| Indication |
For acute and long-term management of signs and symptoms of
osteoarthritis and rheumatoid arthritis, as well as for the management
of pain. |
| Pharmacodynamics |
Etodolac is an anti-inflammatory agent with analgesic and
antipyretic properties. It is used to treat osteoarthritis, rheumatoid
arthritis and control acute pain. The therapeutic effects of etodolac
are achieved via inhibition of the synthesis of prostaglandins involved
in fever, pain, swelling and inflammation. Etodolac is administered as a
racemate. As with other NSAIDs, the S-form has been shown to be active
while the R-form is inactive. Both enantiomers are stable and there is
no evidence of R- to S- conversion in vivo. |
| Mechanism of action |
Similar to other NSAIDs, the anti-inflammatory effects of etodolac
result from inhibition of the enzyme cycooxygenase (COX). This
decreases the synthesis of peripheral prostaglandins involved in
mediating inflammation. Etodolac binds to the upper portion of the COX
enzyme active site and prevents its substrate, arachidonic acid, from
entering the active site. Etodolac was previously thought to be a
non-selective COX inhibitor, but it is now known to be 5 – 50 times more
selective for COX-2 than COX-1. Antipyresis may occur by central action
on the hypothalamus, resulting in peripheral dilation, increased
cutaneous blood flow, and subsequent heat loss. |
| Absorption |
Based on mass balance studies, the systemic bioavailability of
etodolac from either the tablet or capsule formulation is at least 80%. |
| Volume of distribution |
|
| Protein binding |
> 99% bound, primarily to albumin |
| Metabolism |
Etodolac is extensively metabolized in the liver. Renal
elimination of etodolac and its metabolites is the primary route of
excretion (72%). Metabolites found in urine (with percents of the
administered dose) are: unchanged etodolac (1%), etodolac glucuronide
(13%), hydroxylated metabolites (6-, 7-, and 8-OH; 5%), hydroxylated
metabolite glucuronides (20%), and unidentified metabolites (33%). Fecal
excretion accounts for 16% of its elimination. |
| Route of elimination |
It is not known whether etodolac is excreted in human milk;
however, based on its physical-chemical properties, excretion into
breast milk is expected. Etodolac is extensively metabolized in the
liver. The hydroxylated-etodolac metabolites undergo further
glucuronidation followed by renal excretion and partial elimination in
the feces (16% of dose). Approximately 1% of a etodolac dose is excreted
unchanged in the urine with 72% of the dose excreted into urine as
parent drug plus metabolite. |
| Half life |
Terminal t1/2, 7.3 ± 4.0 hours. Distribution t1/2, 0.71 ± 0.50 hours |
| Clearance |
- Oral cl=49.1 mL/h/kg [Normal healthy adults]
- Oral cl=49.4 mL/h/kg [Healthy males (18-65 years)]
- Oral cl=35.7 mL/h/kg [Healthy females (27-65 years)]
- Oral cl=45.7 mL/h/kg [Eldery (>65 years)]
- Oral cl=58.3 mL/h/kg [Renal impairement (46-73 years)]
- Oral cl=42.0 mL/h/kg [Hepatic impairement (34-60 years)]
|
| Toxicity |
Selective COX-2 inhibitors have been associated with increased
risk of serious cardiovascular events (e.g. myocardial infarction,
stroke) in some patients. Current data is insufficient to assess the
cardiovascular risk of etodolac. Etodolac may increase blood pressure
and/or cause fluid retention and edema. Risk of GI toxicity including
bleeding, ulceration and perforation. Risk of direct renal injury,
including renal papillary necrosis. Anaphylactoid and serious skin
reactions (e.g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic
epidermal necrolysis) have been reported. Common adverse events include
abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI
bleeding, GI perforation, nausea, peptic ulcer, vomiting, renal function
abnormalities, anemia, dizziness, edema, liver function test
abnormalities, headache, prolonged bleeding time, pruritus, rash,
tinnitus. Symptoms of overdose include lethargy, drowsiness, nausea,
vomiting, and epigastric pain. |
