Inflammatory mediators as targets for drug action

Question 1

What are the main vascular responses to inflammatory mediators?

Answer 1

Vasodilation - caused by histamine, prostaglandins.

Increased vascular permeability - histamine, platelet activating factor.

Exudation - fluid filters from circulatory system into surrounding tissue, carries leukocytes and components of proteolytic enzyme cascade.

Question 2

What is an eicosanoid?

Answer 2

Generated from phospholipid

Generated on demand and consist of prostaglandins, thromboxanes and leukotrienes.

major involvement in inflammation.

Question 3

What is the path of synthesis of eicosanoids?

Answer 3

1. Phospholipids in plasma membrane are catalysed into arachidonic acid via the enzyme phospholipase A2 in response to stimuli such as bradykinin, thrombin, complement C5a, cell damage.
2. Arachidonic acid is then made into different eicosanoids (prostaglandins, thromboxanes, leukotrienes).
3. Arachidonic acid undergoes endoperoxidase activity action via cyclooxygenase enzyme into PGG2.
4. PGG2 (prostaglandin G2) is then subject to peroxidase activity to the PGH2 by cyclooxygenase also.
5. a. PGH2 is then turned into prostaglandin PGI via prostacyclin synthase
6. b. PGH2 is then turned into PGE2, PGD2, PGf2a by prostaglandin synthase.
7. c. PGH2 is turned into thromboxane A2 (TXA2) via thromboxane synthase.

Question 4

What are the effects of prostaglandins?

Answer 4

Vasodilation of blood vessels

Inhibit platelet aggregation

Bronchodilation

CNS effects -
sensitive nociceptive neurones to action of mediators, they activate pain fibres.

They act on hypothalamus to increase body temperature.
- inflammation causes the release of interleukin 1 from macrophages. This activates the arachidonic acid pathway which produced PGE2, this acts on neurones in preoptic area which increases thermostatic set point.

This causes heat generation from shivering, skin vasoconstriction to destroy infection.

Once inflammation stops, IL-1 production stops, AA pathway reduced, less PGE2 production. This means less acting upon preoptic area lowering thermostatic set point and activation of heat dissipation mechanisms such as sweating, vasodilation.

Question 5

What is the function of COX-1

Answer 5

Maintain tissue homeostasis in cells.

Involved in house keeping - gastric protection, blood clotting, renal blood regulation.

Inflammation is not the main role of COX-1

It has a narrowing binding range.

Question 6

What is the functions of Cox-2?

Answer 6

Induced by inflammation - it is abundant in activated macrophages.

Produces prostanoids - prostaglandin and thromboxane which mediate inflammation.

Binding pocket is wide.

Question 7

What is the function of thromboxane A2?

Answer 7

Bronchoconstriction and the increase in platelet aggregation.