DIURETICS: (know those used to Tx hypertension and HF) Thiazide diuretics: hydrochlorothiazide

1. Normal renal function: urine output (pressure diuresis) MAP  renal perfusion salt output (pressure natriuresis) Davidoff ‘09 • DIURETICS: • (know those used to Tx hypertension and HF) • Thiazide diuretics: hydrochlorothiazide • Loop diuretics: furosemide, ethacrynic acid • Potassium-sparing diuretics: • spironolactone, eplerenone, amiloride • Osmotic diuretics: mannitol • Carbonic anhydrase inhibitors: acetazolamide

2. Rationale for using diuretics For heart failure: Blood volume  preload (cardiac work) congestion (edema) For hypertension:  Blood volume and peripheral resistance   preload (ventricular filling)   CO   BP • Diuretics promote natriuresis (Na+ excretion) • Water tends to follow Na+ (diuresis) • Relative potencies of diuretics: • Loops >> Thiazides >>>>>> K+ sparing

5. Na+ Ca2+ reabsorption Thiaz filtration K+ sparing Na+ secretion Na+ +ALD Loops K+ H+ +ADH Katzung Fig 15-1

6. Thiazides: hydrochlorothiazide • Most commonly used class of diuretics • Differ in their pharmacokinetics • Indicated for mild hypertension • short-term effects  blood volume • long-term effects TPR (lose their diuretic effects) • For moderate or severe hypertension, • used in combination with other antihypertensive drugs • Flat dose-response curve • (i.e., increasing dose does not make them more effective)

7. loss of diuresis is fast Brenner Fig 10-2

8. With whom should care be taken? • Thiazides: (con’t) • Na+ reabsorption by inhibiting Na/Cl co-transport in the distal • convoluted tubule • Modest effect because only 5-10% of Na+ is reabsorbed there • Must be filtered or secreted to work, therefore ineffective • in patients with renal insufficiency/failure • Require renal prostaglandins to work, therefore NSAIDs can • interfere with diuresis • Side effects: • Hypokalemic metabolic alkalosis • Blood glucose, lipids, and uric acid Bonus: Blood Ca2+ (via Ca2+ reabsorption) useful for osteoporosis  Urine Ca2+ useful for kidney stones

9. How do thiazides (and loops) promote K+ loss? Na+ K+ H Loss Na+ tubular Na+ collecting duct Na+ K+ H loss Na+/K+ exchange urine urine

10. Loop diuretics: furosemide, ethacrynic acid • “High ceiling diuretics” - work in a dose-dependent manner • Ethacrynic acid is an alternative if patient has sulfonamide allergy • Extremely effective, rapid onset • Indicated for severe edema (e.g., pulmonary edema, CHF) • not typically used for hypertension • Inhibit Na/K/2Cl transport in ascending loop of Henle • normally responsible for ~35% Na+ reabsorption • Are filtered and secreted • Directly increase renal blood flow, therefore effective with renal insufficiency

11. 'high ceiling diuretics' Diuresis 'flat D-R curve' Dose of diuretic Brenner Fig 13-3

12. Like Thiazides: Loops require renal prostaglandins to work, therefore NSAIDs can interfere with diuresis • Side effects include: • Hypokalemic metabolic alkalosis and hyperuricemia • Hypovolemia • Ototoxicity Loops greater incidence of adverse side effects than thiazides

13. Na+ Ca2+ reabsorption Thiaz filtration K+ sparing Na+ secretion Na+ +ALD Loops K+ H+ +ADH Katzung Fig 15-1

14. Potassium sparing ‘diuretics’ Spironolactone, Eplerenone, Amiloride • Weak diuretics • used in combination with other diuretics • Antagonize aldosterone effects • Aldosterone is a steroid • binds to mineralocorticoid receptors in tubular epithelial cells • stimulates the synthesis of Na/K/H pumps • promotes Na+ reabsorption, K+/H+ secretion • Prevents hypokalemia from thiazide and loop diuretics • Must be cautious of hyperkalemia

15. Spironolactone • Competitively binds to aldosterone receptors - nonselective • (mineralocorticoid, androgenic and progesterone receptors) • Inhibits aldosterone-induced synthesis of pumps • Slow onset (WHY?), long duration (active metabolites) • Weak naturiuretic effects, but lowers BP in some patients with mild/moderate hypertension • Also indicated for hyperaldosteronemia • Shown to improve morbidity and mortality in patients with end-staged heart failure (Pitt et al., NEJM, 1999) • Side effects include: • Men: gynecomastia and erectile dysfunction because of anti-androgenic actions • Women: menstrual irregularities, hirsutism

16. Eplerenone • More specific for aldosterone receptors than spironolactone therefore avoids side effects • (but really expensive) • Currently approved hypertension and post-MI LV dysfunction • CYP450 3A4 inhibitors (e.g., erythromycin, verapamil, and grapefruit juice) can elevate blood levels of eplerenone • Aldosterone is also associated with endothelial dysfunction and fibrotic effects in hypertension, HF and atherosclerosis • (mechanism underlying ACE-I cardioprotection???) • Cardioprotective effects appear similar to spironolactone http://www.jaapa.com/issues/j20040201/articles/0204wcardiomeds.html

17. Amiloride • Directly inhibits pumps in distal tubules and collecting ducts • therefore independent of aldosterone • (blocks Na+ selective channels in apical membrane) • Onset of action much faster than spironolactone • does not involve gene expression • Relatively few side effects (caution about hyperkalemia)

18. JNC VII Compelling Indications for Drug Classes Clinical-Trial Basis Compelling Indication Initial Therapy Options MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-HeFT, RALES Heart Failure Diuretic, BB, ACEI,ARB, Aldo Ant ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS BB, ACEI, Aldo Ant Post-MI ALLHAT, HOPE, ANBP2,LIFE, CONVINCE High CAD Risk Diuretic, BB, ACEI, CCB NKF-ADA Guideline,UKPDS, ALLHAT Diuretic, BB, ACEI,ARB, CCB Diabetes Mellitus NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK Chronic Kidney Disease ACEI, ARB Recurrent Stroke Prevention Diuretic, ACEI PROGRESS ACEI=Angiotensin converting enzyme inhibitor, Aldo Ant=Aldosterone antagonist, ARB=Angiotensin receptor blocker, BB=b-blocker, CAD=Coronary artery disease, CCB=Calcium channel blocker, MI=Myocardial Infarction Chobanian AV et al. JAMA. 2003;289:2560-2572