CASE FILES: BIOCHEMISTRY
A N SW E R S TO C A SE 32: N SA ID -A SSO C IA T E D
G A ST R IT IS
A 63-year-old female with arthritis taking an NSAID with recent
onset of epigastric pain relieved with food, guaiac positive stools, and iron
deficiency anemia. Endoscopic examination reveals gastric ulcers.
Biochemical etiology: Primarily, NSAID inhibition of a gastric enzyme
(COX-1) required for synthesis of prostaglandins that have a protective
effect on the gastric mucosa. A contributory factor is direct mucosal
damage due to the acidic chemistry of NSAIDs.
Decreased gastric side effects with coxibs: Traditional NSAIDs, such
as ibuprofen and aspirin, inhibit both COX-1 and COX-2. The coxibs
are selective inhibitors of COX-2, allowing continued production of
protective prostaglandins by gastric COX-1.
Difference between aspirin and other NSAIDs: Aspirin covalently
modifies platelet COX-1, thus irreversibly blocking thromboxane
formation and reducing platelet function for the lifespan of the affected
platelet (platelets cannot synthesize new proteins). The inhibitory action
of other NSAIDs on platelet COX-1 is not covalent and is eventually
reversed when the agents’ blood levels decline.
C L IN IC A L C O R R E L A T IO N
Nonsteroidal antiinflammatory drugs (NSAIDs), also known as prostaglandin
synthesis inhibitors or cyclooxygenase (COX) inhibitors, can induce upper GI
irritation or ulcers. The NSAIDs include a wide variety of medications includ-
ing aspirin, ibuprofen, naproxen, and indomethacin. These medications are
used for pain, inflammation, dysmenorrhea, headache, arthritis, or fever. These
compounds act as antiinflammatory and antipyretic agents by inhibiting COX
catalysis by prostaglandin H synthase (PGHS). PGHS has two isoenzymes:
PGHS-1 (or COX-1) is generally a basal enzyme found in various tissues
including platelets and gastric mucosa; PGHS-2 (or COX-2) is an inducible
enzyme typically expressed in response to cytokines and mitogens at sites of
inflammation or cell proliferation.
Older NSAIDs, such as aspirin and ibuprofen, inhibit both COX-1 and -2, but
a newer class of NSAIDs, called coxibs, are selective for inhibition of COX-2.
By sparing production of cytoprotective prostaglandins by mucosal COX-1,
coxibs have fewer problems with irritation and ulceration in the upper GI tract.
Thromboxane produced by platelet COX-1 in concert with a downstream
enzyme is prothrombotic, so aspirin and other NSAIDs cause platelet dys-
function and increase bleeding time. Aspirin is unusual in that it causes cova-
lent, irreversible inhibition of the COX protein, whereas other NSAIDs have
noncovalent, reversible actions. Thus, platelets, because they cannot synthesize