HYDROCHLOROTHIAZIDE W/ HYDRALAZINE
Clinical safety rating: safe
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
Hydrochlorothiazide inhibits the Na+/Cl- symporter in the distal convoluted tubule, reducing sodium and water reabsorption. Hydralazine directly relaxes arteriolar smooth muscle via mechanisms involving nitric oxide, leading to vasodilation.
| Metabolism | Hydrochlorothiazide: not extensively metabolized; Hydralazine: metabolized by N-acetyltransferase (NAT2), oxidation, and conjugation. |
| Excretion | Hydrochlorothiazide: ~70% renal (unchanged), 30% metabolized with metabolites excreted renally; Hydralazine: 80-90% renal (metabolites), <10% unchanged, some biliary/fecal. |
| Half-life | Hydrochlorothiazide: 6-15 hours (terminal, prolonged in renal impairment); Hydralazine: 2-4 hours (fast acetylators), 4-8 hours (slow acetylators); clinical context: slow acetylators have higher risk of lupus-like reactions. |
| Protein binding | Hydrochlorothiazide: ~60-70% (albumin); Hydralazine: ~85-90% (albumin and alpha1-acid glycoprotein). |
| Volume of Distribution | Hydrochlorothiazide: 3-4 L/kg (large, extensive tissue distribution); Hydralazine: 1.5-3 L/kg (wide distribution, enters arterial wall). |
| Bioavailability | Hydrochlorothiazide: oral ~70% (variable, food may increase); Hydralazine: oral ~30-50% (due to hepatic first-pass, higher in slow acetylators). |
| Onset of Action | Hydrochlorothiazide: oral diuresis within 2 hours; Hydralazine: oral antihypertensive effect within 20-30 minutes; IV (not in combo): 5-20 minutes. |
| Duration of Action | Hydrochlorothiazide: 6-12 hours (diuresis), 12-24 hours (antihypertensive); Hydralazine: 2-4 hours (oral), 6-8 hours (IV); clinical note: hydralazine often requires TID dosing due to short duration. |
Oral: hydrochlorothiazide 25-50 mg plus hydralazine 25-100 mg, twice daily; maximum hydralazine 300 mg/day.
| Dosage form | TABLET |
| Renal impairment | GFR 10-30 mL/min: hydrochlorothiazide dose interval increase to every 24 hours; GFR <10 mL/min: hydrochlorothiazide not recommended. Hydralazine: no adjustment. |
| Liver impairment | Child-Pugh class B or C: reduce hydralazine dose by 50%; hydrochlorothiazide: contraindicated if severe hepatic impairment. |
| Pediatric use | Not established; use not recommended in children. |
| Geriatric use | Start at lowest dose; monitor for hypotension, electrolyte imbalance, and renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
| FDA category | Animal |
| Breastfeeding | Hydrochlorothiazide: Excreted into breast milk in low concentrations; M/P ratio ~0.4. Potential for suppression of lactation and electrolyte disturbances in nursing infant. Hydralazine: Excreted into breast milk in small amounts; M/P ratio unknown. Infant exposure estimated <1% of maternal weight-adjusted dose. Compatible with breastfeeding with monitoring for adverse effects (e.g., hypotension, arrhythmias). Combination: Use with caution, weighing risks vs benefits. |
■ FDA Black Box Warning
None
| Common Effects | edema |
| Serious Effects |
["Anuria","Hypersensitivity to hydrochlorothiazide, hydralazine, or sulfonamide-derived drugs","Coronary artery disease (hydralazine may exacerbate)","Rheumatic mitral valve disease (hydralazine may exacerbate)"]
| Precautions | ["May cause hypotension, tachycardia, or angina in susceptible patients","May precipitate lupus erythematosus-like syndrome (hydralazine)","Electrolyte imbalances (hypokalemia, hyponatremia) due to hydrochlorothiazide","Monitor renal function and electrolytes","Use with caution in patients with severe renal impairment"] |
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| Teratogenic Risk |
| Hydrochlorothiazide: First trimester use associated with neural tube defects and oral clefts in some studies; second and third trimester use may cause fetal or neonatal jaundice, thrombocytopenia, and electrolyte disturbances. Hydralazine: No clear evidence of teratogenicity in humans; however, maternal hypotension may reduce placental perfusion, leading to fetal distress. Combination: Use only if benefit outweighs risk; consider alternative antihypertensives during pregnancy. |
| Fetal Monitoring | Maternal: Blood pressure, heart rate, electrolytes, liver function tests, and complete blood count. Monitor for signs of lupus-like syndrome (hydralazine). Fetal: Ultrasound growth assessments, fetal heart rate monitoring; consider Doppler velocimetry in cases of hypertension. Newborn: Observe for bradycardia, electrolyte disturbances, and thrombocytopenia. |
| Fertility Effects | Hydrochlorothiazide: No known direct effects on fertility. Hydralazine: No known adverse effects on fertility. Combination: Limited data; no anticipated significant impact on fertility. |