Anti-Inflammatory Drugs Flashcards
What are examples of immune mediators?
Cytokines (interleukins, interferon, TNF-alpha) Chemokines (IL-8, MCP-1) Colony-stimulating factors (GM-CSF) Adhesion molecules (ICAM-1, integrins) Eicosinoids (Prostaglandins) Endocrine (steroids, catecholamines)
How do steroids act?
Via intracellular receptors to regulate gene transcription.
What is a glucocorticoid?
An adrenal steroid that have immuno-suppressive effects.
How is the glucocorticoid receptor activated?
By cortisol and aldosterone.
The glucocorticoid receptor also interferes with what major inflammation-associated transcription factor?
NF-kB
List the pro-inflammatory genes that are down regulated by glucocorticoids.
- pro-inflam cytokines
- COX-2
- Phospholipase A2 (PLA2)
- Cell adhesion molecules
- Endothelins
- Inducible nitric oxide synthase (iNOS)
What are genes that are up regulated by glucocorticoids?
- IL-10/IL-4 (anti-inflam cytokines)
- Lipocortins/annexins (PLA2 inhibitor)
What are different routes for glucocorticoids?
Oral: Prednisone, dexamethasone
Inhalable: Fluticasone (Flixanase)
Topical: Prednisone, dexamethasone (deep heat)
In summary, what are steroidal drugs good for?
General anti-inflam drugs, BUT can have serious side effects.
What do NSAIDs do?
They inhibit prostaglandin (PFH2) biosynthesis via COX enzymes, thus they bock the enzymatic activity of COX.
Name 4 common NSAIDs.
- Aspirin
- Ibuprofen
- Diclofenac
- Naproxen
What does COX convert arachidonic acid into?
Prostaglandin H2
What does Aspirin do?
It irreversibly inhibits COX-1, so is an effective inhibitor of PG-mediated pain.
It also inhibits TXA2 release by platelets (anti-thrombotic)
Usually for migraine
What does Paracetamol do?
Good for fever and pain relief.
It reduces PG synthesis but is a pretty weak inhibitor of COX-1 and COX-2.
Where is Paracetamol metabolised?
Liver, into a toxic intermediate which can cause damage.
What is the therapeutic index?
Very low. 10x the adult dose can be fatal.
What are some adverse effects of NSAIDs?
Gastric ulcers
Renal complications
Early pregnancy loss
What is the concept behind COX-2 selective inhibitors?
To selectively inhibit COX-2 (pain and inflamm) while leaving COX-1 (maintenance/protective) uninhibited.
SO design drug with high affinity to COX-2 only.
What are 2nd generation NSAIDs?
COX-2 selective inhibitors.
e.g. Celecoxib, Rofecoxib
What are the advantages of 2nd generation NSAIDs?
Reduced GI irritation and ulcer rate (similar efficacy to non-selective NSAIDs)
can use long term for chronic conditions
short term pain relief for some
What are some unexpected adverse effects of COX-2 selective inhibitors?
- CV events
- Rofecoxib: increased risk of thrombotic events
- increased BP
- renal impairment
