Pharmacology and Katie Herndon is not speaking on

Clinical Use of Diuretics behalf of Pfizer, but solely as a

medical professional with an
expertise in pharmacotherapy.
Katie Herndon, Pharm.D., BCPS

Objectives Diuretic Classes

• Review the mechanism of action, • Thiazide Diuretics
pharmacokinetics, and pharmacodynamics – Hydrochlorothiazide – Polythiazide
of diuretics – Chlorothiazide – Bendroflumethiazide
– Methyclothiazide
• Contrast the pharmacology of different • Thiazide-Like Diuretics
classes of diuretic agents – Chlorthalidone – Indapamide
• Discuss the clinical use of diuretics – Metolazone
• Loop Diuretics
– Bumetanide – Furosemide
– Ethacrynic acid – Torsemide

Sodium Reabsorption in the Renal Tubule

Diuretic Classes
Lumen Tubular Cell Blood

• Potassium-Sparing Diuretics
– Amiloride
– Triamterene
• Aldosterone Antagonists
Na+
– Spironolactone Na+ K+
– Eplerenone
• Carbonic Anhydrase Inhibitors
– Acetazolamide

Dis Mon 1998;44:254-268

1
 Sodium Reabsorption in the Renal Tubule
Lumen
• Na+ is reabsorbed by a
two-step process:
1. Na+ entrance into the cell via
a Na+ transporter present in
the luminal cell membrane
2. Once Na+ enters the tubular
cell, it is transferred across
the basolateral membrane
into the interstitium and
blood by the Na+-K+-ATPase
pump
• Cell interior is electrically
negative in relation to the
extracellular fluid
Sodium Reabsorption in the Renal Tubule
Tubular Cell Blood Lumen Cell Blood
• The electrochemical
gradient is the force
driving positively charged
Na+ ions across the
luminal membrane into the
cell
Na+ • Na+ movement is facilitated Na+
Na+ K+ by transporters on the Na+ K+
luminal side of the tubular
epithelial cell
• Transporter pathways
differ between various
segments of the nephron
Dis Mon 1998;44:254-268 Dis Mon 1998;44:254-268
Expert Opin Drug Saf 2010;9:243-257 Expert Opin Drug Saf 2010;9:243-257

Principles of Diuretic Action Principles of Diuretic Action

• Diuretics act by inhibiting sodium • Site of action is located on the luminal
reabsorption in the renal tubules, thereby surface of the tubule
increasing urinary sodium, and • Extensively bound to serum albumin
consequently, water loss • Transported into the proximal tubule lumen
• Agents differ with respect to the specific by active secretion
tubular ion transport systems they inhibit – Organic acid secretory pathway: thiazides,
– Site of action within the nephron loop diuretics, acetazolamide
– Natriuretic efficacy – Organic base secretory pathway: potassium-
– Pharmacological effects sparing diuretics
– Clinical indications – Exception: spironolactone and eplerenone
Expert Opin Drug Saf 2010;9:243-257
enter renal tubules from plasma
Expert Opin Drug Saf 2010;9:243-257

Sites of Diuretic Action Sites of Diuretic Action

in the Nephron in the Nephron
• Under physiological • The net effect of carbonic
conditions of Na+ intake, anhydrase inhibitors is
FENa remains under 1% increased Na+, HCO3-, K+,
and water loss
• After formation of a plasma
ultrafiltrate in the • Diuresis is modest because
glomerulus, the tubular Na+ remaining in the lumen
fluid enters the proximal is absorbed at distal
convoluted tubule segments
• 65-70% of filtered Na+ is • Alkaline diuresis
reabsorbed in the proximal leading to metabolic
tubule acidosis

NEJM 2009;361:2153-64
NEJM 2009;361:2153-64 Expert Opin Drug Saf 2010;9:243-257
Expert Opin Drug Saf 2010;9:243-257

2
Sites of Diuretic Action Sites of Diuretic Action
in the Nephron in the Nephron
• Loop diuretics act at the • Thiazides act mainly at the
thick ascending limb of the distal convoluted tubule
loop of Henle where ~ 25% where ~ 5-10% of the filtered
of filtered Na+ is reabsorbed Na+ load is reabsorbed
• Loop diuretics bind to the • Thiazides inhibit Na+ and Cl-
Na+-K+-2Cl- co-transport reabsorption by inhibiting
protein, impairing the the electroneutral Na+–Cl-
reabsorption of symport
Na+, K+, and Cl-

NEJM 2009;361:2153-64 NEJM 2009;361:2153-64

Expert Opin Drug Saf 2010;9:243-257 Expert Opin Drug Saf 2010;9:243-257
Wile D. Diuretics: a review [published Wile D. Diuretics: a review [published online
online ahead of print July 10, 2012]. Ann ahead of print July 10, 2012]. Ann Clin Biochem.
Clin Biochem. doi: doi: 10.1258/acb.2011.011281.
10.1258/acb.2011.011281.

Sites of Diuretic Action

Diuretic Tolerance
in the Nephron
• K+-sparing diuretics • Use of diuretics elicits both short and long-term
(amiloride and triamterene) adaptations intended to protect intravascular
act primarily at the cortical volume
part of the collecting duct
where only ~2% of Na+ is • Short-term tolerance: Decreased response to
reabsorbed the after the first dose of diuretic has been
• Na+ movement creates an administered
electrical gradient that drives – Nephron is primed to avidly reabsorb sodium after
K+ from the epithelial cell to
drug levels decline below the diuretic threshold
the lumen
– Triggered by intravascular volume depletion
• K+-sparing diuretics inhibit
the epithelial Na+ channel – Renin-angiotensin system and sympathetic nervous
of the collecting duct sytem thought to contribute
NEJM 2009;361:2153-64
Expert Opin Drug Saf 2010;9:243-257
– Post-dose sodium retention significantly influenced
Wile D. Diuretics: a review [published online
ahead of print July 10, 2012]. Ann Clin Biochem. by dietary sodium intake NEJM 1998;339:387-395
Semin Nephrol 2011;31:483-494
doi: 10.1258/acb.2011.011281. NEJM 2009;361:2153-64

Diuretic Tolerance Loop Diuretics

• Long-term tolerance: Gradual return of sodium- • Most potent diuretic class with maximally effective
chloride balance to an electroneutral level doses causing excretion of 20-25% of filtered Na+
– Loop diuretics cause sodium to flood more distal • Primary role is edematous disorders (heart failure,
nephron sites cirrhosis, neprotic syndrome), blood pressure and
– Over time, increased exposure to sodium causes volume control in chronic kidney disease
hypertrophy of distal nephron segments with • No evidence of a significant difference in potency if
concomitant increases in the reabsorption of sodium administered in equipotent doses
– Persistent volume removal appears to trigger long- • Not recommended for treatment of uncomplicated
term activation of the renin-angiotension-aldosterone
hypertension due to short duration of action
system
– Up-regulation of sodium transporters downstream
• In normal patients, 40 mg IV furosemide (or
from the primary site of diuretic action equivalent dose of other loop) elicits a maximal
response: 200 to 250 mEq of sodium in 3 to 4 L of
NEJM 1998;339:387-395
Semin Nephrol 2011;31:483-494 urine over 3 to 4 hours NEJM 1998;339:387-395
Expert Opin Drug Saf 2010;9:243-257
NEJM 2009;361:2153-64 Semin Nephrol 2011;31:483-494

3
 Loop Diuretics Pharmacodynamics of a Loop Diuretic
• Amount of loop diuretic absorbed is normal in patients with
edema, although absorption is slower than normal
• Variability of absorption is likely more important than
absolute bioavailability
• 40 mg IV furosemide = 20 mg torsemide = 1 mg bumetanide

Route of
Drug Bioavailability t1/2 IV:PO
Elimination
50%
Furosemide 1.5-2 hr Renal 1:2
(Highly variable)

Bumetanide 80-100% 1 hr Liver 1:1

Torsemide 80-100% 3-4 hr Liver 1:1

Ethacrynic acid ~~100% 1 hr Liver 1:1

Congest Heart Fail 2010;16 (suppl 1):S68-S72

NEJM 1998;339:387-395 Expert Opin Drug Saf 2010;9:243-257 Semin Nephrol 2011;31:483-494

Conditions of Diminished Response to Conditions of Diminished Response to

Loop Diuretics: Renal Insufficiency Loop Diuretics: Renal Insufficiency
• Loop diuretics are diuretics of choice
• With a CrCl = 15 ml/min, 1/5 to 1/10 as much loop
• Pharmacodynamics are not altered; residual diuretic is secreted into the tubular fluid
nephrons retain their responsiveness to the diuretic
• Bioavailability of loop diuretics is the same in
• FeNa is similar to healthy subjects, but absolute Na+
patients with renal insufficiency
excretion is lower due to the decrease in the filtered
Na+ load • Strategies:
– Larger doses should be administered to attain
effective drug amounts at the site of action
– Administer effective doses several times per day
– Add an oral thiazide diuretic
– Continuous intravenous infusion of diuretic
NEJM 1998;339:387-395 NEJM 1998;339:387-395
Expert Opin Drug Saf 2010;9:243-257 Expert Opin Drug Saf 2010;9:243-257
Semin Nephrol 2011;31:483-494 Semin Nephrol 2011;31:483-494

Pharmacodynamics of a Loop Diuretic Conditions of Diminished Response to

Loop Diuretics: Heart Failure
• Access of diuretics to site of action is normal
• Slower po absorption. Use IV for immediate response
Heart Failure
• Patients with NYHA Class II and III HF have 1/4 to 1/3
Cirrhosis
Nephrotic Syndrome
the natriuretic response to maximally effective doses
of loop diuretics
• Diuretic resistance results from an interaction
between the pathophysiology of Na+ retention in HF
and the renal response to diuretic therapy
• Strategies:
– Administer effective doses several times per day
– Add an oral thiazide diuretic NEJM 1998;339:387-395

Congest Heart Fail 2010;16 (suppl 1):S68-S72 – Addition of a K+-sparing agent Expert Opin Drug Saf 2010;9:243-257
Semin Nephrol 2011;31:483-494

4
 Conditions of Diminished Response to
Thiazide Diuretics
Loop Diuretics
• Mainstay in the treatment of hypertension
• Nephrotic Syndrome
– Most have half-lives permitting once-daily dosing
– Mechanism of diminished response to diuretics is unknown
– Reductions in systolic and diastolic blood pressures of 10
– Hypoalbuminemia and albuminuria may have a PK effect
to 15 mm Hg and 5 to 10 mm Hg, respectively
– Strategies: – Combined effectively with most antihypertensive classes,
• 2-3 times higher dose to attain normal amounts of unbound often producing an additive decrease in blood pressure
diuretic in urine
– Multiple studies demonstrating reductions in
• Administer effective doses several times per day
cardiovascular morbidity and mortality
• Add an oral thiazide diuretic
• Generally considered ineffective with CrCl <30
• Cirrhosis ml/min (exception is metolazone)
– Mainstay of diuretic therapy is spironolactone
• Shallow dose-response curve
– Mechanism of diminished response to loop diuretics is
unknown • Lower doses typically prescribed today (12.5 to 25
– Add a thiazide or loop to spironolactone if needed mg of HCTZ) NEJM 2009;361:2153-64
NEJM 1998;339:387-395 Expert Opin Drug Saf 2010;9:243-257
Semin Nephrol 2011;31:483-494 Semin Nephrol 2011;31:495-502

Hemodynamic Effects of Thiazide Diuretics Thiazide Diuretics

• Long-term blood pressure lowering due to a reduction in
systemic vascular resistance (exact mechanism unclear)

Semin Nephrol 2011;31:495-502 NEJM 2009;361:2153-64

Adverse Effects of Diuretics Treatment and Prevention of

• Hypotension and Orthostasis
• Volume Depletion Diuretic-Induced Hypokalemia
• Electrolyte Disorders
– Hypokalemia
– Hypomagnesemia
– Hyponatremia
– Hypocalcemia (loop diuretics)
– Hypercalcemia (thiazides)
• Hyperuricemia
• Hyperglycemia, glucose intolerance
• Dyslipidemia
• Photosensitivity and skin reactions
• Ototoxicity
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• Interstitial nephritis Expert Opin Drug Saf 2010;9:243-257
Semin Nephrol 2011;31:495-502
Expert Opin Drug Saf 2010;9:243-257
Semin Nephrol 2011;31:495-502