Ketorolac

Ketorolac or ketorolac tromethamine is a non-steroidal anti-inflammatory drug (NSAID) in the family of heterocyclic acetic acidderivatives, 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 (e.g. ketoprofen, flurbiprofen, naproxen, ibuprofen,carprofen etc.), ketorolac is an isostere of ketoprofen.^{[citation needed]} 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.

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).^{[medical citation needed]}

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.