Description
Etodolac (etodolic acid) is a non-steroidal antiinflammatory/analgesic agent
useful in the treatment of various inflammatory conditions, including rheumatoid
and osteoarthritis.
Definition
ChEBI: A monocarboxylic acid that is acetic acid in which one of the methyl hydrogens is substituted by a 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl moiety. A preferential inhibitor of cyclo-oxygenase 2 and non-steroidal anti-inflammatory,
it is used for the treatment of rheumatoid arthritis and osteoarthritis, and for the alleviation of postoperative pain. Administered as the racemate, only the (S)-enantiomer is active.
Indications
Etodolac (Lodine) is indicated for the treatment of
osteoarthritis, rheumatoid arthritis, and acute pain. It inhibits
COX-2 with slightly more selectivity than COX-1
and therefore produces less GI toxicity than many other
NSAIDs. Common adverse effects include skin rashes
and CNS effects.
Brand name
Lodine(Wyeth).
General Description
Etodolac (Lodine, Ultradol), a chiral, COX-2 selectiveNSAID drug that is marketed as a racemate, possesses an indolering as the aryl portion of this group of NSAID drugs.It shares many similar properties of this group and is indicatedfor short- and long-term management of pain and OA.
Similar to ketorolac, etodolac exhibits several uniqueenantioselective pharmacokinetic properties. For example,the “inactive” (R)-enantiomer has approximately a 10-foldhigher plasma concentration than the active (S)-enantiomer.Furthermore, the active (S)-enantiomer is less protein boundthan its (R)-enantiomer and therefore has a very large volumeof distribution. It is well absorbed with an elimination halflifeof 6 to 8 hours. Etodolac is extensively metabolized intothree major inactive metabolites, 6-hydroxy etodolac (via aromatichydroxylation), 7-hydroxy-etodolac (via aromatic hydroxylation),and 8-(1'-hydroxylethyl) etodolac (via benzylichydroxylation), which are eliminated as the correspondingether glucuronides. Its unstable, acyl glucuronide, however,is subject to enterohepatic circulation and reactivation tothe parent drug, similar to other NSAIDS in this class.
Biological Activity
Non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2) (IC 50 values are 53 and >100 μ M for COX-2 and COX-1 respectively). Displays anti-inflammatory effects in both adjuvant arthritic and normal rats.
Biochem/physiol Actions
Non-steroidal anti-inflammatory compound that is a non-selective inhibitor of COX-1 and COX-2.
Mechanism of action
The primary mechanism of action appears to be
inhibition of the biosynthesis of prostaglandins at the cyclooxygenase step, with no inhibition of the lipoxygenase
system. Etodolac, however, possesses a more favorable ratio of inhibition of prostaglandin biosynthesis in human
rheumatoid synoviocytes and chondrocytes than by cultured human gastric mucosal cells compared to ibuprofen,
indomethacin, naproxen, diclofenac, and piroxicam.
Clinical Use
Etodolac is promoted as the first of a new chemical class of anti-inflammatory drugs, the pyranocarboxylic acids.
Although not strictly an arylacetic acid derivative (because there is a two-carbon atom separation between the
carboxylic acid function and the hetero-aromatic ring), it still possesses structural characteristics similar
to those of the heteroarylacetic acids and is classified here. It was introduced in the United States in 1991 for acute
and long-term use in the management of osteoarthritis and as an analgetic. It also possesses antipyretic activity.
Etodolac is marketed as a racemic mixture, although only the S-(+)-enantiomer possesses anti-inflammatory activity
in animal models. Etodolac also displays a high degree of enantioselectivity in its inhibitory effects on the
arachidonic acid cyclooxygenase system.
Veterinary Drugs and Treatments
Etodolac is labeled for the management of pain and inflammation
associated with osteoarthritis in dogs. It may find uses, however, for
a variety of conditions where pain and/or inflammation
should be
treated.
Drug interactions
Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists:
antagonism of hypotensive effect, increased risk of
nephrotoxicity and hyperkalaemiaAnalgesics: avoid concomitant use of 2 or more
NSAIDs, including aspirin (increased side effects);
avoid with ketorolac, increased risk of side effects and
haemorrhage.Antibacterials: possibly increased risk of convulsions
with quinolones.Anticoagulants: effects of coumarins and
phenindione enhanced; possibly increased risk of
bleeding with heparin, dabigatran and edoxaban -
avoid long term use with edoxaban.Antidepressants: increased risk of bleeding with
SSRIs and venlafaxine.Antidiabetic agents: effects of sulphonylureas
enhanced.Antiepileptics: possibly increased phenytoin
concentration.Antivirals: increased risk of haematological toxicity
with zidovudine; concentration possibly increased by
ritonavirCiclosporin: may potentiate nephrotoxicityCytotoxic agents: reduced excretion of methotrexate;
increased risk of bleeding with erlotinib.Diuretics: increased risk of nephrotoxicity;
antagonism of diuretic effect; hyperkalaemia with
potassium-sparing diuretics.Lithium: excretion decreased.Pentoxifylline: increased risk of bleedingTacrolimus: increased risk of nephrotoxicity.
Metabolism
Etodolac is metabolized to three hydroxylated metabolites and to glucuronide conjugates, none of which
possesses important pharmacological activity. Metabolism appears to be the same in the elderly as in the general
population, so no dosage adjustment appears necessary.
Etodolac is indicated for the management of the signs and symptoms of osteoarthritis and for the management of
pain.
References
[1] kumagai k1, kubo m, imai s, toyoda f, maeda t, okumura n, matsuura h, matsusue y.the cox-2 selective blocker etodolac inhibits tnfα-induced apoptosis in isolated rabbit articular chondrocytes. int j mol sci. 2013 sep 30;14(10):19705-15.
[2] hakozaki m1, hojo h, kikuchi s, abe m. etodolac, a selective cyclooxygenase-2 inhibitor, induces apoptosis by activating caspases in human malignant rhabdoid tumor cells (frtk-1). oncol rep. 2007 jan;17(1):169-73.
