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Ketorolac

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Ketorolac
Clinical data
Trade namesToradol, Acular, Sprix, others
Other namesketorolac tromethamine
AHFS/Drugs.comMonograph
MedlinePlusa693001
License data
Pregnancy
category
  • AU: C
Routes of
administration		by mouth, I.M., I.V., intranasal, ocular
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100% (All routes)
MetabolismLiver
Elimination half-life3.5 h to 9.2 h, young adults;
4.7 h to 8.6 h, elderly (mean age 72)
ExcretionKidney: 91.4% (mean)
Biliary: 6.1% (mean)
Identifiers
  • (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.110.314 Edit this at Wikidata
Chemical and physical data
FormulaC15H13NO3
Molar mass255.27 g/mol g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • O=C(c1ccc2n1CCC2C(=O)O)c3ccccc3
  • 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) checkY
  • Key:OZWKMVRBQXNZKK-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Ketorolac, sold under the brand name Toradol among others, is a non-steroidal anti-inflammatory drug (NSAID) in the family of heterocyclic acetic acid derivatives, used as an analgesic.[1][2] It is considered a first-generation NSAID.[3] An eye drop is available and is used to treat eye pain.

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.[3]

Ketorolac was developed in 1989 by Syntex Corp. (now part of Roche).[4] It was approved for medical use in the United States in 1989.[5] The eye-drop form was approved by FDA in 1992.[6] An intranasal formulation was approved by FDA in 2010[7] for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level. As of 2015, the cost for a typical course of medication in the United States is less than US$25.[8]

Medical uses

Ketorolac is used for short-term management of moderate to severe pain. It is usually not prescribed for longer than five days.[1][2][9][10] Ketorolac is effective when administered with acetaminophen to control pain in neonates because it does not depress respiration as do opioids.[11] Ketorolac is also an adjuvant to opoids medications and improves pain relief. It is also used to treat dysmenorrhea.[10] Ketorolac is used to treat idiopathic pericarditis where it reduces inflammation.[12]

Ketorolac is used for short-term pain control not lasting longer than five days and can be administered orally, by intramuscular injection, intravenously, and by nasal spray.[1] Ketorolac is initially administered by intramuscular injection or intravenously. Oral therapy is only used as a continuation of the intramuscular or intravenous route.[11][1]

Ketorolac is used during eye surgery to maintain mydriasis, or the 'relaxing' of the iris muscles that will allow surgeons to perform cataract surgery.[13] Ketorolac is effective in treating ocular itching.[14] The ketorolac ophthalmic formulation is associated with a decreased development of macular edema after cataract surgery and is more effective alone rather than as a opioid/keterolac combination treatment.[15][16]

During treatment with ketorolac, clinicians monitor for the manifestation of adverse effects and side effects. This monitoring is recorded in the medical record and may help identify emergent issues during treatment. Monitoring lab tests, such as liver function tests, bleeding time, BUN, serum creatinine and electrolyte levels are often used and help to identify potential complications.[1][2]

Contraindications

Ketorolac is contraindicated in those with hypersensitivity, allergies to the medication, cross-sensitivity to other non-steroidal anti-inflammatory agents, prior to surgery, history of peptic ulcer disease, gastrointestinal bleeding, alcohol intolerance, renal impairment, cerebrovascular bleeding, nasal polyps, angioedema, and asthma.[1][2]

Recommendations exist for cautious use of ketorolac in those who have experienced cardiovascular disease, myocardial infaction, stroke, heart failure, coagulation disorders, renal impairment, and hepatic impairment.[1][2]

Adverse effects

Though uncommon, potentially fatal adverse effects are stroke, myocardial infarction, GI bleeding, Stevens-Johnson Syndrome, Toxic epidermal necrolysis and anaphylaxis. A less serious and more common (>10%) side effect is drowsiness. Infrequent (<1%) side effects are paresthesia, prolonged bleeding time, injection site pain, purpura, sweating, abnormal thinking, increased tearing (eyes), edema, pallor, dry mouth, abnormal taste, urinary frequency increased liver enzymes, itching and others. Ketorolac can cause premature constriction of the ductus arteriosis in an infant during the third trimester of pregnancy.[1][2] The practice of restricting treatment with ketorolac is due to its potential to cause kidney damage.[17] Platelet function is decreased related to the use of ketorolac.[3]

Interactions

Ketorolac can interact with other medications. Probenecid can increase the probability of having an adverse reaction or experiencing a side effect when taken with ketorolac. Pentoxifylline can increase the risk of bleeding. When aspirin is taken at the same time as ketorolac, the effectiveness is decreased. Problematic GI effects are additive and become more likely if potassium supplements, aspirin, other NSAIDS, corticosteroids, or alcohol is taken at the same time. The effectiveness of antihypertensives and diuretics can be lowered. The use of ketorolac can increase serum lithium levels to the point of toxicity. Toxicity to methotrexate is more likely if ketorolac is taken at the same time. The risk of bleeding increases with the concurrent medications clopidogrel, cefoperazone, valproic acid, cefotetan, eptifibatide, tirofiban, and copidine. Anticoagulants and thrombolytic medications also increase the likelihood of bleeding. Medications used to treat cancer can interact with ketorolac along with radiation therapy. The risk of toxicity to the kidneys increases when ketorolac is taken with cyclosporine.[1]}[2]

Interactions with ketorolac exist with some herbal supplements. Panax ginseng, clove, ginger, arnica, feverfew, dong quai, chamomile, and Ginkgo biloba, increases the risk of bleeding.[1][2] Vitamin C may prevent the death of cardiac cells and still retain the ability to provide pain relief.[18]

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 derivative of dihydropyrrolizine carboxylic acid structurally related to indomethacin.[19][citation needed] NSAIDs (non-steroidal anti-inflammatory drugs) 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.[citation needed]

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.[20] It is able to prevent inflammation, pupil contraction, conjunctival hyperemia and changes in intraocular pressure by inhibiting the COX pathway and subsequent production of prostaglandins.[13] Ketorolac has been assessed to be a relatively higher risk NSAID when compared to aceclofenac, celecoxib, and ibuprofen.[12]

History

In the US, ketorolac was the only widely available intravenous NSAID for many years; an IV form of paracetemol became available in Europe in 2009 and then in the US.[11]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular around 2006 and holds the registered trademark on that name, as well as on the name Toradol. The actual product using this brand name was manufactured and distributed by Allergan under license from Syntex.[21] Apotex, a Canadian manufacturer, offers generic Ketorolac tromethamine as a 0.5% ophthalmic solution and as 10 mg tablets under the name "Apo-Ketorolac",[22] 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.[23]

In 2007 there were concerns about the high incidence of reported side effects. This led to restriction in its dosage and maximum duration of use. In the UK, treatment was initiated only in a hospital. Dosing guidelines were published at this time.[24]

Concerns over the high incidence of reported side effects with ketorolac trometamol 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.[25]

References

  1. ^ a b c d e f g h i j Vallerand, April H. (2017). Davis's Drug Guide for Nurses. Philadelphia: F.A. Davis Company. p. 730. ISBN 9780803657052.
  2. ^ a b c d e f g h Physician's Desk Reference 2017. Montvale, New Jersey: PDR, LLC. 2017. pp. S-474-5. ISBN 9781563638381.
  3. ^ a b c Henry, p. 279.
  4. ^ "History of Roche Bioscience – FundingUniverse". Fundinguniverse.com. Retrieved 2013-10-06.
  5. ^ "Ketorolac medical facts from". Drugs.com. Retrieved 2013-10-06.
  6. ^ "Ketorolac ophthalmic medical facts from". Drugs.com. Retrieved 2013-10-06.
  7. ^ "Sprix Information from". Drugs.com. Retrieved 2013-10-06.
  8. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 9. ISBN 9781284057560.
  9. ^ "Ketorolac-tromethamine". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  10. ^ a b Henry, p. 291.
  11. ^ a b c Martin, Lizabeth D; Jimenez, Nathalia; Lynn, Anne M (2017). "A review of perioperative anesthesia and analgesia for infants: updates and trends to watch". F1000Research. 6: 120. doi:10.12688/f1000research.10272.1. ISSN 2046-1402. PMID 28232869.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ a b Schwier, Nicholas; Tran, Nicole (2016). "Non-Steroidal Anti-Inflammatory Drugs and Aspirin Therapy for the Treatment of Acute and Recurrent Idiopathic Pericarditis". Pharmaceuticals. 9 (2): 17. doi:10.3390/ph9020017. ISSN 1424-8247.{{cite journal}}: CS1 maint: unflagged free DOI (link) Cite error: The named reference "SchwierTran2016" was defined multiple times with different content (see the help page).
  13. ^ a b Saenz-de-Viteri, Manuel; Gonzalez-Salinas, Roberto; Guarnieri, Adriano; Guiaro-Navarro, María Concepción (2016). "Patient considerations in cataract surgery – the role of combined therapy using phenylephrine and ketorolac". Patient Preference and Adherence. Volume 10: 1795–1801. doi:10.2147/PPA.S90468. ISSN 1177-889X. {{cite journal}}: |volume= has extra text (help)CS1 maint: unflagged free DOI (link)
  14. ^ Karch, Amy (2017). Focus on nursing pharmacology. Philadelphia: Wolters Kluwer. p. 272. ISBN 9781496318213.
  15. ^ Lim, Blanche X; Lim, Chris HL; Lim, Dawn K; Evans, Jennifer R; Bunce, Catey; Wormald, Richard; Wormald, Richard (2016). "Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery". doi:10.1002/14651858.CD006683.pub3. PMID 27801522. {{cite journal}}: Cite journal requires |journal= (help)
  16. ^ Sivaprasad, Sobha; Bunce, Catey; Crosby-Nwaobi, Roxanne; Sivaprasad, Sobha (2012). "Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery". doi:10.1002/14651858.CD004239.pub3. PMID 22336801. {{cite journal}}: Cite journal requires |journal= (help)
  17. ^ Henry, p. 280.
  18. ^ Kerlin, Kat (25 April 2016). "What's Behind the Heartbreaking Risk of Anti-Inflammatory Drugs". University of California, Davis. Retrieved 31 March 2017.
  19. ^ Martindale, The Complete Drug Reference, 35th Edition, 2007
  20. ^ 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.
  21. ^ Allergan (2006). "ACULAR Ketorolac tromethamine 0.5% ophthalmic solution Product Information". Allergan web site. Allergan. Retrieved 2006-05-08.(subscription required)
  22. ^ Apotex Products Canada (2006-05-08). "APO-KETOROLAC Product Information". Apotex Products Canada Product Catalogue. Apotex Products Canada. Archived from the original on 2007-06-21. Retrieved 2006-05-08. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  23. ^ Albainy-Jenei, Stephen R. (May 24, 2005). "Federal Circuit Reverses Allergan's Patent Validity Decision". Patent Baristas web log. Archived from the original on March 26, 2006. Retrieved 2006-05-08. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  24. ^ MHRA Drug Safety Update October 2007, Volume 1, Issue 3, pp 3-4.
  25. ^ 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).

Bibliography

  • AHFS drug information. Bethesda, MD: American Society of Health-System Pharmacists. 2011. ISBN 9781585282609.
  • Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 9. ISBN 9781284057560.
  • 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.
  • Henry, Norma (2016). RN pharmacology for nursing : review module. Overland Park, KS: Assessment Technologies Institute. ISBN 9781565335738.
  • Kizior, Robert (2017). Saunders nursing drug handbook 2017. St. Louis, MO: Elsevier. ISBN 9780323442916.
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