10/16/2020 Diuretics - AMBOSS

Diuretics
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Overview of diuretics

A. Carbonic anhydrase inhibitors: inhibit carbonic anhydrase and increase elimination of bicarbonate.

B. Osmotic diuretics: predominantly act on the proximal tubule and the descending loop of Henle.

C. Loop diuretics: inhibit Na+-K+-2Cl- cotransporters in the ascending loop of Henle.

D. Thiazide diuretics: inhibit Na+-Cl- cotransporters in the early distal convoluted tubule.

E. Potassium-sparing diuretics: inhibit sodium resorption and potassium secretion in the distal convoluted tubule and proximal
collecting duct.

Clinical Sciences

Summary

Diuretics are a group of drugs that increase the production of urine. Diuretics are categorized according to the renal structures they
act on and the changes they lead to in the volume and composition of urine, as well as electrolyte balance. Some of these effects are
useful in treating disorders such as hypercalcemia, hypocalcemia, and hyperaldosteronism. The most commonly used diuretics with a
pronounced diuretic effect are thiazides, loop diuretics, and potassium-sparing diuretics. Osmotic diuretics and carbonic anhydrase
inhibitors are used in acute settings to lower intracranial and/or intraocular pressure (e.g., cerebral edema, acute glaucoma). The
most serious side effects of the majority of diuretics include volume depletion and excessive changes in serum electrolyte levels
(particularly of sodium and potassium), which increases the risk for cardiac arrhythmias.

Overview of diuretics

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Summary of diuretic drug effects

Main diuretic agents

Agents Effects on serum

Main characteristics and Water Na+

mechanisms elimination pH K+ Ca2+

Thiazide Inhibition of Na+-Cl- Increased Increased Decreased Decreased Increased

[1]
diuretics cotransporters in the
early distal tubule
Effects compared to
loop diuretics
Greater loss of
potassium
↑ Calcium
reabsorption → ↓
urine calcium
Reduced
effectiveness if GFR <
30 mL/min

Loop Inhibition of Na+- Significantly Increased Normal/slightly Decreased Decreased

diuretics K+-2Cl- cotransporters increased decreased
in the thick ascending
loop of Henle
↓ Calcium
reabsorption
(paracellular) → ↑
urine calcium

Potassium- ↓ Reabsorption of Slightly Decreased Decreased Increased No change

sparing sodium and ↓ increased
diuretics secretion of
potassium in the
distal convoluted
tubule and proximal
collecting duct leads
to:
Inhibition of
expression of
Na+ channels in
the collecting
duct
(aldosterone
receptor
antagonists)
or
Blocking of Na+
channels in the
distal
convoluted
tubule and the
collecting duct
(epithelial
sodium channel
blockers)

Osmotic Affect the entire Significantly Variable (see osmotic diuretics below)
diuretics tubule, but increased
predominantly act on
the straight segment
of the proximal tubule
and the descending
loop of Henle
↑ Blood and tubular
fluid osmolarity → ↑
urine flow and ↓
intracranial/intraocular
pressure

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Main diuretic agents

Agents Effects on serum

Main characteristics and Water Na+

mechanisms elimination pH K+ Ca2+

Carbonic Inhibit carbonic Slightly Decreased Slightly Slightly No change

anhydrase anhydrase in the increase decreased decreased
inhibitors proximal convoluted
tubule (small diuretic
effect) → ↑ elimination
of bicarbonate →
acidosis and
alkalanization of urine

Mechanisms of blood acid-base balance changes

Alkalosis

Agents: loop diuretics and thiazides

Mechanisms
Diuresis → volume contraction (i.e., volume loss) → ↑ RAAS → ↑ ATII → ↑ Na+/H+ exchanger in the PCT

→ ↑ HCO3- reabsorption (contraction alkalosis)

K+excretion → hypokalemia, leading to the following effects:
Induction of H+ excretion (instead of K+ excretion) in exchange for Na+ reabsorption in the collecting duct → ↑
HCO3- reabsorption → alkalosis with paradoxical aciduria
Induction of H+/K+-ATPases in all cells in order to counteract the decrease in serum K+→ K+ outflow from the cells
in exchange for H+ → ↓ serum H+ → metabolic alkalosis

Acidosis

Mechanisms
Carbonic anhydrase inhibitors: via decreased HCO3− reabsorption
Potassium-sparing diuretics
Hyperkalemia → influx of K+ to the cells in exchange for H+ via H+/K+exchanger → acidosis
Aldosterone blockers specifically inhibit renal K+ and H+ secretion

References:[2][3][4][5][6]

Thiazide diuretics

Agents
Hydrochlorothiazide (HCTZ)
Chlorthalidone
Chlorothiazide
Metolazone

Mechanism of action
Inhibition of Na+-Cl- cotransporters

in the early distal convoluted tubule

→ ↑ excretion of Na+ (saluresis) and Cl- → ↓ diluting capacity of nephron and ↑ excretion of potassium (kaliuresis) and ↓
excretion of calcium

→ diuresis
Increased reabsorption of Ca2+

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Hyperpolarization of smooth muscle cells → vasodilation

Hyperpolarization of pancreatic beta cells → decreased insulin release [7]
See “Mechanism of blood pH” changes in “Overview of diuretics” for mechanism of alkalosis.

Side effects

Hypokalemia and metabolic alkalosis

Hyponatremia
Hypomagnesemia
Hypercalcemia

Hyperglycemia

Hyperlipidemia (↑ cholesterol, triglycerides)

Hyperuricemia

Allergic reactions (sulfonamide hypersensitivity)

To avoid hypokalemia, thiazide diuretics may be combined with potassium-sparing diuretics (e.g., aldosterone receptor
antagonists).

To remember the side effects of thiazide diuretics, think of “hyperGLUC”: hyperGlycemia, hyperLipidemia, hyperUricemia, and
hyperCalcemia.

Indications
Hypertension
Chronic edema secondary to congestive heart failure, cirrhosis, and kidney disease
Prevention of calcium kidney stones, idiopathic hypercalciuria
Osteoporosis
Nephrogenic diabetes insipidus
[8]
Sequential nephron blockade

Contraindications
Hypersensitivity (including hypersensitivity to any sulfonamide medications) [9]
Anuria
Severe hypokalemia

Thiazides should be used with caution in patients with prediabetes and diabetes mellitus because they can cause hyperglycemia
and changes in glucose concentration.

Interactions
Glucocorticoids: increased hypokalemia
Carbamazepine: increased hyponatremia
Lithium: increased hyponatremia [10]
ACE inhibitors: hypotension (especially first-dose hypotension)
Propranolol: increased hyperlipidemia and hyperglycemia
NSAIDs: decreased diuretic effect

Increased effects of digitalis

, methotrexate, and lithium

References:[11][6][2][12][13][14][15][16]

Loop diuretics

Agents

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Sulfonamides: furosemide, torsemide, bumetanide

Other: ethacrynic acid

Mechanism of action
Blockage of Na+-K+-2Cl- cotransporter

in the thick ascending loop of Henle

Diminishing concentration gradient between the (usually hypertonic) renal medulla and the cortex → concentration of
urine is no longer possible → increased diuresis
Decreased reabsorption of Ca2+ and Mg2+
Increased PGE release (can be inhibited by NSAIDs)
Dilation of renal afferent arterioles → diuresis
General venodilation (rapid venous pooling) → ↓ cardiac preload
See “Mechanism of blood pH” changes in “Overview of diuretics” for mechanism of alkalosis.

To recall that loop diuretics cause increased excretion of calcium, think: loops lose calcium!

Side effects
Metabolic imbalances
Hypokalemia, hypomagnesemia, hypocalcemia, hypochloremia, hyponatremia (moderate)
Metabolic alkalosis
Hyperuricemia/gout

Hyperglycemia

Ototoxicity (potentially permanent hearing damage): especially high risk with ethacrynic acid

Dehydration/hypovolemia

Sulfonamide hypersensitivity (except ethacrynic acid, which can be used for diuresis in patients with allergies to sulfonamides)
→ rash, interstitial nephritis

To recall the side effects of loop diuretics, think of “GO PANDA”: Gout, Ototoxicity, low Potassium, Allergy, Nephritis,
Dehydration, Alkalosis.
To remember that loop diuretics are ototoxic, imagine a vertical loop of a roller coaster and deafening screams of people passing
through it.
Hypokalemia and/or hypomagnesemia can lead to life-threatening arrhythmias!

Indications

Hypertension
Edema
Cardiac (acute and congestive heart failure, peripheral edema, lung edema)
Renal (nephrotic syndrome)
Hepatic (liver cirrhosis)
Renal failure (acute and chronic)
Hypercalcemia
Forced diuresis
Definition: massive diuresis for forced renal elimination of (toxic) substances
Implementation: IV administration of large amounts of fluids in combination with loop diuretics
Indications: hypercalcemic crisis, severe hyperkalemia, rhabdomyolysis, intoxication (e.g., lithium)

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Sequential nephron blockade

Used to overcome resistance to diuretic treatment

Method: combination of loop diuretics and thiazides

→ restoration of diuretic effects

Because of the increased risk of hypokalemia and hypovolemia during forced diuresis, rigorous monitoring is necessary.

Contraindications

Contraindications for loop diuretics

Condition Furosemide Torsemide Bumetanide Ethacrynic acid

Anuria Yes Yes Yes Yes

Sulfonamide hypersensitivity Yes Yes Yes No

Hepatic coma or severe electrolyte depletion No No Yes No

History of severe watery diarrhea (caused by the drug) No No No Yes

References:[2][17][18][19][20][21][22][23][24][25][26]

Potassium-sparing diuretics

Agents

Aldosterone receptor antagonists: spironolactone, eplerenone

Epithelial sodium channel blockers: triamterene, amiloride

To remember that Spironolactone, Triamterene, Eplerenone, and Amiloride are K+-sparing, think of STEAK!

Mechanism of action
Although the molecular pathways differ, both types of potassium-sparing diuretics have very similar clinical effects.
Aldosterone receptor antagonists (spironolactone, eplerenone)
Competitively bind to aldosterone receptors in the late distal convoluted tubule

and the collecting duct → inhibition of the effects of aldosterone → decreased Na+ reabsorption and K+ excretion

→ diuresis
Decreased H+ excretion → acidosis
Evolving hyperkalemia induces H+/K+-ATPases in all cells to counteract the increase in serum K+ → K+ enters cells in
exchange for H+ → amplifies acidosis
Spironolactone also acts (nonspecifically) on sex hormone receptors → endocrine side effects (see section “Gonads” in
generel endocrinology for more information about hormonal effects of spironolactone)

Epithelial sodium channel blockers (triamterene, amiloride): direct inhibition of the epithelial sodium channels (ENaC) in the
distal convoluted tubule and the collecting duct → reduced Na+ reabsorption and reduced K+ secretion → diuresis

Spironolactone and eplerenone are aldosterone receptor antagonists.

Side effects

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General side effects

Metabolic and electrolyte imbalances, such as hyperkalemia, hyponatremia, and metabolic acidosis, can lead to cardiac
arrhythmias
Gastrointestinal disturbances (nausea, vomiting, diarrhea)
Spironolactone-specific side effects: endocrine disturbances
Men: antiandrogenic effects (e.g., gynecomastia, erectile dysfunction)
Women: amenorrhea

Indications

Hypertension (especially if hypokalemia is also present)

Ascites/edema due to congestive heart failure, nephrotic syndrome, or cirrhosis of the liver (mainly spironolactone)

Hyperaldosteronism

Nephrogenic diabetes insipidus (amiloride) [27]

Hypokalemia
Hyperandrogenic states, e.g., polycystic ovary syndrome (spironolactone)

Contraindications

General

Anuria and/or renal insufficiency

Preexisting hyperkalemia
Addison disease
Combination with other potassium-sparing diuretics or potassium supplements

Specific

Spironolactone: Use with caution in patients with CHF with either of the following:
GFR < 30 mL/min
Creatinine ≥ 2.5 mg/dL (men) or ≥ 2 mg/dL (women)
Eplerenone
Concomitant use of strong CYP3A4 inhibitors

Patients with hypertension with concomitant type II diabetes mellitus and microalbuminuria or with renal insufficiency
(serum creatinine > 2.0 mg/dL for men or > 1.8 mg/dL for women; or creatinine clearance < 50 mL/min)
Creatinine clearance < 30 mL/min
Amiloride: diabetic nephropathy

References:[6][14][28][29][30][31]

Osmotic diuretics

Agents
Mannitol
Urea
[32]

Mechanism of action

Increase the osmolality of:

Serum: ↑ shift of water into the intravascular space → ↑ binding of water → ↓ intracranial and intraocular pressure
Glomerular filtrate: ↑ tubular fluid osmolarity → ↑ binding of water → ↑ urine production

No saluresis

Side effects
Dehydration
Initial cardiac volumetric strain

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Metabolic and electrolyte imbalances

Effective glomerular filtration → hypernatremia
Ineffective glomerular filtration

or administration of very high doses → ↑ plasma osmolality → ↑ extracellular fluid volume → pulmonary edema,
potassium fluctuations, hyponatremia or hypernatremia, and/or metabolic acidosis

Indications

Elevated ICP (e.g., cerebral edema)

Acute glaucoma
Prevention of acute renal injury in cases of oliguria

Forced renal excretion of substances (e.g., drugs or toxins)

Contraindications
Anuria

Progressive heart failure

Severe pulmonary edema

Severe dehydration

References:[3][33]

Carbonic anhydrase inhibitors

Agents
Acetazolamide

Mechanism of action
Inhibition of carbonic anhydrase

in the following organs:

Kidney (in the proximal convoluted tubule): → ↑ H+ reabsorption and inhibition of Na+/H+ exchange → ↑ NaHCO3
diuresis and ↑ HCO3- elimination

Eyes: ↓ production of aqueous humor

Brain: ↓ CSF production
Acid-base effects: alkalinizes urine and acidifies blood

Side effects

Hyperammonemia with paresthesias

Proximal renal tubular acidosis → hyperchloremic, nonanion gap metabolic acidosis

Hypokalemia
Sulfonamide hypersensitivity
Calcium phosphate stone formation (alkaline urine promotes precipitation)
Neuropathy

Indications
Acute glaucoma

Idiopathic intracranial hypertension

Altitude sickness
Metabolic alkalosis
Prevention of cystine kidney stones

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Contraindications
Hyponatremia, hypokalemia
Hyperchloremic metabolic acidosis
Adrenocortical insufficiency
Severe renal insufficiency
Hepatic disease or insufficiency
[34]
Long-term use in glaucoma

ACetazolamide causes ACidosis!

References:[35][6]

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