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Etodolac, a non-steroidal anti-inflammatory drug which shows anti-inflammatory, analgesic and antipyretic activities 18. The mechanism of action of Etodolac is not known completely, and it was assumed that it may be related inhibition of prostaglandin synthetase. Etodolac contains both [+]S,[-]R-Etodolac. It has been verified in animals that the dextro form is biologically active. Conversion of [-] R to [+] S in vivo does not take place as both enantiomers are stable.
When compared with the solution the systemic bioavailability of Etodolac is 100% and it was 80% from mass balance studies. Etodolac is absorbed to the maximum extent and posses's bioavailability of 100% during the comparison of 200 mg capsules with Etodolac solution. Mean maximum plasma concentrations C max ranges from 14 ± 4 to 37 ± 9 microgram/ml after administration 200 to 600 mg single doses and it was reached within 80 ± 30 minutes. The dose proportionality is linear incase of doses ranging 600 mg for every 12 hours which depends on area under plasma concentration (AUC). Dose proportionality in peak concentration was observed for both total and free Etodolac upon administration of doses up to 400 mg for every 12 hours, but on administering a 600 mg dose, the peak is about 20% greater than estimated on the basis of smaller doses. Presence of food does not affect the absorption of Etodolac. Food intake reduces the peak concentration reached within one-half and increases the time to reach peak concentration through 1.4 to 3.8 hours.
The apparent volume of distribution (Vd/F) of Etodolac was in the region of 390 ml/kg. Etodolac is approximately 99% bound to plasma proteins, mainly to albumin 40. The free fraction is very minimum and that will be less than 1% and it doesn't depend on total concentration of Etodolac. It is not known that Etodolac is excreted in human milk or not, but excretion into breast milk is expected due to its physical-chemical properties.
Etodolac is widely metabolized in the liver. Cytochrome P450 system exhibits an unknown role in the metabolism of Etodolac. Human urine and plasma contains several metabolites of Etodolac. Other metabolites are to be identified. The metabolites are 6-, 7-, and 8-hydroxylated-etodolac and metabolic product of Etodolac. Upon administering a single dose of Etodolac, hydroxylated metabolites constitute for less than 10% of total drug concentration in serum. The retention of hydroxylated Etodolac metabolites in patients with renal dysfunction is not investigated. The metabolites of Etodolac undergo glucuronidation followed by renal excretion and gets limited elimination in the feces.
The oral clearance of Etodolac upon oral administration is 49 (± 16) ml/h/kg. The amount of elimination of Etodolac in the unchanged form is 1%, which is through urine and about 72% of the dose get excreted though urine as parent drug combined with metabolite:
Etodolac in the unchanged form -----1%
Glucuronidation product of Etodolac -----13%
Hydroxylated glucuronidation product----- 20%
Metabolites that are hydroxylated------(6-, 7-, and 8-OH) 5%
Even though renal elimination is a significant pathway of excreting Etodolac metabolites, there is no need of dosing management in patients with mild to moderate renal problem. The half-life of Etodolac is 6.4 hours. There is no need to dose adjustment in patients with severe renal problem or in patients undergoing hemodialysis. Fecal excretion was about 16% of the dose.
INDICATIONS AND USAGE:
Etodolac tablets are used for acute and long-lasting use in the organization of signs of the following: Rheumatoid arthritis and for the management of acute pain 41
Etodolac (NSAID) is contraindicated in patients with well-known hypersensitivity to Etodolac. Etodolac must not be given to patients who are suffering from urticaria, or other allergic-type reactions which are the side effects of NSAIDs. Severe, incurable, anaphylactic reactions have been reported in those patients. Etodolac is contraindicated for treating preoperative pain in setting the coronary artery bypass graft surgery (CABG).
NSAIDs, such as Etodolac, can direct to onset of new hypertension or deterioration of already existing hypertension, which may contribute to the enhance incidence of CV events. Blood pressure (BP) must be carefully monitored during the beginning of NSAID treatment and during the course of drug treatment.
Heart failure and edema
Retention of fluid and edema are some side effects practically viewed in some patients taking NSAIDs. Etodolac thought to be used with vigilance in patients with failure of heart or retention of fluid.
Inflammation, bleeding, ulceration and perforation of the stomach, small intestine, large intestine, that are incurable are the severe side effects of NSAIDs, such as Etodolac.
Frequent administration of Non inflammatory drugs (NSAIDs) causes renal papillary necrosis and other renal disorders. Within these patients, ingestion of a non-steroidal anti-inflammatory drug (NSAIDS) may cause decrease in prostaglandin formation which is dose dependent and, in renal blood flow, that may precipitate renal decompensation.
Stevens-Johnson Syndrome (SJS), exfoliative dermatitis, and toxic epidermal necrolysis (TEN), are the incurable side effects of Etodolac (NSAID).
Reports advise that NSAIDs may possibly lessen the antihypertensive effect of ACE inhibitors.
When Etodolac is administered in presence of antacids can decrease the peak concentration by 15 to 20% but has no noticeable effect on the tmax
When Etodolac is administered in presence of aspirin, its protein binding get reduced, even though the clearance of open free Etodolac is not changed.
Etodolac has no pharmacokinetic interaction when administered with Furosemide. The natriuretic effect of furosemide and thiazides is reduced due to Etodolac. This response resulted in the inhibition of renal prostaglandin synthesis.
Synergistic effect, GI bleeding is occurred in usage of warfarin with NSAIDS, such that users of both drugs jointly have a danger of severe GI bleeding elevated than that of users of moreover drug alone. Small time pharmacokinetic studies have said that simultaneous administration of Warfarin and Lodine® (Etodolac capsules and tablets) results in decresed protein binding but there is no change in clearance of free Warfarin.
SAFETY PROFILE OF ETODOLAC:
Etodolac is a synthesised anti-inflammatory drug with potent inhibitory activity against interleukin-1 beta (IL-1beta)-induced prostaglandin E2 biosynthesis E2 biosynthesis in chrondocytes.
The pharmacological activities and ulcerogenicity of Etodolac compare with six other nonsteroidal anti-inflammatory drugs: Indomethacin, Diclofenac sodium, Piroxicam, Naproxen, Ketoprofen and Aspirin.
The ulcerogenicity action of anti-inflammatory drugs is due to inhibition of prostaglandin biosynthesis in stomach. Etodolac showed the lowest ulcerogenicity among the 7 drugs tested. 42, 18
Etodolac is considered, overall to be an anti-inflammatory drug with potent antiarthritic activity and weak ulcerogenic activity.
DOSAGE AND ADMINISTRATION
Adult Dosing .
Dosage forms: 200,300,400,500; 400,500,600 ER