physiological role of prostaglandin

PRESENTAION ON PHYSIOLOGICAL ROLE OF PROSTAGLANDIN

1. PHYSIOLOGICAL ROLE OF PROSTAGLANDINS PRESENTED BY : SREYA. S M. Pharmacy Academic year:2019-2021 DEPT OF PHARMACOLOGY

2. INTRODUCTION Autocoids - Greek Autos :- Self, akos :- Healing substance or remedy CLASSIFICATION Amine autacoids :- Histamine, 5-Hydroxytryptamine (Serotonin) Lipid derived autacoids :- Prostaglandins, Leukotrienes , Platelet activating factor Peptide autacoids :- Plasma kinins ( Bradykinin , Kallidin ), Angiotensin

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4. PROSTAGLANDINS The  prostaglandins  ( PG ) are a group of physiologically active lipid compounds called  eicosanoids  having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. Prostaglandins were discovered in human semen in 1935 by the Swedish physiologist Ulf von Euler

5. Biosynthesis   They are synthesized in the cell from the fatty acid  arachidonic acid. Arachidonic acid is created from  diacylglycerol  via phospholipase-A 2, then brought to either the  cyclooxygenase pathway or the  lipoxygenase pathway. The cyclooxygenase pathway produces  thromboxane ,  prostacyclin  and prostaglandin D, E and F

6. INHIBITION OF SYNTHESIS Inhibited by NSAIDs Glucocorticosteroids inhibit the release of arachidonic acid from membrane lipids

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8. Degradation : Most tissues – rapidly – fastest in Lungs Most PGs, TXA2 and Prostacyclins (PGI2) – half life of few seconds only Carrier mediated uptake into cells followed by – side chains are oxidized and double bonds are reduced and finally yield ionactive metabolite, and excreted in urine Types of Prostaglandins Prostaglandin H2(PGH2):- derived from arachidonic acid and is a precursor for other biologically significant prostagladins . Prostagladin D2(PGD2):- works by binding to PTGDR receptor. Actions:- Potent bronchoconstrictor Promotion of sleep Causes vasodilation

9. Prostaglandin E2(PGE2):- Works by binding and activating the prostaglandin E2 receptor Actions:- ↓ gastric acid secretion ↑ gastric mucus secretion uterus contraction (when pregnant) GI tract smooth muscle contraction Bronchodilator, vasodilator Induces pain, heat, fever D) Prostagladin F2 α (PGF2 α ) :- acts by binding to prostaglandin F2 α receptor. Uterus contraction Bronchoconstriction

10. PGs : Pathophysiological CVS Both PGE2 and PGF2 α : Mostly vasodilators - but PGF2 α constricts Pulmonary vein and artery PGI2 – uniform vasodilator and potent hypotensive > PGE2 PGG2 and PGH2 – biphasic response (actually vasoconstrictor) TXA – vasoconstrictor Heart : Stimulates: PGE2 and PGF2 α – direct weak and reflex action Role: No role in systemic Vascular regulation – but PGI2 (COX-2 generated) – local vascular tone (dilator) PGE₂ keeps ductus arteriosus patent (Aspirin & Indomethacin ) Exudation: PGs generated by COX-2 with LTs and other autacoids - inflammation

11. Uterus PGE2 and PGF2 α – uniformly contracts uterus – pregnant and non-pregnant … higher as the pregnancy progresses Consistent contraction – PGF2 α but PGE2 – relaxes not-pregnant and contracts pregnant uterus At term – softens uterus Role Initiation and progression of labour by PGF2 α ( Aspirin delays) Semen in high PGs – movement of female genital tract, transport of sperm and facilitation of fertilization Dysmenorrhoea – Uncoordinated uterine contraction – ischemia – pain (Aspirin effective)

12. Bronchial Muscles PGF2 α, PGD2 ,TXA2 and LTs – Potent bronchoconstrictor PGE2>PGI2 – dilators + inhibit release of Histamine – but no clinical use (irritation) Role: Asthma – imbalance between the above Aspirin: induces asthma – diverts arachidonic acid to produce more LTs (LTC4 and LTD4) In allergic asthma – Leukotriene

13. GIT I ntestine : PGs (PGE2) – increased propulsive activity – colic and watery diarrhoea PGE2 – increases water, electrolyte and mucus secretion …. PGI2 opposes Role : Toxin induced increased fluid movements in secretary diarrhoea (aspirin reduces fluid volume) Colonic polyps and Cancer – reduced colonic cancer and reduced polyp formation Stomach : PGE2>PGI2 reduces all gastric acid secretions (also pepsin) – Gastrin also reduced - even histamine, gastrin and other induced ones Mucus, HCO3 secretion increased with increased blood flow – Antiulcerogenic

14. Role : PGI2 – regulation of gastric mucosal blood flow – natural ulcer protective …. NSAID induced ulcers – due to loss of protective function Gastric mucosal PGs are produced by COX -1 – selective COX-2 inhibitors are NOT ULCEROGENIC Kidneys : PGE2 & PGI2 – Diuretic effect Renal vasodilatation and inhibit tubular reabsorption ( Furosemide like – inhibits Cl - reabsorption TXA2 – renal vasoconstriction Role: PGE2 & PGI2 (produced by COX-2) in kidney – intrarenal blood flow regulation and tubular reabsorption (less) …. NSAIDs - retain salt and water Renin release – PGE2 and PGI2

15. CNS Poor penetration; injected directly – PGE2 – sedation, rigidity and behavioural changes; PGI2 – fever Role : PGE2-Hypothalamus: pyrogen induced fever and malaise (COX-2 involved – selective COX-2 inhibitors – antipyrretic Neuromodulator – pain perception, sleep and other functions ANS Inhibition as well as augmentation of NA release – depends on PG, species and tissue Role : modulate sympathetic neurotransmission

16. Peripheral nerves Sensitize afferent nerve endings to pain inducing chemical and mechanical stimuli – irritate mucous membrane Role : algesic during inflammation (aspirin cause analgesia) Eye PGF2 α – induces ocular inflammation and lowers IOP – enhances uveoscleral and tubular outflow ( latanoprost ) Role: Local PGs facilitate aqueous humor drainage (less COX-2 in glaucoma) Endocrine Facilitate release of Anterior Pituitary hormones – GH, Prolactin , ACTH, FSH, LH --- also Insulin and steroids Role : terminate early pregnancy in women ( luteolysis )

17. Metabolism Antilipolytic – Insuline like effect - mobilize Ca++ from Bone Platelets TXA2 >PGG2>PGH2 – pro-aggregator…… PGI2 and PGD2 – anti-aggregator ….. PGE2 – inconsistent effect Role : TXA2 and PGI2 – mutual antagonists – prevent aggregation in circulation, but induces aggregation during injury TXA2 – produced by COX-1 – amplify aggregation Aspirin (low dose): haemostasis interference by inhibiting platelet aggregation (COX-1 inhibition at portal circulation) – PGI2 not interfered (endothelium

18. CLINICAL APPLICATION OF PGS Abortion Induction/augmentation of labour Cervical priming(ripening) Postpartum haemorrhage (PPH) Peptic ulcer Glaucoma To maintain patency of ductus arteriosus To avoid platelet damage

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20. MISOPROSTOL (PROSTAGLANDIN E 1 ) sold under the brandname   Cytotec Clinical use: NSAID induced peptic ulcer Therapeutic abortion Induction of labour It cause ripening & softening & dilatation of cervix. It binds to myometrial cells to cause strong contraction leading to expulsion of product of conception Common side effects diarrhea  abdominal pain.

21. ALPROSTADIL (PROSTAGLANDIN E1) Prostaglandin E1  ( PGE1 ), also known as  alprostadil It is a naturally occurring prostaglandin which is used as a medication USES  In babies with congenital heart defects, it is used by slow injection into a vein to open the  ductus arteriosus until surgery can be carried out. By injection into the penis or placement in the urethra, it is used to treat erectile dysfunction . Common side effects when given to babies include decreased breathing, fever, and low blood pressure.  When used for erectile dysfunction side effects may include penile pain, bleeding at the site of injection, and prolonged erection ( priapism ).

22. LATANOPROST ( PROSTAGLANDIN F 2 α ) It sold under the brand name  Xalatan   uses To treat increased pressure inside the eye. This includes ocular hypertension and open angle glaucoma.  It is applied as eye drops to the eyes . Onset of effects is usually within four hours, and they last for up to a day. Common side effects  blurry vision, redness of the eye, darkening of the iris .

23. CARBOPROST: Prostaglandin PGF 2 α Carboprost sold under the trade name  Hemabate Uses Used in postpartum hemorrhage caused by uterine atony not controlled by other methods.  termination of pregnancy in the 2nd trimester. Common side effect diarrhea (most common, may be sudden in onset) flushing or hot flashes fever chills nausea/vomiting

24. SIDE EFFECTS Nausea Vomiting Watery diarrhoea Uterine cramps Vaginal bleeding Flushing Shivering Tachycardia Fall in BP

25. CONTRAINDICATIONS Bronchial Asthma Epilepsy Hypersensitivity to the drug Renal disease Hypertension

26. REFERENCES Tripathi K.D. Essentials Of Medical Pharmacology. 7 th ed. Jaypee Brothers Medical Publishers; 2014:[182-191] Rang H.P ,Dale M.M, Ritter J.M, Flower R.J.Pharmacology . 6 th ed.Elsevire : Churchill livingstone;2008:[226-237 http://www.medindia.net/articles/prostaglandin.htm http://en.wikipedia.org/wiki/prostaglandin

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