Ketorolac tromethamine (oral)

Ketorolac tromethamine (oral)

Clinical data
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	oral, I.M., I.V.
ATC code	M01AB15 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	100% (All routes)
Metabolism	Hepatic
Elimination 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
IUPAC name (±)-5-benzoyl-2,3-dihydro- 1H-pyrrolizine-1-carboxylic acid, 2-amino-2-(hydroxymethyl)-1,3-propanediol
CAS Number	74103-06-3
PubChem CID	3826
DrugBank	N/A
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C15H13NO3
Molar mass	376.4 g/mol

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Ketorolac or ketorolac tromethamine (marketed as Toradol - generics have been approved) is a non-steroidal anti-inflammatory drug (NSAID) in the family of propionic acids, often used as an analgesic, antipyretic (fever reducer), and anti-inflammatory. Ketorolac acts by inhibiting bodily synthesis of prostaglandins. Ketorolac in its oral and intramuscular preparations is a racemic mixture of (S)-(−)-ketorolac, the active isomer, and (R)-(+)-ketorolac. An ophthalmic solution of ketorolac is available under the name Acular, and is used to treat eye pain and to relieve the itchiness and burning of seasonal allergies.

The brand name Toradol was coined by the Syntex company of the United States.

Chemistry

Ketorolac, like other 2-arylpropionate derivatives (including ketoprofen, flurbiprofen, naproxen, ibuprofen etc.) contains a chiral carbon in the α-position of the propionate moiety. As such there are two possible enantiomers of ketorolac with the potential for different biological effects and metabolism for each enantiomer.

NSAIDs 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 is inhibited by the presence of aspirin in the blood.

Mechanism of action

The primary mechanism of action responsible for Ketorolac's anti-inflammatory/antipyretic/analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the the enzyme cyclooxygenase (COX). Like most NSAIDs, Ketorolac is a non-selective cyclooxygenase inhibitor.

As with other NSAIDs, the mechanism of the drug is associated with the chiral S form. Conversion of the R enantiomer into the S enantiomer has been shown to occur in the metabolism of ibuprofen; it is unknown whether it occurs in the metabolism of ketorolac.

Indications

Ketorolac is indicated for short-term management of pain (up to five days maximum).

Contraindications

Ketorolac is contraindicated against patients with a previously demonstrated hypersensitivity to ketorolac, and against 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 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).

Adverse effects

Similar to other NSAIDs. See inset "Ketorolac adverse effects."

Ketorolac adverse effects
Body system	Effects
General	Edema. Less frequently, hypersensitivity reactions (such as anaphylaxis, bronchospasm, laryngeal edema, tongue edema, hypotension), flushing, weight gain, or fever. Very infrequently, asthenia.
Cardiovascular	Hypertension. Less frequently, palpitation, pallor, or syncope.
Dermatologic	Rash or pruritus. Less frequently, Lyell's syndrome, Stevens-Johnson syndrome, musculo-papular rash, exfoliative dermatitis, or urticaria.
Gastrointestinal	Nausea, dyspepsia, gastrointestinal pain, constipation, diarrhea, flatulence, gastrointestinal fullness, vomiting or stomatitis. Less frequently, peptic ulceration, gastrointestinal hemorrhage, gastrointestinal perforation, melena, rectal bleeding, gastritis, eructation, anorexia, or increased appetite. Very infrequently, pancreatitis.
Hemic and lymphatic	Purpura. Less frequently, postoperative wound hemorrhage, thrombocytopenia, epistaxis, or anemia. Very infrequently, leukopenia or eosinophilia.
Neurological	Drowsiness, dizziness, headache, sweating, injection site pain. Less frequently convulsions, vertigo, tremors, abnormal dreams, hallucinations, or euphoria. Very infrequently, paresthesia, depression, insomnia, inability to concentrate, nervousness, excessive thirst, dry mouth, abnormal thinking, hyperkinesis, or stupor.
Respiratory	Less frequently, dyspnea, asthma and pulmonary edema. Very infrequently, rhinitis or cough.
Urogenital	Less frequently, acute renal failure. Very infrequently polyuria or increased urinary frequency.

Warnings and precautions

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

As with other NSAIDs, fluid and solute retention and edema have been reported with ketorolac; ketorolac elevated liver protein levels; it also inhibits platelet aggregation and may be associated with an increased risk of bleeding.

It should be noted that 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 can push the blockage through.

Cautions

Ketorolac is not recommended for pre-operative analgesia or co-administration with anesthesia because it inhibits platelet aggregation.

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 has been co-administered with meperidine and morphine without apparent adverse effects.

Ketorolac is not recommended for long-term chronic pain patients.

Dosage, availability and price

Oral dosage is 10 mg; United States price for 20 tablets hovers around US$28. Australian pricing for 20 tablets is around AU$43.39.

Injected dosages are 15, 30 and 60 mg; United States price for 10 vials of 30 mg each is around US$45, making the intramuscular preparation considerably more expensive per dose. One 60-mg dose would require the administration by injection of two vials, at about $9 per dose. Australian pricing for 5 vials is around AU$57.90, or $23.16 per dose. Ketorolac is not available on the Pharmaceutical Benefits Scheme.

In the United States, United Kingdom, Canada and Australia this drug cannot be sold over-the-counter and must be administered only with a prescription.

SYNTEX (U.S.A.) L.L.C., Palo Alto, California, U.S.A. developed the ophthalmic solution Acular, and holds the registered trademark on that name. The brand name Acular product is manufactured and distributed by Allergan, Inc., under license from Syntex.

Apotex Products Group, a Canadian manufacturer, offers generic Ketorolac tromethamine 0.5% ophthalmic solution under the name "APO-KETOROLAC" in Canada and some other countries.

Syntex and Allergan sued Apotex for patent infringement of U.S. Patent No. 5,110,493 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 claims the patent is valid until 2009.

External links

• rxlist.com monograph on ACULAR (ketorolac tromethamine ophthalmic solution) 0.5% Sterile
• allergan.com ACULAR product information
• medicinenet.com information on ketorolac tromethamine - ophthalmic (Acular)
• Druglib published studies related to Toradol (Ketorolac)

References

• 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.
• 1993. Physicians' Desk Reference, Forty-seventh edition. Montvale, N.J., Medical Economics Co. Inc., 2411-2415.