NSAIDs Flashcards
Discuss the three major actions of NSAIDs
Anti-inflammatory –> dec PGE2 and prostacycline reduced vasodil
Antipyretic effects –> inhibition of PG production in the hypothalamus
Analgesics effect –> dec PG production –> dec sensitivity nociceptor nerve endings to inflammatory mediators
What are the classes of NSAIDs?
Acetic acids = diclofenac, indomethacin, ketorolac, sulindac
Fenamates = mefanamic acid
Propionic acids = ibuprophen, ketoprofen, naproxen, tiaprofenic acid
Oxicams = meloxicam, piroxicam
Salicylates = aspirin
Coxibs = celecoxib, parecoxib
Discuss aspirin generally
Weak acid-protonated in acidic stomach env, hydrolysed to salicylate
Modifies both COX-1 and COX-2
What makes aspirin different from other NSAIDs?
Causes irreversible inhibition of COX activity due to acetylation of serine 530 (COX1) and 516 (COX2)
Inhibits platelet cyclooxygenase for 8 to 11 days
Highlight the drugs that aspirin interacts with
Warfarin = inc risk of bleeding
Probenecid
Diuretics and ACE inhibitors = triple whammy
Outline Reyes Syndrome
Rare syndrome that occurs in <18 y/o who have taken aspirin
Typically occurs when the person is recovering from viral illness with aspirin use
abnormal accumulation of fat in liver and inc pressure in brain (encephalopathy)
20-40% mortality
What is the MOA and indication of ibuprofen?
Competitive inhibitor of COX1/2
Better tolerated than aspirin, fewer GIT ADRs
Indication = analgesic, antipyretic, anti-inflam, used in formulations w/ codeine, paracetamol
What drugs interact with ibuprofen?
Warfarin
Probenecid
diuretics, ACE inhibitors = triple whammy
What is the MOA and indication of Indomethacin?
Slow, time-dependent inhibitor of COX1 and COX2 (conformational)
Less well tolerated than aspirin and ibuprofen –> high incidence of GIT reactions
Indication = not normally for analgesic or anti-pyretic, antiinflammatory agent
Which drugs interact with indometacin?
Warfarin
Diuretics, ACEi
probenecid
What is the MOA and indication of paracetamol?
Effective analgesic, anti-pyretic traced to inhibition of PGs in the CNS
Weak anti-inflammatory agents (weak COX inhibitor in the presence of high concentrations of peroxides)
Well tolerated, hepatotoxicity in overdose (10-15g)
Indication = analgesics/anti-pyretic, useful analgesic where aspirin C/I
What are the ADRs of NSAIDs?
Inhibition of gastric COX-1 responsible for production of PGs that inhibit acid secretion and protect mucosa
Cardiac side affects
How do PG protect the GIT?
1) vasodilation –> blood flow
2) inc bicarbonate section
3) inhibit gastric acids
Which NSAIDs carry the greatest risk of GIT complications compared to ibuprofen?
Azapopazone (the most)
indometacin > naproxen > diclofenac > aspirin
What factors inc the risk of GI injury associated with NSAID use?
Age >65 yrs (esp >70)
Hx peptic ulcers
Use of two or more NSAIDs at the same time
Concomitant therapy w/ antiplatelet agents, anticoagulants, corticosteroids
Severe illness
H. pylori infection
What are some renal ADRs of NSAIDs?
renal insufficiency due to dec afferent blood flow caused by PGE2 and PGI2 inhibition
What are some blood ADRs of NSAIDs?
Disturbances in platelet function, inc bleeding time due to TXA2 effects
What are some skin ADRs of NSAIDs?
Mild erythemous, urticarial, photosensitivity
Stevens-Johnson syndrome (ibuprofen in young children)
What are some C/I for NSAID use?
active peptic ulcers, NSAID allergies
Sulfonamide allergy (celecoxib)
COX-2 antagonists may inc thrombotic events
Inc bronchospasms
Explain the MOA behind NSAID induced bronchospasm
Inhibition of COX1/2 > inc arachidonic acid > inc lipoxygenases > Inc H(P)ETE, leukotrienes, lipoxins
How does NSAID induced inc of leukotrienes cause bronchospasms?
LTB4 = initiate inflam response (chemotactic)
Cysteinyl leukotrienes (LTC, D, E) = initiated inflam response
- Constrict bronchial smooth muscle, vasoconstriction
Explain the mechanism of the triple whammy
NSAIDs –> reduce the afferent blood flow to the kidney dec GFR
ACEi –> dilate efferent blood, dec GFR further (asking more blood to leave kidney)
Diuretics –> reduce blood flow to the glomerulus due to inc fluid loss which dec blood vol
Dec renal function –> drying out of kidney
What is used to reverse NSAID toxicity?
NO-NSAIDS (nitric oxide release NSAIDs)
NO-aspirin, NO-diclofenac, NO-Ketoprofen, MO-flurbiprofen
How does COX-2 selectivity work?
COX-2 selective NSAIDs are too large to fit in to the COX-1 binding site and this can’t bind
