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  MAP   renal perfusion  urine output (pressure diuresis)  salt output (pressure natriuresis) Normal renal function: Davidoff ‘09

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 For heart failure:  Blood volume  preload (  cardiac work)  congestion (  edema) Rationale for using diuretics

Katzung Fig 15-1 filtration secretion reabsorption +ADH +ALD Loops Thiaz K + sparing K+H+K+H+ Na + Ca 2+ Na +

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)

Brenner Fig 10-2 loss of diuresis is fast

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 With whom should care be taken? Bonus:  Blood Ca 2+ (via  Ca 2+ reabsorption)useful for osteoporosis  Urine Ca 2+ useful for kidney stones

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

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

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

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

Katzung Fig 15-1 filtration secretion reabsorption +ADH +ALD Loops Thiaz K + sparing K+H+K+H+ Na + Ca 2+ Na +

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 Potassium sparing ‘diuretics’ Spironolactone, Eplerenone, Amiloride

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

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

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)

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE 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: NKF-ADA Guideline, UKPDS, ALLHAT Diabetes Mellitus Clinical-Trial Basis Compelling Indication High CAD Risk ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS Post-MI MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-HeFT, RALES Initial Therapy Options Diuretic, BB, ACEI, CCB BB, ACEI, Aldo Ant Diuretic, BB, ACEI, ARB, Aldo Ant Heart Failure JNC VII Compelling Indications for Drug Classes Recurrent Stroke PreventionPROGRESSDiuretic, ACEI NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK Diuretic, BB, ACEI, ARB, CCB ACEI, ARB Chronic Kidney Disease