EICOSANOIDSEICOSANOIDSProstaglandins Thromboxanes Leukotrienes

EicosaniodsEicosaniods• Derived from 20-crabon polyunsaturated fatty

acids• Short half-lives (10 secs – 5 mins) so that

functions are usually limited to actions on nearby cells.

• Bind to specific cell surface G-protein coupled receptors, and generally increase cAMP levels. May also bind to nuclear receptors and alter gene transcription.

Major Classes of EicosanoidsMajor Classes of Eicosanoids

• Prostaglandins• Thromboxanes• Prostacyclins• Leukotrienes• HETES

• Induction of inflammation• Mediation of pain signals• Induction of fever• Smooth muscle contraction (including uterus)• Smooth muscle relaxation• Protection of stomach lining• Simulation of platelet aggregation• Inhibition of platelet aggregation• Sodium and water retention

Effects of EicosaniodsEffects of Eicosaniods

Precursors of EicosanoidsPrecursors of Eicosanoids

• Arachidonic acid (ω6)• Eicosatrienoic acid (-linolenic acid, ω6)• Eicosapentaenoic Acid (ω3)

Dietary Linoleic Acid (C18: ∆9,12) (from plant oils)

Elongase

Desaturase

Arachidonic Acid (C20: ∆5, 8, 11, 14)

Membrane Phospholipids

Phosphatidyl choline

Arachidonic acid

Phospholipase A2 Ca++

Phosphatidylinositol bisphosphate

Phospholipase C

1,2 Diacylglycerol

Arachidonic acid Monoacylglycerol

DAG lipase

Arachidonic acid

MAG lipase

Arachidonic acid release from membrane Arachidonic acid release from membrane lipidslipids

Stimulus

Prostaglandins – Structural FeaturesProstaglandins – Structural Features

PGA, PGD, PGE, PGF, PGG, PGH, PGIDepending on the functional groups present at X

and YPGF 1, 2 or 3

Depending on the number of double bonds present in the linear hydrocarbon chain

CYCLO-OXYGENASE CYCLO-OXYGENASE PATHWAY PATHWAY

PG and TX synthesisPG and TX synthesis

2GSH

2GSSG

PGD2PGD synthase

PGF2a

PGE 9-keto reductase

PGE2PGE synthase

PGI2PGI synthase

TXA2TXA synthase

In 1930s human semen was found to contract isolated uterine and other smooth muscle strips and to cause fall in BP in animals so named as prostaglandins (assuming derived from prostate)

ProstaglandinsProstaglandins

Blood vessels: PGE2-vasodilatation, decrease blood pressurePGF2-Vasodilatation, larger veins contract, little effect on Blood pressurePGI2-Vasodiatation (marked and widespread) lead to rapid decrease in blood pressureVasocontriction – TXA2

Functions of ProstaglandinsFunctions of Prostaglandins

Heart- PGE2-Weak inotropic, reflex cardiac stimulationPGF2-Weak inotropicPlatelets- Antiaggregatory effect of PGI2Aggregation and release reaction by TXA2Uterus- Contraction , relaxes nongravid human uterus by PGE2Contraction of uterus by PGF2alpha

Functions of ProstaglandinsFunctions of Prostaglandins

Bronchi- PGE2/PGI2-Dilatation, inhibit histamine releaseBronchoconstriction by PGF2, TXA2Stomach- Decrease acid secretion, increase mucus production by PGE2, Decrease acid secretion and mucosal vasodilatation by PGI2Intestine- Contracts longitudinal and relaxes circular muscle, Increase peristalsis/cl-/water secretion

Functions of ProstaglandinsFunctions of Prostaglandins

Intestine- spasmogenic , ↑fluid & electrolyte secretion by PGF2, Inhibit toxin induced fluid secretion- PGI2Weak spasmogenic-TXA2Kidney-Natriuresis, ↓cl- reabsorption, inhibit ADH action, Vasodilatation, renin release-PGE2/PGI2Vasoconstriction by TXA2

Functions of ProstaglandinsFunctions of Prostaglandins

CNS- Pyrogenic, variety of effect on I.C.V injection- sedation, rigidity, behavioral changes, ↑body temperature, fever- PGE2TXA2- not pyrogenicRelease of NA- depending on the PG and species, release of NA and inhibition of NA both are observed Afferent nerves- PGE2/PGI2-sensitize nerve ending to pain inducing chemical/ mechanical stimuli, irritate mucosa membrane and produce long lasting pain

Functions of ProstaglandinsFunctions of Prostaglandins

Endocrine system- PGE2-Release of ant pituitary hormones, steroids, insulin, TSH like actionRelease of gonadotropins and prolactin, luteolysis (in animals)-PGF2Metabolism- Antilipolytic, insulin like action, mobilization of bone calcium – PGE2

Functions of ProstaglandinsFunctions of Prostaglandins

LipoxygenaseLipoxygenase pathway pathway

Straight chain lipoxygenase products of arachidonic acid are produced by more limited no of cells

LTB4- NeutrophilsLTC4/LTD4- Macrophages

LTs are pathophysiologically as important as PGs

Some Functions of ProstaglandinsSome Functions of Prostaglandins

CVS and Blood- LTC4/LTD4 injected i.v evoke a brief rise in BP, followed by more prolonged fall

Note : fall in BP is not due to vasodilatation nor relaxation of Blood vessel it is may be due to

coronary constriction induced ,↓cardiac output, ↓circulation volume, ↑vascular permeability

LTB4- chemotactic , migration of neutrophils

Some Functions of ProstaglandinsSome Functions of Prostaglandins

Smooth muscle- LTC4 and D4- potent constrictors of bronchi and G.I.T, ↑ mucus secretions

Afferent nerves- Like PGE2/I2 the LTB4 also sensitizes afferents carrying pain impulses- ↑pain and ↑inflammation

• Leukotrienes are a hundred times more potent than histamine

• Histamine provided a rapid response to an allergen

• In the later stages leukotrienes are principally responsible for inflammation, smooth muscle constriction, constriction of the airways and mucous secretion form mucosal epithelium

Leukotrienes and allergiesLeukotrienes and allergies

1. Abortion2. Induction/ augmentation of labour3. Cervical priming (ripening)4. Postpartum haemorrhage (PPH)- carboprost 5. Peptic ulcer- Misoprostol6. Glaucoma- latanoprost, travoprost, bimatoprost7. Maintain patency of ductus arteriosus- Alprostadil8. Avoid platelet damage-Epoprostenol9. Peripheral vascular disease- rest pain, healing of

ischemic10.Impotency- Alprostadil

USES of EicosanoidsUSES of Eicosanoids

All prostanoid receptors are G-protein coupled receptors which can be functionally categorized

1. ‘excitatory’ or ‘contractile’ 2. ‘inhibitory’ or ‘relaxant’

•The contractile group (EP1, FP, TP) couple primarily with Gq protein and generate IP3-DAG. •The relaxant group (DP1, EP2, EP4 and IP) couple with Gs protein—activate c AMP

PROSTANOID RECEPTORS

Receptor Subtypes Action Location Nature

DP DP1 and DP2 PGD2/PGE2

Blood vessels Relaxant receptor

EP EP1 EP2 EP3 EP4

PGE2 Smooth muscle, intestinal mucosa, adipose tissue

Contractile EP1Relaxant EP2/4Inhibitory EP3

FP Nil PGF2alpha Genital tract Contractile receptor

TP Nil TXA2 PGH2

Platelet (aggregatory), CVS, Immune cell

Contractile receptor

IP Nil PGI2 PGE2

Heart , lungs, kidney, platelet (anti)

Relaxant receptore

PROSTANOID RECEPTORS

Anti inflammatory Drugs inhibit Anti inflammatory Drugs inhibit Eicosanoid SynthesisEicosanoid Synthesis

LeukotrienesProstaglandins, thromboxanes

NSAIDs

Cyclo-oxyg

enase Lipoxygenase

Membrane lipids

Arachidonic Acid

Steroids

Phospholipase A2

Mechanism of ActionMechanism of Action

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