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Indometacin
53-86-1 · INDOMETHACIN · INDOMETHACINE · 2-(1-(4-chlorobenzoyl)-5-Methoxy-2-Methyl-1H-indol-3-yl)acetic acid · ndomethacin · INDOMETACINE · INDOCIN · Catlep
Identifikatoren & physikalische Daten
| CAS No. | 53-86-1 |
|---|---|
| Summenformel | C19H16ClNO4 |
| Durchschnittliche Molmasse | 357,8 g/mol |
| Monoisotopische Masse | 357,0767857 g/mol |
| SMILES | COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1 |
| InChIKey | CGIGDMFJXJATDK-UHFFFAOYSA-N |
| PubChem CID | 3715 |
| ChEMBL | CHEMBL6 |
| ChEBI | CHEBI:49662 |
| EC No. | 200-186-5 |
| DTXSID | DTXSID9020740 |
| Lokaler Name | Indometacin |
Chemische & physikalische Eigenschaften
| XLogP | 4,3 |
|---|---|
| Polarare Oberfläche (TPSA) | 68,5 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 4 |
| Frei drehbare Bindungen | 4 |
| Schwere Atome | 25 |
| Formalladung | 0 |
| Komplexität | 506 |
| LogP (Verteilungskoeffizient) | 4.27log Kow = 0.91 at pH 7.44.27 at pH 2.03.4 |
| LogS | -4.62 |
| Geruch | Odorless, or has slight odor |
| Geschmack | Slight, bitter |
| Color/Form | Pale-yellow to yellow-tan, crystalline powderCrystals exhibit polymorphism |
| Löslichkeit | 0.937In water, 0.937 mg/L at 25 °CSoluble in ethanol, ether, acetone, castor oilpractically insoluble in water1 g in about 30 mL chloroform2.40e-03 g/Lethanol: 50 mg/mL, clear, yellow-greenSoluble in acetone (40 mg/mL - clear, yellow solution), ethanol (20 mg/mL), ether, castor oilSoluble in chloroform (50 mg/mL - clear, yellow, extremely viscous solution)decomposed by strong alkali but stable in neutral or slightly acidic mediainsoluble in water. |
| Schmelzpunkt | 311 or 323.6 °F (NTP, 1992)151One form of polymorphic crystals melts at about 155 °C, the other at about 162 °CMP: 160 °C158 °C158-162 °C |
| Caco2 Permeability | -4.69 |
| Physical Description | Crystals. (NTP, 1992)Solid |
| Stability/Shelf Life | Light. Stable under recommended storage conditions.SENSITIVE TO LIGHTStable in neutral or slightly acidic media, decomp by strong alkali.STABLE IN AIR AND IN HEAT UNDER USUAL PREVAILING TEMP CONDITIONSCOMPRESSED TABLETS HARDEN ON STORAGE |
| Dissociation Constants | 4.424.5pKa = 4.50 |
| Kovats Retention Index | 26802685 |
| Siedepunkt | 499.4±45.0 °C(Predicted) |
| Dichte | 1.2135 (rough estimate) |
| Brechungsindex | 1.6800 (estimate) |
| Lagerbedingungen | Store at RT |
| pKa (Säurekonstante) | 4.5(at 25℃) |
| Aggregatzustand | White to off-white powder |
| Farbe | White to Light yellow to Light orange |
| Biologische Quelle | synthetic |
| Merck | 14,4968 |
| BRN | 497341 |
| BCS Class | 2 |
| Stabilität | Stable. Incompatible with strong oxidizing agents. |
| InChI | 1S/C19H16ClNO4/c1-11-15(10-18(22)23)16-9-14(25-2)7-8-17(16)21(11)19(24)12-3-5-13(20)6-4-12/h3-9H,10H2,1-2H3,(H,22,23) |
| InChIKey | CGIGDMFJXJATDK-UHFFFAOYSA-N |
| SMILES | COc1ccc2n(c(C)c(CC(O)=O)c2c1)C(=O)c3ccc(Cl)cc3 |
| CAS Datenbank | 53-86-1(CAS DataBase Reference) |
| NIST chemische Informationen | Indomethacin(53-86-1) |
| EPA chemische Informationen | Indomethacin (53-86-1) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH300 (81%): Fatal if swallowed [Danger Acute toxicity, oral]H301 (19%): Toxic if swallowed [Danger Acute toxicity, oral]H317 (24.9%): May cause an allergic skin reaction [Warning Sensitization, Skin]H318 (18.5%): Causes serious eye damage [Danger Serious eye damage/eye irritation]H335 (18.5%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposureRespiratory tract irritation]H336 (18.5%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposureNarcotic effects]H360 (25.4%): May damage fertility or the unborn child [Danger Reproductive toxicity]H373 (19%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]H413 (19%): May cause long lasting harmful effects to aquatic life [Hazardous to the aquatic environment, long-term hazard]P203, P260, P261, P264, P264+P265, P270, P271, P272, P273, P280, P301+P316, P302+P352, P304+P340, P305+P354+P338, P317, P318, P319, P321, P330, P333+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 189 reports by companies from 24 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website. |
|---|---|
| Regulatorische Informationen | Status: Active Update: 28-03-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/12427Indomethacin: Does not have an individual approval but may be used under an appropriate group standard |
| Weitere Sicherheitsinformationen | IMAP assessments - 1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-: Environment tier I assessmentIMAP assessments - 1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-: Human health tier I assessment |
| DOT-Kennzeichnung | Poison |
| Brandgefahren | Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: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.). Corrosives in contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. For electric vehicles or equipment, ERG Guide 147 (lithium ion or sodium ion batteries) or ERG Guide 138 (sodium batteries) should also be consulted. (ERG, 2024) |
| Gesundheitsgefahren | SYMPTOMS: May cause gastrointestinal discomfort and possibly ulcerations. May aggravate psychiatric disturbances, epilepsy, and parkinsonism. May cause drowsiness and headache.ACUTE/CHRONIC HAZARDS: Very toxic. Hazardous decomposition products. May aggravate central nervous system disorders. Suspected teratogen. (NTP, 1992) |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including indomethacin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including indomethacin sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Indomethacin/ |
| Reaktive Gruppe | Acids, CarboxylicAmides and ImidesHydrocarbons, AromaticAryl Halides |
| Special Reports | REVIEW WITH 144 REFERENCES DISCUSSING GI EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY AGENTS COMPARED WITH THOSE OF ASPIRIN, INDOMETHACIN & PHENYLBUTAZONE.[PEMBERTON RE, STRAND LJREVIEW OF THE UPPER GASTROINTESTINAL EFFECTS OF THE NEWER NONSTEROIDAL ANTI-INFLAMMATORY AGENTSDIG DIS 24 (JAN): 53 (1979)]Lione A, Scialli ARReprod Toxicol 9 (1): 7-20 (1995). The developmental toxicity of indomethacin and sulindac. |
| Reactivity Profile | A weak organic acid. |
| Air and Water Reactions | Practically insoluble in water. Decomposes in alkali. |
| Toxic Combustion Products | Special hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx), Hydrogen chloride gas |
| Hazard Classes and Categories | Acute Tox. 2 (81%)Acute Tox. 3 (19%)Skin Sens. 1 (24.9%)Eye Dam. 1 (18.5%)STOT SE 3 (18.5%)Repr. 1A (25.4%)STOT RE 2 (19%)Aquatic Chronic 4 (19%) |
| Brandbekämpfung | This compound is not very flammable but any fire involving this compound may produce dangerous vapors. You should evacuate the area. All firefighters should wear full-body protective clothing and use self-contained breathing apparatuses. You should extinguish any fires involving this chemical with a dry chemical, carbon dioxide, foam, or halon extinguisher. (NTP, 1992) |
| Erste Hilfe | EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.INHALATION: IMMEDIATELY leave the contaminated areatake deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be usedif not available, use a level of protection greater than or equal to that advised under Protective Clothing.INGESTION: If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Generally, the induction of vomiting is NOT recommended outside of a physician's care due to the risk of aspirating the chemical into the victim's lungs. However, if the victim is conscious and not convulsing and if medical help is not readily available, consider the risk of inducing vomiting because of the high toxicity of the chemical ingested. Ipecac syrup or salt water may be used in such an emergency. IMMEDIATELY transport the victim to a hospital. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992) |
| Brandbekämpfungsverfahren | Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. |
| Lagerbedingungen | Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place.Indomethacin capsules should be stored in well-closed containers at a temperature less than 40 °C, preferably at 15 to 30 °C. Indomethacin oral suspension should be stored in tight, light-resistant containers at a temperature less than 30 °Cexposure to temperatures greater than 50 °C should be avoided, and the suspension should be protected from freezing. Indomethacin suppositories should be stored at a temperature less than 30 °Cexposure to temperatures greater than 40 °C (even transiently) should be avoided. |
| Reinigungsverfahren | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dustEnvironmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drainsMethods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. |
| Freisetung ohne Brand | SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, you should dampen the solid spill material with alcohol, then transfer the dampened material to a suitable container. Use absorbent paper dampened with alcohol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with alcohol followed by washing with a strong soap and water solution. Do not reenter the contaminate area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. (NTP, 1992) |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubberContaminated packaging: Dispose of as unused product. |
| Preventive Measures | Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker. |
| Isolation and Evacuation | Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.SPILL: Increase the immediate precautionary measure distance, in the downwind direction, as necessary.FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directionsalso, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024) |
| Personal Protective Equipment (PPE) | RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter).RECOMMENDED GLOVE MATERIALS: Permeation data indicate that nitrile gloves may provide protection to contact with this compound. Nitrile over latex gloves is recommended. However, if this chemical makes contact with your gloves, or if a tear, hole or puncture develops, remove them at once. (NTP, 1992)Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).Skin protection: Handle with gloves.Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). |
| Treatment | Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if the ingestion is recent. If vomiting has not occurred spontaneously, the patient should be induced to vomit with syrup of ipecac. If the patient is unable to vomit, gastric lavage should be performed. Once the stomach has been emptied, 25 or 50 g of activated charcoal may be given. Depending on the condition of the patient, close medical observation and nursing care may be required. The patient should be followed for several days because gastrointestinal ulceration and hemorrhage have been reported as adverse reactions of indomethacin. Use of antacids may be helpful. (L1712) |
| Wechselwirkungen | Severe, sometimes fatal, toxicity has occurred following administration of a NSAIA (e.g., indomethacin, ketoprofen) concomitantly with methotrexate (principally high-dose therapy) in patients with various malignant neoplasms or rheumatoid arthritis. The toxicity was associated with elevated and prolonged blood concentrations of methotrexate. The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination. Further studies are needed to evaluate the interaction between NSAIAs and methotrexate. Caution is advised if methotrexate and a NSAIA are administered concomitantly.A patient experienced a transient deterioration of renal function induced by indomethacin during recovery from idiosyncratic phenylbutazone-associated renal failure. Since both drugs inhibit prostaglandin synthesis, this patient may illustrate a unique enhancement of the more common and clinically unimportant effect of altered glomerular filtration rate induced by such drugs. The renal insufficiency per se associated with the idiosyncratic reaction to phenylbutazone may have also enhanced this patient's reaction to indomethacin. Careful observation of patients during administration of such drugs in this and other settings of acute renal failure appears warranted.The effects of warfarin and NSAIAs on GI bleeding are synergistic.420 Concomitant use of indomethacin and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone. It appears that indomethacin has little, if any, direct influence on the hypoprothrombinemic effect of warfarin or other oral anticoagulants when these drugs are administered concurrently. Because indomethacin may cause GI bleeding and may inhibit platelet aggregation, the drug should be used with caution in patients receiving any anticoagulant or thrombolytic agent (e.g., streptokinase).Severe systemic hypertension developed in a patient who took indomethacin shortly after ingesting an appetite suppressant ('Trimolets') containing phenylpropanolamine. The hypertension was attributed to a drug interaction whereby the inhibition of prostaglandin synthesis by indomethacin exacerbated the sympathomimetic effects of phenylpropanolamine. ...For more Interactions (Complete) data for INDOMETHACIN (40 total), please visit the HSDB record page. |
| Hepatotoxicity | Mild and transient elevations in serum aminotransferase levels are found in up to 15% of patients taking indomethacin chronically. Moderate ALT elevations (>3 times ULN) occur in less than 1% of patients. Frank liver injury with jaundice from indomethacin is rare (estimated at 1.1 per 100,000 prescriptions), and fewer than a dozen cases have been reported in the literature. The latency to onset of symptoms or jaundice is variable, but is usually within 1 to 8 weeks of starting, although instances of latency of 4 to 6 months have been reported. Patients present with anorexia, nausea and vomiting followed by jaundice. Hepatocellular patterns of enzyme elevations are most common, but cholestatic and mixed patterns have been reported. Allergic manifestations and autoimmune features are not common. The injury is usually self-limited, resolving in 1 to 3 months, but several fatal cases have been reported (Case 1), particularly after use of high doses in patients with juvenile rheumatoid arthritis or Still disease. Many of the reported cases of severe indomethacin associated hepatotoxicity have occurred in patients with a pre-existing, underlying chronic liver disease.Likelihood score: C (probable rare cause of clinically apparent liver injury). |
| Ökotoxizitätswerte | LC50Species: Thamnocephalus platyurus (Fairy Shrimp) age <24 hr posthatch, naupliiConditions: freshwater, static, 25 °CConcentration: 16140 ug/L for 24 hr (95% confidence interval: 12590-20960 ug/L) />98.0% purity/Species: Oryzias latipes (Japanese Medaka) age <24 hr posthatch larvaConcentration: 81920 ug/L for 96 hr (95% confidence interval: 75000-90530 ug/L) />98.0% purity/EC50Species: Danio rerio (Zebra Danio) age 4 hr postfertilization, embryo, wild-typeConditions: freshwater, static, 25 °C, pH 6.8-8, hardness 217-235 mg/L CaCO3, dissolved oxygen >80%Concentration: 0.12 mM for 140 hrEffect: increased abnormal development /formulation/Concentration: 0.31 mM for 44 hrFor more Ecotoxicity Values (Complete) data for INDOMETHACIN (9 total), please visit the HSDB record page. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 1300(2) indicates that indomethacin is expected to have low mobility in soil(SRC). The pKa of indomethacin is 4.50(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize. Indomethacin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.9X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Utilizing batch-activated sewage treatment, 31% biodegradation was observed(2) suggesting that biodegradation may be an important environmental fate process in soil(SRC).AQUATIC FATE: Based on a classification scheme(1), a Koc value of 1300(2) indicates that indomethacin is expected to adsorb to suspended solids and sediment(SRC). A pKa of 4.50(3) indicates indomethacin will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water and moist soil surfaces is not expected to be an important fate process(SRC). Bioconcentration is not expected to be an important fate process as anions do not bioconcentrate. Utilizing the DOC river die-away test, biodegradation half-lives of 430 and 410 hours were obtained(2) suggesting that biodegradation may be an important environmental fate process in water(SRC).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), indomethacin, which has an estimated vapor pressure of 9.9X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase indomethacin may be removed from the air by wet and dry deposition(SRC). Indomethacin exhibited an aquatic photodegradation half-lives of 16 and 21 hours(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). |
| Unerwünschte Wirkungen | As a commonly used drug, researchers have conducted numerous studies on the adverse effects. Adverse reactions from the product label are mentioned. Indomethacin (and most other NSAIDs) can impact most body organ systems, including the gastrointestinal, neurological, renal, hematological, and cardiopulmonary systems.* The most common adverse reactions to indomethacin include headache, dizziness, dyspepsia, and nausea. Despite its use in treating various headache disorders, one of the most frequently reported adverse reactions is a headache.* Hypersensitivity reactions to indomethacin can occur and include anaphylaxis, urticaria, and angioedema.* As previously mentioned, indomethacin is a nonselective COX inhibitor, and COX-1 produces prostaglandins crucial for maintaining the gastric mucosa. Inhibition of this process can lead to dyspepsia (indigestion), nausea, constipation, and diarrhea. However, the most severe gastric adverse reaction to indomethacin involves the formation of peptic ulcers, which can manifest as mid-epigastric pain either relieved or exacerbated by eating. Gastric ulcers typically worsen with eating, while the pain associated with duodenal ulcers is alleviated by food intake. Ulcers have the potential to rupture, leading to an acute surgical abdomen.* Indomethacin can also affect the liver, resulting in elevated liver enzymes and jaundice.* Indomethacin can also affect the neurological system, potentially resulting in tinnitus, vertigo, depression, dizziness, and headaches. Severe adverse reactions, including aseptic meningitis, psychosis, and cognitive dysfunction, have also been reported.* COX enzymes are responsible for the synthesis of prostaglandins involved in renal function. Inhibition of this process can result in renal insufficiency. Indomethacin can also result in hyperkalemia and acute interstitial nephritis. Therefore, older individuals and patients with conditions such as dehydration, hypovolemia, renal dysfunction, heart failure, impaired liver function, and those taking diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARBs) are at higher risk of experiencing adverse events.* Indomethacin can have several effects on the hematologic system, including agranulocytosis, aplastic and hemolytic anemia, leukopenia, thrombocytopenia, and thrombocytopenic purpura. In addition, cases of indomethacin-induced leukocytoclastic vasculitis have been reported.* Indomethacin can affect the cardiopulmonary system and result in acute respiratory distress, pulmonary edema, and congestive heart failure.* Arachidonic acid is the precursor to prostaglandin synthesis via the action of COX enzymes. Inhibition of COX enzymes can divert arachidonic acid to the leukotriene synthesis pathway, potentially leading to the formation of nasal polyps in response to indomethacin. This condition may also manifest as respiratory difficulties. Additionally, indomethacin use can result in generalized fatigue and somnolence.Drug-Drug Interactions* Indomethacin may reduce the efficacy of various medications used to manage cardiovascular conditions (eg, ACE inhibitors, ARB inhibitors, or diuretics). Moreover, patients taking NSAIDs, including indomethacin, have reported fluid retention and edema.* NSAIDs can increase lithium levelsthus, concurrent use of indomethacin with lithium should be avoided.* The concurrent use of NSAIDs, including indomethacin, with oral apixaban is associated with an elevated risk of bleeding. Therefore, it is advisable to avoid combining these medications.* Concomitant use of indomethacin and methotrexate can increase methotrexate plasma levels. Therefore, monitoring for signs of methotrexate toxicity is recommended.* Indomethacin can decrease the natriuretic effect of furosemide and thiazide, reducing their efficacy. Combining NSAIDs with diuretics increases the risk of acute kidney injury. |
| Expositionspfade | Parenteral(intravenous)enteral(rectal)oral. Bioavailability is approximately 100% following oral administration and 80-90% following rectal administration. |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Indomethacin is a pale-yellow to yellow-tan, crystalline powder. It is an anti-inflammatory drug. It is also indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g when 48 hours usual medical management is ineffective. HUMAN EXPOSURE AND TOXICITY: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Elderly patients are at greater risk for serious gastrointestinal events. NSAIDs may also cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIDs. Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving indomethacin. Drowsiness, lethargy, mental confusion, nausea, vomiting, paresthesia, numbness, aggressive behavior, disorientation, and seizures have been reported following acute overdosage of the drug. Exposure of the fetus to indomethacin by administration of the drug to the mother may cause many side effects, including premature closure of the ductus arteriosus. Short-term indomethacin administered within 4 days prior to delivery resulted in a transient, yet significant renal dysfunction. ANIMAL STUDIES: Acute oral administration of indomethacin to rats induced macroscopic and microscopic damage to the small intestine, increased translocation of enterobacteria from lumen into the mucosa, myeloperoxidase activity and lipid peroxidation. After subchronic exposure to indomethacin for six to 12 weeks, rats displayed microcytic anemia, hypoalbuminemia, small intestinal ulceration, cecal ulceration and incSigns and Symptoms of OverdoseIndomethacin toxicity is rare, with only a few cases reported in the literature. Documented cases have demonstrated symptoms such as headache, tinnitus, dizziness, lethargy, drowsiness, confusion, disorientation, restlessness, and acute kidney injury secondary to indomethacin toxicity.Management of OverdoseHealthcare providers should offer patients supportive and symptomatic care following indomethacin dosage. A specific antidote for indomethacin toxicity is not available. For adult patients, administering 60 to 100 g of activated charcoal should be considered to decrease the absorption of NSAIDs from the upper gastrointestinal tract. Osmotic cathartics may be used in symptomatic patients observed within 4 hours of overdose or in patients who ingested 5 to 10 times the recommended dosage of indomethacin. The local poison control center should be contacted for detailed information on the treatment protocol.Antiinflammatory effects of Indomethacin are believed to be due to inhibition of cylooxygenase in platelets which leads to the blockage of prostaglandin synthesis. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Indomethacin is a prostaglandin G/H synthase (also known as cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. Indomethacin antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Indomethacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. Indomethacin is more selective for COX-1 than COX-2, which accounts for its increased adverse gastric effects relative to other NSAIDs. COX-1 is required for maintaining the protective gastric mucosal layer. The analgesic, antipyretic and anti-inflammatory effects of indomethacin occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. |
| Signs and Symptoms | The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. There have been reports of paresthesias, numbness, and convulsions. |
| Ongoing Test Status | EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPAICSS Dashboard ApplicationAvailable from, as of December 17, 2015: http://actor.epa.gov/dashboard/] |
| Effluent Concentrations | 72 samples from three conventional wastewater treatment plants in Spain were studied in 8 campaigns over 2 years starting in 2008. Indomethacin exhibited a 65, 58 and 0% frequency of detection in influent, effluent and sludge samples, respectivelydetection limit = 3.0, 2.0 ng/L and 1.0 ng/g, respectively. Overall removal was attributed to chemical and physical transformation, biodegradation and sorption to sludge(1). Indomethacin, influent load of approximately 20 g/day, was 75% removed during a 6-day passage through a municipal treatment plant near Frankfurt/Main, Germany(2). Indomethacin was detected in 21 of 21 influent samples from the Pinedo and Quart-Benager wastewater treatment plants on the Turia River, Valencia Spain, sampled in March 2013 at an average concentration of 0.6 ng/L. It was not detected in the 21 effluent samples(3). The compound was present at 100% frequency (0.1 ug/L median concentration) in influent and 36% detection frequency in effluent (0.06 ug/L median concentration) water from a wastewater treatment plant in A Coruna, Galicia (NW Spain) sampled from November 2007 - September 2008(4). The compound was been detected not quantified in a wastewater treatment work in Ouse, West Sussex, UK(5). Indomethacin was detected, not quantified in surface water downstream from wastewater treatment plants on the Detroit River (Lake Erie) and the Little River (Windsor, Ontario, Canada) sampled in the summer of 2000(6). Based on an average from 7 wastewater treatment plants, an overall removal of 44% has been reported(7).Indomethacin concentration ranged from 10.4 to 80 ug/kg (8.3% frequency of detection) in 45 Chinese municipal sewage sludge samples from 20 cities in 13 provinces throughout the country(1). |
| Soil Adsorption/Mobility | Using an Eliot silt loam soil (2.2% organic carbon, pH 6.6), a Koc of 1300 was reported(1). A log Koc of 2.95 (Kd = 32 L/kg), corresponding to a Koc of 891 , was measured using an agricultural soil (pH 6.3) from Corrstown, Co Dublin, Ireland(2). According to a classification scheme(3), these Koc values suggest that indomethacin is expected to have low mobility in soil. The pKa of indomethacin is 4.50(4), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). A Kd value of 214 L/kg was reported using a digester sludge from wastewater treatment plant, Dublin Ireland (pH 6.3)(2). Koc values of 160, 160 and 400 were reported using river sediments from the Akui, Tamiya and Tatara rivers, Japan, respectively(1). |
| F | 8-10 |
| Wassergefährdungsklasse (WGK) | 3 |
| TSCA-Inventar-Status | TSCA listed |
| UN-Transportnummer | UN 2811 6.1/PG 1 |
| Zollcode | 29339900 |
| RTECS-Nr. | NL3500000 |
| R-Sätze (R) | 28-36/37/38-39/23/24/25-23/24/25 |
| Toxizität | LD50 i.p. in rats: 13 mg/kg (Klaassen) |
| Gefahrensymbole | T+,Xi,T |
| Sicherheitshinweise (S) | 28-36/37-45-36-26 |
| Gefahrenklasse | 6.1Acute Tox. 1 Oral |
| Verpackungsgruppe | I |
| Lagerklasse | 6.1A - Combustible acute toxic Cat. 1 and 2very toxic hazardous materials |
| Gefahrstoffdaten | 53-86-1(Hazardous Substances Data) |
Anwendungen & Verwendung
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.
Verwenden
Inhibits cyclooxygenase (IC50=0.1uM) selectively over liposygenases (IC50=100uM for 5-,12- and 15-LO). A clinically useful NAISD
Herstellung & Synthese
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.