NSAIDs Flashcards
NSAID General Indications
Reduce inflammation (RA/OA/Gout) Pain Relief (Mild/moderate pain, muscle strains, headache/migraine, surgery) Fever reduction (viral infection, common cold/flu) Promote closure of patent ductus arteriosus
ASA specific
Stroke/MI prevention
Inhibition of platelet activation
NSAID MoA
Tissue Damage -> affected tissue -> inflammatory mediators (cytokines and prostaglandins) -> pain, inflammation, fever
NSAIDs act on PG, bind to cyclooxygenases and inhibit
Phospholipase A2 -> Arachidonic acid -> cyclooxygenases -> PG/Tx synthases -> Inflammatory and homeostatic response
Differences in MoA
All NSAIDs except ASA are competitive COX enzyme inhibitors (bind to active site)
ASA is irreversible non-competitive inhibitor, covalently modifies COX in active site
COX1 and COX2
Both catalyze rate-limiting conversion of AA to PG and Tx
COX1: constitutive, expressed in most tissues, general housekeeping (platelet reg, kidney function, stomach and mucous production), inhibited by ASA and tNSAIDs NOT CELECOXIB
COX2: Inducible to proinflammatory stimuli, induced by macrophages/monocytes/chordro/osteo/fibro, constitutive low-level in kidney/endothelium/brain/ovaries/uterus, inhibited by ASA, tNSAIDs AND celecoxib
COX1 Housekeeping
The GI tract
COX1 expressed in stomach, produces PG contitutive (are cytoprotective)
Inhibit gastric acid secretion, increase HCO3 production, Increase gastric mucous production, increase vasodilation/gastric blood flow
COX1 Housekeeping
CV System
Platelets express only COX1 and produce TXA2 (vasoconstriction, platelet aggregation)
Endothelial cells express COX1 and 2 but no TXA2 synthase so only PGI2 (vasodilator, inhibits platelet aggregation)
The TXA2/PGI2 balance regulates BP and thrombogenesis, imbalance leads to hypertension, ischemia, thrombosis, MI and stroke
COX1 Housekeeping
The Kidney
COX 1 and 2 constitutively expressed in the kidney
PGs promote vasodilation, glomerular filtration rate, water and Na excretion
In disease states there are increased vasoconstrictors thus if NSAIDs are present they decrease the PG/vasodilatory protection and pt gets renal ischemia
COX1 Housekeeping
Female Reproduction
PGs play role in stimulating uterine contraction and birth, NSAIDs may delay labor
NSAID treatment during pregnancy may prematurely close fetal ductus arteriosus and adversely affect fetal circulation
Low dose ASA
Treatment of CVD and prophylactic stroke/MI prevention
ASA acetylates COX1 in platelets PERMANENTLY inhibiting its activity and TXA2 (7-10 day lifetime)
Enothelial cells are able to keep making PGI2
This promotes an anti-thrombogenic environment
High dose starts affecting PGI2 and negates the beneficial effect
Other NSAIDs do inhibit COX1 in platelets but it is reversible so the action is not as effective/long lasting as ASA
Major adverse effects of ASA and salicylates
Increased risk of GI complications (ulcers)
Increased risk of bleeding (hemophiliacs)
High dose ASA: Exacerbation of pre-existing hypertension/ heartfailure
Salicylates are 50-90% protein bound, will kick drugs off of plasma proteins and cause drug side-effects
Airway hypersensitivity
Reye’s syndrome (rare and fatal liver degenerative disease, encephalitis, occurs in young children/adolescents during febrile viral infection)
Increased risk of gout (inhibits renal uric acid excretion)
Major adverse effects of traditional NSAIDs
Nonselective for COX1 and COX2
Clinical effect is from inhibition of COX2, adverse effects are from inhibition of COX1
GI toxicity
Kidney impairment
CV, antiplatelet effect, bleeding (the more selective you are for COX2, the more risk of MI/stroke)
Exacerbation of pre-existing hypertension/ heartfailure
NSAID hypersensitivity (not from immune system)
Pregnancy-related adverse effects
Major adverse effects of selective COX2 inhibitors
Coxibs
Good for patients with GI and bleeding complications
Can exhibit similar renal toxicity as other NSAIDs
Increased risk of CV events, especially at higher doses
CONTRAINDICATED FOR PATIENTS WITH/AT RISK FOR CVD
Inhibits COX2 and thus PGI2 in endothelial cells, creates pro-thrombotic vasoconstrictory environment
NSAID Contraindications
History of GI ulcer (not celecoxib)
Renal disorders
Bleeding disorders, anti-coagulants (not celecoxib)
Hx of CVD/hypertension/heart failure (especially celecoxib)
Hypersensitivity to an NSAID
Pregnancy
Hx of gout (ASA/salicylic specific)
Children with febrile viral infections (ASA/salicylic specific)
ASA/ Salicylate toxicity
High dose: zero order kinetics, serum half life dramatically increased
Hyperventilation, metabolic acidosis, hypoglycemia, confusion, tremors, seizure, cerebral edema, respiratory depression, coma, death
Tx: alkalinzation of the urine with HCO3 (traps and excretes ASA)