NSAIDs Flashcards
What are the cardinal signs of inflammation?
Pain, redness, heat, swelling, often loss of function.
What are four roles of COX-1 prostaglandins?
Gastric protection
Renal blood flow
Platelet aggregation
Starting parturition (labour)
COX-_ is constitutive, whereas COX-_ is induced.
COX-1: constitutive
COX-2: induced
Prostaglandins and thromboxanes are both…
eicosanoids
What are two important eicosanoids involved in the therapeutic effect of NSAIDs?
prostaglandins and thromboxanes. Mostly he talks about prostaglandins.
What are two examples of major COX-2 inducers?
IL-1, TNF-a
1) Scientists generally attribute the therapeutic effects of NSAIDs to ___ inhibition, and the side effects to ___ inhibitinon.
2) but now we know that’s an oversimplification. How do we know that?
COX-2 (therapeutic)
COX-1 (side effects)
We know that’s an oversimplification because newer COX-2 selective inhibitors aren’t anywhere near tolerated as we predicted.
What might explain why COX-2 selective inhibitors didn’t work as well as we thought?
COX-2 probably mediates some healing functions (inc. inflammation in general), and after the switch (following unselective inhibitors), damage (esp. GI) took longer to resolve.
What’s the flagship 1st gen NSAID?
What’s the flagship 2nd gen NSAID?
Aspirin
Coxib
What is aspirin’s mechanism of preventing platelet formation?
Irreversible inhibition of COX-1
->Reducing Thromboxane TXA2 synthesis.
To prevent platelet aggregation, aspirin prevents the synthesis of which eicosanoid by COX-1?
the thromboxane TXA2
What do PGs do that normally mediates inflammatory pain?
They sensitise nociceptive nerve fibres to inflammatory mediators like:
bradykinin,
seratonin,
histamine
What (e.g. of) inflammatory mediators are normally responsible for sensitising nociceptive nerve fibres to the basic pain message?
bradykinin, seratonin, histamine
How would NSAIDs help with oedema?
Preventing [PG-mediated] vasodilation
What about inflammation DON’T NDAIDs prevent?
Migration of inflammatory cells.
How do prostaglandins normally adjust the set-point temperature of the body, causing fever?
IL-1 triggers PG production in the hypothalamus, which is used in the process of pyrogenesis.
Bonus: because this is inflammatory-mediated, NSAIDs don’t affect temperature in normal conditions.
What is aspirin’s mechanism of inhibiting COX?
irreversible acetylation of COX [at ser530].
What function of COX-1 in the body is relevant to the side effect of fluid retention?
Increasing renal flow. NSAIDs reduce GFR.
What do prostaglandins do in the stomach - what’s the side effect when they’re inhibited?
They decrease pepsin/acid and increase mucus.
COX-1 inhibition therefore has the opposite effect - leading to mucosal irritation in the tummy.
What are three common indications for aspiring despite high GI effects?
- Mild pain
- CV: antiplatelet following MI or prophylactically for ischaemic syndromes.
- rheumatic fever/arthritis (antipyretic & analgesic).
Why is ibuprofen the drug of choice for inflammatory joint problems, as well as SHOULD be more generally for mild pain management?
Effective and well tolerated - much lower incidence of symptoms.
Recall it’s just a competitive substrate.
What will I find piles of in C’s room?
Ibuprofen - dysmenorrhea.
What’s an example of a [weakly] COX-2 selective NSAID?
Piroxicam.
What’s the downside of paracetamol? (Crossover with toxicology)
NPBQI
Which people suffer most from NSAID side effects?
Recall - what would those side-effects be?
Oldies.
What would scare concerned aussie mums about giving their kids aspirin?
Why are they sorta right?
Reye’s Syndrome (following viral infections).
Kids should be given panadol, not aspirin.
Why have a lot of Coxibs been withdrawn?
- significant gastroduodenal stress
- useless for cardiac events (no antiplatelet action)
- slowed peptic ulcer healing
Aspirin PK:
<600mg (low dose): __th order kinetics with a ___ hour half life.
>4g (anti-inflammatory dose): __ order kinetics with a ___ hour half life.
600mg: 1st; 3.5h
>4g: 0th; >15h
The doses for prophylaxis vs. anti-inflammation are different in magnitude. The kinetics in ______ doses are zero order and the half life is drastically extended.
Antiinflammatory - zero order.
