Arachidonic acid Hero B. Sabr

Hero B. Sabr

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Eicosanoids

prostanoids

Prostaglandin

PG

Prostacycline

PGI

Thromboxane

TX

Leukotrienes

LT

Lipoxines

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CELL PRODUCT

Neutrophils Leukotrienes

Macrophage/Monocyte Prostaglandins+Leukotriene

Platelets Thromboxane

Endothelial Cells Prostacyclin

CELL SPECIFICITY OF ARACHIDONIC ACID-DERIVED PRODUCTS

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PROSTAGLANDINSWhy PG?

Structure

Location

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Prostaglandins ClassificationPG-G & PG-H

A,B,C,D,E…I

PG Subclassification1,2,3

PGF1 &PGF

2α β

PROSTAGLANDINS[PG]

Nomenclature

Classification

Subscript

due to difference in structure of cyclopentane ring.

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Characteristic features :

PG

Show the effects near the site of

synthesis(autocrine & Paracrine effects)

Are not stored in the body

Are very potent in action. Even in minute

very short life span, are

destroyed within

seconds or few minutes

Production increases or decreases in response to

diverse stimuli or

drugs

Act as local

hormones

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PROSTAGLANDINS - FUNCTIONS

Effects on GIT

Effects on Inflammati

on

Effects on Respiratory

tract

Effects on uterus

Effects on CVS

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PROSTAGLANDINS - FUNCTIONS

PGI2

VasodilatationInhibits platelet aggregation

PGA and PGE class prostaglandins lower blood pressure.

Effects on CVS

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PROSTAGLANDINS - FUNCTIONS

PGF2

Inducing labor

Effects on

uterus

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PROSTAGLANDINS - FUNCTIONS

PGF-BronchoconstrictionPGE-Bronchodilator

Effects on

Respiratory tract

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PROSTAGLANDINS - FUNCTIONS

PGE2

Involved in inflammatory response

Effects on Inflammati

on

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PROSTAGLANDINS - FUNCTIONS

PGE2

suppress gastric acid secretion

Effects on GIT

Prostacyclins - Chemistry1)Prostacyclins(PGI) contain another ring between 6 th and 9th carbon atoms & They are synthesized in heart and vascular endothelial cells.

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Inhibit platelet and leukocyte aggregation

Decrease T-cell proliferation

lymphocyte migration

Induce vasodilatation

prevent clot formation

prostacycline - Functions

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First isolated from blood platelets, thrombocytes

TXA2

Subscript number denotes number of double bonds

have a six membered Oxane ring.

Most commo

n

Thromboxanes [TX]

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Increase platelet aggregation

Vasoconstriction

Mobilize intracellular calcium

Smooth muscle contraction

Bronchoconstriction

Thromboxanes - FUNCTIONS

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LEUKOTRINES WERE SO NAMED BECAUSE THEY WERE IN ITIALLY DESCRIBED IN LEUCOCYTES

Grouped into 5 classes [A to E]

Subscript number denotes number of double bonds

LTC4

Leukotrines [LT]

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Increase chemotaxis

Facilitate inflammation & allergic reactions

Contraction of smooth muscle

Bronchoconstriction (asthmatic constriction )

Vasoconstriction

Leukotrines - Functions

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Leukotrienes are a hundred times more potent than histamine which provided a rapid response to an allergen

Lipoxins

Lipoxins are a family of conjugated tetraenes also arising

in leukocytes.

They are formed by the combined action of more than

one lipoxygenase.

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Inhibition of Eicosanoid Synthesis :

NSAIDs usually do not inhibit lipoxygenase activity at concentrations that inhibit COX activity.

NSAIDs may cause more substrate to be metabolized through the lipoxygenase pathways.

This leads to an increased formation of the leukotrienes.

A 5-LOX inhibitor and antagonists of the leukotriene receptors are used clinically in asthma.

Corticosteroids also block all the known pathways of eicosanoid synthesis.

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CVS

GITNSAI

DBronchial Asthma- Ulcerative Colitis Ophthalmolo

gic

Pharmacological applications of Eicosanoids

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1)Cardiovascular uses- pulmonary arterial hypertension, peripheral vascular disease. for keeping the

ductus arteriosus open until surgery in neonates carrying

certain cardiac malformations and platelet anti-aggregating agents.

2) Digestive Uses- indicated in the treatment of gastro

duodenal ulcer and for the prevention of NSAID-induced

ulcers.

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3) Ulcerative Colitis- Mesalamine(mesalazine) or 5

aminosalicyclic acid has antiinflammatory properties in the

colon and is used in the treatment of ulcerative colitis (Crohn's disease) it

also inhibits lipoxygenases.

4)Bronchial Asthma- PGE2 agonists and leukotrienes

receptor antagonists are used for the treatment of bronchial

asthma.

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5) Ophthalmologic Use- lower

intraocular pressure

6) Anti- inflammatory use-Inhibitors of cyclo-

oxygenases include NSAID

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. NSAID The useful effects in therapeutics are-

anti-inflammatory effectanalgesic effectantipyretic effect

inhibition of platelet aggregation

and decrease of thromboembolic risk (well-known with aspirin at low

doses)

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Aspirin inhibits the COX pathway and consequently diverts arachidonic acid metabolites to the LO

pathway.

This also leads to a decrease in the levels of PGE2, the anti-inflammatory PG.

LTC4 synthase overexpression further increases the number of cysteinyl LTs, tilting the balance toward

inflammation and broncho constriction

Reason for Aspirin induced Asthma

Reason for Aspirin induced Asthma

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references