NSAIDs Flashcards
What are functions of COX-1?
Constitutively active across most tissues
Homeostatic: GI protection Platelet aggregation Vascular resistance Maintains renal blood flow
Pathological:
Chronic inflammation
Chronic pain
Raised BP
What are some functions of COX-2?
Inducible, typically in active/inflamed tissues
Homeostatic:
Renal homeostasis
Uterine contractions
Inhibition of platelet aggregation
Pathological: Chronic inflammation Chronic pain Fever Blood vessel permeability Tumour cell growth
What are some examples of prostanoids?
PGE2 PHF2α PGD2 PGI2 - prostacyclin TXA2 - thromboxane
Act locally via GPCRs, action enhanced by local autacoids eg bradykinin, histamine
What is the general mode of action of NSAIDs?
Inhibits COX => decreased prostaglandin, prostacyclin and thromboxane synthesis
Competes with arachidonic acid for binding to COX
What are the analgesic actions of NSAIDs?
Greater efficacy if inflamed
Decrease PGE2 synthesis in the dorsal horn => decreased neurotransmitter release => decreased excitability in pain relay
Full analgesia several days after dosing
What are the anti-inflammatory effects of NSAIDs?
Inflammation => release of local autacoids => increased COX activity => vasodilation and sweating
NSAIDs cause reduction in production of prostaglandins esp PGE2 and PGD2 => reduction in inflammation
What is the anti-pyretic effect of NSAIDs?
Inhibits hypothalamic COX-2
How do NSAIDs inhibit platelet aggregation?
Inhibit COX-1 => decreased thromboxane synthesis
What are some examples of NSAIDs?
Aspirin Ibuprofen Naproxen Diclofenac Celecoxib Parecoxib Etoricoxib
Describe the pharmacokinetics of NSAIDs
Almost complete GI absorption
Typically don’t undergo first pass metabolism
Short - long half life
Highly protein bound, relatively small Vd
Hepatic metabolism
Aspirin => salicylic acid => conjugated with glycine/glucuronic acid
Gets saturated at high doses => overdose
Describe some GI ADRs of NSAIDs
Dyspepsia, nausea, peptic ulceration, bleeding and perforation
Decreased mucus and bicarb secretion
Increased acid secretion
Decreased mucosal blood flow => enhanced toxicity and hypoxia
Decreased hydrophobicity of mucus layer due to acidic nature of NSAIDs
What are some risk factors for GI ADRs of NSAIDs?
Age Prolonged use Glucocorticoid steroids Anticoagulants Smoking Alcohol History of peptic ulcers H pylori
What are some renal ADRs of NSAIDs?
Irreversible drop in GFR
Increase in creatinine
Decrease in renal medullary blood flow
Increase in salt and water retention => HTN and oedema
Decreased renin secretion => hyperkalaemia
What are some risk factors for renal ADRs from NSAIDs?
Underlying CKD
Congestive heart failure, cirrhosis with ascites => blood flow compromise
Greater reliance on prostaglandins for vasodilation and renal perfusion
Very young and very elderly
What are some cardiovascular ADRs of NSAIDs?
Increase salt and water retention => exacerbate HF and increase BP
Vasoconstriction through reduced antagonism of ADH by prostaglandins
Reduced efficacy of antihypertensives
Traditional and COX-2 selection => increased risk of MI
Therefore pts w/ pro-thrombotic risk shouldn’t be prescribed NSAIDs (except low dose aspirin)
