Ketorolac
|
|
| Systematic (IUPAC) name |
(±)-5-benzoyl-2,3-dihydro-
1H-pyrrolizine-1-carboxylic acid,
2-amino-2-(hydroxymethyl)-1,3-propanediol |
| Clinical data |
| Trade names |
Toradol, Acular and Sprix |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a693001 |
| Licence data |
US Daily Med:link |
Pregnancy
category |
- AU: C
- US: C (Risk not ruled out)
|
| Legal status |
- AU: S4 (Prescription only)
- US: ℞-only
|
Routes of
administration |
Oral, I.M., I.V. |
| Pharmacokinetic data |
| Bioavailability |
100% (All routes) |
| Metabolism |
Hepatic |
| Biological half-life |
3.5–9.2 hrs, young adults;
4.7–8.6 hrs, elderly (mean age 72) |
| Excretion |
Renal: 91.4% (mean)
Biliary: 6.1% (mean) |
| Identifiers |
| CAS Number |
74103-06-3 N |
| ATC code |
M01AB15 S01BC05 |
| PubChem |
CID 3826 |
| DrugBank |
DB00465 Y |
| ChemSpider |
3694 Y |
| UNII |
YZI5105V0L Y |
| KEGG |
D08104 Y |
| ChEBI |
CHEBI:6129 N |
| ChEMBL |
CHEMBL469 Y |
| PDB ligand ID |
KTR (PDBe, RCSB PDB) |
| Chemical data |
| Formula |
C15H13NO3 |
| Molar mass |
255.27 g/mol |
| Chirality |
1 : 1 mixture (racemate) |
SMILES
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O=C(c1ccc2n1CCC2C(=O)O)c3ccccc3
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InChI
-
InChI=1S/C15H13NO3/c17-14(10-4-2-1-3-5-10)13-7-6-12-11(15(18)19)8-9-16(12)13/h1-7,11H,8-9H2,(H,18,19) Y
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Key:OZWKMVRBQXNZKK-UHFFFAOYSA-N Y
|
| NY (what is this?) (verify) |
Ketorolac or ketorolac tromethamine is a non-steroidal anti-inflammatory drug (NSAID) in the family of heterocyclic acetic acid derivatives, used as an analgesic. Ketorolac was developed in 1989 by Syntex Corp. (now Roche Bioscience, which is a wholly owned subsidiary of Roche holding Ltd., the parent company of Roche).[1] It was approved by FDA on 30 November 1989 and introduced as Toradol by Syntex.[2] The ophthalmic (i.e., eye-drop) form was approved by FDA on 9 November 1992 and was introduced as Acular eye drops by Allergan under license from Syntex.[3] An intranasal formulation of ketorolac tromethamine was approved by FDA on 14 May 2010 and introduced as Sprix Nasal Spray by Daiichi Sankyo[4] for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.
Ketorolac acts by inhibiting the bodily synthesis of prostaglandins. Ketorolac in its oral (tablet or capsule) and intramuscular (injected) preparations is a racemic mixture of both (S)-(−)-ketorolac, the active isomer, and (R)-(+)-ketorolac. An ophthalmic solution of ketorolac is available and is used to treat eye pain and to relieve the itchiness and burning of seasonal allergies.
Contents
- 1 Medical uses
- 2 Chemistry
- 3 Adverse effects
- 4 Mechanism of action
- 5 Contraindications
- 6 Patent controversy
- 7 References
- 8 External links
Medical uses
Ketorolac is indicated for short-term management of moderate to severe pain.[5] Concerns about the high incidence of reported side effects led to restriction in its dosage and maximum duration of use. In the UK, treatment should be initiated only in a hospital. Maximum duration of treatment should not exceed five days for tablets (per package insert), or two days for continuous daily dosing with intravenous or intramuscular formulations.[6] The ophthalmic formulation can be used instead of steroidal anti inflammatories in cases where a raised intraocular pressure (glaucoma) is to be avoided.
Chemistry
Although its name does not suggest similarity with propionic acid derivatives (e.g. ketoprofen, flurbiprofen, naproxen, ibuprofen, carprofen etc.), ketorolac is an isostere of ketoprofen. More precisely, it is a dihydropyrrolizine carboxylic acid derivative structurally related to indomethacin.[7][citation needed] NSAIDs (non-steroidal anti-inflammatory drug) are not recommended for use with other NSAIDs because of the potential for additive side effects. The protein-binding effect of most non-aspirin NSAIDs are inhibited by the presence of aspirin in the blood.
Adverse effects
Concerns over the high incidence of reported side effects with ketorolac trometamol has led to its withdrawal (apart from the ophthalmic formulation) in several countries, while in others its permitted dosage and maximum duration of treatment have been reduced. From 1990 to 1993, 97 reactions with a fatal outcome were reported worldwide.[8]
Mechanism of action
The primary mechanism of action responsible for ketorolac's anti-inflammatory, antipyretic and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor.[9]
A postmarketing surveillance study[10] indicated a dose-response relationship with average daily dose for both gastrointestinal bleeding and operative site bleeding, and an association between gastrointestinal bleeding and therapy for more than five days.
Contraindications
Ketorolac is contraindicated in patients with a previously demonstrated hypersensitivity to ketorolac, and in patients with the complete or partial syndrome of nasal polyps, angioedema, bronchospastic reactivity or other allergic manifestations to aspirin or other non-steroidal anti-inflammatory drugs (due to possibility of severe anaphylaxis). As with all NSAIDs, ketorolac should be avoided in patients with prior gastric bypass surgery (NSAIDs greatly increase the chance of a potentially dangerous ulcer in roux-en-Y patients).[11] It should also be avoided by patients with renal (kidney) dysfunction. (Prostaglandins are needed to dilate the afferent arteriole; NSAIDs effectively reverse this.) The patients at highest risk, especially in the elderly, are those with fluid imbalances or with compromised renal function (e.g., heart failure, diuretic use, cirrhosis, dehydration, and renal insufficiency).[medical citation needed]
Patent controversy
The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular, and holds the registered trademark on that name, as well as on the name Toradol. The actual product using this brand name is manufactured and distributed by Allergan under license from Syntex.[12]
Apotex, a Canadian manufacturer, offers generic Ketorolac tromethamine as a 0.5% ophthalmic solution and as 10 mg tablets under the name "Apo-Ketorolac",[13] in Canada and some other countries. Syntex and Allergan sued Apotex for patent infringement of US 5110493 , over the generic ketorolac tromethamine product. In May, 2005, the United States Court of Appeals for the Federal Circuit handed Apotex a victory, ruling that a lower court upholding the Syntex patent misapplied the rules for judging whether an invention was obvious. Allergan had claimed that the patent was valid until 2009.[14]
References
- ^ "History of Roche Bioscience – FundingUniverse". Fundinguniverse.com. Retrieved 2013-10-06.
- ^ "Ketorolac medical facts from". Drugs.com. Retrieved 2013-10-06.
- ^ "Ketorolac ophthalmic medical facts from". Drugs.com. Retrieved 2013-10-06.
- ^ "Sprix Information from". Drugs.com. Retrieved 2013-10-06.
- ^ "Ketorolac-tromethamine". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
- ^ MHRA Drug Safety Update October 2007, Volume 1, Issue 3, pp 3-4.
- ^ Martindale, The Complete Drug Reference, 35th Edition, 2007
- ^ Committee on the Safety of Medicines, Medicines Control Agency: Ketorolac: new restrictions on dose and duration of treatment. Current Problems in Pharmacovigilance: June 1993; Volume 19 (pages 5-8).
- ^ Lee, I. O.; Seo, Y. (2008). "The Effects of Intrathecal Cyclooxygenase-1, Cyclooxygenase-2, or Nonselective Inhibitors on Pain Behavior and Spinal Fos-Like Immunoreactivity". Anesthesia & Analgesia 106 (3): 972–977, table 977 contents. doi:10.1213/ane.0b013e318163f602. PMID 18292448.
- ^ Strom BL et al. Parenteral Ketorolac and risk of gastrointestinal and operative site bleeding: a postmarketing surveillance study JAMA 1996; 275:376-82.
- ^ http://www.ssmhealth.com/weightloss/documents/infosheet-pcp-longterm-medissues.pdf
- ^ Allergan (2006). "ACULAR Ketorolac tromethamine 0.5% ophthalmic solution Product Information". Allergan web site. Allergan. Retrieved 2006-05-08.
- ^ Apotex Products Canada (2006-05-08). "APO-KETOROLAC Product Information". Apotex Products Canada Product Catalogue. Apotex Products Canada. Retrieved 2006-05-08.
- ^ Albainy-Jenei, Stephen R. (May 24, 2005). "Federal Circuit Reverses Allergan's Patent Validity Decision". Patent Baristas web log. Retrieved 2006-05-08.
- Handley, D.A., P. Carvoni, J.E. McCray, J.R. McCullough (1998). "Preclinical Enantioselective Pharmacology of (R)- and (S)- Ketorolac.", J Clin Pharmacol 38, 25-35.
- 1993. Physicians' Desk Reference, Forty-seventh edition. Montvale, N.J., Medical Economics Co. Inc., 2411-2415.
External links
- Published studies related to ketorolac, at DrugLib
- MedicineNet.com information on ophthalmic ketorolac
- cme.medscape.com on nasal ketorolac
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Prostanoid signaling
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|
Receptor
(ligands) |
|
|
Enzyme
(inhibitors) |
| COX (PTGS) |
|
|
| PGD2 synthase |
- Retinoids
- Selenium (selenium tetrachloride, sodium selenite, selenium disulfide)
|
|
| PGE synthase |
HQL-79
|
|
| PGF synthase |
Bimatoprost
|
|
| PGI2 synthase |
Tranylcypromine
|
|
| TXA synthase |
- Camonagrel
- Dazmegrel
- Dazoxiben
- Furegrelate
- Isbogrel
- Midazogrel
- Nafagrel
- Nicogrelate
- Ozagrel
- Picotamide
- Pirmagrel
- Ridogrel
- Rolafagrel
- Samixogrel
- Terbogrel
- U63557A
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|
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| Others |
- Precursors: Linoleic acid
- γ-Linolenic acid (gamolenic acid)
- Dihomo-γ-linolenic acid
- Diacylglycerol
- Arachidonic acid
- Prostaglandin G2
- Prostaglandin H2
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See also: Leukotrienergics
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