How do steroidal anti-inflammatory drugs act?
Steroids such as cortisol, progesterone act via intracellular receptors to regulate gene transcription.
What is the main steroid, which produces anti-inflammatory effects?
How do Glucocorticoids function?
The glucocorticoid receptor(GR) is activated by cortisol and aldosterone.
Activated receptor moves from cytoplasm to nucleus and alters transcription of genes
GR also interferes with a major inflammation-associated transcription factor , NF-kB.
Glucocorticoid receptors are globally expressed in the body so the anti-inflammatory response will be spread throughout all cells in body.
Give examples of pro-inflammatory genes that are down-regulated by glucocorticoids?
Inducible nitric oxide synthase
Give examples of genes that are up-regulated by glucocorticoids?
Give some examples of common glucocorticoids?
NSAIDS- Describe the mechanism of action of non-steroidal anti-inflammatory drugs?
NSAIDS block the enzymatic activity of cyclo-oxygenase.(COX) COX converts arachidonic acid to prostaglandin H2. So inhibiting COX inhibits prostaglandin bio-synthesis.
What are NSAIDS used to treat?
Pain(analgesic), inflammation and fever( anti-pyretic).
BUT can have significant side-effects. Blocking COX pathways can have serious cardiovascular, renal, gastrointestinal effects.
Name some of the common NSAIDS?
What are properties of aspirin as a NSAID?
- Irreversibly inhibits COX-1
-Used for migraine
-Effective inhibitor og PG mediated pain
- Inhibits TXA2 release by platelets(anti-thrombotic)
Associated with GI problems
What are properties of paracetamol as a NSAID?
-Good anti-pyretic and analgesic
-Ineffective anti-inflammatory however
_Reduces prostaglandin synthesis
- Metabolised in the liver to a toxic metabolite which causes liver damage.
Very low therapeutic index-requires a high dose to be lethal.
Why do NSAIDS cause serious adverse effects?
Largely due to the fact that they are NON-SELECTIVE. Ibuprofen, Naproxen, Diclofenac are all non-selective. So they can act at other receptors in the body.
Another reason is most are associated with COX-1 inhibition.
Side-effects- GI problems(inhibiton of COX-1 derived PGE2), renal complications, cardiovascular effects, hepatic toxicity and pregnancy loss.
What do COX-2 selective inhibitors do?
They selectively inhibit COX-2 while leaving COX-1 uninhibited. It is used in chronic inflammatory diseases where COX-1 inhibiton causes problems.
-Reduced GI irritation, ulcer rate with similar efficacy to non-selective NSAIDS.
-Useful for long-term use in treatment of chronic conditions.
-Also for good short-term pain relief
What were some of the COX-2 selective inhibitor drugs, that caused unwanted side-effects?
-Celecoxib- cardiovascular effects
-Rofecoxib- increased risk of thrombotic events.
Both cause increased BP and renal impairment.
-Vioxx- increased risk of CVD(heart attack and stroke).