HYDRALAZINE AND HYDROCHLOROTHIAZIDE
Clinical safety rating: safe
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
Hydralazine is a direct-acting smooth muscle vasodilator that relaxes arterioles, reducing peripheral resistance. Hydrochlorothiazide is a thiazide diuretic that inhibits the sodium-chloride symporter in the distal convoluted tubule, increasing excretion of sodium and water.
| Metabolism | Hydralazine is metabolized primarily by N-acetylation (NAT2) and hydrolysis. Hydrochlorothiazide is not extensively metabolized; it is eliminated unchanged in urine. |
| Excretion | Hydralazine: 80-90% renal (mostly as metabolites), <10% unchanged. Hydrochlorothiazide: 95-99% renal (unchanged). |
| Half-life | Hydralazine: 2-4 hours (fast acetylators), 4-8 hours (slow acetylators); extended in renal impairment. Hydrochlorothiazide: 6-15 hours; prolonged in renal impairment. |
| Protein binding | Hydralazine: 85-90% (primarily albumin). Hydrochlorothiazide: 40-70% (albumin). |
| Volume of Distribution | Hydralazine: 1.2-1.5 L/kg; high, tissue distribution. Hydrochlorothiazide: 3-4 L/kg; extensive tissue binding. |
| Bioavailability | Hydralazine: 30-50% oral (first-pass metabolism); 100% IV. Hydrochlorothiazide: 65-75% oral. |
| Onset of Action | Hydralazine: 20-30 min oral; 5-20 min IV. Hydrochlorothiazide: 2 hours oral (diuresis). |
| Duration of Action | Hydralazine: 2-4 hours oral; 2-6 hours IV. Hydrochlorothiazide: 6-12 hours oral. |
| Molecular Weight | Hydralazine: 160.18 Da; Hydrochlorothiazide: 297.74 Da. Combination: not applicable. |
Oral: 1 tablet (hydralazine 25 mg / hydrochlorothiazide 25 mg) 1-2 times daily. Maximum: hydralazine 200 mg/day, hydrochlorothiazide 50 mg/day.
| Dosage form | TABLET |
| Renal impairment | GFR 30-60 mL/min: Use with caution; monitor potassium. GFR <30 mL/min: Avoid hydrochlorothiazide; consider alternative diuretic. Hydralazine may be used with dose adjustment. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce hydralazine dose by 50%. Child-Pugh C: Avoid hydralazine; hydrochlorothiazide may worsen hepatic encephalopathy. |
| Pediatric use | Hydralazine: 0.75-3 mg/kg/day orally in 2-4 divided doses, maximum 200 mg/day. Hydrochlorothiazide: 1-2 mg/kg/day orally in 2 divided doses, maximum 50 mg/day. Use combination only if both agents indicated. |
| Geriatric use | Start at lowest dose (hydralazine 25 mg / hydrochlorothiazide 25 mg once daily) due to increased risk of hypotension, electrolyte imbalance, and renal impairment. Titrate cautiously; monitor serum potassium and creatinine. |
| 1st trimester | Hydralazine and hydrochlorothiazide: Avoid in first trimester. Hydrochlorothiazide is contraindicated due to risk of teratogenicity (neonatal thrombocytopenia, electrolyte disturbances) and decreased placental perfusion. |
| 2nd trimester | Hydralazine: Use only if clearly needed for hypertensive emergency; hydrochlorothiazide: avoid due to risk of fetal/neonatal jaundice, electrolyte imbalances, and potential adverse effects on fetal growth. |
| 3rd trimester | Hydralazine: May cause maternal hypotension and fetal distress; hydrochlorothiazide: can cause neonatal thrombocytopenia, electrolyte disturbances, and may interfere with labor. |
Clinical note
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
| FDA category | Animal |
| Placental transfer | Both hydralazine and hydrochlorothiazide cross the placenta. Hydralazine achieves fetal concentrations similar to maternal; hydrochlorothiazide crosses with fetal serum levels 10-100% of maternal levels. |
■ FDA Black Box Warning
None
| Common Effects | edema |
| Serious Effects |
AnuriaHypersensitivity to hydralazine, hydrochlorothiazide, or sulfonamide-derived drugsAddison's disease (hydrochlorothiazide)Severe renal impairment (creatinine clearance <30 mL/min) (hydrochlorothiazide)Hepatic coma or precoma (hydrochlorothiazide)Systemic lupus erythematosus (hydralazine)
| Precautions | Lupus-like syndrome associated with hydralazine, Hypotension, Electrolyte imbalance (hypokalemia, hyponatremia) due to hydrochlorothiazide, Renal impairment, Exacerbation of systemic lupus erythematosus, Peripheral neuritis |
| Food/Dietary | Avoid high-sodium foods; limit alcohol; take with food or milk to reduce stomach upset. |
Loading safety data…
| Breastfeeding | Hydralazine: Present in low levels in breast milk; considered compatible with infant monitoring. Hydrochlorothiazide: Excreted in breast milk; may suppress lactation or cause neonatal electrolyte disturbances. Use caution, especially in neonates or preterm infants. |
| Lactation Rating | L3 (Moderately Safe) - Hydralazine; L4 (Possibly Hazardous) - Hydrochlorothiazide; combination rating: L4 |
| Teratogenic Risk | Hydralazine: First trimester—No evidence of teratogenicity in humans, but crosses placenta; risk based on maternal hypotension. Second/third trimester—Risk of fetal distress, neonatal thrombocytopenia, lupus-like syndrome. Hydrochlorothiazide: First trimester—Avoid; case reports of congenital anomalies (neural tube defects, cleft lip) with thiazide use. Second/third trimester—Risk of fetal electrolyte disturbances, jaundice, thrombocytopenia; may reduce placental perfusion. |
| Fetal Monitoring | Maternal: Blood pressure (frequent), serum electrolytes (potassium, sodium, bicarbonate), renal function, lupus serologies (ANA, dsDNA) with hydralazine. Fetal: Ultrasound for fetal growth and amniotic fluid volume; nonstress test or biophysical profile in third trimester. |
| Fertility Effects | Hydralazine: No known adverse effects on fertility. Hydrochlorothiazide: No known direct effects, but long-term use may cause electrolyte disturbances that could impair reproductive function (e.g., hypokalemia causing anovulation). |
| Clinical Pearls | Monitor for lupus-like syndrome with hydralazine, especially in slow acetylators; can cause orthostatic hypotension; hydrochlorothiazide may cause hypokalemia and hyponatremia; use with caution in renal impairment. |
| Patient Advice | Take as prescribed; do not stop abruptly. · May cause dizziness or lightheadedness; rise slowly from sitting or lying. · Avoid prolonged sun exposure; may increase sensitivity. · Report unexplained rash, joint pain, or fever to your doctor. · Monitor blood pressure regularly. |