Autocoids: Eicosanoid Pharmacology Flashcards
- Describe the biological origin of the eicosanoids.
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
- Name some of the enzymes that can metabolize arachidonic acid after it is hydrolyzed free by phospholipase A2
cytochrome P450 to epoxyeicosatrienoic acids
lipoxygenases to leukotrienes ad lipoxins
cyclooxygenases to prostaglandins, prostacyclin and thromboxanes
- Name the 5 prostanoid agonists and their receptors from the cyclooxygenase pathway.
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
- Name leukotrienes receptors from the 5-LOX pathway as well as the lipoxin receptors. (2)
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
- What are the sources and effects of LTB4 and LTE4 leukotrienes.
LTB4: neutrophils activating neutrophils and plasma exudation
CysLT: mast cells, basophils, eosinophils causing bronchoconstriction, vasoconstriction (decreasing coronary blood flow, cardiac contractility and plasma exudation)
- Describe the physiological effects of eicosinoids.
GI smooth muscle GI secretions Penis, corpora cavernosa bronchial smooth muscle uterus vascular smooth muscle immune system platelets kidney nervous system
(note chart)
- What are the effects of hydrocortisone (cortisol), the main glucocorticoid in humans.
stimulates gluconeogenesis promote lipolysis and lipogenesis stimulates protein, bone catabolism effects on CNS immunosuppressive, anti-inflammatory effects
- What is the interaction between cortisol, ACTH and CRH axis and immune system?
immune system causes the release of IL-1,2,6 and TNF-a which stimulates hypothalamus outside of the normal negative feedback loops
- What is the signaling mechanism of cortisol?
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
- How are cortisone residues modified to produce more potent forms of glucocorticoids?
binding of modifier molecules increases potency due to chemical change in the molecule
- Describe activators and repressors of corticosteroid binding mediated effects.
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)
- Hydrocortisone (Cortizone-10)
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.
- Prednisone
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
- Fluticasone (Cutivate and flovent).
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