Ketorolac

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Ketorolac
Ketorolac.png
Ketorolac ball-and-stick.png
Systematic (IUPAC) name
(±)-5-benzoyl-2,3-dihydro-<brF />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 cat. C (AU) C (US)
Legal status Prescription Only (S4) (AU) -only (US)
Routes Oral, I.M., I.V.
Pharmacokinetic data
Bioavailability 100% (All routes)
Metabolism Hepatic
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
ChemSpider 3694 YesY
UNII YZI5105V0L YesY
KEGG D08104 YesY
ChEBI CHEBI:6129 N
ChEMBL CHEMBL469 YesY
PDB ligand ID KTR (PDBe, RCSB PDB)
Chemical data
Formula C15H13NO3 
Mol. mass 255.27 g/mol
 N (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. In India it is available as Ketanov by Ranbaxy, which is owned by Daiichi Sankyo.

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.

Medical uses[edit]

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[edit]

Although its name does not suggest similarity with propionic acid derivatives (including ketoprofen, flurbiprofen, naproxen, ibuprofen, etc.), ketorolac is an isostere of ketoprofen. More precisely, it is a dihydropyrrolizine carboxylic acid derivative structurally related to indomethacin.[7] 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.

Mechanism of action[edit]

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.[8]

Adverse effects[edit]

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.[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.

Allergic reactions (anaphylactoid reactions, asthma, bronchospasm, Stevens–Johnson syndrome, toxic epidermal necrolysis) have been reported.

Fluid retention and edema have been reported with the use of ketorolac and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions.

When this ophthalmic formulation is instilled into the eye it can lead to an unpleasant short term burning pain for 4–5 seconds.

Other adverse effects are similar to the ones associated with other NSAIDs. The most serious risks associated with ketorolac are those associated with other NSAIDs, i.e. gastrointestinal ulcers, bleeding and perforation; renal (kidney) events ranging from interstitial nephritis to complete kidney failure; hemorrhage, and hypersensitivity.

Ketorolac also causes rise in serum transaminase levels.

When administered intravenously through the same IV catheter as morphine, the two drugs have been known to sometimes combine to form a precipitate in the IV, which may block the line. Line flushing with a syringe of saline solution can push the blockage through.

Ketorolac is not recommended for pre-operative analgesia or co-administration with anesthesia because it inhibits platelet aggregation and thus may be associated with an increased risk of bleeding. Ketorolac is not recommended for obstetric analgesia because it has not been adequately tested for obstetrical administration and has demonstrable fetal toxicity in laboratory animals.

Ketorolac is not recommended for long-term chronic pain patients. However, ketorolac has been co-administered with meperidine and morphine without apparent adverse effects on patients.

Ketorolac adverse effects
Body system Effects
General Edema. Less frequently, hypersensitivity reactions (such as anaphylaxis, bronchospasm, laryngeal edema, tongue edema, hypotension), flushing, weight gain, or fever. Very infrequently, asthenia.
Cardiovascular Hypertension. Less frequently, palpitation, pallor, or fainting (syncope).
Dermatologic Rash or pruritus. Less frequently, Lyell's syndrome, Stevens–Johnson syndrome, musculo-papular rash, exfoliative dermatitis, or urticaria.
Gastrointestinal Nausea, dyspepsia, gastrointestinal pain, constipation, diarrhea, flatulence, gastrointestinal fullness, vomiting or stomatitis. Less frequently, peptic ulceration, gastrointestinal hemorrhage, gastrointestinal perforation, melena, rectal bleeding, gastritis, eructation, anorexia, or increased appetite. Very infrequently, pancreatitis.
Hemic and lymphatic Purpura. Less frequently, postoperative wound hemorrhage, thrombocytopenia, epistaxis, or anemia. Very infrequently, leukopenia or eosinophilia.
Neurological Drowsiness, dizziness, headache, sweating, injection site pain. Less frequently convulsions, vertigo, tremors, abnormal dreams, hallucinations, or euphoria. Very infrequently, paresthesia, depression, insomnia, inability to concentrate, nervousness, excessive thirst, dry mouth, abnormal thinking, hyperkinesis, or stupor.
Respiratory Less frequently, dyspnea, asthma and pulmonary edema. Very infrequently, rhinitis or cough.
Urogenital Less frequently, acute renal failure. Very infrequently polyuria or increased urinary frequency.

Contraindications[edit]

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 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).

Patent controversy[edit]

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.[11]

Apotex, a Canadian manufacturer, offers generic Ketorolac tromethamine as a 0.5% ophthalmic solution and as 10 mg tablets under the name "Apo-Ketorolac",[12] in Canada and some other countries. Syntex and Allergan sued Apotex for patent infringement of US 5110493 , over the generic ketorolac tomethamine 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.[13]

References[edit]

  1. ^ "History of Roche Bioscience – FundingUniverse". Fundinguniverse.com. Retrieved 2013-10-06. 
  2. ^ "Ketorolac medical facts from". Drugs.com. Retrieved 2013-10-06. 
  3. ^ "Ketorolac ophthalmic medical facts from". Drugs.com. Retrieved 2013-10-06. 
  4. ^ "Sprix Information from". Drugs.com. Retrieved 2013-10-06. 
  5. ^ "Ketorolac-tromethamine". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
  6. ^ MHRA Drug Safety Update October 2007, Volume 1, Issue 3, pp 3-4.
  7. ^ Martindale, The Complete Drug Reference, 35th Edition, 2007
  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.  edit
  9. ^ 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).
  10. ^ Strom BL et al. Parenteral Ketorolac and risk of gastrointestinal and operative site bleeding: a postmarketing surveillance study JAMA 1996; 275:376-82.
  11. ^ Allergan (2006). "ACULAR Ketorolac tromethamine 0.5% ophthalmic solution Product Information". Allergan web site. Allergan. Retrieved 2006-05-08. 
  12. ^ Apotex Products Canada (2006-05-08). "APO-KETOROLAC Product Information". Apotex Products Canada Product Catalogue. Apotex Products Canada. Retrieved 2006-05-08. 
  13. ^ 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.

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