Eicosanoids Flashcards
What are eicosanods?
Derived from 20-C(eicosa) fatty acids
- Lipid derived mediators
- Synthesuzed by a variety of tissues
- Generally have local effects(autocoids)
- Synthesized in small amounts; short life
- Biological effects mediated by binding to G-protein coupled receptors which result in intracellular changes in cAMP levels or intracellularCa2+ levels (Gi, Gs, Gq)
What are prostanoids ?
Formed from arachidonic acid by cyclopxygenaase (COX)
-Produced by a variety of tissues in a cell specific manner
Type of prostanoid produced depends on
The tissue
The stimulus
the substrate lipid (Arachidonic acid)
PGE2- Activated macrophages
PGF2a-uterine tissue
PGI2- Endothelium
TXA2- activated platelets
What are prostanoids ?
Formed from arachidonic acid by cyclopxygenaase (COX)
-Produced by a variety of tissues in a cell specific manner
Type of prostanoid produced depends on
The tissue
The stimulus
the substrate lipid (Arachidonic acid)
PGE2- Activated macrophages
PGF2a-uterine tissue
PGI2- Endothelium
TXA2- activated platelets
What is the purpose COX pathway?
Results in formation of prostanoids
Two types of COX
- COX-1- Constitutive enzyme
- COX-2- Inducibke enzyme (inflammation)
-PGG2 and PGH2 unstable; depending on the tissues further converted to PGE2, PGF2, PGI2 or TXA2 depending on the next enzyme present in various cell types
What is the biological activity of PGE2?
Mediator of inflammation; released from activated macrophages
- Cause local vasodilation (redness); pain; fever (signs of inflammatory response)
- protect gastric mucosa
What is the biological activity of PGF2?
Uterine tissue: induction of labor in pregnant uterus
What is the biological activity of PGI2?
PGI2 (Prostacyclin): from endothelium, inhibits platelet aggregation; vasodilation
What is the biological activity of TXA2?
From activated platelets; facilitates platelet aggregation and formation of platelet plug; vasoconstriction
- Note that PGI2 and TXA2 are antagonists of each other
- Ratio of PGI2: TXA2 determines platelet aggregation
How are prostaglandins involved in blood regulation?
Synthesized by various tissues
Regulate blood flow to various organs
In general, PGE2 and PGI2 cause vasodilation and vascular smooth muscle relaxation
PGF2a and TXA2 cause vasoconstriction and reduce blood flow to organs and vascular smooth muscle contraction
What are the precursors to eicosanoids?
Arachidonic acid (20 C fatty acid with four double bonds; omega-6 fatty acid)
- linoleic acid. (Essential omega-6 fatty acid precursor)
- most common precursor of series 2 prostanoids
- PGI2, TXA2
Eicosapentenoic acid (20C fatty acid with 5 double bonds; omega-3 fatty acid)
- precursor of series 3 prostanoids
- Alpha-linoleic acid (essential omega-3 fatty acid precursor)
- PGI3 and TXA3
TXA3 less potent than TXA2 for platelet aggregation
Increasing dietary omega-3 fatty acids increases TXA3 and decreases risk of platelet aggregation
What are the inhibitors of eicosanoid synthesis ?
Cortisol: inhibits COX 2
Aspirin, NSAID
How does cortisol inhibit eicosanoid synthesis?
Cortisol inhibits Phospholipase A2: inhibits release of arachidonic acid from membrane phospholipids; cortisol also inhibits COX-2; anti-inflammatory agent
How does aspirin inhibit eicosanoid synthesis?
Aspirin and non-steroidal anti-inflammatory drugs (NSAID) inhibit COX-1Cand COX-2
What are the selective COX -2 inhibitors?
Celecoxib, diclofenac
What is the effect of low dose aspirin (81 mg)?
Aspirin irreversible inhibitor inhibitor of COX
- Inhibits platelet COX (platelets cannot synthesize new enzyme as they do NOT have nucleus ) less of TXA2 synthesis
- Endothelium can make new enzyme as it has a nucleus; PG2 synthesis not affected
- PGI2 »_space; TXA2 inhibits platelet aggregation (used as anti-thrombogenic agent)
What is the main use of arachidonic acid in making eicosanoids?
Phospholipase A2 cleaves arachidonic acid(20 C fatty acid) from membrane phospholipid /glycerol)
The lipoxygenase. Pathway first firms leukotrienes (LTA4
From LTA4, it firm LTB4 from one pathway, another pathway firms LTC4,LTD4, LTE4 from LTA4
in cycloxygenaee pathway prostanoids formed from arachidonic acid
Prostanoids go to firm PGE2, PGF2a, PGI2, TXA2
What are the biological effects of eicosanoids ?
Cysteinyl leukotrienes (LTC4, LTD4, LTE4)
Released by mast cells
Mediate allergic and anaphylactic response
Bronchoconstriction (asthma) and airway obstruction
Components of SRS-A (slow reacting substance of anaphylaxes )
Explain anaphylaxis
Headache and anxiety
Stridor and shortness of breath
Abdominal pain
Fast heart rate and low blood pressure
Itchiness and swelling
Caused by allergens/triggers causes mast cells -degranulation (seconds) via histamine and eicosanoid release (minutes) leukotrienes (LTC4, LTD4, LTE4)
Explain cortisol inhibit eicosanoids
Cortisol: inhibits Phospholipase A2, decreases formation of arachidonic acid and inhibits synthesis of both prostaglandins and leukotrienes; used as anti-inflammatory and anti-allergic agent
Lipoxygenase inhibitors reduce formation of leukotrienes; used as anti-allergic agents (management of asthma)
