NSAIDs Flashcards
What are the 3 major activities of NSAIDs?
- antipyretic
- analgesic [mild to moderate pain, esp pain associated with inflammation]
- anti-inflammatory
* *inhibition of prostaglandin synthesis mediates these effects
Tx: gout, colon cancer, niacin tolerability (inhibits intense flushing mediated by release of PGD2 from skin), closure of ductus arteriosus
What is the major mechanism of action of NSAIDs?
NSAIDs inhibit the cyclooxygenase (COX) enzyme therefore inhibit the production of prostaglandins and thromboxanes.
COX-1 – constitutive enzyme expressed in most tissue involved in cell to cell signaling and tissue homeostasis. It is the dominant isoform in gastric epithelial cells and major source of cytoprotective prostaglandin formation. It is mainly involved in the formation of prostaglandins
COX-2 – inducible enzyme that acts as an immediate early-response gene product that is upregulated by stress, growth factors, tumor promoters and cytokines. COX-2 is the major source of eicosanoids in inflammation and cancer. In the kidney and brain though it is a constitutive enzyme that produces prostacyclins in the endothelial cells.
Most NSAIDs inhibit both enzymes [COX-1 and COX-2]. Gastric damage is due to inhibition of COX-1. COX-2 selective inhibitors have increased CV risk.
AE - GI effects (most common due to inhibition of COX-1 in gastric epithelial cells and local irritation of mucosa leading to ulceration), cardiovascular effects (by screwing up balance b/t TXA2 and PGI2 leadin to vasoconstriction, platelet aggregation and thrombosis) , renal effects, aspirin hypersensitivity
What are the nonselective COX inhibitors?
Aspirin (low risk GI adverse effects)
Diclofenac (low risk GI adverse effects)
Ibuprofen (low risk GI adverse effects)
Indomethacin (medium risk GI adverse effects)
Ketorolac
Naproxen (medium risk GI adverse effects)
Piroxicam (high risk GI adverse effects)
What are the COX-2 selective inhibitors?
Celecoxib (lowest risk GI adverse effects)
Meloxicam
What is Indomethacin?
NSAID commonly used in acute gout. [most NSAIDs can be used in tx of gout other than aspirin as it inhibits urate excretion at low doses therefore increasing risk of gout]
*drug of choice for closure of ductus arteriosus in premature infants
What is the cardiovascular risk associated with COX-2 selective inhibition?
Platelets produce COX-1 leading to TXA2 production which promotes platelet aggregation leading to vasoconstriction.
Endothelial cells produce COX-1 and COX-2 leading to the production of PGI2 which inhibits platelet aggregation leading to vasodilation.
Non-selective NSAIDs inhibit both COX-1 and COX-2 therefore the balance b/t TXA2 and PGI2 remains intact. With COX-2 selective inhibition there is a decrease in PGI2 synthesis from endothelial cells but there is still the production of TXA2 from platelets leading to platelet aggregation and vasoconstriction.
Although COX-2 selective inhibitors have increased CV risk, they have fewer GI side effects.
What is Celecoxib?
Only selective COX-2 selective inhibitor available in the USA. Celecoxib is a sulfonamide and may cause hypersensitivity reactions (typically rashes).
What is Rofecoxib and valdecoxib?
COX-2 selective inhibitors - these were withdrawn from the market as they are associated with thrombotic events.
What is Meloxicam?
COX-2 selective inhibitor but is not as selective as Coxibs.
What are the adverse effect of COX-2 selective inhibitors?
Decreased renal blood flow - in pts with CHF, CKD, and other situations where renal perfusion is decreased vasodilation by prostaglandins are crucial in maintaining GFR. Prostaglandins dilate the afferent arteriole and vasoconstrict the efferent via Ang II. In a pt with CHF there is increased PG in the afferent and increased Ang Ii acting on the efferent. NSAIDs come in and decrease PG synthesis on the afferent leading to vasoconstriction therefore decreases renal blood flow and worsens kidney function, elevates BP and causes fluid retention.
Analgesic nephropathy - chronic interstitial nephritis is caused by prolonged excessive consumption of analgesics. Ex. the NSAID phenacetin which is no longer available was particularly associated with analgesic nephropathy.
What is the result of aspirin hypersensitivity?
There is an increase in leukotriene biosynthesis due to diversion of arachidonate to lipoxygenase metabolism as a consequence of COX inhibition.
Vasomotor rhinitis Angioedema Urticaria bronchial Asthma laryngeal edema bronchoconstriction flushing hypotension shock
What is the drug interaction of NSAIDs with ACE-inhibitors?
ACE-inhibitors act partly by preventing breakdown of kinins that stimulate prostaglandin production. [elevated bradykinin stimulates vasodilatory PG synthesis and NO synthesis causing vasodilation and decreased BP]
NSAIDs may then diminish the antihypertensive effect of ACE-inhibitors by blocking the production of vasodilating prostaglandins.
What is the Triple Whammy drug interaction?
This is a triple combination of drugs [ACEI (or ARB) is combined with diuretic and NSAIDs] that may lead to acute kidney injury. This combination should be avoided in the elderly, pts with renal insufficiency or heart failure.
- NSAIDs constrict the afferent arteriole and reduce GFR
- ACEIs dilate the efferent arteriole and reduce GFR
- Diuretics reduce plasma volume and GFR
*monitor with creatinine and potassium levels
What is the drug interaction b/t corticosteroids with NSAIDs?
NSAIDs increase frequency or severity of gastrointestinal ulcerations when combined with corticosteroids.
What is the drug interaction b/t Warfarin and NSAIDs?
NSAIDs may increase the risk of bleeding in pts receiving warfarin.
