Autocoids: Eicosanoid Pharmacology

Question 1

1. Describe the biological origin of the eicosanoids.

Answer 1

biosynthesis of eicosanoids is limited by availability of free arachidonic acid which is released from membrane phospholipids by phospholipase A2; PLA is activated by physical, hormonal and chemical signals via Ca++ and calmodulin

Question 2

1. Name some of the enzymes that can metabolize arachidonic acid after it is hydrolyzed free by phospholipase A2

Answer 2

cytochrome P450 to epoxyeicosatrienoic acids
lipoxygenases to leukotrienes ad lipoxins
cyclooxygenases to prostaglandins, prostacyclin and thromboxanes

Question 3

1. Name the 5 prostanoid agonists and their receptors from the cyclooxygenase pathway.

Answer 3

thromboxane TXA2 (TP)
PGE2 (EP)
PGF-a (FP)
PDG2 (DP)
prostacyclin PGI2 (IP)

prostanoid receptors and their signaling pathways increase or decrease cAMP based on signaling

Question 4

1. Name leukotrienes receptors from the 5-LOX pathway as well as the lipoxin receptors. (2)

Answer 4

BLT1 and 2 are activated by LTB4
CysLT1 and CysLT2 are activated by LTC4, LTD4, LTE4 and LTF4

ALX activated by LXA4 and LXB4
**CysLT1 receptors are completely inhibited by LXA and LXB

Question 5

1. What are the sources and effects of LTB4 and LTE4 leukotrienes.

Answer 5

LTB4: neutrophils activating neutrophils and plasma exudation

CysLT: mast cells, basophils, eosinophils causing bronchoconstriction, vasoconstriction (decreasing coronary blood flow, cardiac contractility and plasma exudation)

Question 6

1. Describe the physiological effects of eicosinoids.

Answer 6

GI smooth muscle
GI secretions
Penis, corpora cavernosa 
bronchial smooth muscle
uterus
vascular smooth muscle
immune system
platelets
kidney
nervous system

(note chart)

Question 7

2. What are the effects of hydrocortisone (cortisol), the main glucocorticoid in humans.

Answer 7

stimulates gluconeogenesis
promote lipolysis and lipogenesis
stimulates protein, bone catabolism
effects on CNS
immunosuppressive, anti-inflammatory effects

Question 8

3. What is the interaction between cortisol, ACTH and CRH axis and immune system?

Answer 8

immune system causes the release of IL-1,2,6 and TNF-a which stimulates hypothalamus outside of the normal negative feedback loops

Question 9

3. What is the signaling mechanism of cortisol?

Answer 9

nuclear receptors regulated gene transcription: heat shock protein blocks the active domain of the the receptor which is removed with cortisol binding
receptors dimerize and translocation to the nucleus for glucose response elements (GRE) resulting in altered gene expression

Question 10

2. How are cortisone residues modified to produce more potent forms of glucocorticoids?

Answer 10

binding of modifier molecules increases potency due to chemical change in the molecule

Question 11

3. Describe activators and repressors of corticosteroid binding mediated effects.

Answer 11

activation: annexin 1 (blocks phospholipid A2 cleavage), secretory leukoprotease inhibitor, IL-10 and inhibitor of nuclear factor kB
repression: cytokines, chemokines, adhesion molecules, inflammatory enzymes, molecules, receptors (these molecules are important for migration into tissues or inflammatory cells)

Question 12

3. Hydrocortisone (Cortizone-10)

Answer 12

natural steroid hormone secreted by the adrenal cortex used as a anti-inflammatory; is a low potency topical corticosteroids

acts via nuclear receptors that modulate gene expression by repressing COX-2 expressing and decreased endogenous inflammatory mediators

moderate biological half-life

adverse rxns essentially none with large doses, systemic corticosteroids administered can result in HPA suppression, contraindicated with Cushing’s syndrome, must be weaned from use.

Question 13

3. Prednisone

Answer 13

immunosuppressive oral corticosteroid

mechanism of action: prodrug prednisolone; acts via nuclear receptors, acting as an anti-inflammatory, represses COX-2 expression

metabolized in the liver to prednisolone

adverse rxns. CNS (headache, insomnia, vertigo etc.) GI gastritis, anorexia, cataracts, opportunistic infections, and precaution around Cushing’s syndrome and HPA axis suppression

Question 14

3. Fluticasone (Cutivate and flovent).

Answer 14

medium potency steroid used to relieve dermatosis and rhinitis and asthma prophylaxis

acts via nuclear receptors to modulate gene expression, anti-inflammatory by decreasing COX2 expression

metabolism mostly by 3A4

adverse reactions, mild and self-limiting; oropharyngeal candidiasis with the inhaled form; caution with Cushing’s syndrome, high dose and long term therapy risks HPA axis suppression; risk of cataracts