Potassium-sparing Diuretics

Potassium-sparing diuretics are medications that act in the principal cells in the collecting ducts to
induce diuresis that does not result in excretion of potassium. These diuretics include 2 subclasses:
sodium channel blockers and aldosterone antagonists. Because these agents act so distally in the
nephron, there is no significant potassium wasting associated with their use. These agents are
typically used in the treatment of mineralocorticoid excess, which may be either primary (e.g., Conn
syndrome) or secondary (e.g., states of depleted intravascular volume, especially in heart failure
patients). Additionally, spironolactone can be used for its antiandrogenic properties in women with
androgen excess (e.g., hirsutism) and for androgen suppression in transgender women (male-to-
female). These drugs are contraindicated in cases of hyperkalemia.

Last updated: July 10, 2023

CONTENTS

Overview
Chemistry and Pharmacodynamics
Pharmacokinetics
Indications
Adverse Effects and Contraindications
Comparison of Medications
References

Overview
Definition
Potassium-sparing diuretics are medications that act in the principal cells in the collecting ducts
(CDs) to induce diuresis that does not result in excretion of potassium.

Potassium-sparing diuretics work in the collecting ducts in the nephron.

Image by Lecturio. License: CC BY-NC-SA 4.0

Overview of antihypertensive agents

 Table: Drugs used to treat hypertension

Location of Class Subclasses

action

Renal drugs Drugs affecting the RAAS ACEis

ARBs
Direct renin inhibitors

Diuretics Thiazide diuretics

Loop diuretics
Potassium-sparing diuretics

Extrarenal Direct vasodilators Calcium channel blockers

drugs Potassium channel openers
Nitrodilators
Endothelin antagonists

Agents acting via the Drugs affecting CNS sympathetic

sympathetic nervous outflow (e.g., clonidine)
system Drugs affecting the ganglia (e.g.,
hexamethonium)
Drugs affecting the nerve
terminals (e.g., guanethidine,
reserpine)
Drugs affecting the α and β
receptors

Drugs in the potassium-sparing diuretic class

Drugs in this class include:

Aldosterone antagonists:
Spironolactone
Eplerenone
Sodium channel blockers:
Triamterene
Amiloride

Chemistry and Pharmacodynamics

Chemical structure
Spironolactone and eplerenone: synthetic steroids
Triamterene: pteridine derivative
Amiloride: pyrazine derivative

Structure of triamterene

Image: “Structure of Triamterene” by NEUROtiker. License: Public Domain

Mechanism of action (MOA) and physiologic effects

Aldosterone antagonists (spironolactone, eplerenone):
 Also called mineralocorticoid receptor antagonists (MRAs)
MOA: binds to the basolateral mineralocorticoid receptor in the collecting duct as a competitive
aldosterone receptor antagonist, blocking the effects of aldosterone
Effects of aldosterone:
Aldosterone stimulates production of the following proteins within the principle cells in
the CD:
Na+/K+-ATPase on the basolateral side
ENaC (epithelial sodium channel) on the lumen side: allows Na+ reabsorption from
the lumen into the principal cells
Renal outer medullary potassium channel (ROMK) on the lumen side: allows
excretion of K+ into the urine
Aldosterone stimulates Na+ reabsorption from the renal tubules:
Water follows the Na+
Creates a negative electrical gradient across the lumen, promoting the secretion of
K+ and H+ into the urine
Results of aldosterone antagonists:
↓ Na+ reabsorption → water stays in the tubular lumen with the Na+ → diuresis
↓ K+ excretion → potassium-sparing
↓ H+ excretion → trend toward metabolic acidosis
Antiandrogenic effects:
Spironolactone (significant antiandrogenic effects):
Nonselective MRA, which also can bind estrogen and progesterone receptors →
can ↑ aromatization of testosterone to estradiol
↓ Testosterone production
Binds to androgen receptors and competitively inhibits testosterone and
dihydrotestosterone
Can help improve acne, but also causes gynecomastia, impotence, decreased
libido, and menstrual irregularities
Eplerenone:
More selective for the mineralocorticoid receptor, with much fewer antiandrogenic
effects
Better tolerated
Antiinflammatory effects (low-dose eplerenone):
↓ Myocardial perfusion defects after an MI → ↓ cardiac mortality
May slow the progression of albuminuria in diabetic patients

Sodium channel blockers (triamterene, amiloride):

Cations that bind to and directly block the ENaCs on the apical side of cells lining the distal
convoluted tubules (DCTs) and CDs.
Results:
↓ Na+ reabsorption
↓ K+ excretion
Water always follows Na+ → water stays with Na+ in the tubules (rather than being
reabsorbed).
Physiologic effects:
Diuresis results from the osmotic effect of Na+ in the tubules.
No significant loss of potassium
Mechanism of action of aldosterone antagonists and sodium channel blockers

Image by Lecturio.

Pharmacokinetics
Absorption:
All are absorbed well orally.
Peak activity occurs at about 2–4 hours.
Metabolism:
Spironolactone and triamterene are metabolized to active metabolites.
Eplerenone is metabolized to inactive metabolites.
Amiloride is not metabolized hepatically.
Excretion: primarily via the kidneys; secondarily via the bile/feces
 Table: Pharmacokinetics of the potassium-sparing diuretics

Drug Absorption Distribution Metabolism Excretion

Spironolactone Bioavailability: Protein Rapid and Urine

approximately binding: > extensive (primarily a
90% when 90% hepatic metabolite
taken with metabolism Bile
food to active (secondar
Peak activity: metabolites
approximately
2.5–4 hours

Eplerenone Bioavailability: VD: 42– Hepatic Urine (67%

approximately 90 L metabolism Feces (32
70% Protein by CYP3A4 Half-life: 3
Peak activity: binding: to inactive 6 hours
2 hours 50% metabolites

Triamterene Rapidly VD: 1.5 L/kg Hepatic Excreted

absorbed metabolism renally
Bioavailability: by CYP1A2
50% to active
Peak activity: metabolites
3 hrs

Amiloride Readily VD 350– Not Urine (50%

absorbed 380 L metabolized Feces (40
Peak activity: Protein Half-life: 6
3–4 hours binding: 9 hours
minimal

VD: volume of distribution

Indications
General indications
The potassium-sparing diuretics are most useful for treating edema related to states of
mineralocorticoid excess, which may be either primary or secondary. Indications include:
 Edema due to primary causes of mineralocorticoid excess:
Conn syndrome
Ectopic adrenocorticotropic hormone (ACTH) production
Edema due to states of depleted intravascular volume resulting in secondary
mineralocorticoid excess:
Heart failure/post-MI (especially eplerenone)
Cirrhosis
Nephrotic syndrome
Resistant hypertension (typically in addition to 1st-line antihypertensive agents)

Unique indications of spironolactone

Spironolactone has additional indications owing to its antiandrogenic properties:

States of hyperandrogenism in females, including:

Acne vulgaris
Hirsutism
Polycystic ovary syndrome
Congenital adrenal hyperplasia
Hormone therapy for transgender women (male-to-female)

Adverse Effects and Contraindications

Adverse effects of potassium-sparing diuretics
Fluid and electrolyte abnormalities:
Hyperkalemia (↑ K+)
Hyperchloremic metabolic acidosis
Hyponatremia (↓ Na+)
Hypomagnesemia (↓ Mg2+)
Hypocalcemia (↓ Ca2+)
Hypovolemia
Symptoms:
Dizziness
Headache
Muscle cramps
GI distress: abdominal cramping, nausea, vomiting, diarrhea
Photosensitivity (triamterene)
Additional effects specific to spironolactone (related to its antiandrogenic properties):
Gynecomastia
Impotence and ↓ libido
Menstrual abnormalities

Contraindications
 Hyperkalemia
Addison disease/adrenal insufficiency
Anuria or severe/progressive CKD
Severe hepatic disease
Pregnancy (especially the aldosterone antagonists, which may cause feminization of a male
fetus)

Precautions
Diabetes (especially triamterene and amiloride)
Gout
Lactation

Comparison of Medications
Some of the other most common diuretics include thiazide diuretics (e.g., hydrochlorothiazide),
loop diuretics (e.g., furosemide), carbonic anhydrase inhibitors (e.g., acetazolamide), and
osmotic diuretics (e.g., mannitol).
Table: Comparison of diuretics

Medication Mechanism Physiologic Indication

effect
Medication Mechanism Physiologic Indication
effect

Thiazide diuretic: ↓ Reabsorption ↓ Blood Hypertension

Hydrochlorothiazide of NaCl in the pressure Edema
DCT through ↓ Edema
the inhibition of
Na+/Cl-
cotransporter

Loop diuretic: Inhibits the ↓ Edema Edema/ascites

Furosemide luminal ↓ Blood HF
Na+/K+/Cl- pressure Hypertension
cotransporter in
the thick
ascending limb
of the loop of
Henle

Potassium-sparing ↓ ↓ Blood HF
diuretic: Reabsorption pressure Edema/ascites
Spironolactone of Na ↓ Edema Hypertension
through the Does not Hirsutism in
ENaC cause ↑ females
channels in excretion Primary
the CD of K+ hyperaldosteronism
Inhibition of Anti-
aldosterone androgenic
receptors in effects
the CD

Carbonic anhydrase Inhibits both ↑ Urinary Edema in patients

inhibitor: the hydration of excretion with metabolic
Acetazolamide CO2 in the PCT of HCO3– alkalosis
epithelial cells → Altitude sickness
and the metabolic ↑ Intraocular
dehydration of acidosis pressure
H2CO3 in the ↓ Off label: normal
PCT lumen; Intraocular pressure
hydrocephalus
results in ↑ pressure
HCO3– and Na+
excretion
 Medication Mechanism Physiologic Indication
effect

Osmotic diuretics: ↑ Osmotic ↓ Free Increased

Mannitol pressure in the water intracranial
glomerular ↓ Cerebral pressure
filtrate → ↑ blood Increased
tubular fluid volume intraocular
and prevents pressure
water
reabsorption

PCT: proximal convoluted tubule

DCT: distal convoluted tubule
HF: heart failure

The sites of action within the nephron for the diuretic drug classes

Image by Lecturio. License: CC BY-NC-SA 4.0

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