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CNS Drug Reviews 2006Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs.... (Review)
Review
Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Pain
PubMed: 17227290
DOI: 10.1111/j.1527-3458.2006.00250.x -
Archives de Pediatrie : Organe Officiel... Oct 2015In neonates, paracetamol is mainly used for its analgesic action. This drug is actually preferred by neonatologists because of its broad therapeutic index. Recently, it... (Review)
Review
In neonates, paracetamol is mainly used for its analgesic action. This drug is actually preferred by neonatologists because of its broad therapeutic index. Recently, it has been demonstrated that paracetamol is also an anti-cyclooxygenase (COX) medication through its inhibitory action on the peroxidase arm of central and peripheral COX (Boutaud et al., 2002; Toussaint et al., 2010; Graham et al., 2013; Hinz et al., 2008; Hinz and Brune, 2011). As such, this drug interferes with the synthesis of prostaglandins. This inhibition of peroxidase is, however, limited to a low concentration of arachidonic acid (AA) (around 2μM, in vitro) when the plasmatic concentration of paracetamol is experimentally 10μM, actually within the same range as compared to the therapeutic concentrations in vivo. This may partly explain its low anti-inflammatory effect as compared to ibuprofen and indomethacin, which exert their inhibition on COX whatever the AA concentrations are. This new well-demonstrated action of paracetamol on peripheral COX-2 of intact cells could explain recent observations making this drug a potential alternative in treating patent ductus arteriosus. However, the higher dosages that have been claimed by some authors in this indication still remain to be validated. This inhibition that paracetamol shows on the physiological synthesis of prostaglandins E2 (PGE2) could also explain some long-term immune deviations because the physiological concentration of PGE2 is a well-known actor in the genesis of immune homeostasis in the submucosal area. Indeed, recent epidemiology studies have pointed out immune deviations in children repeatedly exposed to paracetamol earlier in life. Consequently, this is actually the new discovery of an old drug. From these new data on paracetamol, a more focused pharmacovigilance on the long-term effects of paracetamol repeatedly given in the early stage should be urgently initiated.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Cyclooxygenase 2 Inhibitors; Ductus Arteriosus, Patent; Female; Humans; Infant, Newborn; Kidney; Liver; Pregnancy; Prenatal Exposure Delayed Effects; Prostaglandin Antagonists
PubMed: 26299912
DOI: 10.1016/j.arcped.2015.07.003 -
Minerva Anestesiologica Nov 2009Paracetamol is widely used in the management of acute and chronic pain. The purpose of this review is to give anesthesiologists answers to some of the most common... (Review)
Review
Paracetamol is widely used in the management of acute and chronic pain. The purpose of this review is to give anesthesiologists answers to some of the most common questions about paracetamol, specifically the following questions. What is the mechanism of action of paracetamol? Is paracetamol a NSAID? Which endogenous analgesic systems are influenced by paracetamol? Are the perceived concerns about paracetamol use real? What new research is there into paracetamol-induced liver failure? Is paracetamol safe for use by patients with liver disease or those taking anticoagulants? How effective is paracetamol for the management of postoperative pain? Does paracetamol have any opioid-sparing effects? Which formula has the best analgesic efficacy? Which route of administration has the better pharmacokinetic profile? Is the concentration of paracetamol in blood or cerebrospinal fluid relevant to the analgesic effect? Which starting dose should be administrated in intravenous infusion?
Topics: Acetaminophen; Analgesia; Analgesics, Non-Narcotic; Anesthesiology; Humans; Pain, Postoperative
PubMed: 19881460
DOI: No ID Found -
The American Journal of Nursing Feb 2003
Topics: Acetaminophen; Adult; Child; Drug Labeling; Humans; Patient Education as Topic
PubMed: 12582346
DOI: 10.1097/00000446-200302000-00035 -
L'union Medicale Du Canada Jul 1978
Topics: Acetaminophen; Acute Disease; Adolescent; Adult; Clinical Enzyme Tests; Drug Hypersensitivity; Humans; Liver; Male; Suicide, Attempted; Transaminases
PubMed: 664109
DOI: No ID Found -
Journal of Clinical Pharmacy and... Dec 2010Although paracetamol (acetaminophen), N-(4-Hydroxyphenyl)acetamide, is one of the world's most widely used analgesics, the mechanism by which it produces its analgesic... (Review)
Review
WHAT IS KNOWN AND BACKGROUND
Although paracetamol (acetaminophen), N-(4-Hydroxyphenyl)acetamide, is one of the world's most widely used analgesics, the mechanism by which it produces its analgesic effect is largely unknown. This lack is relevant because: (i) optimal pain treatment matches the analgesic mechanism to the (patho)physiology of the pain and (ii) modern drug discovery relies on an appropriate screening assay.
OBJECTIVE
To review the clinical profile and preclinical studies of paracetamol as means of gaining insight into its mechanism of analgesic action.
METHODS
A literature search was conducted of clinical and preclinical literature and the information obtained was organized and reviewed from the perspective of its contribution to an understanding of the mechanism of analgesic action of paracetamol.
RESULTS
Paracetamol's broad spectrum of analgesic and other pharmacological actions is presented, along with its multiple postulated mechanism(s) of action. No one mechanism has been definitively shown to account for its analgesic activity.
WHAT IS NEW AND CONCLUSION
Further research is needed to uncover the mechanism of analgesic action of paracetamol. The lack of this knowledge affects optimal clinical use and impedes drug discovery efforts.
Topics: Acetaminophen; Acetanilides; Analgesia; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Antipyretics; Drug Discovery; Humans; Hyperalgesia; Pain; Pain Measurement
PubMed: 21054454
DOI: 10.1111/j.1365-2710.2009.01143.x -
Environment International Nov 2023Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study...
Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.
Topics: Humans; Acetaminophen; Biological Monitoring; Mass Spectrometry; Liver; Biomarkers; Sulfates
PubMed: 37951015
DOI: 10.1016/j.envint.2023.108299 -
Pediatric Pharmacology (New York, N.Y.) 1983Acetaminophen (paracetamol, APAP) is one of the safest and most widely used analgesic-antipyretics in children. When compared to other analgesic-antipyretics,...
Acetaminophen (paracetamol, APAP) is one of the safest and most widely used analgesic-antipyretics in children. When compared to other analgesic-antipyretics, acetaminophen has been shown in many clinical studies to have equivalent efficacy. Based on available clinical and pharmacokinetic data, acetaminophen should be dosed with single doses in the range of 10-15 mg/kg at 4-hour intervals. However, many dosing schedules recommend inadequate amounts of acetaminophen. Dosing schedules based on weight can be constructed that will accurately keep each dose within the recommended range. Dosing also can be adapted to an age-based schedule, which will provide consistent dosing from infancy to adolescence. The principles used to derive the age-based dosing schedule have potential application for use with other pharmacologic agents, particularly nonprescription drugs.
Topics: Acetaminophen; Age Factors; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Fever; Humans; Infant; Kinetics
PubMed: 6677877
DOI: No ID Found -
Current Drug Targets. Cardiovascular &... Oct 2005For over 50 years, acetaminophen (paracetamol) has been a staple in industrialized and non-industrialized countries for the treatment of pain and fever. Although its... (Review)
Review
For over 50 years, acetaminophen (paracetamol) has been a staple in industrialized and non-industrialized countries for the treatment of pain and fever. Although its precise mechanisms of action are not known, the drug generates dose-dependent reduction in circulating prostaglandins, inhibits myeloperoxidase and the oxidation of lipoproteins, and appears to confer cardioprotection by blocking the effects of hydroxyl radical, peroxynitrite, and hydrogen peroxide. The drug might inhibit cyclooxygenase, although its ultimate target(s) is (are) still unclear. Sadly, since most investigations of acetaminophen have focused on its analgesic/antipyretic properties and hepatotoxicity, the effects of the drug on other mammalian organ systems, including the heart and circulation, have been ignored. Recently, work in our laboratory has shown acetaminophen to have a protective role in the injured mammalian myocardium. The cardioprotection was first observed in isolated, perfused guinea pig hearts subjected to ischemia-reperfusion injury. Hearts pretreated with acetaminophen recovered greater ventricular function and exhibited improved myofibrillar ultrastructure when compared to vehicle-treated hearts. More recent in vitro investigations have suggested protective roles for acetaminophen in barbiturate-induced arrhythmogenesis and myocardial hypoxia-reoxygenation injury. We have also extended our work to the in vivo arena. There, we found that acetaminophen reduced infarct size in dogs exposed to 60 minutes regional myocardial ischemia and 180 minutes reperfusion. We invite and encourage readers of this review to repeat/duplicate our experiments. Such work is needed to either challenge or support our findings. Further, more clinically-relevant work depends on these basic and related translational experiments.
Topics: Acetaminophen; Animals; Cardiotonic Agents; Humans; Myocardial Ischemia; Myocardium
PubMed: 16248834
DOI: 10.2174/156800605774370335 -
FASEB Journal : Official Publication of... Feb 2008For more than three decades, acetaminophen (INN, paracetamol) has been claimed to be devoid of significant inhibition of peripheral prostanoids. Meanwhile, attempts to...
For more than three decades, acetaminophen (INN, paracetamol) has been claimed to be devoid of significant inhibition of peripheral prostanoids. Meanwhile, attempts to explain its action by inhibition of a central cyclooxygenase (COX)-3 have been rejected. The fact that acetaminophen acts functionally as a selective COX-2 inhibitor led us to investigate the hypothesis of whether it works via preferential COX-2 blockade. Ex vivo COX inhibition and pharmacokinetics of acetaminophen were assessed in 5 volunteers receiving single 1000 mg doses orally. Coagulation-induced thromboxane B(2) and lipopolysaccharide-induced prostaglandin E(2) were measured ex vivo and in vitro in human whole blood as indices of COX-1 and COX-2 activity. In vitro, acetaminophen elicited a 4.4-fold selectivity toward COX-2 inhibition (IC(50)=113.7 micromol/L for COX-1; IC(50)=25.8 micromol/L for COX-2). Following oral administration of the drug, maximal ex vivo inhibitions were 56% (COX-1) and 83% (COX-2). Acetaminophen plasma concentrations remained above the in vitro IC(50) for COX-2 for at least 5 h postadministration. Ex vivo IC(50) values (COX-1: 105.2 micromol/L; COX-2: 26.3 micromol/L) of acetaminophen compared favorably with its in vitro IC(50) values. In contrast to previous concepts, acetaminophen inhibited COX-2 by more than 80%, i.e., to a degree comparable to nonsteroidal antiinflammatory drugs (NSAIDs) and selective COX-2 inhibitors. However, a >95% COX-1 blockade relevant for suppression of platelet function was not achieved. Our data may explain acetaminophen's analgesic and antiinflammatory action as well as its superior overall gastrointestinal safety profile compared with NSAIDs. In view of its substantial COX-2 inhibition, recently defined cardiovascular warnings for use of COX-2 inhibitors should also be considered for acetaminophen.
Topics: Acetaminophen; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Humans; Isoenzymes; Monocytes; Time Factors
PubMed: 17884974
DOI: 10.1096/fj.07-8506com