1. Diuretics

2. Why do we want to know about diuretics? What do kidneys do? What can go wrong? Interventions that can be used how do they work? Effects, side effects

3. Functions of the kidney? Excretion of waste products regulation of salt and electrolyte content and volume of extra -cellular fluid acid -base balance

4. How? Several hundred litres of plasma filtered/day filtrate - very little protein/protein bound substances 99% of sodium is reabsorbed, some substances secreted 1.5 litres voided as urine Diuretics increase salt and water excretion

5. Why diuretics? important group of drugs employed for their effects on the kidney to enhance salt and water excretion (only when needed) when used: heart failure, other causes of salt and water retention (renal failure, liver failure), hypertension

6. Variety of compounds with diuretic activity Xanthines - theophylline, caffeine osmotic diuretics - urea carbonic-anhydrase inhibitors thiazides loop diuretics aldosterone antagonists potassium sparing diuretics

7. How do they work? Direct effect on cells of the nephron.. where most of the active and selective solute reabsorption occurs ascending loop of Henle early distal tubule collecting tubules and ducts OR modifying the content of the filtrate by their presence

8. Loop diuretics (Rang and Dale p361-363) Frusemide, bumetanide, piretanide act on thick segment of ascending loop inhibit NaCl transport OUT of tubule by inhibiting Na + /K + /2Cl - carrier (co-transporter) in luminal membrane ( acting on chloride binding site) Reduces the hypertonic interstitial area in the medull, so reducing water re-absorption increases Na + solute concentration in the distal tubule which is exchanged for K + and H + (hypokalemia and alkalosis) Can increase the excreted sodium from 1% to 15% of filtrate Also reduce peripheral vascular resistance

9. Loop diuretics Kinetics oral and IV preparations bound to plasma protein, secreted into tubule metabolised by the liver ( P450) act within 1 hour half life about 90 minutes; longer in renal failure duration - 3-6 hours (Lasts Six Hours – Lasix)

10. Loop diuretics Effects pass urine – in large amounts! Side effects electrolyte depletion Hypovolemia other reactions rare Main Use Heart failure – particularly acute left ventricular failure Hepatic cirrhosis Nephrotic syndrome Renal failure

11. thiazide diuretics bendrofluazide, hydrochlorothiazide, indapamide act on distal convoluted tubule bind to chloride site of Na + /Cl co–transport system and inhibit action decrease active Na resorption decrease water resorption changes in Ca, magnesium and uric acid

12. thiazide diuretcis kinetics rapidly absorbed orally secreted into the tubule maximal effect 4- 6 hours, duration 8-12 hours

13. thiazide diuretics effects increase urine output side effects electrolyte disturbances increased cholesterol impotence hypersensitivity reactions (rare) Main uses hypertension mild heart failure

14. aldosterone antagonists spirololactone inhibits action of aldosterone (intracellular receptor binding anatagonism), increases sodium and decreases potassium secretion kinetics well absorbed orally, active metabolite half life of 16 hours effects limited diuresis Main uses – heart failure and cirrhosis side effects Hyperkalemia, estrogen like effects

15. other potassium sparing diuretics Triamterene, amiloride act on collecting ducts inhibit Na resorption, decrease potassium excretion effects limited diuresis side effects electrolyte disturbances

16. clinical choices Uses: cardiac failure hypertension fluid overload NOT for everyone with oedema (eg from venous insufficiency) acute versus chronic evidence of benefit

17. references Rang & Dale, 5th edition Cardiovascular Therapeutic Guidelines Australian Medicines Handbook