EICOSANOIDS

PRESENTER : Dr DNYANESH AMLEMODERATOR: Dr SARITA AGARWAL

INTRODUCTION

Eicosanoids: Greek: eikosi twenty→ Physiologically and pharmacologically active

substances derived from 20 C Poly-unsaturated Fatty Acids

Produced by Almost all mammalian cells Not synthesised in advance /stored : synthesised as

and when needed Act as short range messengers : Autocrine/paracrine

History

1930 Ulf von Euler – Prostaglandins 1960- aspirin like drugs acts by inhibiting PG

synthesis 1982 John vane ,Sune bergstrom and Bengt

Samuelsson got nobel prize for work on eicosanoids

The eicosanoids include: 1. the prostaglandins 2. thromboxanes 3. leukotrienes 4. hydroperoxyeicosatetraenoic acids (HPETEs)

5. hydroxyeicosatetraenoic acids (HETEs)6. lipoxins

5

Eicosanoid

LeukotrienesProstanoid

Thromboxane

Prostacyclin

Prostaglandins

Lipoxins

Three major precursors of eicosanoids DiHomo ϒ LA Archidonic Acid Eicosa Pentanoic Acid

Sources

Cell membrane: Phospatidyl choline Phospatidyl inositol/ethanolamine

phosphoglycerides Mostly ER Released by action of PLA2

PLA2 is stimulated by verious stimuli eg. Histamin, bradykinin, epinephrine,cytokines etc

Inhibited by corticosteroids

Arachidonic acid is synthesised From linoleic acid Phospholipid Hydrolysis

Phospholipase A 2 Phospholipase C

arachidonic acid : m o s t p re va le nt e ic o s a no id p re c urs o r in hum a ns

ω 6 fatty acid

ARACHIDONIC ACID METABOLISM

/Lipoxins/LXA4

PROSTAGLANDINS

Pro s ta g la nd ins : d e riva tive s o f the hyp o the tic a l C2 0 fa tty a c id prostanoic acid in which carbon atoms 8 to 12 fo rm a c y c lo p e nta ne ring

PG A – PG I :substituents on the cyclopentane ring

Thromboxanes

Numerical subscript : number of double bonds contained on the side chains of the cyclopentane ring

PGH Synthase

Also called prostaglandin H synthase /prostaglandin endoperoxide synthase/COX

Heme-containing enzyme Mambrane bound Contains two catalytic activities

cyclooxygenase activity peroxidase activity

Cyclooxygenase Is a “Suicide Enzyme” 15 hydroxyprostaglandin dehydrogenase

Fate of PGH2

Fate of PGH2 thus synthesised ,depends on the relative activities of the enzymes catalyzing the specific interconversions

Platelets thromboxane synthase, which mediates

the formation of thromboxane A2 (TxA2), a vasoconstrictor

and stimulator of platelet aggregation (an initial

step in blood clotting; Section 35-1).Vascular endothelial

cells contain prostacyclin synthase, which catalyzes the synthesis

of prostacyclin I2 (PG I2)

MECHANISM OF ACTION

G protein coupled receptors Second messengers

cAMP: PGD,PGE,PGF Ca: TXA2,PGF2α

Adenylate cyclase-cAMP-Protein kinase A Sometimes by direct activation on cAMP

CATABOLOISM

Eicosanoids: Very short half life Catabolised by

1. Oxidation of hydroxyl group(c-15)2. Reduction of double bonds(c-13)3. Β oxidation

TXA2 : initial modification involving clevage of bond between C9-C11

LINEAR PATHWAY

Lipoxigeneses Introduce hydro-peroxy (–OOH) groups Lipoxigenes 5-Neutrophils Lipoxigenes 12 – platelets Lipoxigenes 15 - eosinophils

Arachidonic acid hydroperoxy-eicosatetraenoic →acids(HPETEs) by the 5-, 12-,& 15-lipoxygenases

Hepoxilins hydroxy epoxy derivatives of 12 →HPETE

Leukotrienes: synthesized by: WBC, mast cells,lung, spleen,

brain and heart Peptidoleukotrienes (LTC4,D 4,E 4): SRS-A LTB4: Chemotactic factor Implicated in

Asthma Hypersensitivity reactions Myocardial infarction

LIPOXINS

Lipoxins: antiinflammatory eicosanoids FLAP

5-LO activity requires the presence of 5-lipoxyge-nase-activating protein

facilitates enzyme–substrate binding 5-LO’s interaction with the membrane Inhibited by MK-591 rsulting in inhibition of

synthesis of leukotriens

NSAIDs Inhibit PGH Synthase Aspirin Acetylation of serine 530 Tyrosine 385 Low doses of aspirin Triggers asthma

aspirin-acetylated COX-2 retainsa residual 15-LO activity (Steps 3 and 4 in Fig. 25-71)through which it initiates a pathway that converts arachi-donic acid to the anti-inflammatory agents called aspirin-triggered epi-lipoxins

Aspirin-triggered Epi-lipoxins

Theraputic aspects

COX1 and COX 2 COX inhibitors COX2 Specific inhibitor COX3 TXA2 and PGI2

Actions:

Vascular smooth muscle PGE2 and PGI2 are potent vasodilators in

most vascular beds. Thromboxane is a potent

vasoconstrictor.

Inflammation

PGE2 and PGI2 cause an increase in blood flow and promote, but do not cause, edema.

HETEs (5-HETE, 12-HETE, 15-HETE) and leukotrienes B4 - chemotaxis

LT C4,D4,E4 – SRS OF anaphylaxis

Bronchial smooth muscle

PGFs - smooth muscle contraction. PGEs- smooth muscle relaxation Leukotrienes and thromboxane are potent

bronchoconstrictors and are the most likely candidates for mediating allergic bronchospasm

Zielueton : lipoxigenes 5 inhibitor

Montelukast,zafirlukast leukotrien eceptor antagonist

Uterine smooth muscle

PGE2 and PGF2α

contraction of uterine smooth muscle in pregnant women

Nonpregnant uterusonpregnant uterus – variable response to PGs

PGF2a causes contraction

PGE2 causes relaxation. Induction of labor at term. Induction of labor is produced by:

infusion of PGF2a (carboprost tromethamine) [Hemabate] or

PGE2 (dinoprostone) [Prostin E].

Therapeutic abortion:A.Inducing abortion in the second trimester:

Infusion of carboprost tromethamine (PGF2α) or

Administration of vaginal suppositories containing dinoprostone(PGE2)

B.inducing first-trimester abortion: these prostaglandins are combined with

mifepristone (RU486)

PGE2 and PGI2 inhibit acid and pepsinogen Secretion in the stomach

Prostaglandins increase mucus, water, and electrolyte

secretion in the stomach and the intestine.

Misoprostol [Cytotec] a methylated derivative of PGE1

is approved for use in patients taking high doses of NSAIDs to reduce gastric ulceration.

Gastrointestinal tract

PGE2 and PGF2a increase the rate of longitudinal

contraction in the gut and decrease transit time.

The leukotrienes potent stimulators of gastrointestinal

smooth muscle.

TXA2 is a potent inducer of platelet aggregation.

PGI2 and PGE2 inhibit platelet aggregation.

PGEs induce erythropoiesis by stimulating the renal

release of erythropoietin. 5-HPETE

stimulates release of histamine PGI2 and PGD

inhibit histamine release.

Blood

Management of ductus arteriosus

Maintenance: is produced by PGE1 [Prostin VR] infusion PGE1 will maintain patency of the ductus

arteriosus, which may be desirable before surgery

Closure Indomethacin is given at birth to close the

PDA

Erectile dysfunction:

Alprostadil (PGE1) injected directly into the corpus cavernosum or

administered as a transurethral suppository to cause vasodilation and enhance tumescence.

Mimic endocrine hormones: Bind to G-protein-coupled receptors Secondary messenger- cAMP Profound physiological effects at extremely low

concentrations Mediate

Inflammatory response Production of pain and fever Regulation of blood pressure The induction of blood clotting Control of several reproductive functions such As the induction of labor Regulation of the sleep/wake cycle

But….Unlike endocrine hormones Not transported in the bloodstream Chemically and biologically unstable

substances Local mediators(paracrine/auto crine)

Act in the same environment in which they are synthesized