NSAIDs Flashcards
used to treat…
inflammation, pain, and fever by inhibiting the binding of arachidonic acid to COXs to prevent the production of prostaglandins and thromboxane
COX-1
Cox-1 = homeostasis
-constitutive expression in all cells located in the ER
COX-2
COX-2 = inflammation
- inducible in: WBCs, endothelial cells, and cartilage cells by pro-inflammatory cytokines
- constitutively active in kidney, endothelium, brain, ovaries, uterus, and small intestine
TXA2
thromboxane
- causes vasoconstriction and promotes platelet aggregation and activation
- made by platelets which only have COX-1
PGI2
- prostacyclin
- made by endothelial cells which have both COX-1 and COX-2 but lack TXA2 synthetase
- vasodilator and inhibits platelet aggregation
NSAIDs and the kidney
-decreases renal blood flow, decr GFR, and promotes water/salt retention which can compromise kidney function, especially in pts with underlying kidney disease or conditions of volume depletion like heart failure or cirrhosis
NSAIDs and pregnancy
- can delay labor
- in late pregnancy, can cause the closing of the ductus arteriosus in the fetus which is kept open by prostaglandins
- associated with miscarriage and post-partum hemmorhage
Aspirin and other salicylates
- weak acid (easily absorbed in stomach)
- short serum half life b/c metabolized by serum esterases to salicyclic acid and ascetic acid
- non-selective inhibitor of both COX-1 and COX-2
- irreversibly inhibits COX-1 by acetylating the enzyme in the active site to prevent binding of the arachidonic substrate
- same mechanism to inhibit COX-2 but it has less of an effect on COX-2
- salicylate only acts as a competitive antagonist for COXs
- low dose has anti-platelet activity for anti-thrombogenic state to treat heart disease (because only affects COX-1 in platelets– this effect can be countered by other NSAIDs) and higher dose = analgesic
salsalate
-dimer of salicylic acid and then converted to salicylic acid so ~ same effects as it
diflunisal
- salicylic acid derivative
- more potent anti-inflammatory agent
- can’t cross the BBB so has no anti-pyretic effect (fever reducing)
Who should not take aspirin/NSAIDs?
- pts with asthma (can cause an asthma attack (hypersensitivity rxn))
- pts with incr risk of GI complications
- pts with bleeding tendencies (b/c it prolongs bleeding time by blocking TXA2 production): shouldn’t take NSAIDs ~4-5 half lives before surgery (wks)
- pts with gout should not take ASPIRIN and salicylates only (affects uric acid secretion– low doses incr uric acid)
- high doses for ppl with hypertension or heart failure (b/c it promotes vasoconstriction)
- children should not take ASPIRIN only (Reye’s syndrome)
- the elderly b/c they are susceptible to most of the above complications
- they can also incr the toxicity of lithium, methotrexate, and aminoglycosides
- pts with previous hypersensitivity to aspirin
other salicylates
- sodium thiosalicylate
- choline salicylate
- magnesium salicylate
- methyl salicylate (Oil of Wintergreen*)
how to treat salicylate overdose
-alkalize the urine to incr its excretion
mechanism of salicylate toxicity
- they cause incr respiration resulting in an initial respiratory alkalosis and a compensatory metabolic acidosis
- acidified blood promotes the transport of the drug into the CNS causing toxicity, cerebral edema, neural hypoglycemia, coma, respiratory depression, and death
NSAIDs and GI
- PGE2 and PGI2 which are produced by COX-1, are cytoprotective for the stomach by limiting the damage to the stomach lining caused by gastric acid and digestive enzymes
- NSAIDs inhibit these
- can cause GI bleeding and can aggravate/promote ulcer development
- protect from this by giving misoprostol or omeprazole
