Indomethacin

Structural formula
General
Non-proprietary name	Indomethacin
other names	Indomethazine; Indometazine; 2- [1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1 H -indol-3-yl] acetic acid; [1- (4-chlorobenzoyl) -5-methoxy-2-methylindol-3-yl] acetic acid ( Pharmacopoeia ) ;
Molecular formula	C 19 H 16 ClNO 4
Brief description	pale beige, polymorphic crystals
External identifiers / databases
EC number	200-186-5
ECHA InfoCard	100,000,170
PubChem	3715
ChemSpider	3584
DrugBank	DB00328
Wikidata	Q409231
Drug information
ATC code	M01 AB01 ; S01 BC01 ; M02 AA23 ;
Drug class	Non-steroidal anti-inflammatory drug
Mechanism of action	Cyclooxygenase - inhibitor
properties
Molar mass	357.79 g · mol -1
Physical state	firmly
Melting point	148 ° C (α-polymorph) ; 154 ° C (γ-polymorph) ;
pK s value	4.5
solubility	Slightly soluble in water (8.4 ± 0.2 mg l −1 (pH 4.5)); soluble in ethanol , diethyl ether , chloroform and castor oil ;
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 300-317-360FD
	P: 201-280-301 + 310 + 330-302 + 352-308 + 313
Toxicological data	13 mg kg −1 ( LD 50 , rat , ip )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Indomethacin is an analgesic from the group of non-steroidal anti-inflammatory drugs .

Overview

Indomethacin is mainly used for the symptomatic therapy of rheumatic diseases ( e.g. rheumatoid arthritis , ankylosing spondylitis ), for prophylaxis against periarticular ossification (PAO) in hip joint operations and in acute gout attacks . 50 mg indomethacin and 600 mg acetylsalicylic acid correspond in their potency. Further areas of application are the treatment of episodic and chronic paroxysmal hemicrania and hemicrania continua . The effectiveness of indomethacin is a diagnostic criterion for these headache disorders.

Indomethacin is a non-selective inhibitor of cyclooxygenases ( COX-1 and COX-2 ).

With chronic administration, there is a significant increase in side effects, including those affecting the central nervous system, which could force discontinuation of the substance.

Thanks to its inhibitory effect on prostaglandin synthesis , indomethacin is also used very successfully for the medicinal closure of a persistent ductus arteriosus in premature infants.

The following are known to be side effects in 10 to 30 percent of patients:

Gastrointestinal disorders ( ulcers )
a headache
Dizziness
mental changes
nausea
Sensation of pressure in the epigastric region
Loss of appetite

The gastrointestinal complaints can be reduced by giving suppositories .

Combinatorial interactions exist between indomethacin and probenecid as an increase in the effect of indomethacin and with glucagon .

The mean plasma half-life is estimated to be around 4.5 hours, with both renal and biliary excretion.

The maximum serum concentration is reached after one to two hours. Indomethacin is the drug of choice for acute gout attacks.

history

The American company Merck, Sharp & Dohme has been researching new analgesics since 1953 under the supervision of Charles A. Winter. When the structures of tryptophan and serotonin were clarified in 1958 , the head of development Tsung H. Shen synthesized approx. 2500 indole derivatives . Among them was indomethacin, which was a pharmacological success in 1960. The clinical effectiveness was proven in 1961 and the market launch took place in 1965.

Physical Properties

The compound occurs in two polymorphic crystal forms. The α form melts at 148 ° C with a heat of fusion of 31.36 kJ mol ⁻¹ , the γ form at 154 ° C with 36.17 kJ mol ⁻¹ . Both forms are monotropic to one another, with the γ form being the thermodynamically more stable one. The solubilities in water at 35 ° C are 8.7 mg · l ⁻¹ for the α form and 6.9 mg l ⁻¹ for the γ form . The β-form is a 1: 1 solvate with this solvent obtained by crystallization from benzene .

Analytics

The reliable quantitative determination in examination materials such as B. Serum, plasma or urine succeeds after adequate sample preparation by using the coupling of chromatographic methods with mass spectrometry . Due to the frequency of the use of indomethacin preparations, indomethacin is now also found in the water of rivers.

Trade names

Monopreparations : Amuno (D), Elmetacin (CH), Indocid (A, CH), Indocolir (D), Indophtal (CH), Indo-paed (D), Indo Top (D), Indomet pain spray (D), Indobe ( A), Luiflex Spray (A), various generics (D, CH)

Individual evidence

↑ ^a ^b ^c ^d Entry on indomethacin. In: Römpp Online . Georg Thieme Verlag, accessed on November 12, 2014.

↑ ^a ^b ^c N. Kaneniwa, M. Otsuka, T. Hayashi: Physicochemical Characterization of Indomethacin Polymorphs and the Transformation Kinetics in Ethanol. In: Chem. Pharm. Bull. 33, 1985, pp. 3447-3455, doi : 10.1248 / cpb.33.3447 , pdf .

↑ K. Tsinman, A. Avdeef, O. Tsinman, D. Voloboy: Powder Dissolution Method for Estimating Rotating Disk Intrinsic Dissolution Rates of Low Solubility Drugs. In: Pharm Res . 26, 2009, pp. 2093-2100. doi: 10.1007 / s11095-009-9921-3

↑ ^a ^b Entry on indomethacin in the GESTIS substance database of the IFA , accessed on July 23, 2016(JavaScript required) .

↑ Guideline for cluster headache and trigeminal autonomic headache . Published by the guidelines commission of the German Society for Neurology , the German Migraine and Headache Society , the Austrian Society for Neurology , the Swiss Neurological Society and the Professional Association of German Neurologists . Status: May 14, 2015, valid until May 13, 2020. Accessed on October 31, 2017.

↑ W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology . 9th edition. Urban & Fischer, Munich 2005, ISBN 3-437-42521-8 .

↑ Thomas Karow, Ruth Lang-Roth: Pharmacology and Toxicology. 17th edition. 2009.

^ Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2nd, revised and expanded edition. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2005, ISBN 3-8047-2113-3 , p. 139 .

^ S. Thomas, A. Sutton, U. Garg: Quantitation of indomethacin in serum and plasma using gas chromatography-mass spectrometry (GC-MS). In: Methods Mol Biol. 603, 2010, pp. 297-305. PMID 20077081

^ Y. Liu, F. Guan, X. Wang, X. Zhang, X. Di: Development of a liquid chromatography-tandem mass spectrometry method for measuring plasma and uterine tissue levels of indomethacin in rabbits treated with indomethacin-medicated Cu-IUDs . In: Contraception. 85 (4), Apr 2012, pp. 419-424. PMID 22067752

↑ X. Wang, DI Vernikovskaya, TN Nanovskaya, E. Rytting, GD Hankins, MS Ahmed: A liquid chromatography method with single quadrupole mass spectrometry for quantitative determination of indomethacin in maternal plasma and urine of pregnant patients. In: J Pharm Biomed Anal. 78-79, May 5, 2013, pp. 123-128. PMID 23474812

↑ K. Hoshina, S. Horiyama, H. Matsunaga, J. Haginaka: Simultaneous determination of non-steroidal anti-inflammatory drugs ammatory drugs in river water samples by liquid chromatography-tandem mass spectrometry using molecularly imprinted polymers as a pretreatment column. In: J Pharm Biomed Anal. 55 (5), Jul 15, 2011, pp. 916-922. PMID 21470812

[RÖMPP_Online-1] Entry on indomethacin. In: Römpp Online . Georg Thieme Verlag, accessed on November 12, 2014.

[Kaneniwa-2] N. Kaneniwa, M. Otsuka, T. Hayashi: Physicochemical Characterization of Indomethacin Polymorphs and the Transformation Kinetics in Ethanol. In: Chem. Pharm. Bull. 33, 1985, pp. 3447-3455, doi : 10.1248 / cpb.33.3447 , pdf .

[3] K. Tsinman, A. Avdeef, O. Tsinman, D. Voloboy: Powder Dissolution Method for Estimating Rotating Disk Intrinsic Dissolution Rates of Low Solubility Drugs. In: Pharm Res . 26, 2009, pp. 2093-2100. doi: 10.1007 / s11095-009-9921-3

[GESTIS-4] Entry on indomethacin in the GESTIS substance database of the IFA , accessed on July 23, 2016(JavaScript required) .