Indometacin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H300：Lebensgefahr bei Verschlucken.

• Sicherheit

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P301+P310：BEI VERSCHLUCKEN: Sofort GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

Indometacin Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R28:Sehr giftig beim Verschlucken.
  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S28:Bei Berührung mit der Haut sofort abwaschen mit viel . . . (vom Hersteller anzugeben).
  S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
  S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.

• Beschreibung

  Aqueous solutions of indomethacin are not stable because of the ease of hydrolysis of the p-chlorobenzoyl group. The original synthesis of indomethacin by Shen et al. involved the formation of 2-methyl-5-methoxyindole acetic acid and subsequent acylation after protection of the carboxyl group as the t-butyl ester. It was introduced in the United States in 1965. It is still one of the most potent NSAIDs in use. It also is a more potent antipyretic than either aspirin or acetaminophen, and it possesses approximately 10 times the analgetic potency of aspirin.

• Chemische Eigenschaften

  Crystalline Solid

• Originator

  Indocin,MSD,US,1965

• Verwenden

  Indomethacin is used in rheumatoid arthritis, nonspecific infectious polyarthritis, gouty arthritis, osteoarthritis, ankylosing spondylitis, arthrosis, back pain, neuralgia, myalgia, and other diseases accompanied by inflammation.

• Verwenden

  antiinflammatory, antipyretic, analgesic

• Verwenden

  Inhibits cyclooxygenase (IC50=0.1uM) selectively over liposygenases (IC50=100uM for 5-,12- and 15-LO). A clinically useful NAISD

• synthetische

  acylation of sodium 2-(4- methoxyphenyl)hydrazine-1-sulfonate with 4-chlorobenzoyl chloride followed by heating yields 1-(4- chlorobenzoyl)-1-(4- methoxyphenyl)hydrazine. Condensation with levulinic acid in a Fischer indole synthesis affords indomethacin.
  

• Definition

  The antiinflammatory drug indomethacin.

• Indications

  Indomethacin (Indocin) is used in the treatment of acute gouty arthritis, rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. It is not recommended for use as a simple analgesic or antipyretic because of its potential for toxicity.While indomethacin inhibits both COX-1 and COX-2, it is moderately selective for COX- 1. It produces more CNS side effects than most of the other NSAIDs. Severe headache occurs in 25 to 50% of patients; vertigo, confusion, and psychological disturbances occur with some regularity. GI symptoms also are more frequent and severe than with most other NSAIDs. Hematopoietic side effects (e.g., leukopenia, hemolytic anemia, aplastic anemia, purpura, thrombocytopenia, and agranulocytosis) also may occur. Ocular effects (blurred vision, corneal deposits) have been observed in patients receiving indomethacin, and regular ophthalmological examinations are necessary when the drug is used for long periods. Hepatitis, jaundice, pancreatitis, and hypersensitivity reactions also have been noted.

• Manufacturing Process

  (A) 2-Methyl-5-Merhoxy-3-Indolylacetic Anhydride: Dicyclohexylcarbodiimide (10 g, 0.049 mol) is dissolved in a solution of 2-methyl-5-methoxy-3-indolylacetic acid (22 g, 0.10 mol) in 200 ml of THF, and the solution is allowed to stand at room temperature for 2 hours. The precipitated urea is removed by filtration, and the filtrate is evaporated in vacuo to a residue and flushed with Skellysolve 6. The residual oily anhydride is used without purification in the next step.
  (B) t-Butyl 2-Methyl-5-Merhoxy-3-Indolylacetate: t-Butyl alcohol (25 ml) and fused zinc chloride (0.3 g) are added to the anhydride from Part A. The solution is refluxed for 16 hours and excess alcohol is removed in vacuo. The residue is dissolved in ether, washed several times with saturated bicarbonate, water, and saturated salt solution. After drying over magnesium sulfate, the solution is treated with charcoal, evaporated, and flushed several times with Skellysolve B for complete removal of alcohol. The residual oily ester (18 g, 93%) is used without purification.
  (C) t-Buryl 1-p-Chlorobenzoyl-2-Methyl-5-Mefhoxy-3-Indolylacetate: A stirred solution of ester (18 g, 0.065 mol) in dry DMF (450 ml) is cooled to 4°C in an ice bath, and sodium hydride (4.9 g, 0.098 mol, 50% susp.) is added in portions. After 15 minutes, p-chlorobenzoyl chloride (15 g, 0.085 mol) is added dropwise during 10 minutes, and the mixture is stirred for 9 hours without replenishing the ice bath. The mixture is then poured into one liter of 5% acetic acid, extracted with a mixture of ether and benzene, washed thoroughly with water, bicarbonate, saturated salt, dried over magnesium sulfate, treated with charcoal, and evaporated to a residue which partly crystallizes. This is shaken with ether, filtered and the filtrate is evaporated to a residue (17 g) which solidifies after being refrigerated overnight.
  The crude product is boiled with 300 ml of Skellysolve 6, cooled to room temperature, decanted from some gummy material, treated with charcoal, concentrated to 100 ml, and allowed to crystallize. The product thus obtained (10 g) is recrystallized from 50 ml of methanol and gives 4.5 g of analytically pure material, MP 103° to 104°C.
  (D) 1 -p-Chlorobenzoyl-2-Methyl-5-Methoxy-3-Indolylacetic Acid: A mixture of 1 g ester and 0.1 g powdered porous plate is heated in an oil bath at 210°C with magnetic stirring under a blanket of nitrogen for about 2 hours. No intensification of color (pale yellow) occurs during this period. After cooling under nitrogen, the product is dissolved in benzene and ether, filtered, and extracted with bicarbonate. The aqueous solution is filtered with suction to remove ether, neutralized with acetic acid, and then acidified weakly with dilute hydrochloric acid. The crude product (0.4 g, 47%) is recrystallized from aqueous ethanol and dried in vacuo at 65°C: MP 151°C.

• Trademarks

  Amuno (MSD Sharp & Dohme, Germany), Arthrexin (Lennon Generics, South Africa), Confortid (Dumex, Denmark, Sweden, Finland), Doctucid (Coctum, Greece), Dynamectin (Dynamed, South Africa), Flexidin (Mundipharma, Austria), Inacid (Merck Sharp & Dohme, Spain), Indobene (Merckle, Austria, CIS), Indocin (Merck, USA), Reumadolor (Bros, Greece), Zoflam (Norpharma, Denmark).

• Therapeutic Function

  Antiinflammatory

• Weltgesundheitsorganisation (WHO)

  Indometacin was introduced in 1963 and it is one of the first NSAIDs. Convulsions are rarely reported in relation with the use of this group of agents. Indometacin farnesil is a pro-drug of indometacin, and the occurrence of gastro-intestinal adverse effects could be expected. See also under nonsteroidal antiinflammatory agents.

• Biologische Funktion

  Indomethacin (Indocin) is an acetic acid derivative related functionally to sulindac (Clinoril), a prodrug with a long half-life, and etodolac (Lodine).They are metabolized in the liver and excreted as metabolites in the bile and via the kidney. They are potent inhibitors of COX and thus extremely effective antiinflammatory agents.

• Allgemeine Beschreibung

  From the time of its introduction in 1965, indomethacin(Indocin) has been widely used as an analgesic to relieve inflammatorypain associated with RA, OA and ankylosingspondylitis, and, to a lesser extent, in gout. Although both itsanalgesic and anti-inflammatory activities are well established,its use is often limited because of frequent GI distressand potential drug interactions, especially with warfarinfurosemide, and lithium (i.e., it elevates blood levels oflithium as a result of reducing renal blood flow and thereforeincreases lithium toxicities).
  Following oral administration, indomethacin is rapidlyabsorbed and is 90% protein bound at therapeutic plasmaconcentrations. The drug has a biological half-life ofabout 5 to 10 hours and a plasma clearance of 1 to 2.5 ml/kgper minute. It is metabolized to its inactive, O-desmethyl,N-deschlorobenzoyl-, and O-desmethyl, N-deschlorobenzoylindomethacinmetabolites.

• Allgemeine Beschreibung

  Crystals.

• Air & Water Reaktionen

  Practically insoluble in water. Decomposes in alkali.

• Reaktivität anzeigen

  A weak organic acid.

• Brandgefahr

  Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidizers and may ignite combustibles (wood, paper, oil, clothing, etc.). Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated.

• Pharmazeutische Anwendungen

  Indomethacinis a nonsteroidal anti-inflammatory agent used in pain and moderate to severe inflammation in rheumatic diseases and other musculoskeletal disorders. It is a COX (cyclooxygenase) inhibitor and therefore interrupts the production of prostaglandins.

• Pharmazeutische Anwendungen

  Indomethacin is a nonsteroidal anti-inflammatory agent used in pain and moderate to severe inflammation in rheumatic diseases and other musculoskeletal disorders. It is a COX (cyclooxygenase) inhibitor and therefore interrupts the production of prostaglandins.
  A series of new silicon compounds, based on the structure of indomethacin, have been synthesised and are under investigation as novel anticancer agents. The carboxyl group of indomethacin was reacted with a series of amino-functionalised silanes. The resulting products have been shown to be significantly more lipophilic and more selective to COX-2. Furthermore, in vitro testing has shown an increased uptake of the new compounds at the tumour site. The silane-functionalised indomethacin derivatives exhibited a 15-fold increased antiproliferative effect when tested against pancreatic cancer .

• Biologische Aktivität

  Cyclooxgenase (COX) inhibitor; displays selectivity for COX-1 (IC 50 values are 230 and 630 nM for human COX-1 and COX-2 respectively). Widely used anti-inflammatory agent.

• Biochem/physiol Actions

  Cyclooxygenase (COX) inhibitor that is relatively selective for COX-1.

• Clinical Use

  Indomethacin is available for the short-term treatment of acute gouty arthritis, acute pain of ankylosing spondylitis, and osteoarthritis. An injectable form to be reconstituted also is available as the sodium trihydrate salt for IV use in premature infants with patent ductus arteriosus. Because of its ability to suppress uterine activity by inhibiting prostaglandin biosynthesis, indomethacin also has an unlabeled use to prevent premature labor.

• Nebenwirkungen

  All of these drugs produce analgesic effects, antipyresis, and antiinflammatory effects.Due to the high incidence of gastric irritation, headache, nausea, and other side effects, including hematological effects and coronary vasoconstriction, they are not useful as an initial treatment for pain. GI irritation and ulceration occur to a lesser extent with etodolac. Indomethacin is useful in the treatment of acute gout, osteoarthritis, ankylosing spondylitis, and acceleration of the closure of the ductus arteriosus in premature infants. The tocolytic effects of indomethacin to prevent preterm labor are the result of its effects on prostaglandin synthesis. However, the toxicity of the drug limits such application, since it increases fetal morbidity. Indomethacin is contraindicated in pregnancy, in asthmatics, and in those with gastric ulcers or other ulceration of the GI tract. Indomethacin may increase the symptoms associated with depression or other psychiatric disturbances and those associated with epilepsy and Parkinson’s disease. The drug should be used with caution in such patients.

• Synthese

  Indomethacin, 1-(n-chlorobenzoyl)-5-methoxy-2-methylindol-3-acetic acid (3.2.51), has been synthesized by various methods. All of the proposed methods of synthesis start with 4-methoxyphenylhydrazine. According to the first method, a reaction is done to make indole from phenylhydrazone (3.2.46) by Fischer?ˉs method, using levulinic acid methyl ester as a carbonyl component, hydrogen chloride as a catalyst, and ethanol as a solvent, to give the methyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.47). This product is hydrolyzed by an alkali into 5-methoxy-2-methyl-3-indolylacetic acid (3.2.48), from which tert-butyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.49) is formed by using tert-butyl alcohol and zinc chloride in the presence of dicyclohexylcarbodiimide. The resulting product undergoes acylation at the indole nitrogen atom by p-chorobenzoyl chloride in dimethylformamide, using sodium hydride as a base. The resulting tert-butyl ester of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid (3.2.50), further undergoes thermal decomposition to the desired acid, indomethacin (3.2.51) [111,112].

  

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemia.
  Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with ketorolac (increased risk of side effects and haemorrhage).
  Antibacterials: possibly increased risk of convulsions with quinolones.
  Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparins, dabigatran and edoxaban - avoid long term use with edoxaban.
  Antidepressants: increased risk of bleeding with SSRIs and venlaflaxine.
  Antidiabetic agents: effects of sulphonylureas enhanced.
  Antiepileptics: effects of phenytoin enhanced.
  Antipsychotics: possible severe drowsiness with haloperidol.
  Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir.
  Ciclosporin: increased risk of nephrotoxicity.
  Cytotoxics: reduced excretion of methotrexate.
  Diuretics: increased risk of nephrotoxicity, hyperkalaemia with potassium-sparing diuretics; antagonism of diuretic effect
  . Lithium: lithium excretion reduced.
  Pentoxifylline: possibly increased risk of bleeding.
  Probenecid: excretion of indometacin reduced.
  Tacrolimus: increased risk of nephrotoxicity.

• Stoffwechsel

  Indometacin is metabolised in the liver primarily by demethylation and deacetylation; it also undergoes glucuronidation and enterohepatic circulation. Indometacin is mainly excreted in the urine, approximately 60%, the pH of the urine can affect this amount. Lesser amounts are excreted in the faeces.

• Lager

  Room temperature

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