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
Normal renal function:
MAP  renal perfusion
urine output
(pressure diuresis)
salt output
(pressure natriuresis)
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
+
Na
Ca2+
reabsorption
Thiaz
filtration
Na+
secretion
Na+
+ALD
K+
H+
Loops
+ADH
Katzung Fig 15-1
K+
sparing
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)
loss of
diuresis
is fast
Brenner Fig 10-2
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)
 Urine Ca2+
With whom should
care be taken?
useful for osteoporosis
useful for kidney stones
Na+
How do thiazides
(and loops) promote
K+ loss?
collecting
duct
tubular Na+
Na+
Na+
K+ H loss
K+ H Loss
Na+/K+ exchange
urine
urine
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
Diuresis
'high ceiling diuretics'
'flat D-R curve'
Dose of diuretic
Brenner Fig 13-3
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
+
Na
Ca2+
reabsorption
Thiaz
filtration
Na+
secretion
Na+
+ALD
K+
H+
Loops
+ADH
Katzung Fig 15-1
K+
sparing
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
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
http://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 spironolactone
does not involve gene expression
•Relatively few side effects (caution about hyperkalemia)
JNC VII Compelling Indications for Drug Classes
Initial Therapy Options
Clinical-Trial Basis
Heart Failure
Diuretic, BB, ACEI,
ARB, Aldo Ant
MERIT-HF, COPERNICUS, CIBIS,
SOLVD, AIRE, TRACE, Val-HeFT,
RALES
Post-MI
BB, ACEI, Aldo Ant
ACC/AHA Post-MI Guideline, BHAT,
SAVE, Capricorn, EPHESUS
High CAD Risk
Diuretic, BB, ACEI, CCB
Compelling Indication
Diabetes Mellitus
Chronic Kidney Disease
Recurrent Stroke Prevention
Diuretic, BB, ACEI,
ARB, CCB
ACEI, ARB
Diuretic, ACEI
ALLHAT, HOPE, ANBP2,
LIFE, CONVINCE
NKF-ADA Guideline,
UKPDS, ALLHAT
NKF Guideline, Captopril Trial,
RENAAL, IDNT, REIN, AASK
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