Lecture 25- Anti-inflammatory drugs

Question 1

How do steroidal anti-inflammatory drugs act?

Answer 1

Steroids such as cortisol, progesterone act via intracellular receptors to regulate gene transcription.

Question 2

What is the main steroid, which produces anti-inflammatory effects?

Answer 2

Glucocorticoids

Question 3

How do Glucocorticoids function?

Answer 3

• 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.

Question 4

Give examples of pro-inflammatory genes that are down-regulated by glucocorticoids?

Answer 4

• Cytokines
• COX-2
• Phospholipase A2(PLA2)
• Cell-adhesion molecules
• Endothelins
• Inducible nitric oxide synthase

Question 5

Give examples of genes that are up-regulated by glucocorticoids?

Answer 5

• IL 10/Il-4
• Lipocortins

Question 6

Give some examples of common glucocorticoids?

Answer 6

Oral- Dexamethasone

Inhalable-Flixotide

Topical- Prednisone

Question 7

NSAIDS- Describe the mechanism of action of non-steroidal anti-inflammatory drugs?

Answer 7

NSAIDS block the enzymatic activity of cyclo-oxygenase.(COX) COX converts arachidonic acid to prostaglandin H2. So inhibiting COX inhibits prostaglandin bio-synthesis.

Question 8

What are NSAIDS used to treat?

Answer 8

Pain(analgesic), inflammation and fever( anti-pyretic).

BUT can have significant side-effects. Blocking COX pathways can have serious cardiovascular, renal, gastrointestinal effects.

Question 9

Name some of the common NSAIDS?

Answer 9

1. Asirin
2. Ibuprofen
3. Diclofenac
4. Naproxen

Question 10

What are properties of aspirin as a NSAID?

Answer 10

• Irreversibly inhibits COX-1
• Used for migraine
• Effective inhibitor og PG mediated pain
• Inhibits TXA2 release by platelets(anti-thrombotic)

Associated with GI problems

Question 11

What are properties of paracetamol as a NSAID?

Answer 11

• Good anti-pyretic and analgesic
• Ineffective anti-inflammatory however

_Reduces prostaglandin synthesis

• Non-selective
• Metabolised in the liver to a toxic metabolite which causes liver damage.

Very low therapeutic index-requires a high dose to be lethal.

Question 12

Why do NSAIDS cause serious adverse effects?

Answer 12

• 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.

Question 13

What do COX-2 selective inhibitors do?

Answer 13

They selectively inhibit COX-2 while leaving COX-1 uninhibited. It is used in chronic inflammatory diseases where COX-1 inhibiton causes problems.

Advantages

• 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

Question 14

What were some of the COX-2 selective inhibitor drugs, that caused unwanted side-effects?

Answer 14

• 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).