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	Acular and Toradol
AHFS/Drugs.com	monograph
MedlinePlus	a693001
Licence data	US Daily Med:link
Pregnancy cat.	C (AU) C (US)
Legal status	℞-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
PubChem	CID 3826
DrugBank	DB00465
ChemSpider	3694 Y
UNII	YZI5105V0L Y
KEGG	D08104 Y
ChEMBL	CHEMBL469 Y
Chemical data
Formula	C15H13NO3
Mol. mass	255.27 g/mol
SMILES O=C(c1ccc2n1CCC2C(=O)O)c3ccccc3
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 Key:OZWKMVRBQXNZKK-UHFFFAOYSA-N Y
N (what is this?)  (verify)

Ketorolac or ketorolac tromethamine (marketed under the trademarks Toradol and Acular in the US, where generics have also been approved, and various other brand names Todol "{Opsonin Pharma Limited,Bangladesh},"Minolac" {ACI Pharmaceuticals},"K-nil" {Rephco Pharmaceuticals}. "Ketolac" {Nucleus Pharmaceuticals} around the world) is a non-steroidal anti-inflammatory drug (NSAID) in the family of heterocyclic acetic acid derivatives, often used as an analgesic. 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 (i.e., eye-drop) solution of ketorolac is available and is used to treat eye pain and to relieve the itchiness and burning of seasonal allergies.The FDA has approved an intranasal formulation of ketorolac tromethamine (Sprix Nasal Spray) for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.

  Medical uses

Ketorolac is indicated for short-term management of moderate to severe pain.^[1] 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 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.^[2] The ophthalmic formulation can be used instead of steroidal anti inflammatories in cases where a raised intraocular pressure (glaucoma) is to be avoided.

  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.^[3] A post-marketing surveillance study^[4] 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.

  Warnings and precautions

This section does not cite any references or sources. (November 2011)

The most serious risks associated with ketorolac are, as with other NSAIDs, gastrointestinal ulcers, bleeding and perforation; renal (kidney) events ranging from interstitial nephritis to complete kidney failure; hemorrhage, and hypersensitivity reactions.

As with other NSAIDs, fluid and solute retention and edema have been reported with ketorolac. Ketorolac also elevates liver protein 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.

  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 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).

  Mechanism of action

This section does not cite any references or sources. (November 2011)

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.

  Chemistry

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.^[5]

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.

  Availability

In the United States,^[6] United Kingdom,^[7] Canada,^[8], Australia^[9] and Lithuania this drug cannot be sold over-the-counter and must be administered only with a prescription. It is commonly available over-the-counter in Mexico and other areas of Latin America, at the pharmacist's discretion. It is not approved for oral use in Belgium and Spain.

  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.^[10]

In Colombia (South America) it is marketed under Ketrón from Laboratorios Bussié.

Apotex, a Canadian manufacturer, offers generic Ketorolac tromethamine as a 0.5% ophthalmic solution and as 10 mg tablets under the name "Apo-Ketorolac",^[11] 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.^[12]

Ranbaxy, an Indian manufacturer, makes ketorolac in tablets and ampoules under a name "Ketanov". Another Indian manufacturer Dr. Reddy's makes ketorolac under a name "Ketorol".

  References

  External links

• Published studies related to ketorolac, at DrugLib
• MedicineNet.com information on ophthalmic ketorolac
• cme.medscape.com on nasal ketorolac