Uses
prostaglandin F2a analogue
Definition
ChEBI: Ketorolac is a racemate comprising equimolar amounts of (R)-(+)- and (S)-(-)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid. While only the (S)-(-) enantiomer is a COX1 and COX2 inhibitor, the (R)-(+) enantiomer exhibits potent analgesic activity. A non-steroidal anti-inflammatory drug, ketorolac is mainly used (generally as the tromethamine salt) for its potent analgesic properties in the short-term management of post-operative pain, and in eye drops to relieve the ocular itching associated with seasonal allergic conjunctivitis. It was withdrawn from the market in many countries in 1993 following association with haemorrhage and renal failure. It has a role as a cyclooxygenase 2 inhibitor, a cyclooxygenase 1 inhibitor, a non-steroidal anti-inflammatory drug and an analgesic. It contains a (R)-ketorolac and a (S)-ketorolac. It is a conjugate acid of a ketorolac(1-).
Indications
Ketorolac (Toradol), an NSAID chemically related
to indomethacin and tolmetin, is mainly used as an analgesic,
not for the treatment of inflammatory disease. It
is available in oral, parenteral, and topical formulations.
Brand name
Acular (Allergan); Toradol (Roche).
World Health Organization (WHO)
Ketorolac is a nonsteroidal anti-inflammatory agent used in the
management of moderate to severe acute post-operative pain. It remains on the
market in many countries with restrictions on its use.
Biological Functions
Ketorolac (Toradol) is an NSAID with very mild antiinflammatory
and antipyretic activity. It is a potent analgesic
for postoperative pain. Its efficacy is equivalent to
that of low doses of morphine in the control of pain. For
this reason it is often combined with opioids to reduce
opioid dose and related side effects while providing adequate
pain relief. It is also used to replace the opioids in
some patients with opioid sensitivity. The mechanism of
action of ketorolac involves the inhibition of COX and
decreased formation of prostaglandins. However, some
evidence exists that ketorolac may stimulate the release
of endogenous opioids as a part of its analgesic activity.
General Description
Ketorolac tromethamine (Toradol), marketed as a mixture of(R)- and (S)-ketorolac enantiomers, is a potent NSAID analgesicindicated for the treatment of moderately severe, acutepain. It should be noted that the pharmacokinetic dispositionof ketorolac in humans is subject to marked enantioselectivity.Thus, it is important to monitor the individual blood levelsso an accurate assessment of its therapeutic action can bemade correctly. However, it should be noted that, beingone of the conventional NSAIDs with highest risk of GIcomplications, its administration should not exceed 5 days.
Clinical Use
Ketorolac is a nonsteroidal
anti-inflammatory drug mainly used
for the treatment of moderate to severe postoperative
pain. Ketorolac shows a balanced inhibition
of COX-1 and COX-2 in cultured human
cells . Ketorolac is mostly used as
the tromethamine salt. Due to a number of severe
side effects including gastrointestinal disturbances,
impairment of liver functions, renal
failures, skin irritations, and other hypersensitivity
reaction it has been withdrawn in many
countries.
Synthesis
Benzoylation of 2-methylthiopyrrole
with N,N-dimethylbenzamide in the
presence of POCl3 in refluxing CH2Cl2 gives
5-benzoyl-2-methylthiopyrrole, which is condensed
with spiro-5,7-dioxa-6,6-dimethyloctane-
4,8-dione by means of NaH in DMF.
Oxidation of this product with m-chloroperbenzoic
acid in CH2Cl2 affords the sulfone, which
is submitted to methanolysis with methanol and
HCl giving 1-(3,3-dimethoxycarbonylpropyl)-
2-methanesulfonyl-5-benzoylpyrrole. Cyclization with NaH inDMFyields dimethyl-5-benzoyl-
1,2-dihydro-3H-pyrrolopyrrole-1,1-
dicarboxylate, which is finally hydrolyzed and
decarboxylated withKOHin refluxing methanol
.
