NSAIDS
® COX 2 Inhibitors: Celecoxib, Meloxicam
o Fewer GI side effects, but more CVS risks
o Meloxicam preferentially inhibits COX 2 over COX 1, but not as selective as celecoxib
o Rofecoxib & valdecoxib withdrawn from US d/t thrombotic events
Anti-inflammatory Actions
COX inhibitionà ¯PG synthesisàno PG
mediated inflammation
-Occurs with high doses of salicylates
Analgesic Actions
PGE2 sensitizes nerve endings to
bradykinin, histamine, etc.
NSAIDSà¯PGE2àrepression of pain
-Occurs with low doses of salicylates
Antipyretic Actions
Cytokines released from WBC during
infection/HSN/malignancy/inflammationà
­PGE2à­set point of the anterior
hypothalamic thermoregulatory center
NSAIDSà¯PGE2àno fever
-Occurs with low doses of salicylates
Drug interactions
ACE-I: ¯antihypertensive effect of
ACE-I + potential renal failure
Diuretics: loop, thiazide and K sparing
depend on PGà¯diuretic effect
Triple Whammy: NSAIDS constrict
afferent arteriole & ¯GFR; ACE-I/ARBs
dilate efferent arteriole & ¯GFR;
diuretics ¯plasma volume and ¯GFR;
Combo of NSAIDS + ACE-I +
Diureticàacute renal failure (monitor
for creatinine and K+)
Corticosteroids: ­frequency/severity
of GI ulceration
Warfarin: ­risk of bleeding
Fernanda Ponce pg. 7
® Nonselective COX inhibitors: Aspirin, Diclofenac, Ibuprofen, Indomethacin (DOC for closure of the
ductus arteriosus in premies), Ketorolac, Naproxen, Piroxicam
o Aspirin: irreversibly acetylates COX (unique), all other salicylates are reversible; rapidly
deacetylated by esterases in the body forming salicylateàcan produce pharmacologic effects as
well
Mechanism of Action:
® Inhibition of COXàinhibition of the production of prostaglandins and thromboxanes
® COX 1: constitutive enzyme expressed in most tissues (including platelets) involved in cell-cell signaling
and in tissue homeostasis
o Dominant isoform in gastric epithelial cells
o Major source of cytoprotective PG formationàinhibition causes gastric damage
® COX 2: inducible isoform that is an immediate early-response gene product upregulated by stress,
growth factors, tumor promoters, and cytokines
o Major source of prostaglandins in inflammation and canceràinhibition=anti-inflammatory
o Constitutive in the kidney and brain
o Endothelial COX 2àprimary source of vascular prostacyclin
® Ability to relieve HA d/t inhibition of PG mediated vasodilation of cerebral vasculature
Contraindications Gout Adverse Effects
Aspirin and other salicylates are GI: d/t inhibition of PGI2 & PGE2 via inhibition of COX 1àgastric damage
contraindicated in children and -DOCàIndomethacin
-local irritation from contactàulceration
young adults (<20) with fever d/t -Do not use aspirin, salicylates and
-TXT: misoprostol, PPIs, AND H2 blockers
viral illnessàReye’s Syndrome tolemtin
-lowest risk: Celecoxib; high risk: Piroxicam
(hepatitis + cerebral edema) -Aspirin @ low dosesàinhibits
CVS: Imbalance b/w TXA2 and PGI2à vasoconstriction, platelet aggregation,
DOCàacetaminophen for secretion and thus urate excretion
antipyresis in children/teens
and @high dosesà­risk of renal
thrombosisàMI, stroke, death
calculi by inhibiting reabsorption
Renal: PGE2/PGI2 needed in pts w/ CHF, CKD,HTN, ¯renal perfusion to maintain
Aspirin in pregnancy (Category C
GFR; inhibitionà¯PGà¯GFR, Na/H20 retention, edema, ­BP, hyperkalemia &
risk in 1st & 2nd trimester; Category
Colon Cancer renal failure
D in 3rd)
-prolonged excessive useàanalgesic nephropathy (chronic interstitial nephritis)
Salicylates in pts with chronic liver Aspirin decreases risk by
50%àUsed in pts with FAP Aspirin HSN: d/t an ­in biosynthesis of leukotrienes
disease
Fun fact: aspirin also inhibits PGD2 -usually seen in pts w/ asthma, nasal polyps, or chronic urticariaàrhinitis,
Aspirin in pts w/ hepatic damage,
mediated flushing associated with angioedema, bronchial asthma, hypotension, shock etc.
hypoprothrombinemia, Vit K def.
or hemophilia d/t hemorrhage risk niacin used to ¯serum cholesterol, Celecoxib HSN: sulfonamide that usually causes rashes
¯LDL and ­HDL Hepatic: high doses of salicylates cause reversible hepatic injury
Therapeutic Uses Actions of Aspirin
Lungs: salicylates uncouple oxidative phosphorylationà­CO2 and ­alveolar ventilation
-Superior to opioids in the mgmt. of pain associated with inflam. -High doses directly affect medullaàhyperventilation and resp alkalosis;
-Pain from hollow viscera NOT relieved (Exception= menstrual Salicylism (mild intoxication)àdizzy, tinnitus, difficulty hearing, dim vision, mental
pain) confusion, sweat, thirst etc.
-TXT of musculoskeletal disorders @ high dosesà RA and -Toxic dosesàmixed resp alkalosis and metabolic acidosisàcentral resp. paralysis
osteoarthritis (symptomatic relief only, DOES NOT stop Platelets:
progression) Low doses irreversible inhibits TXA2 w/o affecting PGI2 production in endothelial cells à
-Approved for TXT: RA, osteoarthritis, acute gouty arthritis, ¯platelet aggregation & ­bleeding timeàcardioprotective;
ankylosing spondylitis, and dysmenorrhea Lack of TXA2 lasts for the lifetime of the platelet (7-10 days) b/c no nuclei=no synthesis of new
-Low doses are used prophylactically to: ¯ risk of recurring TIAs, COX
stroke, death; death in pts having acute MI; recurrent nonfatal
MI/death in pts w/ prior MI or unstable angina; MI and sudden Aspirinà salicylate + acetic acid
death in pts with chronic stable angina At low doses, salicylate conjugated to glycine & glucoronate by liverà1st order kinetics
Dose >1gàconjugation enzymes become saturatedàzero order kinetics
Acetaminophen: NOT an NSAID
® Analgesic and antipyretic drug lacking anti-inflammatory or anti-platelet effects
® Weak COX 1/COX 2 inhibitor in peripheral tissues
® Used to treat mild-moderate pain when an anti-inflammatory effect is not
necessaryàHA, myalgia, postpartum pain
® DOC for pain relief in osteoarthritis d/t safety and effectiveness
® DOC for short-term TXT of fever/minor pain in pregnancy
® DOC for TXT of fever/flu-like sxs in children
® Low GI, bleeding and renal risks
® Preferable to aspirin in pts with hemophilia, history of PUD or pts in which
bronchospasm is precipitated by aspirin
® Small amount is metabolized in liver by CYP2E1 to NAPQIàconjugated to glutathione
and excreted in urine
o ODàdepleted glutathione storesà ­NAPQIàhepatotoxicity
o AntidoteàN-acetylcysteine (donates a sulfhydryl group usually done by
glutathione)
® Narrow therapeutic rangeà pts w/ pre-existing liver disease or alcoholics have
increased risk of acetaminophen hepatotoxicity
® OD= most common cause of acute liver failure

Triple Whammy

Fernanda Ponce pg. 8