Prostaglandins& Related Compounds

Objectives

•Origin of ecosanoids •Ecosanoids role•Overview of the structure•Role of phospholipase A2 •Cyclooxgenase isoenzymes•Inhibitors of prostaglandin synthesis•Aspirin induced asthma•Low –dose aspirin therapy

•The eicosanoids are a group of molecules derived from the C20 polyunsaturated fatty acids•The dietary precursor of PG is linoleic acid(18:2) which is elongated & desaturated to arachidonic acid(20:4)•The eicosanoids derived compounds include the prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs)and lipoxins(LXs). •The PGs ,TXs and prostacyclins are collectively identified as prostanoids.

They are extremely potent compoundswith wide range of physiological,

pathological & pharmacological effects

Gastric integrity&

renal function

Regulate smooth muscle contraction

( SI & uterus )

Platelet homeostasis

Blood Vessel Diameter

Inflammatory responses

Hypersensitivity reactions

Properties of Ecosanoids

•They simulate hormones but:•Produced in very small amounts•Produced in almost all tissues•Locally rather than transported•Not stored•Extremely short half-life•Act through plasma membrane receptors

Prostanoids

Naming of Prostaglandins

Prostacyclin

Thromboxane

Leukotrienes & Lipoxins

Leukotriene

Lipoxin

PG endoperoxidesynthase

AC

hormone signal outside GPCR plasma membrane

GTP GDP ATP cAMP + PP i

cytosol

GDP GTP

G-proteins linked receptors

Cyclooxygenase Isoenzymes

• There are 2 forms of the COX activity. •COX-1 is expressed constitutively in gastric mucosa, kidney, platelets, and vascular endothelial cells (imp for healthy tissue).

•COX-2 is inducible and is expressed in macrophages and monocytes ( limited number of cells) in response to inflammation. It mediates pain, hotness, redness by PG synthesis

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• TXA2

•Produced in platelets

•induces platelet aggregation,

•Vasoconstriction•Mobilizes intracellular calcium•Contraction of smooth muscles

•PGI2•Produced in vascular endothelial cells

•inhibits platelet aggregation

•induces vasodilation and production of cAMP

Inhibitors of Prostaglandin synthesis•Cortisol inhibits the phospholipase A2•Aspirin, indomethacin , and phenylbutazone (NASIDs) inhibit both COX1 & COX2 •Aspirin toxicity is due to COX1 inhibition reflected on damage of stomach, kidneys and impaired clotting of blood.•Selective inhibitors of COX2 as celebrix but the use of some of them may lead to increased risk of heart attack

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•Leukotrienes are mediators of allergic response and inflammation

•Aspirin-induced asthma is a response to overproduction of leukotrienes with NASIDs use.

•NASIDs also favor synthesis of lipoxins lipid mediator with anti-inflammatory effects

• Role of Prostaglandins in Platelet homeostasis

Role of Aspirin

•Aspirin has antithrombogenic effect.•It inhibits TXA2 synthesis from arachidonic acid in platelets by irreversible acetylation & inhibition of COX-1•This irreversible cannot be overcome in anucleated platelets but can be overcomed by endothelial cells b/c they have nucleus•This is the basis of low-base aspirin therapy