Description: Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) of the acetic acid chemical class. Ketorolac possesses antipyretic and analgesic properties. As a pyrrolo-pyrrole, ketorolac is chemically related to indomethacin and tolmetin. The onset and efficacy of analgesia after systemic administration are claimed to be comparable to that of morphine, but ketorolac causes less drowsiness, nausea, and vomiting. Post-marketing studies have not found IM ketorolac to be superior to oral ibuprofen for the treatment of acute musculoskeletal pain.[918] Unlike other NSAIDs, ketorolac should only be used for up to 5 days consecutive days. Also, oral use is only for therapy continuation after parenteral administration. Ketorolac was approved by the FDA for parenteral use in November 1989, oral use in December 1991, and ophthalmic use in November 1992. A preservative-free (Acular® PF) and a lower strength (Acular LS™) ophthalmic solution were FDA-approved in November 1997 and May 2003, respectively.

Mechanism of Action: Ketorolac competitively inhibits both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, by blocking arachidonate binding resulting in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. The enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step of the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).
•Anti-inflammatory Activity: The anti-inflammatory mechanism of ketorolac is due to decreased prostaglandin synthesis via inhibition of COX-1 and COX-2. It appears that the anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme. However, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis.
•Analgesic Activity: Ketorolac is effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, ketorolac has an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.
•Antipyretic Activity: Ketorolac promotes a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE2, in circumventricular organs in and near the hypothalamus. Ketorolac may mask fever in some patients, especially with high or chronic dosing.
•Ophthalmic Activity: Following topical application to the eye, ketorolac inhibits miosis by inhibiting the biosynthesis of ocular prostaglandins. Prostaglandins play a role in the miotic response produced during ocular surgery by constricting the iris sphincter independently of cholinergic mechanisms. In the eye, prostaglandins also have been shown to disrupt the blood-aqueous humor barrier, cause vasodilation, increase vascular permeability, promote leukocytosis, and increase intraocular pressure (IOP). The degree of ocular inflammatory response is correlated with prostaglandin-induced increases in ciliary epithelium permeability. When applied topically to the eye, NSAIDs inhibit the synthesis of prostaglandins in the iris, ciliary body, and conjunctiva. Thus, NSAIDs may prevent many of the manifestations of ocular inflammation. Ketorolac does not affect intraocular pressure or tonographic aqueous outflow resistance and does not interfere with the action of acetylcholine administered during ocular surgery. Ketorolac also does not prevent increases in intraocular pressure or decreases in aqueous outflow induced by topical corticosteroids.
•GI Effects: Gastrointestinal side effects of ketorolac are primarily contributed to COX-1 inhibition; however, potential role of COX-2 inhibition in the GI tract has not been fully elucidated. In comparison to other NSAIDs, ketorolac has been associated an increased incidence of GI effects and has dosing restrictions to limit these effects.
•Platelet Effects: The inhibition of platelet aggregation seen with ketorolac is due to dose-dependent inhibition of COX-1 in platelets leading to decreased levels of platelet thromboxane A2 and an increase in bleeding time (see Adverse Reactions). The inhibition of platelet aggregation is reversible within 24—48 hours of ketorolac discontinuation. This differs from aspirin, which irreversibly binds to COX-1 in platelets inhibiting this enzyme for the life of the cell.
•Renal Effects: In the kidney, prostaglandins, produced by both COX-1 and COX-2, are important regulators of sodium and water reabsorption through PGE2 and of renal function and hemodynamics via PGI2 in response to vasoconstrictive factors (e.g., endothelin-1, a factor that increases peripheral vascular resistance) and through effects on the renin-angiotensin system. In the setting of decreased volume, PGI2, helps maintain renal blood flow by counteracting other vasoconstrictive autocoids. In conditions where renal blood flow is dependent upon prostaglandin synthesis, administration of NSAIDs can result in significant decreases in renal blood flow leading to acute renal failure. In addition, alterations in sodium and water reabsorption may worsen increased blood pressure, which can be significant in selected individuals.


Pharmacokinetics: Ketorolac is administered orally, parenterally, or as an ophthalmic solution. Parenteral and oral dosages produce similar pharmacokinetic profiles. Absorption is rapid and complete; bioavailability is 100% after oral, IV, or IM administration. Food decreases the rate, but not the extent, of absorption. Peak plasma concentrations after IM injection and oral administration are achieved within an hour. When ketorolac 10 mg is administered systemically every 6 hours, peak plasma concentrations at steady state are about 960 ng/ml. Measurable, but low, serum concentrations are detectable after ophthalmic administration. Following instillation of one drop (0.05 ml) of 0.5% ketorolac solution into the eye, only 5 of 26 subjects had detectable plasma concentrations of ketorolac (range 10.7—22.5 ng/ml) at treatment day 10. Ketorolac is more than 99% bound to albumin. Ketorolac crosses the placenta and is distributed into breast milk in small quantities (see Contraindications). The mean elimination half-life of ketorolac after IM or oral dosing is 5.3 hours with a range of 3.5—9.2 and 2.4—9 hours, respectively. Ketorolac is metabolized through hydroxylation in the liver to form p-hydroxyketorolac, which has a potency of less than 1% of the parent drug. Conjugation with glucuronic acid also occurs. Ketorolac and its metabolites are primarily excreted in the urine (91%), and the remainder is eliminated in the feces.

Following IM or IV injection, the onset of analgesia occurs in about 30 minutes, with a peak effect around 1—2 hours, and a duration of action of 4—6 hours. Following oral administration, analgesia occurs in 30—60 minutes, with a duration of action of 6—8 hours. Duration of analgesia increases with larger doses, but the time to peak analgesic effect is similar.

•Special Populations: The elimination half-life of ketorolac in children 4—8 years of age ranged from 3.5—10 hours and between 3.4—19.2 hours for patients with renal impairment (serum creatinine between 1.9—5 mg/dl); dosage adjustments may be necessary (see Dosage). As compared to patients younger than 65 years of age, the mean elimination half-life in the elderly was prolonged (7 hours after an IM dose and 6.1 hours after an oral dose). The pharmacokinetics of ketorolac do not appear to be significantly altered in patients with hepatic disease. An increase in the free fraction of the drug may be expected for patients with hypoalbuminemia.

References
918. Turturro MA et al. Intramuscular ketorolac versus oral ibuprofen in acute musculoskeletal pain. Ann Emerg Med 1995;26:117—20.


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