SPIRONOLACTONE W/ HYDROCHLOROTHIAZIDE
Clinical safety rating: avoid
ACE inhibitors and ARBs may increase risk of hyperkalemia Can cause hyperkalemia and gynecomastia.
Spironolactone is a potassium-sparing diuretic that competitively inhibits aldosterone binding to mineralocorticoid receptors in the distal convoluted tubule, reducing sodium reabsorption and potassium excretion. Hydrochlorothiazide is a thiazide diuretic that inhibits the sodium-chloride symporter in the distal convoluted tubule, increasing excretion of sodium, chloride, and water.
| Metabolism | Spironolactone is extensively metabolized by the liver to active metabolites (e.g., canrenone, 7α-thiomethylspironolactone) via desulfurization and glucuronidation. Hydrochlorothiazide is not metabolized and is excreted unchanged in urine. |
| Excretion | Spironolactone: Renal (about 50% as metabolites, <10% as unchanged drug) and biliary/fecal (remainder). Hydrochlorothiazide: Renal (≥95% as unchanged drug via tubular secretion). |
| Half-life | Spironolactone: Terminal half-life 1.4 hours (parent drug); active metabolite canrenone has half-life 16.5 hours, leading to prolonged effects. Hydrochlorothiazide: Terminal half-life 6–15 hours (average 10 hours), extended in renal impairment. |
| Protein binding | Spironolactone: >90% bound to albumin and alpha-1 acid glycoprotein. Hydrochlorothiazide: 40–68% bound to albumin. |
| Volume of Distribution | Spironolactone: Vd approximately 0.05 L/kg (parent drug minimal tissue distribution; metabolite distributes more). Hydrochlorothiazide: Vd approximately 0.8–1.5 L/kg (large distribution, accumulates in erythrocytes). |
| Bioavailability | Spironolactone: Oral bioavailability about 60–90% (extensive hepatic metabolism). Hydrochlorothiazide: Oral bioavailability about 65–75%. |
| Onset of Action | Spironolactone: Diuresis begins 2–4 hours after oral dose. Hydrochlorothiazide: Diuresis begins within 2 hours. |
| Duration of Action | Spironolactone: Duration 12–24 hours after single dose (due to metabolite). Hydrochlorothiazide: Duration 6–12 hours. |
Oral: 1-4 tablets daily, each tablet containing spironolactone 25 mg and hydrochlorothiazide 25 mg. Typically once or twice daily with meals.
| Dosage form | TABLET |
| Renal impairment | GFR ≥30 mL/min: No adjustment. GFR 10-29 mL/min: Avoid or use with extreme caution; consider alternative therapy. GFR <10 mL/min: Contraindicated. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Use with caution; reduce dose or titrate slowly. Child-Pugh C: Contraindicated due to risk of hyperkalemia and hepatic encephalopathy. |
| Pediatric use | Dosing extrapolated from adult data; not FDA-approved for pediatric use. Typically spironolactone 1-2 mg/kg/day and hydrochlorothiazide 1-2 mg/kg/day, given in 1-2 divided doses, adjusted based on response. |
| Geriatric use | Start with lowest dose (e.g., half tablet or one tablet once daily) due to increased risk of hypotension, electrolyte imbalances, and renal impairment. Monitor renal function and electrolytes closely. |
| 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: Present in breast milk; M/P ratio not established. Canrenone (active metabolite) also excreted. Theoretical risk of antiandrogenic effects in nursing infants. Hydrochlorothiazide: Excreted in breast milk in low amounts; M/P ratio ~0.1-0.2; may suppress lactation. Use with caution; consider alternative if breastfeeding. |
| Teratogenic Risk |
■ FDA Black Box Warning
No FDA boxed warning for this combination product.
| Common Effects | hypertension |
| Serious Effects |
["Anuria","Acute or chronic renal insufficiency (CrCl <30 mL/min)","Hyperkalemia","Addison's disease","Concurrent use with eplerenone or other potassium-sparing diuretics","Hypersensitivity to spironolactone, hydrochlorothiazide, or sulfonamide-derived drugs (thiazides)"]
| Precautions | ["Risk of hyperkalemia due to spironolactone; monitor serum potassium regularly","May cause hyponatremia, hypomagnesemia, hyperuricemia","Can exacerbate renal impairment; avoid in severe renal disease (CrCl <30 mL/min)","May precipitate hepatic encephalopathy in cirrhotic patients","Risk of hypotension and electrolyte imbalance","Hydrochlorothiazide may increase calcium retention; caution in hypercalcemia"] |
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| First trimester: Spironolactone has antiandrogenic potential; theoretical risk of feminization of male fetus based on animal data, but human data limited. Hydrochlorothiazide crosses placenta; associated with congenital anomalies (neural tube defects, oral clefts) in some studies, but risk low. Second/third trimester: Hydrochlorothiazide may cause fetal electrolyte disturbances, thrombocytopenia, and neonatal jaundice; spironolactone may affect fetal diuresis and electrolyte balance. Avoid during pregnancy unless essential; risk-benefit assessment required. |
| Fetal Monitoring | Monitor maternal blood pressure, serum electrolytes (potassium, sodium, chloride), renal function, and uric acid. Monitor fetal growth and amniotic fluid volume by ultrasound. In neonates, monitor for electrolyte imbalances, hyperbilirubinemia, and thrombocytopenia if exposed near term. |
| Fertility Effects | Spironolactone may cause menstrual irregularities, anovulation, and reversible infertility due to antiandrogenic effects. Hydrochlorothiazide has no direct effect on fertility. Impact on male fertility unknown. |