LIPID DERIVED AUTACOIDS.pptx

LIPID DERIVED AUTACOIDS:
ECOISANOIDS AND PAF (Platelet activating factor)

1. LIPID DERIVED AUTACOIDS: Eicosanoids and platelet activating factor Dr. Sarita Sharma Associate Professor MMCP, MMDU

2. Biologically active derivatives of 20 C-atoms polyunsaturated essential fatty acids that are released from cell membrane phospholipids. Derived from A rachidonic acids . Two major types of eicosanoids- Prostaglandins (PGs) Leukotrienes (LTs) The eicosanoids are impor tant local hormones and they may act as circulating hormones as well. In the body PGs, TXs and LTs are all derived from eicosa (Referring to 20c atoms) tri, tetra, penta enoic acids; so that they are collectively called eicosanoids. LIPID DERIVED AUTACOIDS PROSTAGLANDINS leukotriens

3. Eicosanoids

4. WHAT ARE PROSTAGLANDINS ? Group of hormone-like lipid compounds Derived enzymatically from fatty acids Perform important functions in the body Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring . They are produced in many places throughout the body and their target cells are present in the immediate vicinity of the site of their secretion . They are autocrine and paracrine lipid mediators that act upon platelets, endothelium, uterine and mast cells . They are synthesized in the cell from the essential fatty acids (EFAs ).

5. BIOSYNTHESIS AND ACTIONS OF PROSTAGLANDINS: Ring structures Open chain structures

6. BIOSYNTHESIS AND ACTIONS OF PROSTAGLANDINS Membrane phospholipids Arachidonate Cyclic e ndoperoxide Phospholipase A 2 enzyme Cyclooxygenase enzymes prostacyclin P rostaglandins Thromboxane P G F 2 α PGE2 PGD2 Bronchoconstriction Myometrial Contraction Inhibits Platelet aggregation Vasodilator Vasodilator Hyperalgesic

7. PHARMACOLOGICAL ACTIONS CVS/ Regulation of Blood Pressure PGE 2 and PGI 2 are vasodilators in vascular beds Increased blood flow and decreased peripheral Lower BP TXA2= produce vasoconstriction resistance

8. 2) PLATELETS: TXA2 which can be produced locally by platelets, is a potent inducer of aggregation and release reaction. In other side PGI2(generated by vascular endothelium) is a potent inhibitor of platelet aggregation 3)Uterus PGE 2 AND PGF 2α causes contraction of Uterine smooth muscles in pregnant as well as non pregnant women. Sensitivity is higher in during pregnancy.

9. 4) Bronchial muscles: PGF 2 α , PGD 2 and TXA 2 are potent bronchoconstrictors (more potent than histamine) while PGE 2 is a powerful bronchodilator Asthmatics are more sensitive to constrictor as well as dilator effects of PGs. 5) GIT: In isolated preparations, the longitudinal muscles of GIT is contracted by PGE 2 and PGF 2 α while the circular muscles is either contracted or relaxed PGE2 CAUSES watery diarrhoea as side effect.

10. 6) Kidney: PGE 2 & PGI 2 increase water, Na+ and K+ excretion Diuretic action PGE 2 antagonize ADH action TXA 2 renal vasoconstriction PGE 2 , PGI 2 & PGD 2 evoke release of renin . 7) CNS: PGs injected IV penetrate brain poorly & no prominent action. If injected intracerebroventricular PGE 2 sedation, rigidity, behavioral changes & hyperthermia .

11. 8) ANS: Depending on PG, both inhibition & augmentation of NA release from adrenergic nerve endings has been observed. 9) Peripheral nerves: PGs (especially E2 & I2) sensitize afferent nerve endings to pain inducing chemical and mechanical stimuli They irritate mucous membranes and produce long lasting dull pain on intradermal injection.

12. 10 ) Pain and Fever It acts on thermoregulatory centre of hypothalamus to produce fever Pyrogens (fever producing agents) promotes PG synthesis Formation of PGE2 in hypothalamus FEVER & Pain

13. 11 ) Effect on respiratory function PGEs causes bronchial smooth muscle relaxation PGFs causes bronchial smooth muscle constriction thus PGE and PGF oppose the action of each other in the lungs 12) Eye: It decreases intraocular pressure First line drug in treatment of glaucoma

14. 13) Metabolism: Anti lipolytics Exert insulin like action on carbohydrate metabolism & metabolize ca + from bones(may cause hypercalcaemia by bony metastasis) 14) Endocrine system : Causes release oF anterior pituitary gland hormones –GH, LH, FSH, ACTH, Prolactin Also have TSH-like action on thyroid gland

15. WHAT HAPPENS WHEN THERE IS INCREASE IN PROSTAGLANDIN SECRETION ? Conditions such as arthritis, heavy menstrual bleeding and painful menstrual cramps and certain types of cancer including colon and breast cancer might happen . Anti-inflammatory drugs - aspi r in a n d ib u p r o f en, work b y blo cking t h e a c tion o f the cyclooxygenase enzymes and so reduce prostaglandin levels.

16. IF LESS PROSTAGLANDINS ? Manufactured prostaglandins can be used to increase prostaglandin levels in the body under certain circumstances . Administration of prostaglandins can induce labour at the end of pregnancy or abortion in the case of an unwanted pregnancy . They can also be used to treat stomach ulcers, glaucoma and congenital heart disease in new born babies.

17. DRUG USE BRAND Misoprostol Abortion, PPH , Peptic Ulcer Mifenac (East west Pharma), Safeguard (Pulse Pharma) Methotrexate Abortion, PPH Folitrax (IPCA), Caditrex (Cadila), Oncotrex (Sun) Carboprost Abortion, PPH Deviprost (Dr. Reddy), Caboprost (Neon labs) Enprostil Peptic Ulcer Aciphex (Eisai Pharma) Epoprostenol Platelet aggregation, Pulmonary hypertension Flolan, Veletri Latanoprost Glaucoma 9PM (Cipla), Ioptama (Cadila) Bimatoprost Glaucoma Careprost (Sun pharma) Travoprost Glaucoma Lupitros (Lupin) Tadalafil Erectile Dysfunction 36 hours (Cadila), Forzest (Ranbaxy) Sildenafil Pulmonary hypertension Alsigra (Alembic), Cavetra (Ranbaxy)

18. Leukotrienes : Straight chain lipoxygenase product of arachidonic acid are produced by a more limited number of tissues. (neutrophils & macrophages) Pathophysiologically as important as PGs. CVS & blood: LTC4 & LTD4 injected I.V. Rise in BP & prolonged fall. LTB4 highly chemotactic for neutrophils and monocytes Promotes Migration of neutrophils through capillaries & their clumping at the sites of inflammation in tissues

19. 2) Smooth muscles: LTC 4 & D 4 contraction Potent bronchoconstrictor & induce spastic contractions of GIT at low concentration. 3) Afferent nerves: like PGE2 & I2, LTB4 also sensitize afferent carrying pain impulses contribute to pain

20. Uses of PGs: 1 . Abortion: During first trimester, termination of pregnancy, Intravaginal PGE2 pessary inserted 3 hours trauma to the cervix by reducing resistance to dilatation. Medical termination of pregnancy of upto 7 weeks has been achieved with high success rate by administering mefepristone ( antiprogestin )600 mg orally 2 days before a single oral dose of misoprostol 400 μ g. 2. Induction/augmentation of labour : not potent than oxytocin for induction of labour. They are less reliable and show wider individual variation in action . PGE2 and PGF2α (rarely) have been used in place of oxytocin in toxaemic and renal failure patients, because they do not cause fluid retention.

21. 3. Cervical priming: Applied intravaginally or in the cervical canal, low doses make the cervix soft and compliant . This procedure has yielded good results in cases with unfavourable cervix . 4. Postpartum haemorrhage (PPH ): Carboprost (15-methyl PGF2α) injected i.m . is an alternative for control of PPH. 5. Peptic ulcer: Stable analogue of PGE1 (misoprostol ) is occasionally used for healing peptic ulcer, especially in patients who need continued NSAID therapy or who continue to smoke.

22. 6. Glaucoma: 7 . To maintain patency of ductus arteriosus : in neonates with congenital heart defects, till surgery is undertaken. PGE1 ( Alprostadil ) is used; apnoea occurs in few cases. 8. To avoid platelet damage: can be used to prevent platelet aggregation and damage during haemodialysis or cardiopulmonary bypass .

23. SIDE EFFECTS Side effects are common in the use of PGs, but their intensity varies with the PG, the dose and the route . nausea , vomiting , watery diarrhoea , uterine cramps, forceful uterine contractions, vaginal bleeding, flushing, shivering , fever , malaise, fall in BP, tachycardia, chest pain.

24. Platelet activating factor (PAF) Like eicosanoids, PAF is a cell membrane derived polar lipid with intense biological activity . Synthesis & degradation: from precursor phospholipids present in cell membrane by following reactions: PAF is acetyl- glyceryl ether- phosphoryl choline. Synthesis of PAF is quite limited—mainly WBC, platelets, vascular endothelium and kidney cells

25. Actions 1.Platelets: Aggregation and release reaction; also releases TXA2 ; i.v. injection results in intravascular thrombosis. 2) WBC: PAF is chemotactic to neutrophils, eosinophils and monocytes . It stimulates neutrophils to aggregate, to stick to vascular endothelium and migrate across it to the site of infection. It also prompts release of lysosomal enzymes 3) Blood vessels: Vaso dilatation → fall in BP on i.v. injection . 4) Visceral smooth muscle: Contraction occurs by direct action as well as through release of LTC4, TXA2 and PGs . 5) Stomach: PAF is ulcerogenic : erosions and mucosal bleeding occur shortly after i.v. injection.

26. Mechanism of action By Membrane bound specific PAF receptors , they are G-protein coupled receptor which exerts most of the actions through intracellular messengers IP3/DAG → Ca2+ release. As mentioned above, many actions of PAF are mediated/augmented by PGs, TXA2 and LTs which may be considered its extracellular messengers.

27. Pathophysiological roles PAF has been implicated in many physiological processes and pathological states, especially those involving cell-to-cell interaction. These are : Inflammation : Generated by leukocytes at the site of inflammation, PAF causes vasodilatation , exudation, cellular infiltration and hyperalgesia . 2. Bronchial asthma: Along with LTC4 and LTD4, PAF appears to play a major role by causing bronchoconstriction, mucosal edema and secretions. It is unique in producing prolonged airway hyper-reactivity.

28. 3. Anaphylactic (and other) shock conditions: are associated with high circulating PAF levels . 4. Haemostasis and thrombosis: PAF may participate by promoting platelet aggregation . 5. Rupture of mature graafian follicle and implantation: Early embryos which produce PAF have greater chance of implanting. However, PAF is not essential for reproduction.

29. Thank you