Diuretics

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+ andH+ (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