NSAIDs Flashcards
How do all NSAIDs have their therapeutic effects?
Inhibit conversion of arachidonic acid to prostaglandin H2 (precursor of prostacyclins, other prostaglandins and thromboxane) by COX enzymes (rate limiting step)
What is the difference between NSAIDs and paracetamol?
Paracetamol has NO anti-inflammatory effect, tf not an NSAID
What are the side effects of NSAID use?
- Exacerbation of asthma symptoms
- Renal toxicity
- Gastric irritation and ulceration
- CV effects - small BP rise, salt and water retention, vasoconstriction, reduce effectiveness of anti-hyperrtensives
- Prolonged bleeding times (aspirin)
Why have COX-2 inhibitors proved less successful than hoped?
Although COX-2 inhibitors were hypothesised to be gastroprotective, there’s increasing evidence that they pose higher risk of CVD than conventional NSAIDs (unclear mechanism)
- A contributory factor may be that they selectively inhibit PGI2 production whilst sparing production of TxA2
What are prostanoids?
Prostaglandins, thromboxane, prostacyclin
Why are prostanoids important?
Variety of actions, including acting as inflammatory mediators
Compare COX-1 and COX-2
COX-1:
- Constitutive (present all the time)
- Found in many cell types
- Main roles are in regulation of homeostatic functions (EXAMPLES)
COX-2:
- Mainly inducible
- In particular by pro-inflammatory cells, e.g. leukocytes
- Both pathological and physiological functions
What reactions does COX catalyse?
- Oxygenation, which converts arachidonate to PGG2
2. Peroxidation, catalysed by a different part of enzyme, which converts PGG2 to product PGH2
Why is aspirin different to all other NSAIDs?
- Binds irreversibly to COX enzymes
- Tf actions are much longer-lasting
- Can only be reversed by de novo synthesis of new enzyme
What are the unwanted effects of aspirin?
- Gastric irritation, ulceration, bleeding and, in extreme cases, perforation
- Reduced creatinine clearance and possible nephritis
- Prolonged bleeding times, due to reduced platelet aggregation
- Bronchoconstriction in susceptible individuals
What are the wanted effects of aspirin?
Analgesic
Antipyretic
Anti-inflammatory
Why are there so many common, unwanted effects of aspirin?
Aspirin binds 200-fold more avidly to COX-1 than to COX-2
Why does aspirin prolong bleeding times but other NSAIDs do not?
Aspirin is IRREVERSIBLE COX inhibitor
- Platelets have no nucleus so cannot synthesise new enzymes once they’re blocked - can’t make thromboxane to induce platelet aggregation
- Endothelial cells CAN make new COX bc they have a nucleus –> can make prostacyclin –> inhibits platelet aggregation
Why is the incidence of unwanted side effects higher in aspirin than other NSAIDs?
- Irreversibly blocks COX
In which patients should COX-2 selective inhibitors only be used?
- Those with a history of ulcers/GI bleeding
- Patients over 65
- Patients taking other drugs which increase risk of GI side effects
- Patients needing maximal doses of NSAIDS long-term
What are the unwanted effects of PGE2?
- Sensitises nociceptors, lowering pain threshold and causing pain
- Stimulates hypothalamic neurones to increase body temp
- Enhances Th1 differentiation (–> IFN-gamma) and Th17 expansion (IL-17) - both pro-inflammatory
- Tumorigenesis
- Inhibits apoptosis - increases likelihood of necrosis
What are the desirable actions of PGE2?
- Gastroprotection
- Regulation of renal blood flow
- Bronchodilation
- Vasoregulation
Why should NSAIDs not be given to asthmatics?
- Most COX products cause bronchodilation
- COX inhibition favours production of leukotrienes - bronchoconstrictors
Why can NSAIDs cause renal toxicity?
- PGE2 usually increases renal blood flow
- NSIDs cause constriction of afferent arteriole
- Reduction in renal artery flow
- Reduced GFR
Why can NSAIDs increase risk of ulceration?
- PGE2 usually downregulates HCl secretion and stimulates mucus and bicarbonate secretion
- NSAIDs block this protective action (protecting stomach cells from acidic environment
What are the effects of NSAIDs on the CVS?
Seriously unwanted CVS effects:
- Small rise in BP
- Salt and water retention
- Vasoconstriction
- Reduce effectiveness of anti-hypertensives
- Increase incidence of MI and stroke in chronic use
Effects are dose-dependent
What are the uses of NSAIDs?
- Analgesia
- Anti-inflammatory
- Anti-pyretic
- Aspirin - anti-platelet
What strategies are there other than COX-2 selective NSAIDs for limiting GI side effects of NSAIDs?
- Topical application
- Minimise NSAID use in patients w/history of GI ulceration
- Treat H pylori if present
- Administer w/PPI
- Minimise NSAID use in patients w/other risk factors
