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
misoprostol
-PGE1 analog that promotes gastric mucous production and prevents damage to the stomach wall
omeprazole
proton pump blocker
Reye’s syndrome
- rare, fatal liver degeneration disease
- only seen with aspirin
- caused by the administration of aspirin during the course of a febrile viral infection in young kids — so don’t give aspirin to kids
traditional NSAIDs general properties
- nonselective, reversible competitive inhibitors of COX activity
- block the production of prostaglandins
- weak acids = well absorbed in stomach
- highly protein bound (can interact with other protein bound like warfarin)
- accumulate in sites of inflammation
- metabolized by liver and excreted by kidneys
ibuprofen
tNSAID
-GI bleeding occurs less than with aspirin
naproxen (Aleve)
tNSAID
- 20x more potent than aspirin
- rapid onset of action (60 mins) = ideal for anti-pyretic use
- take 2x day
- one of the safest NSAIDs
indomethacin
tNSAID
- 10-40x more potent than aspirin as an anti-inflammatory drug
- most effective NSAID at reducing fever
- not well tolerated
- drug of choice to promote closure of patent ductus arteriosus
sulindac
tNSAID
keterolac
tNSAID
- used as IV analgesic for moderate/severe post-surgical pain
- can be used as a replacement for opiod analgesic
acute interstitial nephritis and NSAIDs
- rare but clinically important
- drug induced kidney failure assoc with inflammatory cell infiltration
NSAIDs and cardiovascular
- all NSAIDs have an increased risk of heart attack and stroke EXCEPT aspirin and naproxen
- risk is small
- can worsen hypertension
selective COX-2 inhibitor drug names
- Celecoxib
- Rofecoxib (withdrawn)
- Valdecoxib (withdrawn)
- both withdrawn due to incr MI and stroke risk
selective COX-2 inhibitor characteristics
- fewer GI side effects
- same incidence of kidney issues
- not more efficacious than other NSAIDs
- incr cadiovascular risk b/c they selectively inhibit production of anti-thrombotic prostaglandin PGI2 while NOT blocking the pro-thrombotic prostaglandin TXA2 from COX-1 to shift the balance toward incr platelet aggregation
acetaminophen
- treats pain and fever
- doesn’t inhibit peripheral COX-2 or platelet COX-1 so no anti-inflammatory or anti-platelet activity
- decr side effects
- selectively metabolized in the brain to AM404 which inhibits COX-1 and COX-2 in the CNS and acts on the canabinoid system and both cause decr pain and fever
- metabolized by the liver
- peak blood levels at 30-60 min and T1/2 = 2-3 hrs
- better for headaches, ppl allergic to aspirin, for kids, ppl with hemophilia, ppl with GI ulcers, and gout
- can cause liver failure (especially with alcohol) b/c of buildup of NAPQ == treat with N-acetyl cysteine
oxaproxin
tNSAID
-take once a day b/c long T1/2
dilofenac
- tNSAID
- relatively selective for COX-2 so greater risk of MI/stroke
