SPIRONOLACTONE AND HYDROCHLOROTHIAZIDE

Clinical safety rating: avoid

ACE inhibitors and ARBs may increase risk of hyperkalemia Can cause hyperkalemia and gynecomastia.

How it works

Spironolactone is a competitive aldosterone antagonist that inhibits sodium reabsorption in the cortical collecting tubule, increasing potassium retention. Hydrochlorothiazide inhibits sodium and chloride reabsorption in the distal convoluted tubule, enhancing diuresis and reducing blood pressure.

What the body does with it

Metabolism	Spironolactone is extensively metabolized by the liver to active metabolites including canrenone. Hydrochlorothiazide is not metabolized and is excreted unchanged in urine.
Excretion	Spironolactone: Renal (80% as active metabolites, 10% as canrenone); Fecal (minor). Hydrochlorothiazide: Renal (≥95% unchanged).
Half-life	Spironolactone: Terminal half-life of active metabolites ~12-15 h (canrenone 16-24 h). Hydrochlorothiazide: 6-15 h (renal impairment prolongs).
Protein binding	Spironolactone: >90% (albumin), Hydrochlorothiazide: 40-70% (albumin).
Volume of Distribution	Spironolactone: ~0.05 L/kg (low, extensive tissue binding). Hydrochlorothiazide: 3-15 L/kg.
Bioavailability	Oral: Spironolactone ~90% (metabolized first-pass), Hydrochlorothiazide ~70%.
Onset of Action	Oral: Spironolactone 3-4 days (steady-state diuresis), Hydrochlorothiazide 2 h.
Duration of Action	Spironolactone: 2-3 days after cessation (metabolite persistence). Hydrochlorothiazide: 6-12 h.

Classification & Brands

Dosing & administration

Oral, 1 tablet (spironolactone 25 mg / hydrochlorothiazide 25 mg) once daily; may increase to 2 tablets per day if needed.

Dosage form	TABLET
Renal impairment	Contraindicated if GFR <30 mL/min. For GFR 30-60 mL/min, use with caution; consider reducing dose or dosing interval.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B or C: contraindicated due to risk of electrolyte imbalances and hepatic encephalopathy.
Pediatric use	Not recommended for pediatric use; safety and efficacy not established.
Geriatric use	Start at lowest dose (half tablet) to avoid hyperkalemia and electrolyte disturbances; monitor renal function and potassium closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

ACE inhibitors and ARBs may increase risk of hyperkalemia Can cause hyperkalemia and gynecomastia.

FDA category	Positive
Breastfeeding	Spironolactone and its metabolite canrenone are excreted into breast milk; M/P ratio not well established. Hydrochlorothiazide is excreted in low amounts. Use with caution; may suppress lactation and cause electrolyte disturbances in infant.
Teratogenic Risk	First trimester: Spironolactone has antiandrogenic effects; potential risk of feminization of male fetus. Hydrochlorothiazide may cause fetal or neonatal jaundice, thrombocytopenia. Second/third trimester: Both drugs reduce placental perfusion; risk of fetal growth restriction, oligohydramnios, neonatal electrolyte abnormalities. Avoid in pregnancy unless essential.

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Common Effects	hypertension
Serious Effects

Absolute Contraindications

["Anuria","Acute or chronic renal insufficiency","Hyperkalemia (serum potassium >5.5 mEq/L)","Addison's disease","Concomitant use of other potassium-sparing diuretics or potassium supplements","Hypersensitivity to spironolactone, hydrochlorothiazide, or sulfonamides"]

Clinical Precautions

Precautions

["Hyperkalemia risk, especially with renal impairment or other potassium-sparing drugs","Electrolyte disturbances (hyponatremia, hypomagnesemia, hypochloremic alkalosis)","Monitor renal function and electrolytes regularly","May precipitate hepatic encephalopathy in cirrhotic patients","Sulfa allergy cross-reactivity with hydrochlorothiazide"]

Clinical Tips & Counseling

Drug interactions

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SPIRONOLACTONE AND HYDROCHLOROTHIAZIDE

Clinical safety rating: avoid

ACE inhibitors and ARBs may increase risk of hyperkalemia Can cause hyperkalemia and gynecomastia.

How it works

What the body does with it

Metabolism	Spironolactone is extensively metabolized by the liver to active metabolites including canrenone. Hydrochlorothiazide is not metabolized and is excreted unchanged in urine.
Excretion	Spironolactone: Renal (80% as active metabolites, 10% as canrenone); Fecal (minor). Hydrochlorothiazide: Renal (≥95% unchanged).
Half-life	Spironolactone: Terminal half-life of active metabolites ~12-15 h (canrenone 16-24 h). Hydrochlorothiazide: 6-15 h (renal impairment prolongs).
Protein binding	Spironolactone: >90% (albumin), Hydrochlorothiazide: 40-70% (albumin).
Volume of Distribution	Spironolactone: ~0.05 L/kg (low, extensive tissue binding). Hydrochlorothiazide: 3-15 L/kg.
Bioavailability	Oral: Spironolactone ~90% (metabolized first-pass), Hydrochlorothiazide ~70%.
Onset of Action	Oral: Spironolactone 3-4 days (steady-state diuresis), Hydrochlorothiazide 2 h.
Duration of Action	Spironolactone: 2-3 days after cessation (metabolite persistence). Hydrochlorothiazide: 6-12 h.

Classification & Brands

Dosing & administration

Oral, 1 tablet (spironolactone 25 mg / hydrochlorothiazide 25 mg) once daily; may increase to 2 tablets per day if needed.

Dosage form	TABLET
Renal impairment	Contraindicated if GFR <30 mL/min. For GFR 30-60 mL/min, use with caution; consider reducing dose or dosing interval.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B or C: contraindicated due to risk of electrolyte imbalances and hepatic encephalopathy.
Pediatric use	Not recommended for pediatric use; safety and efficacy not established.
Geriatric use	Start at lowest dose (half tablet) to avoid hyperkalemia and electrolyte disturbances; monitor renal function and potassium closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

ACE inhibitors and ARBs may increase risk of hyperkalemia Can cause hyperkalemia and gynecomastia.

FDA category	Positive
Breastfeeding	Spironolactone and its metabolite canrenone are excreted into breast milk; M/P ratio not well established. Hydrochlorothiazide is excreted in low amounts. Use with caution; may suppress lactation and cause electrolyte disturbances in infant.
Teratogenic Risk	First trimester: Spironolactone has antiandrogenic effects; potential risk of feminization of male fetus. Hydrochlorothiazide may cause fetal or neonatal jaundice, thrombocytopenia. Second/third trimester: Both drugs reduce placental perfusion; risk of fetal growth restriction, oligohydramnios, neonatal electrolyte abnormalities. Avoid in pregnancy unless essential.

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Common Effects	hypertension
Serious Effects