Exam 2: Lecture 1, Eicosanoids Flashcards
What are Autacoids?
Physiologically active endogenous molecules producing powerful widespread physiological and pharmacological effect
What makes up the eicosanoids?
Prostaglandins, thromboxane and leukotrienes
Hormone info
Produced: Gland/Tissue
Stored: Gland/Tissue
Binding: Receptor
Transport: Blood
Neurotransmitter info
Produced: Neuron
Stored: Vesicle
Binding: Receptor
Transport: Synapse
Autacoid info
Produced: Cell
Stored: Membrane/Vesicle
Binding: Receptor
Transport: Tissue
How are Eicosanoids made?
Made from the oxygenation of polyunsaturated long-chain FA fatty acids
When are Eicosanoids released?
In response to a wide variety of physical, chemical and hormonal factors
Eicosanoids General Info 1:
Fatty Acids of membranes = source
Produced de novo from biological membrane
Not stored, short life (secs to min)
Biological membranes composed of 500-1000 lipid species, 7nm thick
Eicosanoids General Info 2:
Oxygenation of FA = makes them
Formed from 20-carbon FA, contain 3-5 Double bonds
Affect all cells and tissues, perform function of local hormones
Arachidonic Acid metabolites
Arachidonic Acid is…
Most abundant of eicosanoid precursors
Has 4 double bonds
Chemical/physical/inflammatory stimulation = intense and sustained AA production
3 Classes of Phospholipase A2
cytosolic cPLA2
Secretory sPLA2
Calcium independent iPLA2
cPLA2
Acute release of AA
sPLA2
Sustained production of AA
iPLA2
Negligible AA production
Under Normal Conditions, AA is….
incorporated into the cell membrane and there is negligible AA biosynthesis
Zileuton (Zuflo)
Selectively inhibits 5-Lipoxygenase enzyme
Effective against exercise/antigen/aspirin- induced asthma attacks
Side effect: Headache/Respiratory infections/Nausea/Diarrhea/Abdominal pain
Notable: Live functions Test, possible interaction with (Theophylline/warfarin)
Zafirlucast (Accolate)
Leukotriene (LTD4) receptor antagonist
Effective against exercise/antigen/aspirin- induced asthma attacks
Side effects: Headache/Respiratory infections/Nausea/Diarrhea/Abdominal pain
Iloprost (Ventavis)
…
Epoprostenol (Flolan)
PGI2
Occasionally used in dialysis machines to prevent platelet aggregation
Alprostadil (Caverject, Edex, Muse, Prostin)
PGE1
used in impotence treatment.
available for injection into the penis or for insertion into the urethra
Misoprostol (Cytotec)
PGE1 Analog
Approved in the USA for peptic ulcer prevention in patients taking high doses of NSAID’s for arthritis
Used in Pediatrics as an infusion to maintain potency of ductus arteriosus in infants during surgical correction
Used in combo with Mifepristone for abortion Europe
Dinoprostone (Prostin E2, Prepidil, Cervidil) + Latanorpost
produce strong uterine contraction
used as efficient abortifacients in 2nd trimester of pregnancy for priming the cervix before abortion
side effect: nausea/vomiting/diarrhea
Dinoprostone (Prostin E2, Prepidil, Cervidil) + Latanorpost
produce strong uterine contraction
used as efficient abortifacients in 2nd trimester of pregnancy for priming the cervix before abortion
side effect: nausea/vomiting/diarrhea
2 Major Pathways of Arachidonic Acid Oxygenation
Cyclooxygenase (COX) and Lipoxygenase (LOX)
Two Isoforms COX
COX I - found in many tissues, important under normal conditions
COX II - found in inflammatory tissue, expressed during inflammation
COX pathway
Prostaglandins PGG2, PGH2, PGE2, PGF2a, PGI2 and TXA2
LOX pathway
LTA4, LTB4, LTC4, LTD4, Lipoxins, 5-HPETE, and 5-HETE
Receptor: DP1
Ligand: PGD2
G-protein/2nd Messanger: Gc, increase cAMP
Receptor: EP1
Ligand: PGE2
G-protein/2nd Messanger: Gq, increase Ca
Receptor: EP4
Ligand: PGE2
G-protein/2nd Messanger: Gs, increase cAMP
Receptor: BLT1
Ligand: LTB4
G-protein/2nd Messanger: Gi, Increase Ca, Decrease AMP
Receptor: CysLT1
Ligand: LTB4
G-protein/2nd Messanger: Gq, Increase Ca, Increase PLC
Physiological Effects Eicosanoid Agonists
Produce multiple diverse effects upon smooth muscles, platelets and the CNS
Regulate vascular tone, bronchial tone, uterine tone, chemotaxis, and platelet aggregation
Important in some pathologies and participate in “Slow-reacting substance of anaphylaxis”. some are released in large amounts from endometrium during menstruation
PGE2 agonist effect
Vascular tone, gastric protection, uterine tone, fever, platelet aggregation
PGF2a agonist effect
Vascular tone, bronchoconstriction, intense pain, uterine contraction
PGE1 agonist effect
Vasodilation, heat, and redness during inflammation
PGI2 agonist effect
inhibition of platelet aggregation, vasodilation, gastric protection, inflammation
TXA2 agonist effect
powerful vasoconstrictor, powerful platelet activator
PGD2 (produced in mast cells)
vasodilation, platelet inhibitor
Eicosanoid Agonists Surface Receptors Info
Eicosanoid effect is close to site of synthesis
major effects seems to be produced by the activation of cell surface receptors specific to different eicosanoids
Gs-protein coupled receptors
DP1, EP2, EP4, and FP
IP3 and DAG receptors
EP1, FP and TP
Target: Phospholipase A2
Corticosteroids (antagonist)
Target: COX I and II
NSAIDs (antagonist)
Target: 5-Lipoxygenase Enzyme
Zileuton
Target: LTD4 Receptor
Zafirlukast
LTs first found in…
Leukocytes
PGs first found in…
seminal fluid
TXs first found in…
thrombocytes
LOX pathway forms….
LTB4, LTC4, LTD4, and LTE4
Leukotriene LTB4 is a…
chemotactic factor important in all types of inflammation
LTD4 acts on receptors causing…
WBC adherence, chemotaxis and activation of monocytes
LTC4 and LTD4 are active participants in….
Slow-reacting substance of anaphylaxis (SRS-A)
important mediator of bronchoconstriction
Relative potency of vasoconstrictor effects….
LTD4>LTC4>LTE4> Histamine
PGE2 and PGI2 limit…
in vitro T-lymphocytes proliferation
PGE2 inhibits…
B-Lymphocytes differentiation
Eicosanoids and Immune System
Immune system affects eicosanoid synthesis
T and B-cells probably supply AA to monocytes and macrophages
May mediate cell-cell interaction
Leukotrienes, TXA2, and PAF stimulate….
T-cell clonal expansion
Leukotrienes stimlate…..
interleukin formation, receptor expression and interferon release
