Diuretics by P.Ravisankar

Introduction to diuretics.
Therapeutic approaches.
Normal physiology of urine formation.
Classification of drugs .
Mechanism of action of Acetazolamide.
Mechanism of action of Thiazides.
Mechanism of action of Loop diuretics.
Mechanism of action of potassium sparing diuretics &aldosterone antagonists.

1. 1 9/13/2014 DIURETICS Presented by B.RAVALI Reg.no:11AB1R0008 Under the guidance of Mr. P.RAVI SANKAR M . Pharm ( Ph.D ) Associate professor Department of Pharmaceutical chemistry Vadlamudi , Guntur Dt , A.P , INDIA. PIN:522213

2. CONTENTS Introduction to diuretics. Therapeutic approaches. Normal physiology of urine formation. Classification of drugs . Mechanism of action of Acetazolamide. Mechanism of action of Thiazides. Mechanism of action of Loop diuretics. Mechanism of action of potassium sparing diuretics &aldosterone antagonists.

3. Diuretics (“water pills”) are the drugs which increase the urine out put (or) urine volume . What is natreuretic agent ? Any drug when introduce into the body increases the out put of sodium ie., loss of sodium in urine. DIURETICS

4. Diuretics are very effective in the treatment of conditions like:- chronic heart failure nephrotic syndrome chronic hepatic diseases hypertension Pregnancy associated oedema Cirrhosis of the liver. Therapeutic approaches

5. NORMAL PHYSIOLOGY OF URINE FORMATION Two important functions of the kidney are:- To maintain a homeostatis balance of electrolytes and water. To excrete water soluble end products of metabolites. Each kidney contains approximately one million nephrons and is capable of forming urine independently. The nephrons are composed of glomerulus, proximal tubule, loop of henle, distal tubule.

6. Approximately 1200 ml of blood per minute flows through both kidneys. Ions such as sodium, chloride,calcium are reabsorbed. Total amount of glucose, amino acids, vitamins, proteins are reabsorbed. If the urine contains above it represents the disorders. For example proteins such as albumin in higher amounts causes albuminaria.

7. LOOP DIURETICS Furosemide CARBONIC ACID INHIBITORS Acetazolamide CLASSIFICATION OF DRUGS

8. POTASSIUM SPARING DIURETICS Aldosterone antagonist Amiloride Spironolactone

9. Hydrochlor thaizide Chlorothiazide THIAZIDE DIURETICS

10. Chlor thalidone Metolazone THIAZIDE LIKE DIURETICS

11. GFR FORMATION 1 cardiac output -5 lit/min. Out of that 20% goes to kidneys i.e.1 lit/min. 1 lit of blood of has 40%of cells and 60%of plasma. 600 ml of plasma is not entered into glomerulus only a part of plasma can enter into it and the rest pass through the efferent arteriole. Only 20% can enter into glomerelus that is 120 ml. This 120 ml/min makes glomerular filtrate.

12. MECHANISM OF ACTION OF ACETAZOLAMIDE It is a sulfonamide derivative which is a non competitive reversible inhibitor of “ carbonic anhydrase enzyme”. This enzyme is responsible for catalytic reversible hydration of carbon dioxide and dehydration of carbonic acid. ADVERSE EFFECTS : Hypo kalaemia. Renal calculi. Nausea,loss of hearing,loss of apetite.

13. MECHANISM OF ACTION OF THIAZIDES These drugs compete for the chloride binding site of the sodium/chloride symporter and inhibit the re-absorption of sodium &chloride.

14. Uses Treatment of glaucoma . Reduces the intra occular pressure . Alkalizing the urine. These are given in combination with amiloride,allopurinol to prevent the formation of calcium stones in hyper calciuric patients.

15. ADVERSE EFFECTS GI effects - Anorexia CNS effects - Dizziness, vertigo. CVS effects- Ortho static hypotension.

16. SAR OF THIAZIDES The position 2 can tolerate the presence of small alkyl groups such as methyl. Substituents in 3 position determines the potency,duration of action.

17. SAR OF THIAZIDES Loss of c-c double bond between 3&4 positions of nucleus increases diuretic potency approximately three to ten fold . Direct substitution of the 4,5 or 8 position with an alkyl group usually results in diminished diuretic activity. Substitution of the 6 -position with an activating group is essential for diuretic activity . The best substituent's include Cl,Br,CF 3 and No 2 groups . The sulphamoyl group in the7-position is a prerequisite for diuretic activity.

18. chlorothiazide R 1 =H hydrochlorothiazide R 1 =H,R=Cl trichlormethiazide R 1 =CHCl 2, R=Cl methyclothiazide R 1 =CH 2 Cl,R=Cl hydroflumethiazide R 1 =H,R=CF 3 DRUGS SUBSTITUENTS

19. MECHANISM OF ACTION OF LOOP DIURETICS These agents produce a peak diuresis much greater than observed with other commonly used diuretics. They act by inhibiting the luminal Na/K/2Cl symporter.

20. Furosemide is preferred usually to ethacrynic acid for a number of reasons: It is less ototoxic. It has broader dose response curve. It is more convenient for i.v. use. It causes fewer git side effects.

21. SYNTHESIS OF FUROSEMIDE

22. Loop diuretics Thiazide diuretics They inhibit Na/K/2Cl symporetr. Acts at thick ascending loop of henle. These are Ca wasting drugs. They cause heavy diuresis. Para thyroid hormone independent Ca absorption. It can reabsorb 25%to 30% of Na. They act by inhibiting Na/Cl symporter. Acts at distal convoluted tubule. These are Ca retaining drugs. They cause mild diuresis. Para thyroid hormone dependent Ca absorption. It can reabsorb 8% of Na.

23. Mechanism of action of osmotic diuretics. Osmotic agents such as Mannitol are low molecular weight compounds that are freely filtered through bowmans capsule. They have limited reabsorption because of high water solubility. Osmotic diuretics increase the volume of water and almost all of the electrolytes.

24. Mechanism of action of potasssium sparing diuretic They act by inhibiting sodium reabsorption in the late distal tubule and thus indirectly spare potassium excretion. USES:- Liddle’s syndrome(pseudo-hyper aldosteronism). Amiloride is used to treat lithium induced nephrogenic diabetes insipidus.

25. Mechanism of action of SPIRONOLACTONE Aldosterone,by binding to its receptor in the cytoplasm increases expression &function of Na channel and sodium pump. Spironolactone competitively inhibits the binding of aldosterone and abolishes its biological effect.

26. Spironolactone - 17-hydroxy-7- α -mercapto-3-oxo-17 α preg-4-ene-21-carboxlic acid- ϒ -lactone acetate

27. Generic name Trade name Chlorothiazide Diuril Metalazone Zaroxylon Furosemide Lasix Chlorthalidone Thalitone Indapamide Lozol Hydroflumethiazide Saluron

28. CONCLUSION Diuretics are the first line agents to treat hypertension. When it is not controlled it can be given in the form of combinations with other anti hypertensive's. Some of these agents has the capacity to reabsorb more calcium so they can be prescribed for the patients suffering from osteoporosis.

29. Thomas L Lemke /David A Williams –Foye’s principles of Medicinal chemistry 6 th edition pg.no:722-735. Lippincott Williams & Wilkins – Remington The science &practice of pharmacy 21 st edition pg.no:1422-1431. D. Sriram, P.Yogeeswari –Medicinal chemistry pg.no:171-181. REFERENCES

30. References Wilson & Gisvold’s Text book of Organic Medicinal & Pharmaceutical chemistry 11 th edition pg. no:596-621 . Bertram G.Katzung –Basic & Clinical pharmacology 12 th edition pg.no:251-269.

31. ACKNOWLEDGEMENTS I oblige to pay my deep gratitude for the patience hearing of my presentation delivered by me with reference to power point. I thank one and all. I would like to thank my guide Mr. P.RAVI SANKAR for his extreme support & guidance. I would like to thank our principal Dr.P.SRINIVAS BABU I also would like to thank our o rganizing committee.

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