L10 - NSAIDs Flashcards
What is the COX enzyme substrate and products?
substrate: arichidonic acid
products: thromboxane, prostaglandins, prostacyclins
How do NSAIDs work?
they inhibit COX to cause a reduction in the mediators produced by it (thromboxane, prostaglandins, prostacyclins)
Where is COX1 found and what function is it involved in?
- expressed in almost all cells
- involved in PGE1, PGE2 and PGI2 production in the stomach which is involved in the mucous layer which protects the stomach lining from the acidic contents of the stomach
What roles do PGE2 and PGI2 have? How are they produced and where?
- produced by COX1 enzyme which is found in most cells
- have a gastroprotective role by stimulating mucosal secretion and inhibiting gastric acid production
Why do NSAIDs produce GI side effects?
Because the NSAID drugs that inhibit COX1 enzyme reduce the mucous layer of the stomach which results in ulcerations or perforations for example
What NSAIDs non-selectively inhibit COX enzyme? i.e. inhibit COX1 and COX2
- aspirin
- paracetamol
- ibuprofen
- diclofenac
- indomethacin
What is the NSAID that selectively inhibits COX2 enzyme? What are the associated risks and who is prescribed to use them?
- celecoxib (Celebrex)
- it increases the risk of heart attack so currently only prescribed to patients with GI side effects with NSAIDs and whose cardiovascular risk has been assessed
What is a feature of aspirin that makes it different from other NSAIDs?
- it irreversibly binds via covalent bonding which means it has cumulative effects
- it irreversibly binds to TXA2 which causes reduced rate of blood clot formation
What are the common adverse side effects of aspirin?
- GIT effects incl. nausea and vomiting
- microscopic bleeding
- increased bleeding time
- allergies
Aspirin has opposite effects in two different parts of the clotting process. Explain why and how dosing affects the effect.
- in the portal circulation, aspirin affects TXA2 which normally causes platelet aggregation so has the effect of inhibiting platelet aggregation.
- in the vascular endothelium aspirin affects PGI2 which normally inhibits platelet aggregation so has the effect of increased platelet aggregation
- low dose affects the portal circulation more resulting in overall effect of reduced platelet aggregation
What effect does indomethacin have?
it is a potent anti-inflammatory agent
What effect does ibuprofen have?
anti-inflammatory and analgesic
What effect does diclofenac have?
analgesic treatment for inflammatory pain
What effects does paracetamol have?
analgesic and anti-pyretic, no anti-inflammatory
What is a feature about indomethacin?
more selective for COX1 so associated with more adverse side effects
What are the adverse effects of indomethacin?
GI upset, impaired renal function
What is a feature of ibuprofen?
safest NSAID with fewer side effects but weaker anti-inflammatory properties compared to other NSAIDs
What are the common side effects of ibuprofen?
GI disturbances
What are 2 features of diclofenac?
- more potent than indomethacin
- powerful analgesic systemically but achieve targeted effects when used locally as gel
What are the side effects of diclofenac?
GI upset and headaches
What are 4 features of paracetamol?
- well absorbed when given orally
- peak plasma after 30-60 min
- health life 2-4 hours at therapeutic doses
- narrow therapeutic range as toxic dose 2-3X max therapeutic dose causing hepatotoxicity
What are the adverse effects of paracetamol?
adverse effects are uncommon at therapeutic doses, no GI effects, liver toxicity if regular high intake for a long time
What are the adverse effects associated with NSAIDs?
- GI
- renal
- headaches
- dizziness
- skin reactions
What are is the effect of celecoxib (Celebrex)?
it has a high therapeutic potential for inflammatory conditions
