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
intravenous, eye drops, nasal spray
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80–100% (oral) 100% IV/IM
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
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

muscle, and as eye drops.[3][4] Effects begin within an hour and last for up to eight hours.[3]

Common side effects include sleepiness, dizziness, abdominal pain, swelling, and nausea.

heart attacks, bronchospasm, heart failure, and anaphylaxis.[3] Use is not recommended during the last part of pregnancy or during breastfeeding.[3] Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2), thereby decreasing production of prostaglandins.[3][6]

Ketorolac was patented in 1976 and approved for medical use in 1989.

generic medication.[4] In 2021, it was the 210th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[8][9]

Due to a series of deaths due to gastrointestinal bleeding and kidney failure, ketorolac as a pain medication was removed from the German market in 1993.[10] When ketorolac was introduced into Germany, it was often mis-used as an opioid replacement in pain therapy because its side effects were perceived as much less severe, it did not produce any dependence, and a dose was effective for 7–8 hours compared to morphine with 3–4 hours. As a very potent prostaglandin inhibitor, ketorolac diminishes the kidney's own defenses against vasoconstriction-related effects, e.g. during blood loss or high endogenous catecholamine levels.[11]

Medical uses

Ketorolac package from Russia

Ketorolac is used for short-term management of moderate to severe pain.[2] It is usually not prescribed for longer than five days,[12][13][14][15]: 291  due to its potential to cause kidney damage.[15]: 280 

Ketorolac is effective when administered with paracetamol (acetominophen) to control pain in newborns because it does not depress respiration as do opioids.[16] Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is also used to treat dysmenorrhea.[15]: 291  Ketorolac is used to treat idiopathic pericarditis, where it reduces inflammation.[17]

For systemic use, ketorolac can be administered

orally, under the tongue, by intramuscular injection, intravenously, and by nasal spray.[12] Usually, it is initially administered by intramuscular injection or intravenously,[2] with oral therapy used as a continuation after the initial IM or IV dose.[12][16]

Ketorolac is also used as an eye drop. It can be given during eye surgery to help with pain,[18] and is effective in treating ocular itching.[19] There is not enough evidence to decide that non-steroidal anti-inflammatory drugs help in preventing cystoid macular edema.[20][21] Ketorolac eye drops have also been used to manage pain from corneal abrasions.[22]

During treatment with ketorolac, clinicians monitor for the manifestation of adverse effects. Lab tests, such as

serum creatinine and electrolyte levels are often used and help to identify potential complications.[12][13]

Contraindications

Ketorolac is

hepatic impairment.[12][13]

Adverse effects

A common (>10%) side effect is

itching and others. Platelet function can be decreased by use of ketorolac.[15]
: 279 

Though uncommon, potentially fatal adverse effects include

GI bleeding, Stevens–Johnson syndrome, toxic epidermal necrolysis and anaphylaxis. In terms of safety, ketorolac has been assessed to be a relatively higher-risk NSAID when compared to aceclofenac, celecoxib, and ibuprofen.[17]

Like all NSAIDs, ketorolac can cause premature constriction of the ductus arteriosus in the infant if taken by the mother during the third trimester of pregnancy.[12][13]

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.[23][24] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[23][24]

Interactions

Ketorolac can interact with other medications.

cyclosporine.[12][13]

Interactions with ketorolac also exist with some

dong quai, chamomile, and Ginkgo biloba increases the risk of bleeding.[12][13]

Mechanism of action

Chemically ketorolac functions as a carboxylic acid derivative serving non-selectively to block the prostaglandin synthesis by inhibition of prostaglandin G/H synthesis 1 and 2. Prostaglandin functions in the body as a messenger for contraction/relaxation of smooth muscle and modulation of inflammation. Resultant, inhibition of prostaglandin synthesis prevents inflammation.[25] 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.[26] It is considered a first-generation NSAID.[15]: 279 

History

In the US, ketorolac is the only widely available intravenous NSAID.[16]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular[27] around 2006, which is currently licensed by Allergan, Inc.[28][29]

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, although this was not designed to exclude its use in prehospital care and mountain rescue settings.[2] Dosing guidelines were published at that time.[30]

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.[31]

The eye-drop formulation was approved by the FDA in 1992.[32]

An intranasal formulation (Sprix) was approved by the FDA in 2010[33] for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.

Ketorolac has also been used in collegiate and professional sports, and is reported to be routinely used in the National Football League and National Hockey League. Competitive athletes, particularly in contact sports, are often expected by their coaches and/or teammates to play through injuries, generally with the help of painkillers. However, more recent research has indicated that encouraging players to play in an injured state tends to result in more severe injuries.[34][35] A lawsuit alleging widespread league-sanctioned abuse of painkillers was filed by former players against the National Football League in 2017.[36]

References

  1. ^ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  2. ^
    doi:10.12968/jpar.2017.9.12.522
    . Retrieved 2 June 2018.
  3. ^ a b c d e f g h i "Ketorolac Tromethamine Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
  4. ^
    ISBN 9780857113382
    .
  5. ^ "TORA-DOL Inj Lös 30 mg/ml". Kompendium (in German). 1 March 2022. Die Behandlung mit Ampullen ist bei akuten und schweren Schmerzzuständen angezeigt und sollte nicht länger als 2 Tage dauern.
  6. ^ "DailyMed - ketorolac tromethamine tablet, film coated". dailymed.nlm.nih.gov. Retrieved 14 April 2019.
  7. ISBN 9783527607495
    .
  8. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  9. ^ "Ketorolac - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  10. ^ "Abverkauf von Ketorolac (TORATEX) gestoppt" [Sale of Ketorolac (TORATEX) stopped]. 1993.
  11. ^ "Warnhinweis: Wie lange noch Analgetikum Ketorolac (Toratex)?" [Warning notice: How long anymore analgesic Ketorolac (Toratex)?] (in German). Arznei-Telegramm. 1993.
  12. ^
    ISBN 9780803657052
    .
  13. ^
    ISBN 9781563638381
    .
  14. ^ "Ketorolac-tromethamine". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  15. ^
    ISBN 978-1-56533-573-8
    .
  16. ^
    PMID 28232869
    .
  17. ^
    PMID 27023565
    .
  18. PMID 27695298
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  19. ISBN 9781496318213
    .
  20. PMID 27801522
    .
  21. PMID 36520144
    .
  22. PMID 28516471
    .
  23. ^ a b "FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications". U.S. Food and Drug Administration (FDA) (Press release). 15 October 2020. Retrieved 15 October 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  24. ^ a b "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration. 21 July 2017. Retrieved 15 October 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  25. ^ "Ketorolac". PubChem. National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 18 April 2020.
  26. S2CID 5894373
    .
  27. ^ "Acular (Ketorolac Tromethamine): Uses, Dosage, Side Effects, Interactions, Warning". RxList. Retrieved 6 May 2021.
  28. ^ "Label: ACULAR® Eye Drops (ketorolac trometamol)" (PDF). December 2011.
  29. ^ "Label: ACULAR® (ketorolac tromethamine ophthalmic solution)" (PDF). Allergan, Inc. U.S. Food and Drug Administration.
  30. ^ "Ketoprofen and ketorolac: gastrointestinal risk" (PDF). MHRA Drug Safety Update. 1 (3). Medicines and Healthcare products Regulatory Agency (MHRA): 3–4. October 2007.
  31. ^ Committee on Safety of Medicines (1993). "Ketorolac: new restrictions on dose and duration of treatment". Current Problems in Pharmacovigilance. 19: 5–6.
  32. ^ "Ketorolac ophthalmic medical facts from". Drugs.com. Retrieved 6 October 2013.
  33. ^ "Sprix Information from". Drugs.com. Retrieved 6 October 2013.
  34. ^ Klemko R. "Toradol Lawsuit: NFL Can't Outrun Legacy of Abuse". Sports Illustrated. Retrieved 18 April 2020.
  35. PMID 23016110
    .
  36. ISSN 0190-8286
    . Retrieved 18 April 2020.

Further reading
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