Diuretics

1. Diuretics Moustafa K.Soltan

2. Diuretic is substance that increases the urine excretion by kidney so decrease body fluids mainly the extracellular fluids. *the functional unit in the kidney is the nephron and each kidney has about one million nephron. *To increase water excretion, a diuretic has to increase Na+ secretion from blood to nephron lumen, Or decrease Na+ reabsorption from lumen to blood. *Natriuretic is substance increase Na+ excretion, Saliuretic is substance increase Na+ and Cl- excretion, Kaliuretic is substance increase K+ excretion. General used of diuretics: 1)treatment of all types of edema associated with congestive heart failure, liver dysfunction or cirrhosis, Renal failure and during pregnancy. 2)used in treatment of hypertension either alone if hypertension is mild or in combination with antihypertensive drug if severe hypertension.

3. I] Classification due to site of action: A} Agents that exert their effects in the proximal (convoluted) tubules: Mercurial drugs, thiazides, osmotic diuretics, xanthines. B} Agents that affect the loop of Henle (high ceiling or loop diuretics) Mercurial drugs, thiazides, frusemide, ethacrynic acid. C} Agents that exert their action on the distal (convoluted) tubules: Potassium sparing diuretics (SPIRONOLACTONE), potassium excreting agents THIAZIDES.

4. II] Classification duo to chemical structure A} Water and osmotic agents (urea, mannitol). B} Acidifying salts ( NH4Cl, NH4NO3). C} Mercurial agents: mersalyl sodium. D} α,β-unsaturated ketones: Ethacrynic acid. E} Purine or xanthine diuretics: aminophylline. F} Pyrimidines ( uracil derivatives): Aminometradin, amisometradin. G} Sulphonamides: I] Carbonic anhydrase inhibitors: Acetazolamide, methzolamide, dichlorophenamide. II] Benzothiadiazine derivatives ( thiazides) : Chlorothiazide, hydrochlorothiazide, bendrofluazide, trichlormethiazide, benzthiazide, cyclothiazide,cyclopenthiazide, altizide, polythiazide. III] Quinazoline derivatives: Quinethazone, metolazone,. IV] Phthalimidine derivatives: Chlorothalidone. V] Sulphamyl benzoic acid derivatives and their related compounds: Frusemide, clopamide, mefruside, indapamide. H} Steroidal diuretics: Spironolactone. G}Miscellaneous compounds: Triamterene, amiloride.

5. α,β-unsaturated ketones MOA: it inhibit Na+ reabsorption in ascending loop of Henle, and in distal tubule and commonly called ( Loop diuretic ), thus increase also Cl- excretion so cause systemic alkalosis. Uses: used in refractory edema.

6. Purine or xanthine diuretics ***Assay: 1) for ethylene diamine: dissolve in water and then titrate with standard acid and methyl orange indicator. 2) for theophylline: to the above neutral solution add Kn xss of AgNO3, which pricipitate theophylline as insoluble silver salt liberate equivalent amount of HNO3 titrated with st base, indicator , or determine residual AgNO3 by st SCN-, ferric alum aminophylline used as diuretic and bronchodilator

7. Sulphonamides. 1-Carbonic anhydrase inhibitors General mechanism of action: they act mainly in proximal tubules. they have SONH2 group which is structurally similar to carbonic acid so inhibit carbonic anhydrase enzyme which catalyze the following process: When carbonic anhydrase is inhibited, the H+ conc. is decreased what will decrease Na+ / H+ exchange, Increasing Na+ excretion, decreasing its reabsorption so cause diuresis. *** It decrease H+excretion so cause systemic acidosis that make inhibitors of carbonic anhydrase ineffective, So drug administration should be stopped till acid-base balance is returned.

8. Uses.1)reduces intraocular pressure so useful in treatment of glaucoma. 2) diuretic but less useful than other agents why? (***) acetazolamide just used for 2-3 days as after this it becomes ineffective due to compensatory mechanism of the kidney to overcome systemic acidosis results from the drug that must be stopped till acid base balance is returned.

9. SAR of carbonic anhydrase inhibitors: • the amino group in the SO2NH2 group should be primary and free, substitution of one or the two sulfonamide hydrogens will abolishes activity. • 2) aromatic sulfonamides are more active than aliphatic ones. • 3) 1,3,4-thiadiazolesulfonamides are 100 times as active as sulfanilamide, ex acetazolamide. • 4) methylation of acetazolamide leads to methazolamide has the same activity as acetazolamide. • 5) p-carboxybenzenesulfonamide is several times more active than sulfanilamide. • 6) introduction of another SO2NH2 group will increase activity, addition of another Cl atom will increase potency • as in dichlorophenamide. • 7) if acyl group is removed from the nitrogen atom, activity is decreased. • 8) highly ionized agents are more firmly bound to carbonic anhydrase enzyme so have more diuretic activity

10. II] Benzothiadiazine derivatives ( thiazides) : MOA: Inhibit Na+ reabsorption in proximal tubule and ascending loop of Henle what cause diuresis. They have SO2NH2 so has certain degree of carbonic anhydrase inhibition SAR: 1) Cl, F, CF3 in the position 6 activates the nucleus. 2) substitution on the position 5 or 8 reduces the activity. 3) free sulfamoyl group is essential for activity, removal or replacement of one of the two hydrogens of sulfamoyl group by methyl group abolishes activity 4) free sulfamoyl group in position 7 is equal in activity to that in position 5, if in position 6 it will reduce the activity

11. 5) substitution of ring nitrogens in position 2 or 4 will reduce the activity, but if by lower alkyl group as methyl in the position 2, it will enhance the activity. 6) saturation of the double bond in the position 3-4 give 10 fold increase in the activity as in hydrochlorothiazide. 7) substitution in the position 3 by hydrophobic group like alkyl, cycloalkyl, haloalkyl and aralkyl will increase the activity, α hydrogen is essential for activity. Uses: 1) oedema associated with heart failure and hepatic or renal disorders. 2) hypertension alone or with other antihypertensives.

12. Phthalimidine derivatives Sulphamyl benzoic acid derivatives

13. Steroidal diuretics: Spironolactone (STEROIDAL POTASSIUM SPARING DIURETICS) MOA: aldosterone stimulate Na+ reabsorption and K+ excretion so cause hypokalemia and decrease diuresis, Spironolactone antagonize the effects of aldosterone in the collecting duct so as to decrease Na+ rabsorption and also decrease K+ excretion so called potassium sparing diuretic and it has steroidal structure. ** spironolactone is metabolized to an active metabolite which is canrenone.

14. Miscellaneous compounds: NON STEROIDAL POTASSIUM SPARING DIURETICS) MOA:1) act in the late distal convoluted tubule and in the early collecting duct. 2)It exerts the same action of spironolactone but without any relation to the aldosterone. 3) it is really mild natriuretic, saliuretic and antikaliuretic. Uses: 1) mild edema associated with congestive heart failure or liver cirrhosis. 2)not enough alone in treatment of hypertension. 3) mainly used with hydrochlorothiazide to prevent associated hypokalemia of the latter.