Lipid Mediators

Question 1

How is the potency of NSAIDs measured?

Answer 1

Potency of NSAID action paralleled by potency of inhibition of prostaglandins.

Question 2

What is arachidonic acid?

Answer 2

• a precursor for biologically active lipids

Question 3

What are PUFA?

Answer 3

PUFA: poly-unsaturated fatty acids

Question 4

Where are PUFAs usually found?

Answer 4

The diet is usually dominated by omega-6 PUFAs

Question 5

Where is AA stored?

Answer 5

Stored esterified in membrane phospholipids (plasma membrane & nuclear membrane)

Question 6

How is AA released from membranes?

Answer 6

• Phospholipase A2 is activated by increase in intracellular calcium. - Many snake venoms contain Phopholipase A2 in large amounts.

Question 7

Explain AA Metabolism.

Answer 7

Metabolism to Eicosanoids (which are biologically active metabolites of AA). The type of eicosanoid depends on the cell type. Metabolism occurs by two types of cyclo-oxygenase which is expressed in all cells: - constitutive (COX-1) - physiological prostaglandins (PGs) - inducible (COX-2) - gene induced by inflammatory stimuli (IL-1: pathophysiological PG overproduction) Metabolism also occurs by lipoxygenase which is expressed in inflammatory cells such as eosinophils and mast cells and whose production is associated with inflammation. Cyclic-endoperoxides are highly unstable and rapidly converted into stable prostaglandins.

Question 8

How is the nomenclature of PGs dictated?

Answer 8

Nomenclature: letter denotes ring structure; subscript denotes # double bonds

Question 9

Explain the action of: PGE2

Answer 9

relaxes vascular smooth muscle - vasodilator/natriuretic; decreases BP; hyperanalgesic (sensitises nerves to painful stimuli); pyrogenic (fever producing)

Question 10

Explain the action of: PGF2α

Answer 10

bronchoconstrictor

Question 11

Explain the action of: PGD2

Answer 11

bronchoconstrictor

Question 12

PGE2, PGF2α and PGD2 do not circulate; what do they do?

Answer 12

These prostaglandins (PGs) do not circulate - degraded by endothelial cells of pulmonary capillaries and act locally at the site of production.

Question 13

When are NSAIDs indicated?

Answer 13

Anti-inflammatory: acute and chronic conditions (RA, gout) Analgesia: headache, menstrual pain, musculo-skeletal pain Antipyretic: paracetamol often preferred.

Question 14

What is a major side effect of NSAIDs?

Answer 14

One major adverse effect is gastric irritation/ulceration.

Question 15

What is pain? (biochemically)

Answer 15

Long term interactions causes IL-1beta to induce an increase in BK1 receptors and an increase in COX-2 and PLA2 which causes increased pain.

Question 16

What is fever? (biochemically)

Answer 16

Inflammation leads to macrophage activation which releases cytokines. This is also associated with increased PGE2 release which raises the temperature through cAMP in the hypothalamus.

Question 17

What is the gastric role of PGE2?

Answer 17

PGE2 promotes blood flow and angiogenesis as well as increasing mucus secretion. It also reduces the gastric acid secretion which acts as a protective mechanism from gastric ulcers.

Question 18

What are prostacyclin and thromboxane? Where/When are they produced?

Answer 18

During the AA cascade, prostacyclin and thromboxane are also produced. Prostacyclin is chemically unstable with a half life of around 3 minutes. It is produced by endothelial cells and is used to reduce platelet activation and as a vasodilator. It also protects against coronary artery disease. Thromboxane A2 is also chemically unstable with a half life of around 30 seconds. It is produced by platelets and increases platelet activation and acts as a vasoconstrictor. It promotes coronary artery disease. The actions directly oppose those of PGI2.

Question 19

Explain Aspirin?

Answer 19

Aspirin is ‘special’ in that it causes acetylation of COX and vascualar protection as well as by triggering lipotoxins.

Question 20

What is the significance of the enzyme 5-lipoxygenase?

Answer 20

• Active in the AA cascade to produce LTs - restricted to distribution to inflammatory cells - no known physiological role beyond inflammation - activated by increase in intracellular calcium by stimuli produced in infection, allergic response and other forms of inflammation.

Question 21

List some properties of Leukotrienes.

Answer 21

• bronchoconstrictors - vasocactive - leaky vessels can cause tissue oedema - implicated in asthma - Leukotriene receptor antagonists (such as montelukast) block cysteinyl-leukotrienes

Question 22

What is the action of LT B4?

Answer 22

Leukotriene B4: no direct actions on smooth muscle; promoted inflammation by attracting leukocytes

Question 23

Where are some sites of action of NSAIDs in the AA cascade?

Answer 23