Pharmacology of Eicosanoid
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Pharmacological actions and histopathological actions of prostaglandins thromboxanes and leukotrienes
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Pharmacology of Eicosanoid
- 2. 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.
- 3. Major Classes of EicosanoidsMajor Classes of Eicosanoids • Prostaglandins • Thromboxanes • Prostacyclins • Leukotrienes • HETES
- 4. • 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
- 5. Precursors of EicosanoidsPrecursors of Eicosanoids • Arachidonic acid (ω6) • Eicosatrienoic acid (γ-linolenic acid, ω6) • Eicosapentaenoic Acid (ω3)
- 6. Dietary Linoleic Acid (C18: ∆9,12 ) (from plant oils) Elongase Desaturase Arachidonic Acid (C20: ∆5, 8, 11, 14 ) Membrane Phospholipids
- 7. 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 membraneArachidonic acid release from membrane lipidslipids Stimulus
- 9. Prostaglandins – Structural FeaturesProstaglandins – Structural Features PGA, PGD, PGE, PGF, PGG, PGH, PGI Depending on the functional groups present at X and Y PGF 1, 2 or 3 Depending on the number of double bonds present in the linear hydrocarbon chain
- 10. CYCLO-OXYGENASECYCLO-OXYGENASE PATHWAYPATHWAY PG and TX synthesisPG and TX synthesis 2GSH 2GSSG PGD2 PGD synthase PGF2a PGE 9-keto reductase PGE2 PGE synthase PGI2 PGI synthase TXA2 TXA synthase
- 11. 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
- 12. Blood vessels: PGE2-vasodilatation, decrease blood pressure PGF2-Vasodilatation, larger veins contract, little effect on Blood pressure PGI2-Vasodiatation (marked and widespread) lead to rapid decrease in blood pressure Vasocontriction – TXA2 Functions of ProstaglandinsFunctions of Prostaglandins
- 13. Heart- PGE2-Weak inotropic, reflex cardiac stimulation PGF2-Weak inotropic Platelets- Antiaggregatory effect of PGI2 Aggregation and release reaction by TXA2 Uterus- Contraction , relaxes nongravid human uterus by PGE2 Contraction of uterus by PGF2alpha Functions of ProstaglandinsFunctions of Prostaglandins
- 14. Bronchi- PGE2/PGI2-Dilatation, inhibit histamine release Bronchoconstriction by PGF2, TXA2 Stomach- Decrease acid secretion, increase mucus production by PGE2, Decrease acid secretion and mucosal vasodilatation by PGI2 Intestine- Contracts longitudinal and relaxes circular muscle, Increase peristalsis/cl-/water secretion Functions of ProstaglandinsFunctions of Prostaglandins
- 15. Intestine- spasmogenic , ↑fluid & electrolyte secretion by PGF2, Inhibit toxin induced fluid secretion- PGI2 Weak spasmogenic-TXA2 Kidney- Natriuresis, ↓cl- reabsorption, inhibit ADH action, Vasodilatation, renin release-PGE2/PGI2 Vasoconstriction by TXA2 Functions of ProstaglandinsFunctions of Prostaglandins
- 16. CNS- Pyrogenic, variety of effect on I.C.V injection- sedation, rigidity, behavioral changes, ↑body temperature, fever- PGE2 TXA2- not pyrogenic Release 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
- 17. Endocrine system- PGE2-Release of ant pituitary hormones, steroids, insulin, TSH like action Release of gonadotropins and prolactin, luteolysis (in animals)-PGF2 Metabolism- Antilipolytic, insulin like action, mobilization of bone calcium – PGE2 Functions of ProstaglandinsFunctions of Prostaglandins
- 18. LipoxygenaseLipoxygenase pathwaypathway Straight chain lipoxygenase products of arachidonic acid are produced by more limited no of cells LTB4- Neutrophils LTC4/LTD4- Macrophages LTs are pathophysiologically as important as PGs
- 20. 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
- 21. 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
- 22. •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 Leukotrienes and allergiesLeukotrienes and allergies
- 23. 1. Abortion 2. Induction/ augmentation of labour 3. Cervical priming (ripening) 4. Postpartum haemorrhage (PPH)- carboprost 5. Peptic ulcer- Misoprostol 6. Glaucoma- latanoprost, travoprost, bimatoprost 7. Maintain patency of ductus arteriosus- Alprostadil 8. Avoid platelet damage-Epoprostenol 9. Peripheral vascular disease- rest pain, healing of ischemic 10.Impotency- Alprostadil USES of EicosanoidsUSES of Eicosanoids
- 24. 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
- 25. Receptor Subtypes Action Location Nature DP DP1 and DP2 PGD2/PG E2 Blood vessels Relaxant receptor EP EP1 EP2 EP3 EP4 PGE2 Smooth muscle, intestinal mucosa, adipose tissue Contractile EP1 Relaxant EP2/4 Inhibitory 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
- 26. Anti inflammatory Drugs inhibitAnti inflammatory Drugs inhibit Eicosanoid SynthesisEicosanoid Synthesis LeukotrienesProstaglandins, thromboxanes NSAIDs Cyclo-oxygenase Lipoxygenase Membrane lipids Arachidonic Acid Steroids Phospholipase A2
- 27. Mechanism of ActionMechanism of Action