Haematology and immunology: Pharmacology - Eicosanoids

Question 1

• Tell me about the arachadonic acid pathways (Fig 18-1, Fig 18-2)
• What do the products of arachadonic acid do? Tell me about prostaglandins
  and thromboxanes
• What are eicosanoids? What clinical uses do they have?

Question 2

What are eicosanoids? What is the most abundant eicosanoid precursor?

Answer 2

Oxidation products of polyunsaturated 20-carbon LCFAs
Most abundant precursor is arachidonic acid

Question 3

Describe the pathways of arachidonic acid release and metabolism

Answer 3

AA mobilised from membrane phospholipids by phospholipase A2
May then be oxygenated by four routes:
1. Cyclooxygenases (COX)
2. Lipoxygenases (LOX)
3. CYP450
4. Non-enzymatically via isoeicosanoid pathway (direct free radical-based action)

Question 4

Describe the pathway of prostanoid synthesis

Answer 4

AA is oxygenated by COX-1 and COX-2 to produce PGG2, which is then further modified by COX to produce PGH2
PGH2 is converted to prostaglandins (PGD2, PGE2. PGF), thromboxane (TXA2), and prostacyclin (PGI2) by the action of downstream isomerases and synthases

Question 5

What is the difference in expression between COX-1 and COX-2?

Answer 5

COX-1 expressed constitutively
COX-2 inducible (major source of prostanoids in inflammation and cancer)

Question 6

Give three examples of selective COX-2 inhibitors

Answer 6

Celecoxib
Meloxicam
Diclofenac

Question 7

Describe the mechanism of action of aspirin at low vs high doses

Answer 7

Non-selective irreversible COX inhibitor
Low dose: preferentially inhibits platelet COX-1
High dose: inhibits systemic COX-1 and COX-2

Question 8

Mechanism of action and clinical applications of misoprostol

Answer 8

PGE1 derivative
Prevents peptic ulcer, used in combination with mifepristone (an antiprogestin) for termination of early pregnancy

Question 9

Mechanism of action and clinical applications of latanoprost

Answer 9

PGF-2a derivative
Reduce IOP

Question 10

Clinical applications of epoprostenol

Answer 10

Prostacyclin derivative
Potent vasodilator and inhibitor of platelet aggregation, used in RV failure and pulmonary HTN

Question 11

In what cells are leukotrienes predominantly generated?

Answer 11

Leukocytes

Question 12

Five effects of TXA2

Answer 12

1. Vasoconstrictor
2. Platelet aggregation
3. Bronchoconstriction
4. Uterine muscle contraction
5. Smooth muscle mitogen

Question 13

Which prostaglandins function as vasodilators and which function as vasoconstrictors?

Answer 13

Vasoconstrictors: PGF-2a, TXA2
Vasodilators: PGI2, PGE2

Question 14

Five effects of PGI2 (prostacyclin)

Answer 14

1. Vasodilation (causes oedema and leukocyte infiltration in inflammation)
2. Inhibitor of platelet aggregation
3. Bronchodilation
4. Increased GFR (via local vasodilation)
5. Uterine muscle relaxation

Question 15

What are the major products of endothelial-derived COX-1 and COX-2?

Answer 15

COX-1: TXA2
COX-2: PGI2

Question 16

What are the major renal eicosanoid products and what are their effects?

Answer 16

PGE2, PGI2
Vasodilatory - increase GFR

Question 17

Ten effects of PGE2

Answer 17

1. Vasodilation (causes oedema and leukocyte infiltration in inflammation)
2. Enhance platelet aggregation at low doses and inhibit at high doses
3. Fever
4. Bronchodilation
5. Increased GI motility
6. Increased GFR (via local vasodilation)
7. Contract uterine muscle at low doses and relax at high doses
8. Increased pain perception
9. Increased bone turnover
10. Decreased IOP

Question 18

Mechanism of action of montelukast

Answer 18

Leukotriene-receptor antagonist
Inhibits leukotriene-mediated bronchoconstriction

Question 19

What is the effect of corticosteroids on eicosanoid production?

Answer 19

Reduces, by stimulating inhibitory proteins (annexins or lipocortins) and inhibiting phospholipase A2

Question 20

Four effects of leukotrienes

Answer 20

1. Chemoattractant and neutrophil/eosinophil activator
2. Increased endothelial permeability
3. Bronchoconstriction
4. Increased airway mucus secretion and vascular permeability