Gastrointestinal Damage from Nonsteroidal Anti-Inflammatory Drugs

Abstract

The mechanisms underlying the development of gastrointestinal (GI) damage by the NSAIDs differ considerably from drug to drug. Aside from environmental or intersubject influence (e.g., concurrent disease, physical or sociopsychologic stress, dietary and genetic status), the intrinsic pharmacokinetic and physicochemical differences in these drugs account for variations in their rate of absorption or uptake from the circulation into the GI mucosa. Differences in the preference for absorption in the direrent regions of the GI tract account for the propensity of these drugs to cause injury in those regions wherein they accumulate. Bacterial flora and food antigens may be particularly important in promoting injury in the lower intestinal tract, whereas in the sterile environment of the normal stomach these may have less significance (except in achlorhydric states).The multiple cellular actions of NSAIDs are reviewed and the consequences of inhibiting prostaglandin cyclo-oxygenase considered. Under some conditions, the excess production of vasoconstrictor leukotriened HETES relative to effects of cyclo-oxygenase inhibition is postulated to have particularly important consequences in the pathogenesis of mucosal injury by NSAIDs. These consequences are separate from the concept of prostaglandin deficiency previously suggested by others.

Bioinversion of R‐flurbiprofen to S‐flurbiprofen at various dose levels in rat, mouse, and monkey

“…Prior to the drug dose for Day 4, blood was obtained via retro-orbital puncture from animals in Groups 2 and 4 to give a 24-h point for Day 3. On Day 4, blood was collected at the same time points (1,2,4,8,12, and 24 h) using the same methods described for the single-dose studies.…”

“…This has been best demonstrated with R-flurbiprofen, which is an antihyperalgesic in the rat 5 and a antineoplastic in the Min mouse model of colon cancer 6 and the TRAMP mouse model of prostate cancer. 7 As opposed to the chiral switch from the racemate to the S-enantiomer for ibuprofen and ketoprofen in Europe for the same indication, the commercialization of R-flurbiprofen for cancer and perhaps other indications would be considered a new indication-chiral switches (Structure 1).The cyclooxygenase inhibiting property of the antiinflammatory S-enantiomers is primarily responsible for the ulcerogenic properties of the APA class of NSAIDs (reviews 8,9 ). In the case of racemic flurbiprofen, the R-enantiomer exhibits 1,000-fold less cyclooxygenase activity in vitro compared to the S-enantiomer.…”

“…The cyclooxygenase inhibiting property of the antiinflammatory S-enantiomers is primarily responsible for the ulcerogenic properties of the APA class of NSAIDs (reviews 8,9 ). In the case of racemic flurbiprofen, the R-enantiomer exhibits 1,000-fold less cyclooxygenase activity in vitro compared to the S-enantiomer.…”

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“…Even though Ibuprofen is very potent and widely used among other clinically used NSAIDs, Literature is abundant with its gastric and other side effects because of free carboxylic group. These reactions range, in both severity and frequency leading to GI bleeding, ulceration and haemorrhage 2,3 . The major factor in the development of GI ulceration and haemorrhage induced by NSAIDs is the inhibition of prostaglandin synthesis, as the endogenous prostaglandins are known to have cytoprotective action on the gastric mucosa 4 .…”

Synthesis, Stability Studies, Anti-inflammatory Activity and Ulcerogenicity of Morpholinoalkyl Ester Prodrugs of Niflumic Acid

“…Isosteric modifications of fenamates such as mefenamic acid, meclofenamic acid, flufenamic acid, etc [10− 12] acid (niflumic acid) [13] and its β-morpholinoethyl ester (morniflumate) [14] are widely used (see structure formulas). Gastrointestinal (GI) side effects constitute the most frequent of all the adverse reactions of NSAIDs [15,16] that vary in both severity and frequency from relatively mild to the more serious and potentially life-threatening states, such as GI ulcers and hemorrhage [17,18]. The GI mucosal injury produced by NSAIDs is normally believed to be caused by two different mechanisms [19− 21].…”