EICOSANOIDS biochemistry and metabolism and uses

case sineario

1. CASE SCENARIO 1 A 29 yr / F, presented with chief complaints of fever x 4 days, continuous, associated with chills and rigor. No H/O cough, cold/ nasal congestion/ vomiting/ diarrhoea No significant comorbidities O/E :- pallor + PR – 100 bpm, BP – 110/70 mm Hg no specific findings on systemic examination Provisional diagnosis : Pyrexia of Unknown Origin Advice: CBC, Urine routine T. PARACETAMOL 500 mg 1 – 1 – 1 T. RANITIDINE 150mg 1 – 0 – 1 T. BCT 1 – 0 – 0 Review with reports HOW PARACETAMOL SUBSIDES FEVER ?

2. CASE SCENARIO 2 A 49/M, presented to Upgraded PHC with chest pain over the left side for the past 6 hrs, compression type of pain, radiating to left shoulder. Patient also complained of shortness of breath. Known case of Hypertension and Type II Diabetes Mellitus on regular medication Known smoker and alcoholic x 20 yrs O/E :- pt dyspneic PR – 102 bpm, BP – 150/100 mmHg ECG – ST segment elevation in V2

3. CASE SCENARIO 2 Being diagnosed as a case of Acute Myocardial Infarction , was given loading dose of T. ASPIRIN 150 mg 2 tabs T. CLOPIDOGREL 75 mg 4 tabs T. ATORVASTATIN 10 mg 8 tabs STAT And was referred to a tertiary care centre, wherein THROMBOLYSIS was done with STREPTOKINASE and maintenance dose of INJ. HEPARIN four times a day was started. WHAT IS THE ROLE OF ASPIRIN IN THIS CONDITION ?

4. EICOSANOIDS DR MAHADEVI J FINAL YEAR POST GRADUATE INSTITUTE OF BIOCHEMISTRY MADRAS MEDICAL COLLEGE

5. OBJECTIVES Chemistry Metabolism Biochemical function Related disorders Therapeutic applications

6. INTRODUCTION Group of biologically active lipids Synthesized from Eicosaenoic acid (C20 PUFA) [Greek – eikosi – 20] Group of 5 types of molecules Prostaglandins (PG) Prostacyclins (PI) Thromboxanes (TX) Leukotrienes (LT) Lipoxins (LX) Local hormones

7. CHEMISTRY What are the Essential Fatty acids ? Linoleic acid Linolenic acid Arachidonic acid (semi essential)

8. CHEMISTRY Diet Membrane Phospholipids Diet ↓ ↓ ↓ Linoleate Arachidonate Linolenate ↓ ↓ ↓ Eicosatrienoate → Eicosatetraenoate Eicosapentaenoate ↓ ↓ ↓ Group I Eicosanoids Group II Eicosanoids Group III Eicosanoids Group II Eicosanoids Group III Eicosanoids

9. CHEMISTRY

10. SYNTHESIS Corticosteroids

11. Arachidonic acid Cyclooxygenase (COX) PGG 2 Peroxidase 2GSH GSSG PGH 2 NSAIDS Aspirin Indomethacin Ibuprofen - - SYNTHESIS PG H synthase COX PEROXIDASE Prostaglandin endoperoxide synthase Cycloxygenase pathway

12. PGH 2 PGD 2 (Mast cells) TXA 2 (Platelets) PGF 2 α PGI 2 PGE 2 Isomerase Thromboxane synthase Isomerase Prostacyclin synthase Reductase Reductase Reductase (Endothelium) Imidazole - SYNTHESIS Cycloxygenase pathway

13. Arachidonic acid 5-Lipoxygenase 5-hydroperoxy eicosatetraenoic acid (5-HPETE) LTA 4 LTC 4 LTB 4 LTD 4 LTE 4 Glutathione Glutamate Glycine H 2 O Synthesis of Leukotrienes 1-Glutathione-S-transferase 2- γ glutamyl transpeptidase 3-Cysteinyl glycine dipeptidase Leukotriene A 4 epoxide hydrolase 1 2 3 15-Lipoxygenase 15-hydroperoxy eicosatetraenoic acid (15-HPETE) LTA 4 5-Lipoxygenase LXA 4 15-Lipoxygenase Synthesis of Lipoxins 12-hydroperoxy eicosatetraenoic acid (12-HPETE) 12-Lipoxygenase Lipoxygenase pathway

14. SYNTHESIS Protaglandin endoperoxide synthase (PGH synthase) 5-Lipoxygenase 15- lipoxygenase 12-lipoxygenase cyclooxygenase 5- Hydroperoxy 15- Hydroperoxy 12- Hydroperoxy PGG 2 endoperoxidase PGH 2 (Prostaglandin endoperoxide) eicosatetraenoic acid eicosatetraenoic acid eicosatetraenoic acid (5 - HPETE) (15 - HPETE) (12 - HPETE) 5-Lipoxygenase LTA4 Lipoxins 15- lipoxygenase Isomerases Thromboxane synthase Prostacyclin synthase Prostaglandins (PGs) Thromboxane (TXA2) Prostacyclin (PGI) LTB4 LTC4, LTD4, LTE4 PGD 2 PGE 2 PGF 2 α TXB 2 Lipoxygenase pathway Cycloxygenase pathway

15. CATABOLISM Cyclooxygenase – suicidal enzyme – self catalyzed destruction PGs – very rapidly removed from circulation – metabolised in lungs, brain, liver and other tissues MOA : G-protein coupled receptor activity PGD, PGE and PGF series cAMP PGF2 α and TXA2 intracellular Ca level

16. PROSTAGLANDINS Originally isolated from Prostate tissue Almost present in all the tissues Most potent -1ng/ml →cause smooth muscle contraction T1/2 – 30 seconds Types :- PG (A to I) – 9 types PGD2 - vasodilation PGE2 - Elgesic PGF2α - Vasoconstriction

17. BIOLOGICAL ROLE Inflammation :- PG - Natural mediators of inflammation Metabolism :- Mediation of cAMP→ PGE2 -↓lipolysis ↑glucogenesis Mobilisation of calcium from bone Inflammatory disorders – corticosteroids, NSAIDS DISORDERS / THERAPEUTIC APPLICATIONS

18. BIOLOGICAL ROLE PGE – bronchodilator PGF – Bronchoconstrictor PGE – Increases GFR → Increases urine output Ensure blood vessel diameter :- PGs – Vasodilators PGE series – Bronchial asthma Sodium and wate retention Hypertension Hemodynamic acute kidney injury Treatment of Hypertension DISORDERS / THERAPEUTIC APPLICATIONS

19. BIOLOGICAL ROLE Regulate smooth muscle contraction Uterus Increase intestinal motility inhibit gastric secretion Medical termination of Pregnancy Induction of Labour Arresting Post partum hemorrhage Causes Diarrhoea Used in treatment Acid Peptic disease DISORDERS / THERAPEUTIC APPLICATIONS

20. Prostaglandins used therapeutically Natural Prostaglandins Dinoprostone (PGE 2 ) Dinoprost (PGF 2α ) Alprostadil (PGE 1 ) Epoprostenol (PGI 2 ) Synthetic Prostaglandins Carboprost (15 – methyl PGF 2α ) Misoprostol (methyl PGE1 ester) Latanoprost (PGE2 analogue) Induction / Augmentation of labour Post partum hemorrhage Missed abortion Midterm abortion Medical termination of Pregnancy

21. THROMBOXANE Produced by platelets TXA2 – Platelet aggregation vasoconstriction Mobilizes intracellular calcium Contraction of smooth muscles

22. PROSTACYCLIN Produced by vascular endothelium PGI2 – Inhibits Platelet aggregation vadodilation Platelet homeostasis :- TX –(+)→ Platelet aggregation PGI –(-)→ Platelet aggregation ↑ TX activity – thrombosis PGI – inhibits thrombus fromation

23. LEUKOTRIENES LTA4 – Leucocytes, Platelets, mast cells, heart, lungs & vascular tissues LTB4 ↑ chemotaxis of polymorphonuclear leucocytes Release of lysosomal enzymes Adhesion of WBCs LTC4→LTD4 →LTE4 Contraction of smooth muscles Bronchoconstriction Vasoconstriction ↑vascular permeability Components of slow – reacting substance on anaphylaxis (SRS – A) Hypersensitivity reaction to drug, insect bite, etc – Anaphylactic shock Leukotriene antagonist :- MONTELULKAST ZAFIRLUKAST LTA4 hydrolase LTC4 synthase

24. LIPOXINS Types :- LxA4, LxB4, LxC4, LxD4, LxE4 Function :- vasoactive immunoregulatory function

25. Differential Actions of Cyclooxygenases NSAIDs COX1 Constitutive COX2 Inducible Inflammatory Endothelial integrity Vascular patency Gastric mucosal integrity Bronchodilation Renal function Platelet function Inflammation Unwanted side-effects Therapeutic anti-inflammatory effects PGE 2 PGF 2a Proteases PGI 2 PGE 2 TXA 2 Housekeeping - - COX – 2 inhibitors ACECLOFENAC DICLOFENAC ETORICOXIB Non selective COX inhibitors ASPIRIN PARACETAMOL IBUPROFEN MEFENAMIC ACID

26. What are the differences between Endocrine hormones and Eicosanoids ?

27. Differences Endocrine hormones Eicosanoids Produced at one site –transported through blood – act at a distant site act on the neighbouring cells Synthesized by specialized glands only Produced by all tissues Synthesized and stored Not stored; synthesized upon appropriate stimulus Produced in large quantity Produced in small amount Comparably longer T 1/2 Extremely short T 1/2 Action varies – intracellular & membrane receptors Action via G-protein coupled receptors

28. CASE SCENARIO 1 PYREXIA OF UNKNOWN ORIGIN PARACETAMOL – Non - selective COX inhibitor Fever is produced through generation of pyrogens which induce the synthesis of PGE2 – act on hypothalamus to raise your body temperature Inhibition of COX → PGE2 not synthesized → no raise in the body temperature

29. CASE SCENARIO 2 ACUTE MYOCARDIAL INFARCTION T. ASPIRIN - Non - selective COX inhibitor Thromboxane A2 Prostacyclin (PGI2) COX – 1 COX - 2 causes platelet aggregation inhibits platelet aggregation Inhibits COX – 1 at low dose inhibits COX – 2 at high dose Thus used in patients with MI & stroke to prevent re-infarction

30. SUMMARY Lipids – 20 C – Local hormones

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