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  1. 1. Prostaglandins
  2. 2. • PG is generic name for group of closely related cyclic, oxygenated, 20C containing unsaturated fatty acids.(PG,TAX2,LT,PAF) • Derived from prostanoic acid 20c fatty acid • Discovered in semen in 1930by Ulf • “prostaglandin” name form prostate gland where they were first thought to originate.
  3. 3. • The main inflammatory mediator derived from membrane phospholipids are eicosanoids Phospholipids Phospholipase A2 Arachidonic acid (Eicosa tetraenoic acid) Eicosanoids (PGs,TAX2,LT,PAF) prostanoids Eicosa=20carbon,tetra =4 double bond
  4. 4. Biosynthesis of eicosanoids Phospholipids Phospholipase A2 Arachidonic acid (Eicosa tetraenoic acid) LT PG EET DHET Esterified Arachidonic acid EET=Epoxy eicosa trienoic acids DHET= Dihydroxy eicosa trienoic acid
  5. 5. Biosynthesis of Prostanoids Membrane phospholipids Phospholipase A2 (or PLC) Arachidonic acid Cyclooxygenase-I Widely present Cyclooxygenase-II Induced by cytokines during inflammatio PGG2 PGH synthase PGH2 PGI2 synthase PGI2 (PC) Vascular endothelium PGE2,PGF2α,PGD2 PGE synthase TAX synthase TXA2 In platelets Corticosteriods NSAIDS (aspirin)
  6. 6. COX1Constitutive PGI2 PGE2 TXA2 Housekeeping Endothelial integrity Vascular patency Gastric mucosal integrity Bronchodilation Renal function Platelet function COX2 Inducible Inflammatory PGE2 PGF2a Proteases Inflammation Fever Pain NSAIDs COX-1: platelets, gastric, renal constitutively expressed COX-2: vessel wall, renal, induced in inflammation and cancer. COX-3: controversial, thought to be a splice variant.
  7. 7. LT synthesis • Leucko-trines first found in leucocytes, trines- conjugated “triene” system of double bond. • Leuckotrines are products of lipoxygenase pathway • Lipoxygenase enzyme present in cytosol.
  8. 8. Biosynthesis of LT(Lipoxygenase pathway) Membrane phospholipids Phospholipase A2 (or PLC) Arachidonic acid 5-Lipoygenase associated with protein FLAP 5HPETE LTA4 LTB4, LTC4 LTD4 LTE4 5-Hydroperoxy eicosatetraenoic acid FLAP:- 5-lipoxygenase activating protein
  9. 9. • Leukotriene Modulators:  5-Lipoxygenase Inhibitor : Zileuton  LT – Receptor Antagonists : Zafirlukast, Montelukast, Iralukast, Pranlukast
  10. 10. Platelet activating factor Membrane phospholipids Phospholipase A2 (or PLC) Lyso-PAF Arachidonic acid AcCoA PAF deacet ylation Acetyl transferase Acyl PAF
  11. 11. • PAF- Gq-IP3/DA-Ca+2 Pharmacological actions of PAF:- • Vasodilatation • Vascular permeability • Chemotatic to eosinophils and neutrophils • Activation and aggregation of platelets • PAF produced by foetus at final term, involved in progression of labour. • Most potent ulcerogen. • PAF synthesis inhibited by Glucocorticoids.
  12. 12. Prostanoid receptors: • Five main classes Endogenous Ligand Receptor type G protein II messenger PGD2 DP GS cAMP PGF2 FP Gq IP3,DAG PGI2 IP GS cAMP TAX2 TP Gq IP3,DAG PGE2 EP1 Gq IP3,DAG EP2 GS cAMP EP3 GS,Gi OR cAMP Gq IP3,DAG EP4 GS cAMP
  13. 13. Pharmacological action of prostanoids: • Eye: PGF2 and PGE2 IOP by uveoscleral pathway ( Drainage) Respiratory system: PGE2,PGI2- broncho dilatation PGF2,TAX2, LT, PGD2-broncho constriction broncho dilatation : broncho constriction LT are powerful constrictors.
  14. 14. CVS: PGE2 – Vasodilatation Weak inotropic CO Capillary permeability Ductus arteriosus continually keep it patent, maintain placental blood flow PGI2- Vasodilator Peripheral, pulmonary and coronary resistance PGF2α , TAX2- Potent vasoconstrictor
  15. 15. GIT: PGE2 Mucous production PGE2,PGI2 Mucosal blood flow Acid secretion PGE2 water and electrolytic secretion (Diarrhoea) Kidney: produced by renal medulla PGE2,PGI2- Natriuresis Renal vasodilatation Inhibit ADH action Stimulate renin release PGE2 Cl- reabsorption TAX2- Vasoconstriction ADH like action
  16. 16. Platelet: PGE1,PGI2 inhibit platelet aggregation TAX2 -Platelet aggregation -Low dose of aspirin acts an platelet (Inhibit TAX2 production, platelets lack of nucleus so it can’t synthesis cox-1 but vascular produce cox-I) platelets TX PGHS-1: collagen, thrombin, ADP. PGI PGHS-2: shear, bradykinin, acetylcholine + -
  17. 17. Uterus: PGE2,PGF2α • In vivo – Contraction • In vitroPGE2 – Pregnant- Contraction Non pregnant – Relax PGF2α- Contraction PG in low dose-Soften cervix Male reproductive system: Enhance penile erection ( Smooth muscle relaxation blood flow) CNS: PGE1,PGE2- Pyrogenic
  18. 18. • Peripheral nerve ending: PGs are inflammatory mediators, sensitize pain receptors • Endocrine: Facilitate release of GH,TSH, ACTH, FSH, LH and prolactin • Bone metabolism: Stimulate bone resorption
  19. 19. Therapeutic uses of prostanoids and analogues: • Obstetrics:- • PGE2, PGF2α used in terminate pregnancy • First trimester:- Misoprostal PGE1, orally with mefepristone/ Methotrexate to induce abortion in first few weeks of pregnancy • Second trimester:- Dinoprost(PGF2α) , • Carboprost intra amniotic inj- abortion least use due to side effects. • Dinoprostone(PGE2):- PGE2 –Vaginally for inducing abortion, ripening of cervix for induction of labour at full term. side effect- prolong bleeding.
  20. 20. Facilitation of Labour, Cervical priming and postpartum haemorrhage: • For induction of labour oxytocin is DOC. • PG is used for oxytocin CI i.e, renal failure, pre-eclampsia, eclampsia. Advantage is PG is does not cause Na, water retention. • Demeprost / Denoproste used viginally • Carboprost:- To control post- partum haemorrhage.
  21. 21. Healing of peptic ulcer:- • PGE2,PGI2 Mucous production Mucosal blood flow Acid secretion (Anti ulcerogenic, cAMP) Misoprostol-oral -200µg- QD. Enoprostil- NSAIDs induced ulcer/chronic smokers
  22. 22. To prevent platelet aggregation:- PGI2- inhibit platelet aggregation epoprostenol- renal dialysis. To Treat Pulmonary Hypertension:- • PGI2 lower peripheral pulmonary and coronary resistance. IV infusion Epoprostenol, Treprostinil Peripheral vascular disease: Beraprost- oral PGI2 –thrice a day Treating glaucoma:LatanoprostPGF2α - uveoscleral pathway (Drainage), Bimatoprost, travaprost, Unoprostone
  23. 23. For Patency of Ductus Arteriosus:- PGE2,PGI2 having vasodilators, inhibit platelet aggregation IV infusion – congenital heart disease, pulmonary artery stenosis. Alprostadil(PGE1), Epoprostenol(PGI2). Male impotence:-Enhance penile erection Bronchial asthma:- Bronchodilatation, but cough side effect.
  24. 24. Side effects of Prostanoids:- • PGs exhibit dose related adverse effects bronchoconstriction, Hypotension, Vomiting, diarrhoea, fever, dizziness, and flushing. • Carboprost:- Intra amniotic injection to induce second trimester abortions can cause anaphylactic shock and CVS collapse.
  25. 25. • Alprostadil – maintaining the patency of ductus arteriosus for long time leads ductus fragility and rupture. • Misoprostol, Enprostil – GIT discomfort and diarrhoea. • PGE (EP4) osteoclast and osteoblast activity, induce hypercalciuria.
  26. 26. Drug Preparation Use Dinoprostone Vaginal tab/gel Induction labour Mid term abortion Dinoprost Intra amniotic inj Mid term abortion Carboprost IM, Intra amniotic inj Mid term abortion Control of PPH Gemeprost Vaginal pessary Cervical priming in early pregnancy Alprostadil IV infusion, IV inj Intra cavernosal inj Maintenance of a patent ductus arteriosus in neonates Erectile dysfunction Misoprostol Enoprostil Oral Abortion & Peptic ulcer Peptic ulcer Epoprostenol IV infusion Pulmonary hypertension Latanoprostol Topical Glaucoma iloprost IM Dec. infact size, when given IM after MI