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

+ALDLoops

ThiazK+

sparing

K+

H+

Na+

Ca2+Na+

Na+

Thiazides: hydrochlorothiazide

•Most commonly used class of diuretics

•Differ in their pharmacokinetics

•Indicated for mild hypertensionshort-term effects blood volumelong-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 alkalosisBlood glucose, lipids, and uric acid With whom

should care be taken?Bonus:

Blood Ca2+ (via Ca2+ reabsorption) useful for osteoporosis Urine Ca2+ useful for kidney stones

Na+

K+ H loss

tubular Na+

urine

K+ H Loss

Na+ Na+

urine

How do thiazides(and loops) promoteK+ loss?

Na+/K+ exchange

collectingduct

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 Henlenormally 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

Diu

resi

s

'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

+ALDLoops

ThiazK+

sparing

K+

H+

Na+

Ca2+Na+

Na+

•Weak diureticsused in combination with other diuretics

•Antagonize aldosterone effects

•Aldosterone is a steroidbinds to mineralocorticoid receptors in tubular

epithelial cellsstimulates the synthesis of Na/K/H pumpspromotes 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 actionsWomen: 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 spironolactonehttp://www.jaapa.com/issues/j20040201/articles/0204wcardiomeds.html

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 spironolactonedoes 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;289:2560-2572

NKF-ADA Guideline,UKPDS, ALLHAT

Diabetes Mellitus

Clinical-Trial BasisCompelling 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 Prevention PROGRESSDiuretic, ACEI

NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

Diuretic, BB, ACEI,ARB, CCB

ACEI, ARBChronic Kidney Disease