Indometacin
Synonym(s):1-( p-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic Acid;1-(p-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic Acid;1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid;IDM;Indomethacin - CAS 53-86-1 - Calbiochem
- CAS NO.:53-86-1
- Empirical Formula: C19H16ClNO4
- Molecular Weight: 357.79
- MDL number: MFCD00057095
- EINECS: 200-186-5
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-20 15:18:15
What is Indometacin?
Absorption
Indometacin displays a linear pharmacokinetics profile where the plasma concentrations and area under the curve (AUC) are dose-proportional, whereas half-life (T1/2) and plasma and renal clearance are dose-dependent. Indometacin is readily and rapidly absorbed from the gastrointestinal tract. The bioavailability is virtually 100% following oral administration and about 90% of the dose is absorbed within 4 hours. The bioavailability is about 80-90% following rectal administration.
The peak plasma concentrations following a single oral dose were achieved between 0.9 ± 0.4 and 1.5 ± 0.8 hours in a fasting state. Despite large intersubject variation as well using the same preparation, peak plasma concentrations are dose-proportional and averaged 1.54 ± 0.76 μg/mL, 2.65 ± 1.03 μg/mL, and 4.92 ± 1.88 μg/mL following 25 mg, 50 mg, and 75 mg single doses in fasting subjects, respectively. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.
Toxicity
Acute oral LD50 is 2.42 mg/kg in rats and 13 mg/kg in mice. The oral LD50 of indomethacin in mice and rats (based on 14-day mortality response) was 50 and 12 mg/kg, respectively.
Symptoms of overdose may be characterized by nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. In addition, there have been reports of paresthesias, numbness, and convulsions. In case of an overdose, the patient should receive symptomatic and supportive treatment with stomach emptying through induced vomiting or gastric lavage. The patient should then be closely monitored for any signs of gastrointestinal ulceration and hemorrhage. Antacids may be useful.
Description
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.
Chemical properties
Crystalline Solid
Originator
Indocin,MSD,US,1965
The Uses of Indometacin
Indomethacin inhibits cyclooxygenase (IC50=0.1uM) selectively over lipoxygenases (IC50=100uM for 5-,12- and 15-LO). Also, a clinically helpful NAISD. It has anti-inflammatory, antipyretic, and analgesic. 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.
Background
The NSAID chemical classification of indometacin is an indole-acetic acid derivative with the chemical name 1- (p-chlorobenzoyl)25-methoxy-2-methylindole-3-acetic acid. The pharmacological effect of indometacin is not fully understood, however, it is thought to be mediated through potent and nonselective inhibition of the enzyme cyclooxygenase (COX), which is the main enzyme responsible for catalyzes the rate-limiting step in prostaglandin and thromboxane biosynthesis via the arachidonic acid (AA) pathway. Indometacin was first discovered in 1963 and it was first approved for use in the U.S. by the Food and Drug Administration in 1965, along with other acetic acid derivatives such as diclofenac and sulindac that were also developed during the 1960s. Since then, indometacin has been extensively studied in clinical trials as one of the most potent NSAIDs in blocking prostaglandin synthesis and was among the first NSAIDs to be used in the symptomatic treatment of migraine and for headaches that eventually became known as “indomethacin-responsive” headache disorders.
What are the applications of Application
Indomethacin is an inhibitor of Cox-1 and activator of PPARγ
Definition
The antiinflammatory drug indomethacin.
Indications
Most commonly used in rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, acute shoulder pains, and acute gouty arthritis, indometacin is currently available as oral capsules as well as other methods of administration, including rectal and intravenous formulations. Intravenous indometacin is indicated to induce closure of a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1750 g when after 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support, etc.) is ineffective. Ophthalmic indometacin has been studied and used in the symptomatic treatment of postoperative ocular inflammation and pain and/or complications after cataract surgery.
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.
brand name
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
World Health Organization (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.
Biological Functions
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.
General Description
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.
Air & Water Reactions
Practically insoluble in water. Decomposes in alkali.
Reactivity Profile
A weak organic acid.
Fire Hazard
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.
Pharmaceutical Applications
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 .
Pharmaceutical Applications
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.
Biological Activity
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.
Pharmacokinetics
Indometacin is an NSAID with analgesic and antipyretic properties that exerts its pharmacological effects by inhibiting the synthesis of factors involved in pain, fever, and inflammation. Its therapeutic action does not involve pituitary-adrenal stimulation. Indometacin primarily works by suppressing inflammation in rheumatoid arthritis by providing relief of pain as well as reducing fever, swelling, and tenderness. This effectiveness has been demonstrated by a reduction in the extent of joint swelling, the average number of joints displaying symptoms of inflammation, and the severity of morning stiffness. Increased mobility was demonstrated by a decrease in total walking time and by improved functional capability seen as an increase in grip strength. In clinical trials, indometacin was shown to be effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis. Due to its pharmacological actions, the use of indometacin is associated with the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, as well as gastrointestinal effects such as bleeding, ulceration, and perforation of the stomach or intestines.
In a study of healthy individuals, acute oral and intravenous indometacin therapy resulted in a transiently diminished basal and CO2 stimulated cerebral blood flow; this effect disappeared in one study after one week of oral treatment. The clinical significance of this effect has not been established. Compared to other NSAIDs, it is suggested that indometacin is a more potent vasoconstrictor that is more consistent in decreasing cerebral blood flow and inhibiting CO2 reactivity. There have been studies that show indometacin directly inhibiting neuronal activity to some extent in the trigeminocervical complex after either superior salivatory nucleus or dural stimulation.
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.
Side Effects
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.
Synthesis
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].
Drug interactions
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.
Metabolism
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.
Metabolism
Indometacin undergoes hepatic metabolism involving glucuronidation, O-desmethylation, and N-deacylation. O-desmethyl-indomethacin, N-deschlorobenzoyl-indomethacin, and O-desmethyl-N-deschlorobenzoyl-indomethacin metabolites and their glucuronides are primarily inactive and have no pharmacological activity. Unconjugated metabolites are also detected in the plasma. Its high bioavailability indicates that indometacin is unlikely to be subject to the first-pass metabolism.
storage
Room temperature
Properties of Indometacin
Melting point: | 158-162 °C |
Boiling point: | 499.4±45.0 °C(Predicted) |
Density | 1.2135 (rough estimate) |
refractive index | 1.6800 (estimate) |
storage temp. | Store at RT |
solubility | ethanol: 50 mg/mL, clear, yellow-green |
form | White to off-white powder |
pka | 4.5(at 25℃) |
color | White to Light yellow to Light orange |
Water Solubility | Soluble in acetone (40 mg/mL - clear, yellow solution), ethanol (20 mg/mL), ether, castor oil; Soluble in chloroform (50 mg/mL - clear, yellow, extremely viscous solution); decomposed by strong alkali but stable in neutral or slightly acidic media; insoluble in water. |
Sensitive | Light Sensitive |
Merck | 14,4968 |
BRN | 497341 |
Stability: | Stable. Incompatible with strong oxidizing agents. |
CAS DataBase Reference | 53-86-1(CAS DataBase Reference) |
NIST Chemistry Reference | Indomethacin(53-86-1) |
EPA Substance Registry System | Indomethacin (53-86-1) |
Safety information for Indometacin
Signal word | Danger |
Pictogram(s) |
Skull and Crossbones Acute Toxicity GHS06 |
GHS Hazard Statements |
H300:Acute toxicity,oral |
Precautionary Statement Codes |
P264:Wash hands thoroughly after handling. P264:Wash skin thouroughly after handling. P301+P310:IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
Computed Descriptors for Indometacin
InChIKey | CGIGDMFJXJATDK-UHFFFAOYSA-N |
Abamectin manufacturer
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