 2005. p. 39. ISBN 9780803620278. https://books.google.com/books?id=tV72AAAAQBAJ&pg=PA39. Retrieved 7 September 2017.
- ↑ 54.0 54.1 Eyers SJ (April 2012). The effect of regular paracetamol on bronchial responsiveness and asthma control in mild to moderate asthma (Ph.D. thesis). University of Otago). Archived from the original on 24 August 2021. Retrieved 24 August 2021.
- ↑ 55.0 55.1 "Paracetamol – the best selling antipyretic analgesic in the world". An introduction to pharmaceutical sciences: production, chemistry, techniques and technology. Oxford: Biohealthcare. 2011. p. 270. ISBN 978-1-908818-04-1. https://books.google.com/books?id=0IdmAgAAQBAJ&pg=PA270. Retrieved 24 August 2021.
- ↑ Essentials of emergency medicine. Jones & Bartlett Publishers. 22 October 2010. p. 814. ISBN 978-1-4496-1846-9. https://books.google.com/books?id=HnbKaRQAXOIC&pg=PA814.
- ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- ↑ Tarascon pocket pharmacopoeia : 2013 classic shirt-pocket edition (27th ed.). Burlington, Massachusetts: Jones & Bartlett Learning. 2013. p. 12. ISBN 9781449665869. https://books.google.com/books?id=lwueJ4IAl4oC&pg=PA12.
- ↑ "The Top 300 of 2020". ClinCalc. https://clincalc.com/DrugStats/Top300Drugs.aspx.
- ↑ "Acetaminophen – Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Acetaminophen.
- ↑ "Definition of ACETAMINOPHEN". https://www.merriam-webster.com/dictionary/acetaminophen.
- ↑ "Definition of PARACETAMOL". https://www.merriam-webster.com/dictionary/paracetamol#:~:text=etymology,phenol.
- ↑ "A History of Paracetamol, Its Various Uses & How It Affects You". https://www.fevermates.com/blogs/news/a-history-of-paracetamol-and-its-various-uses.
- ↑ "Acetaminophen (paracetamol) for the common cold in adults". Cochrane Database Syst Rev 2013 (7): CD008800. July 2013. doi:10.1002/14651858.CD008800.pub2. PMID 23818046.
- ↑ "PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2): Results of a Randomized, Double-Blind Placebo-Controlled Clinical Trial". Stroke 48 (4): 977–982. April 2017. doi:10.1161/STROKEAHA.116.015957. PMID 28289240.
- ↑ "Paracetamol for dengue fever: no benefit and potential harm?". Lancet Glob Health 7 (5): e552–e553. May 2019. doi:10.1016/S2214-109X(19)30157-3. PMID 31000122.
- ↑ "Paracetamol for treating fever in children". Cochrane Database Syst Rev 2002 (2): CD003676. 2002. doi:10.1002/14651858.CD003676. PMID 12076499.
- ↑ 68.0 68.1 68.2 "Recommendations. Fever in under 5s: assessment and initial management". 7 November 2019. https://www.nice.org.uk/guidance/ng143/chapter/Recommendations#antipyretic-interventions.
- ↑ "Use of antipyretics for preventing febrile seizure recurrence in children: a systematic review and meta-analysis". Eur J Pediatr 180 (4): 987–997. April 2021. doi:10.1007/s00431-020-03845-8. PMID 33125519.
- ↑ "Effectiveness of paracetamol versus ibuprofen administration in febrile children: A systematic literature review". J Paediatr Child Health 53 (8): 800–807. August 2017. doi:10.1111/jpc.13507. PMID 28437025.
- ↑ "Comparison of Acetaminophen (Paracetamol) With Ibuprofen for Treatment of Fever or Pain in Children Younger Than 2 Years: A Systematic Review and Meta-analysis". JAMA Netw Open 3 (10): e2022398. October 2020. doi:10.1001/jamanetworkopen.2020.22398. PMID 33125495.
- ↑ 72.0 72.1 "Risk of wheezing and asthma exacerbation in children treated with paracetamol versus ibuprofen: a systematic review and meta-analysis of randomised controlled trials". BMC Pulm Med 20 (1): 72. March 2020. doi:10.1186/s12890-020-1102-5. PMID 32293369.
- ↑ "Paracetamol: new vistas of an old drug". CNS Drug Rev 12 (3–4): 250–75. 2006. doi:10.1111/j.1527-3458.2006.00250.x. PMID 17227290.
- ↑ "2018 update of the EULAR recommendations for the management of hand osteoarthritis". Ann Rheum Dis 78 (1): 16–24. January 2019. doi:10.1136/annrheumdis-2018-213826. PMID 30154087.
- ↑ "An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)". Semin Arthritis Rheum 49 (3): 337–350. December 2019. doi:10.1016/j.semarthrit.2019.04.008. PMID 31126594.
- ↑ "Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults". Cochrane Database Syst Rev 4 (4): CD008040. 2013. doi:10.1002/14651858.CD008040.pub3. PMID 23633349.
- ↑ "Use of a fixed combination of acetylsalicylic acid, acetaminophen and caffeine compared with acetaminophen alone in episodic tension-type headache: meta-analysis of four randomized, double-blind, placebo-controlled, crossover studies". J Headache Pain 15 (1): 76. November 2014. doi:10.1186/1129-2377-15-76. PMID 25406671.
- ↑ "The pharmacological management of dental pain". Expert Opin Pharmacother 21 (5): 591–601. April 2020. doi:10.1080/14656566.2020.1718651. PMID 32027199.
- ↑ "Nonsteroidal Anti-Inflammatory Drugs and Opioids in Postsurgical Dental Pain". J Dent Res 99 (7): 777–786. July 2020. doi:10.1177/0022034520914254. PMID 32286125.
- ↑ "Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain". Cochrane Database Syst Rev 2019 (6): CD010210. June 2013. doi:10.1002/14651858.CD010210.pub2. PMID 23794268.
- ↑ "Analgesic Efficacy of an Acetaminophen/Ibuprofen Fixed-dose Combination in Moderate to Severe Postoperative Dental Pain: A Randomized, Double-blind, Parallel-group, Placebo-controlled Trial". Clin Ther 40 (10): 1765–1776.e5. October 2018. doi:10.1016/j.clinthera.2018.08.019. PMID 30245281.
- ↑ "Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults". Cochrane Database Syst Rev 2009 (1): CD001547. January 2009. doi:10.1002/14651858.CD001547.pub2. PMID 19160199.
- ↑ "A Critical Review on the Relevance of Paracetamol for Procedural Pain Management in Neonates". Front Pediatr 8: 89. 2020. doi:10.3389/fped.2020.00089. PMID 32257982.
- ↑ "Paracetamol (acetaminophen) for prevention or treatment of pain in newborns". The Cochrane Database of Systematic Reviews 1 (1): CD011219. January 2020. doi:10.1002/14651858.CD011219.pub4. PMID 31985830.
- ↑ "Oral non-steroidal anti-inflammatory drugs (single dose) for perineal pain in the early postpartum period". Cochrane Database Syst Rev 1 (1): CD011352. January 2021. doi:10.1002/14651858.CD011352.pub3. PMID 33427305.
- ↑ "The Use of Intravenous Acetaminophen for Acute Pain in the Emergency Department". Academic Emergency Medicine 23 (5): 543–53. May 2016. doi:10.1111/acem.12921. PMID 26824905.
- ↑ "Caffeine as an analgesic adjuvant for acute pain in adults". The Cochrane Database of Systematic Reviews 3 (3): CD009281. March 2012. doi:10.1002/14651858.CD009281.pub2. PMID 22419343.
- ↑ 88.0 88.1 "Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants". The Cochrane Database of Systematic Reviews 2022 (12): CD010061. December 2022. doi:10.1002/14651858.CD010061.pub5. PMID 36519620.
- ↑ "Effects of acetaminophen on risk taking". Social Cognitive and Affective Neuroscience 15 (7): 725–732. September 2020. doi:10.1093/scan/nsaa108. PMID 32888031.
- ↑ 90.0 90.1 "FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen". 1 August 2013. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-rare-serious-skin-reactions-pain-relieverfever-reducer.
This article incorporates text from this source, which is in the public domain.
- ↑ "Is acetaminophen associated with a risk of Stevens-Johnson syndrome and toxic epidermal necrolysis? Analysis of the French Pharmacovigilance Database". Br J Clin Pharmacol 84 (2): 331–338. February 2018. doi:10.1111/bcp.13445. PMID 28963996.
- ↑ "Acetaminophen use and risk of renal impairment: A systematic review and meta-analysis". Kidney Res Clin Pract 39 (1): 81–92. March 2020. doi:10.23876/j.krcp.19.106. PMID 32172553.
- ↑ "The association between paracetamol and asthma is still under debate". The Journal of Asthma 54 (1): 32–8. January 2017. doi:10.1080/02770903.2016.1194431. PMID 27575940.
- ↑ "Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis". Archives of Disease in Childhood 100 (1): 81–9. January 2015. doi:10.1136/archdischild-2012-303043. PMID 25429049. http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-37262-5. Retrieved 28 October 2022.
- ↑ "Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis". Clinical and Experimental Allergy 41 (4): 482–9. April 2011. doi:10.1111/j.1365-2222.2010.03691.x. PMID 21338428.
- ↑ "Prenatal paracetamol use and asthma in childhood: A systematic review and meta-analysis". Allergol Immunopathol (Madr) 45 (6): 528–533. 2017. doi:10.1016/j.aller.2016.10.014. PMID 28237129.
- ↑ "Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies". Am J Epidemiol 187 (8): 1817–1827. August 2018. doi:10.1093/aje/kwy086. PMID 29688261.
- ↑ "Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood". JAMA Psychiatry 77 (2): 180–189. February 2020. doi:10.1001/jamapsychiatry.2019.3259. PMID 31664451.
- ↑ "Acetaminophen Information". 14 November 2017. https://www.fda.gov/drugs/information-drug-class/acetaminophen-information.
This article incorporates text from this source, which is in the public domain.
- ↑ "Using Acetaminophen and Nonsteroidal Anti-inflammatory Drugs Safely". 26 February 2018. https://www.fda.gov/drugs/safe-use-over-counter-pain-relievers-and-fever-reducers/using-acetaminophen-and-nonsteroidal-anti-inflammatory-drugs-safely.
This article incorporates text from this source, which is in the public domain.
- ↑ "Acetaminophen safety and hepatotoxicity--where do we go from here?". Expert Opinion on Drug Safety 6 (4): 341–355. July 2007. doi:10.1517/14740338.6.4.341. PMID 17688378.
- ↑ "Epidemiology of acute liver failure". Curr Gastroenterol Rep 9 (1): 66–73. 2007. doi:10.1007/s11894-008-0023-x. PMID 17335680.
- ↑ "Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure". Hepatology 40 (1): 6–9. 2004. doi:10.1002/hep.20293. PMID 15239078.
- ↑ "Prescription Drug Products Containing Acetaminophen: Actions to Reduce Liver Injury from Unintentional Overdose". US Food and Drug Administration. 14 January 2011. http://www.regulations.gov/#!documentDetail;D=FDA-2011-N-0021-0001.
This article incorporates text from this source, which is in the public domain.
- ↑ "FDA: Acetaminophen doses over 325 mg may lead to liver damage". CNN. 16 January 2014. https://www.cnn.com/2014/01/15/health/fda-acetaminophen-dosage/index.html.
- ↑ 106.0 106.1 "Acetaminophen (APAP) hepatotoxicity—Isn't it time for APAP to go away?". Journal of Hepatology 67 (6): 1324–1331. December 2017. doi:10.1016/j.jhep.2017.07.005. PMID 28734939.
- ↑ "Acetaminophen poisoning and toxicity". Pediatrics 55 (6): 871–876. 1975. doi:10.1542/peds.55.6.871. PMID 1134886.
- ↑ "Paracetamol". University of Oxford Centre for Suicide Research. 25 March 2013. http://cebmh.warne.ox.ac.uk/csr/resparacet.html.
- ↑ 109.0 109.1 109.2 "Metabolism of Paracetamol (Acetaminophen), Acetanilide and Phenacetin". 25 August 2012. https://pharmaxchange.info/2012/08/metabolism-of-paracetamol-acetaminophen-acetanilide-and-phenacetin/.
- ↑ "Highlights of Prescribing Information". Acetadote. http://acetadote.com/Acetadote21-539-12_PI_Clean_June2013.pdf.
- ↑ "Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine". September 2012. pp. A1. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON185624.
- ↑ "Treating paracetamol overdose with intravenous acetylcysteine: new guidance". 11 December 2014. https://www.gov.uk/drug-safety-update/treating-paracetamol-overdose-with-intravenous-acetylcysteine-new-guidance.
- ↑ "Pharmacological modification of gastric emptying: effects of propantheline and metoclopromide on paracetamol absorption". Br Med J 1 (5853): 587–9. March 1973. doi:10.1136/bmj.1.5853.587. PMID 4694406.
- ↑ 114.0 114.1 114.2 114.3 114.4 114.5 "Drug interactions with paracetamol". Am J Ther 12 (1): 56–66. 2005. doi:10.1097/00045391-200501000-00009. PMID 15662293.
- ↑ "Does cytochrome P450 liver isoenzyme induction increase the risk of liver toxicity after paracetamol overdose?". Open Access Emerg Med 3: 69–76. 2011. doi:10.2147/OAEM.S24962. PMID 27147854.
- ↑ "A review of warfarin dosing with concurrent acetaminophen therapy". J Pharm Pract 26 (5): 518–21. October 2013. doi:10.1177/0897190013488802. PMID 23736105.
- ↑ "Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy". Pharmacotherapy 31 (6): 591–7. June 2011. doi:10.1592/phco.31.6.591. PMID 21923443.
- ↑ "Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial". Eur J Clin Pharmacol 67 (3): 309–14. March 2011. doi:10.1007/s00228-010-0975-2. PMID 21191575.
- ↑ 119.0 119.1 119.2 119.3 119.4 119.5 "Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity". Pharmacological Research 109: 119–31. July 2016. doi:10.1016/j.phrs.2016.02.020. PMID 26921661.
- ↑ 120.0 120.1 "The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings". Inflammopharmacology 21 (3): 201–32. June 2013. doi:10.1007/s10787-013-0172-x. PMID 23719833.
- ↑ "First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid". J Pain Res 10: 2703–2709. 2017. doi:10.2147/JPR.S143500. PMID 29238213.
- ↑ "Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action". Front Pharmacol 11: 580289. 2020. doi:10.3389/fphar.2020.580289. PMID 33328986.
- ↑ 123.0 123.1 "TRPV1 mediates the anticonvulsant effects of acetaminophen in mice". Epilepsy Research 145: 153–159. September 2018. doi:10.1016/j.eplepsyres.2018.06.016. PMID 30007240.
- ↑ "The paracetamol metabolite N-acetylp-benzoquinone imine reduces excitability in first- and second-order neurons of the pain pathway through actions on KV7 channels". Pain 160 (4): 954–964. April 2019. doi:10.1097/j.pain.0000000000001474. PMID 30601242.
- ↑ "Kinetics and metabolism of paracetamol and phenacetin". British Journal of Clinical Pharmacology 10 (Suppl 2): 291S–298S. October 1980. doi:10.1111/j.1365-2125.1980.tb01812.x. PMID 7002186.
- ↑ 126.0 126.1 "The modern pharmacology of paracetamol: Therapeutic actions, mechanism of action, metabolism, toxicity, and recent pharmacological findings". Inflammopharmacology 21 (3): 201–232. June 2013. doi:10.1007/s10787-013-0172-x. PMID 23719833.
- ↑ 127.0 127.1 Rosen's Emergency Medicine – Concepts and Clinical Practice. Elsevier Health Sciences. 2013. ISBN 9781455749874.
- ↑ 128.0 128.1 128.2 "Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis". Pharm Res 30 (9): 2174–87. September 2013. doi:10.1007/s11095-013-1007-6. PMID 23462933.
- ↑ 129.0 129.1 "Ullmann's Encyclopedia of Industrial Chemistry". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_269.pub2.
- ↑ "US Patent 2998450". https://patents.google.com/patent/US2998450A/en.
- ↑ "Selective reduction of aromatic nitro compounds with stannous chloride in non acidic and non aqueous medium". Tetrahedron Letters 25 (8): 839–842. January 1984. doi:10.1016/S0040-4039(01)80041-1.
- ↑ Davenport KG, Hilton CB, "Process for producing N-acyl-hydroxy aromatic amines", US patent 4524217, published 18 June 1985, assigned to Celanese Corporation
- ↑ "Indophenol method for acetaminophen in serum examined". Clin. Chem. 30 (6): 884–6. 1984. doi:10.1093/clinchem/30.6.884. PMID 6723045.
- ↑ "Das Antifebrin, ein neues Fiebermittel" (in de). Centralblatt für klinische Medizin 7: 561–4. 1886. https://babel.hathitrust.org/cgi/pt?num=561&u=1&seq=5&view=image&size=100&id=mdp.39015009239362. Retrieved 21 February 2019.
- ↑ 135.0 135.1 135.2 135.3 "Paracetamol: New vistas of an old drug". CNS Drug Reviews 12 (3–4): 250–75. 2006. doi:10.1111/j.1527-3458.2006.00250.x. PMID 17227290.
- ↑ "Ueber eine neue Darstellungsmethode der Acetylamidophenole" (in de). Berichte der deutschen chemischen Gesellschaft 11 (1): 232–233. 1878. doi:10.1002/cber.18780110151. https://zenodo.org/record/1425148. Retrieved 28 December 2023.
- ↑ 137.0 137.1 137.2 137.3 Bad Medicine: The Prescription Drug Industry in the Third World. Stanford University Press. 1992. pp. 88–90. ISBN 978-0804716697. https://archive.org/details/badmedicinepresc0000silv.
- ↑ "Beitrage zur Kenntniss der Antipyretica". Ther Monatsch 7: 577–587. 1893.
- ↑ 139.0 139.1 Drug Discovery: A History. Hoboken, NJ: Wiley. 2005. p. 439. ISBN 978-0471899808. https://books.google.com/books?id=jglFsz5EJR8C&pg=PA439.
- ↑ "The metabolic fate of acetanilid and other aniline derivatives: II. Major metabolites of acetanilid appearing in the blood". J. Pharmacol. Exp. Ther. 90 (1): 68–75. 1947. PMID 20241897. http://jpet.aspetjournals.org/cgi/reprint/90/1/68.
- ↑ "The estimation of acetanilide and its metabolic products, aniline, N-acetyl p-aminophenol and p-aminophenol (free and total conjugated) in biological fluids and tissues". J. Pharmacol. Exp. Ther. 94 (1): 22–28. 1948. PMID 18885610.
- ↑ "The fate of acetanilide in man". J. Pharmacol. Exp. Ther. 94 (1): 29–38. 1948. PMID 18885611. http://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdf.
- ↑ "The effect on the pain threshold of N-acetyl p-aminophenol, a product derived in the body from acetanilide". J. Pharmacol. Exp. Ther. 94 (1): 76–77. 1948. PMID 18885618.
- ↑ "The fate of acetophenetidin in man and methods for the estimation of acetophenetidin and its metabolites in biological material". The Journal of Pharmacology and Experimental Therapeutics 97 (1): 58–67. September 1949. PMID 18140117. https://jpet.aspetjournals.org/content/97/1/58.
- ↑ 145.0 145.1 "Acetaminophen". Ann Intern Med 87 (2): 202–9. August 1977. doi:10.7326/0003-4819-87-2-202. PMID 329728.
- ↑ 146.0 146.1 "The history and usage of paracetamol". J Int Med Res 4 (4 Suppl): 1–6. 1976. doi:10.1177/14732300760040S403. PMID 799998.
- ↑ Pharmaceutical Innovation: Revolutionizing Human Health. Chemical Heritage Foundation. 1999. pp. 248–249. ISBN 978-0-941901-21-5. https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA248.
- ↑ "Our Story". McNEIL-PPC, Inc.. http://www.tylenol.com/news/about-us.
- ↑ "Medication and Drugs". MedicineNet. 1996–2010. http://www.medicinenet.com/acetaminophen/article.htm.
- ↑ "SEC Info – Eastman Kodak Co – '8-K' for 6/30/94". http://www.secinfo.com/dUGc.bs.htm.
- ↑ "FDA May Restrict Acetaminophen". Webmd. 1 July 2009. http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen.
- ↑ "FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings" (Press release). U.S. Food and Drug Administration (FDA). 13 January 2011. Archived from the original on 15 January 2011. Retrieved 13 January 2011.
This article incorporates text from this source, which is in the public domain.
- ↑ 153.0 153.1 "FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver Failure". U.S. Food and Drug Administration (FDA). 13 January 2011. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit.
This article incorporates text from this source, which is in the public domain.
- ↑ "FDA orders lowering pain reliever in Vicodin". The Boston Globe. Associated Press. 13 January 2011. https://www.boston.com/lifestyle/health/articles/2011/01/13/fda_orders_lowering_pain_reliever_in_vicodin/.
- ↑ 155.0 155.1 "F.D.A. Plans New Limits on Prescription Painkillers". The New York Times. 13 January 2011. https://www.nytimes.com/2011/01/14/health/policy/14fda.html.
- ↑ "FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings". U.S. Food and Drug Administration (FDA) (Press release). 15 January 2011. Archived from the original on 15 January 2011. Retrieved 23 February 2014.
This article incorporates text from this source, which is in the public domain.
- ↑ "Liquid paracetamol for children: revised UK dosing instructions introduced". Medicines and Healthcare products Regulatory Agency (MHRA). 14 November 2011. http://www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con134921.pdf.
- ↑ "Use Only as Directed". This American Life. Episode 505. Chicago. 20 September 2013. Public Radio International. WBEZ. Archived from the original on 27 September 2013. Retrieved 24 September 2013.
- ↑ "Use Only as Directed". ProPublica. 20 September 2013. https://www.propublica.org/article/tylenol-mcneil-fda-use-only-as-directed.
- ↑ "Dose of Confusion". ProPublica. 20 September 2013. https://www.propublica.org/article/tylenol-mcneil-fda-kids-dose-of-confusion.
- ↑ "Infodemic and the spread of fake news in the COVID-19-era". European Journal of Emergency Medicine 27 (5): 327–328. October 2020. doi:10.1097/MEJ.0000000000000713. PMID 32332201.
- ↑ "Covid-19: ibuprofen can be used for symptoms, says UK agency, but reasons for change in advice are unclear". BMJ 369: m1555. April 2020. doi:10.1136/bmj.m1555. PMID 32303505.
- ↑ "Ibuprofen use and clinical outcomes in COVID-19 patients". Clinical Microbiology and Infection 26 (9): 1259.e5–1259.e7. September 2020. doi:10.1016/j.cmi.2020.06.003. PMID 32535147.
- ↑ "Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists". BMJ 368: m1086. March 2020. doi:10.1136/bmj.m1086. PMID 32184201.
- ↑ TGA Approved Terminology for Medicines. Therapeutic Goods Administration, Department of Health and Ageing, Australian Government. July 1999. p. 97. http://www.tga.gov.au/pdf/medicines-approved-terminology-chemical.pdf.
- ↑ 166.0 166.1 166.2 166.3 Clinical Pain Management Second Edition: Acute Pain. CRC Press. 26 September 2008. p. 85. ISBN 978-0-340-94009-9. https://books.google.com/books?id=CLcsngfC9gQC&pg=PA85.
- ↑ "International Non-Proprietary Name for Pharmaceutical Preparations (Recommended List #4)". WHO Chronicle 16 (3): 101–111. March 1962. https://www.who.int/medicines/publications/druginformation/innlists/RL04.pdf. Retrieved 21 March 2018.
- ↑ "APAP: An Error-Prone Abbreviation". Pharmacy Times. October 2013 Diabetes 79 (10). 8 October 2013. https://www.pharmacytimes.com/view/apap-an-error-prone-abbreviation. Retrieved 6 June 2021.
- ↑ "Acetaminophen". Physicians' Desk Reference (63rd ed.). Montvale, N.J.: Physicians' Desk Reference. 2009. pp. 1915–1916. ISBN 978-1-56363-703-2. OCLC 276871036.
- ↑ "IV, PO, and PR Acetaminophen: A Quick Comparison". https://www.pharmacytimes.com/contributor/stephanie-nam-pharmd-candidate-2017/2016/08/iv-po-and-pr-acetaminophen-a-quick-comparison.
- ↑ "Acetaminophen and Codeine (Professional Patient Advice)". 29 June 2019. https://www.drugs.com/ppa/acetaminophen-and-codeine.html.
- ↑ "Codeine information hub". 10 April 2018. https://www.tga.gov.au/codeine-info-hub.
- ↑ "Acetaminophen, Caffeine, and Dihydrocodeine (Professional Patient Advice)". 2 October 2019. https://www.drugs.com/ppa/acetaminophen-caffeine-and-dihydrocodeine.html.
- ↑ "Oxycodone and Acetaminophen (Professional Patient Advice)". 11 November 2019. https://www.drugs.com/ppa/oxycodone-and-acetaminophen.html.
- ↑ "Hydrocodone and Acetaminophen (Professional Patient Advice)". 2 January 2020. https://www.drugs.com/ppa/hydrocodone-and-acetaminophen.html.
- ↑ "Propoxyphene and Acetaminophen Tablets". 21 June 2019. https://www.drugs.com/pro/propoxyphene-and-acetaminophen-tablets.html.
- ↑ "APOHealth Paracetamol Plus Codeine & Calmative". 3 February 2020. https://www.drugs.com/international/apohealth-paracetamol-plus-codeine-calmative.html.
- ↑ 178.0 178.1 "Increased Phenylephrine Plasma Levels with Administration of Acetaminophen". New England Journal of Medicine 370 (12): 1171–1172. 2014. doi:10.1056/NEJMc1313942. PMID 24645960.
- ↑ "Ascorbic acid/Phenylephrine/Paracetamol". NHS Choices. National Health Service. http://www.nhs.uk/medicine-guides/pages/selectorshow.aspx?medicine=Ascorbic%20acid/Phenylephrine/Paracetamol.
- ↑ "Phenylephrine/Caffeine/Paracetamol dual relief". NHS Choices. National Health Service. http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?medicine=Phenylephrine/Caffeine/Paracetamol%20dual%20relief.
- ↑ "Beechams Decongestant Plus With Paracetamol". NHS Choices. National Health Service. http://www.nhs.uk/Conditions/Painkillers-paracetamol/Pages/MedicineOverview.aspx?medicine=Beechams%20Decongestant%20Plus%20With%20Paracetamol.
- ↑ "Simultaneous High-Performance Liquid Chromatographic Determination of Paracetamol, Phenylephrine HCl, and Chlorpheniramine Maleate in Pharmaceutical Dosage Forms". Journal of Chromatographic Science 40 (2): 97–100. 2002. doi:10.1093/chromsci/40.2.97. PMID 11881712.
- ↑ "Bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference product". Journal of International Medical Research 42 (2): 347–359. 2014. doi:10.1177/0300060513503762. PMID 24553480.
- ↑ "Paracetamol – phenylephrine hydrochloride – guaifenesin". NPS MedicineWise. National Prescribing Service (Australia). http://www.nps.org.au/medicines/respiratory-system/cough-and-cold-medicines/for-individuals/cough-and-cold-medicines-active-ingredients/paracetamol-phenylephrine-hydrochloride-guaifenesin.
- ↑ "Phenylephrine/Guaifenesin/Paracetamol". NHS Choices. National Health Service. http://www.nhs.uk/Conditions/Flu/Pages/selectorshow.aspx?medicine=Phenylephrine/Guaifenesin/Paracetamol.
- ↑ "The diagnosis of acetaminophen toxicosis in a cat". The Canadian Veterinary Journal 44 (6): 509–10. June 2003. PMID 12839249.
- ↑ 187.0 187.1 187.2 "Management of acetaminophen and ibuprofen toxicoses in dogs and cats". Journal of Veterinary Emergency and Critical Care 10 (4): 285–291. 2000. doi:10.1111/j.1476-4431.2000.tb00013.x. http://www.aspcapro.org/mydocuments/c-veccs_july00.pdf.
- ↑ 188.0 188.1 Small Animal Clinical Pharmacology. Elsevier Health Sciences. 2002. pp. 260–1. ISBN 978-0702025730.
- ↑ 189.0 189.1 189.2 "Pardale-V Oral Tablets". NOAH Compendium of Data Sheets for Animal Medicines. The National Office of Animal Health (NOAH). 11 November 2010. http://www.noahcompendium.co.uk/Dechra_Veterinary_Products/documents/S3428.html.
- ↑ "Ibuprofen, aspirin and acetaminophen toxicosis and treatment in dogs and cats". Veterinary and Human Toxicology 40 (3): 156–62. June 1998. PMID 9610496.
- ↑ "The 10 Most Common Toxicoses in Dogs". Veterinary Medicine: 142–148. March 2006. http://veterinarymedicine.dvm360.com/toxicology-brief-10-most-common-toxicoses-dogs. Retrieved 28 October 2019.
- ↑ "Ibuprofen toxicosis in dogs, cats, and ferrets". Veterinary Medicine: 580–586. 2004. http://veterinarymedicine.dvm360.com/vetmed/Medicine/ArticleStandard/Article/detail/651048.
- ↑ "Phylogenetic origins for severe acetaminophen toxicity in snake species compared to other vertebrate taxa". Comp Biochem Physiol C Toxicol Pharmacol 215: 18–24. 2019. doi:10.1016/j.cbpc.2018.09.003. PMID 30268769. https://tigerprints.clemson.edu/cgi/viewcontent.cgi?article=1115&context=bio_pubs.
- ↑ "Risk assessment of an acetaminophen baiting program for chemical control of brown tree snakes on Guam: evaluation of baits, snake residues, and potential primary and secondary hazards". Environ Sci Technol 36 (17): 3827–3833. 2002. doi:10.1021/es015873n. PMID 12322757. Bibcode: 2002EnST...36.3827J.
- ↑ "Tylenol-loaded mice dropped from air to control snakes". CNN. 7 September 2010. http://news.blogs.cnn.com/2010/09/07/tylenol-loaded-mice-dropped-from-air-to-control-snakes/.
- ↑ "It's Raining Mice". The Scientist. 1 May 2012. https://www.the-scientist.com/notebook/its-raining-mice-41065.
External links
![]() | Original source: https://en.wikipedia.org/wiki/Paracetamol.
Read more |