Exam 2: Lecture 1, Eicosanoids Flashcards by Patryk Lasiuk

What are Autacoids?

Physiologically active endogenous molecules producing powerful widespread physiological and pharmacological effect

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What makes up the eicosanoids?

Prostaglandins, thromboxane and leukotrienes

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Hormone info

Produced: Gland/Tissue
Stored: Gland/Tissue
Binding: Receptor
Transport: Blood

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Neurotransmitter info

Produced: Neuron
Stored: Vesicle
Binding: Receptor
Transport: Synapse

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Autacoid info

Produced: Cell
Stored: Membrane/Vesicle
Binding: Receptor
Transport: Tissue

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How are Eicosanoids made?

Made from the oxygenation of polyunsaturated long-chain FA fatty acids

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When are Eicosanoids released?

In response to a wide variety of physical, chemical and hormonal factors

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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

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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

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Arachidonic Acid is…

Most abundant of eicosanoid precursors

Has 4 double bonds

Chemical/physical/inflammatory stimulation = intense and sustained AA production

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3 Classes of Phospholipase A2

cytosolic cPLA2

Secretory sPLA2

Calcium independent iPLA2

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cPLA2

Acute release of AA

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sPLA2

Sustained production of AA

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iPLA2

Negligible AA production

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Under Normal Conditions, AA is….

incorporated into the cell membrane and there is negligible AA biosynthesis

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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)

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Zafirlucast (Accolate)

Leukotriene (LTD4) receptor antagonist

Effective against exercise/antigen/aspirin- induced asthma attacks

Side effects: Headache/Respiratory infections/Nausea/Diarrhea/Abdominal pain

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Iloprost (Ventavis)

…

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Epoprostenol (Flolan)

PGI2

Occasionally used in dialysis machines to prevent platelet aggregation

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Alprostadil (Caverject, Edex, Muse, Prostin)

PGE1

used in impotence treatment.

available for injection into the penis or for insertion into the urethra

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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

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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

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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

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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