Metamizole

Metamizole, with its analgesic (pain relief), antipyretic (fever reduction), and spasmolytic (relax muscle contractions) properties, is utilized in the management of acute pain, fever, and pain caused by muscle spasms. It is primarily used for perioperative pain, acute injury, colic, cancer pain, other acute/chronic forms of pain and high fever unresponsive to other agents. Special populations Its use in pregnancy is advised against, although animal studies are reassuring in that they show minimal risk of birth defects. Its use in the elderly and those with liver or kidney impairment is advised against, but if these groups of people must be treated, a lower dose and caution is usually advised. Its use during lactation is advised against, as it is excreted in breast milk. ==Adverse effects==

While metamizole is a relatively safe medication, Metamizole has a potential of blood-related toxicity (blood dyscrasias), but causes less kidney, cardiovascular, and gastrointestinal toxicity than non-steroidal anti-inflammatory drugs (NSAIDs). Serious side effects include agranulocytosis, aplastic anaemia, hypersensitivity reactions (like anaphylaxis and bronchospasm), toxic epidermal necrolysis and it may provoke acute attacks of porphyria, as it is chemically related to the sulfonamides. Genetics may play a significant role in metamizole sensitivity. It is suggested that some populations are more prone to suffer from metamizole induced agranulocytosis than others. As an example, metamizole-related agranulocytosis seems to be an adverse effect more frequent in British population as opposed to Spaniards. An assessment report by the European Medicines Agency remarked that "the potential to induce agranulocytosis may be associated with genetic characteristics of the population studied". A 2015 meta-analysis concluded that on the evidence available "for short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics", but that the "results were limited by the mediocre overall quality of the reports" analysed. A systematic review from 2016 found that metamizole significantly increased the relative risk of upper gastrointestinal bleeding, by a factor of times; however, none of the studies included in that review accounted for duration of therapy or dose. A study by one of the manufacturers of the drug found the risk of agranulocytosis within the first week of treatment to be a in a million, versus in a million for diclofenac. Therapeutic effect of metamizole on intestinal colic is attributed to its analgesic properties, with no evidence of interference in small bowel or colon motility. Contraindications Previous hypersensitivity (such as agranulocytosis or anaphylaxis) to metamizole or any of the excipients (e.g. lactose) in the preparation used, acute porphyria, impaired haematopoiesis (such as due to treatment with chemotherapy agents), third trimester of pregnancy (potential for adverse effects in the newborn), lactation, children with a body weight below 16 kg, history of aspirin-induced asthma and other hypersensitivity reactions to analgesics. == Interactions ==

A clinically severe interaction has been identified between aspirin and metamizole for patients who regularly take aspirin to manage vascular disease: this interaction occurs due to steric hindrance at the active aspirin binding site of COX-1 by metamizole; to manage this interaction, it is recommended to make a delay between the intake of each of these drugs, with aspirin being taken at least 30 minutes before metamizole. Oral anticoagulants (blood thinners), lithium, captopril, triamterene and antihypertensives may also interact with metamizole, as other pyrazolones are known to interact adversely with these substances. Overdose It is considered fairly safe on overdose, but in these cases supportive measures are usually advised as well as measures to limit absorption (such as activated charcoal) and accelerate excretion (such as haemodialysis). ==Physicochemistry==

Metamizole is a sulfonic acid and comes in calcium, sodium and magnesium salt forms. ==Pharmacology==

The precise mechanism of action of metamizole is unknown, although it is believed that metamizole generally exerts its action by inhibiting the COX-3 enzyme which is responsible for the biosynthesis of prostaglandins in the central nervous system (CNS)—in the brain and spinal cord. Prostaglandins are lipid compounds that play a role in inflammation, pain, and fever. By inhibiting the COX-3 enzyme in the CNS, metamizole reduces the production of prostaglandins, thereby alleviating pain, reducing fever, and potentially lessening inflammation. The inhibition of COX-1 and COX-2 by metamizole is less potent than the inhibition of these enzymes by traditional NSAIDs. Metamizole is metabolized in the liver, where it is converted into active metabolites through the process of N-demethylation. The mechanism of action of metamizole is believed to be exerted via its active metabolites, specifically, arachidonoyl-4-methylaminoantipyrine (ARA-4-MAA) and arachidonoyl-4-aminoantipyrine (ARA-4-AA). This mechanism of action has been compared to paracetamol and its active arachidonic acid metabolite AM404. The CB1 receptor inverse agonist AM-251 was able to reduce the cataleptic response and thermal analgesia of metamizole. Another study found its antihyperalgesic effect reversed by the CB2 inverse agonist AM-630 Although it seems to inhibit fevers caused by prostaglandins, especially prostaglandin E2, metamizole appears to produce its therapeutic effects by means of its metabolites, especially N-methyl-4-aminoantipyrine (MAA) and 4-aminoantipyrine (AA) which form through the FAAH enzyme to create arachidonoyl-4-methylaminoantipyrine (ARA-4-MAA) and arachidonoyl-4-aminoantipyrine (ARA-4-AA). Metamizole likely induces the CYP2B6 and CYP3A4 enzymes. ==History==

Ludwig Knorr was a student of Emil Fischer, who won the Nobel Prize for his work on purines and sugars, which included the discovery of phenylhydrazine. In the 1880s, Knorr was trying to make quinine derivatives from phenylhydrazine, and instead made a pyrazole derivative, which after a methylation, he made into phenazone, also called antipyrine, which has been called "the 'mother' of all modern antipyretic analgesics." Sales of that drug exploded, and in the 1890s chemists at Teerfarbenfabrik Meister, Lucius & Co. (a precursor of Hoechst AG which is now Sanofi), made another derivative called pyramidon which was three times more active than antipyrine. finally in 1920, metamizole was synthesized. Metamizole is a methyl derivative of melubrine and is also a more soluble prodrug of pyramidon. Metamizole was first marketed in Germany as "Novalgin" in 1922. ==Society and culture==

Legal status Metamizole is banned in several countries, available by prescription in others (sometimes with strong warnings, sometimes without), and available over the counter in yet others. For example, approval was withdrawn in Sweden (1974), the US (1977), and India (2013, ban lifted in 2014). Although metamizole is banned in the US because of its risk of agranulocytosis, it was reported by small surveys that 28% of Hispanics in Miami have possession of it, and 38% of Hispanics in San Diego reported some usage. There were unauthorized sales and use of metamizole in horses in the US. After reviewing trial data on its safety, the FDA approved it for treating fever in equines. A 2019 Israeli conference also justified the approved status as a preventive to opioid dependence, and metamizole being safer than most analgesics for renally-impaired patients. Metamizole is the most sold medication in São Paulo, Brazil, accounting for 488 tons in 2016. Given this contrasting consumption compared to other countries, the Brazilian Health Regulatory Agency (ANVISA) convened an international panel for evaluating its safety in 2001, and the conclusion was that the benefits substantially outweighed the risks, and imposing restrictions would lead to significant negative consequences to the population. The Bulgarian pharmaceutical Sopharma produces it under the brand Analgin, which as of 2014, has been the top-selling analgesic in Bulgaria for over a decade. In Germany, the drug is the most commonly prescribed pain reliever. In 2018, investigators in Spain looked into Nolotil (as metamizole is marketed in Spain) after the death of several British people in Spain. A possible factor in these deaths might have been a side effect of metamizole that can cause agranulocytosis (a lowering of white blood cell count). Brand names Metamizole is the international nonproprietary name, and in countries where it is marketed, it is available under many brand names. In Romania metamizole is available as the original marketed pharmaceutical product by Zentiva as Algocalmin, as 500 mg immediate release tablets. It's also available as an injection with 1 g of metamizole sodium dissolved in 2 ml of solvent. In Israel it is sold under the brand name "Optalgin" (), manufactured by Teva. In Czechia it is available under the brand name "Algifen Neo" in the form of drops containing 500 mg/ml of Metamizole and 5 mg/ml of Pitofenone, manufactured by Teva. It is known as Sulpyrin and Sulpyrine in South Korea () and Japan. () In Brazil, it is popularly known as "dipirona". It can be found under the brand names Novalgina, Dorflex, Neosaldina, Lisador Dip, Benegrip, among others. No prescription is required for consumption. Analgin Analgin () is a generic name used in the former USSR pharmacopeia, continuing in use in Slavic nations. A firm in Russia tried unsuccessfully in 2011 to claim the name as their trademark. In Bulgaria, Sopharma succeeded in registering Analgin as a trademark in 2004. Analgin is also the common term used in the Indian pharmacopeia. == See also ==