HYDRALAZINE HYDROCHLORIDE W/ HYDROCHLOROTHIAZIDE 25/25
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 arteriolar vasodilator that reduces peripheral resistance through relaxation of vascular smooth muscle, likely via nitric oxide-mediated increases in cGMP. Hydrochlorothiazide is a thiazide diuretic that inhibits the Na+/Cl- cotransporter in the distal convoluted tubule, reducing sodium and water reabsorption and decreasing plasma volume.
| Metabolism | Hydralazine undergoes extensive hepatic metabolism via N-acetylation (polymorphic NAT2), also conjugated with glucuronic acid. Hydrochlorothiazide is not significantly metabolized; eliminated unchanged in urine. |
| Excretion | Hydralazine: 80% renal (as metabolites, 5-10% unchanged); Hydrochlorothiazide: 95% renal (as unchanged drug). |
| Half-life | Hydralazine: 2-8 hours (terminal half-life; prolonged in renal impairment; acetylator phenotype affects clearance); Hydrochlorothiazide: 6-15 hours (terminal half-life; increased in renal impairment). |
| Protein binding | Hydralazine: 87-90% bound to plasma proteins (primarily albumin); Hydrochlorothiazide: 40-68% bound to plasma proteins (primarily albumin). |
| Volume of Distribution | Hydralazine: 1.6 L/kg (large, indicating extensive tissue binding); Hydrochlorothiazide: 0.8 L/kg (distributes into extracellular fluid). |
| Bioavailability | Hydralazine: 30-50% (oral, due to first-pass metabolism; lower in fast acetylators); Hydrochlorothiazide: 65-75% (oral; food may increase absorption). |
| Onset of Action | Hydralazine: 10-20 minutes (oral, with peak effect at 30-120 minutes); Hydrochlorothiazide: 2 hours (oral, with peak effect at 4-6 hours). |
| Duration of Action | Hydralazine: 6-8 hours (antihypertensive effect; acetylator phenotype influences duration); Hydrochlorothiazide: 12-16 hours (diuretic and antihypertensive effects). |
| Molecular Weight | Hydralazine HCl: 196.64 Da; Hydrochlorothiazide: 297.74 Da; Combined product: Not applicable; individual weights. |
One tablet orally twice daily, titrated based on blood pressure response; maximum dose: one tablet four times daily.
| Dosage form | CAPSULE |
| Renal impairment | For GFR 30-50 mL/min: one tablet once daily. GFR <30 mL/min: not recommended due to thiazide component. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: initial dose reduced by 50%. Child-Pugh Class C: contraindicated. |
| Pediatric use | 0.75-1.0 mg/kg/day hydralazine component divided every 6-12 hours; maximum 7.5 mg/kg/day. Hydrochlorothiazide 0.5-1.0 mg/kg/dose every 12-24 hours; maximum 2.5 mg/kg/day. Use caution in neonates. |
| Geriatric use | Initiate at one-half tablet orally once daily; titrate slowly due to increased risk of hypotension, hypokalemia, and renal impairment. |
| 1st trimester | Hydralazine crosses the placenta. Hydrochlorothiazide is associated with adverse fetal effects including jaundice, thrombocytopenia, and electrolyte disturbances. Use only if clearly needed. |
| 2nd trimester | Continued caution. Hydrochlorothiazide may cause fetal electrolyte imbalance. Hydralazine associated with maternal hypotension reducing placental perfusion. |
| 3rd trimester | Avoid hydrochlorothiazide due to risk of neonatal thrombocytopenia, jaundice, and electrolyte disturbances. Hydralazine may cause maternal hypotension and fetal distress. |
Clinical note
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
| FDA category | Animal |
| Placental transfer | Hydralazine and hydrochlorothiazide cross the placenta. Hydrochlorothiazide is detected in fetal blood with maternal-fetal ratio ~1. |
■ FDA Black Box Warning
None
| Common Effects | edema |
| Serious Effects |
AnuriaSulfonamide allergy (cross-sensitivity with thiazides)Concomitant use with dofetilideHypersensitivity to hydralazine or hydrochlorothiazide
| Precautions | May cause a lupus-like syndrome (especially with hydralazine) - monitor for symptoms (fever, arthralgia, serositis); discontinue if positive ANA or lupus-like reaction., Hydralazine may cause tachycardia, angina, or myocardial infarction in susceptible patients; use caution in coronary artery disease., Hydrochlorothiazide may cause electrolyte disturbances (hypokalemia, hyponatremia, hypomagnesemia), volume depletion, and acute angle-closure glaucoma., Can precipitate gout due to increased serum uric acid., May increase blood glucose, cholesterol, and triglycerides., Use caution with impaired renal or hepatic function. |
| Food/Dietary |
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| Breastfeeding | Both hydralazine and hydrochlorothiazide are excreted into breast milk in small amounts. Hydrochlorothiazide may suppress lactation. Monitor infant for hypotension and electrolyte disturbances. |
| Lactation Rating | L3 - Moderate Risk |
| Teratogenic Risk | Hydralazine: Risk in first trimester uncertain; associated with maternal hypotension and potential fetal hypoxia in second/third trimester. Hydrochlorothiazide: Avoid in first trimester (oligohydramnios, fetal electrolyte disturbances); second/third trimester risk of fetal/neonatal jaundice, thrombocytopenia, electrolyte abnormalities. Both: Fetal bradycardia, hypovolemia, and metabolic effects possible. |
| Fetal Monitoring | Maternal: Blood pressure, heart rate, serum electrolytes, renal function, lupus serology (ANA). Fetal: Growth ultrasound, amniotic fluid index, heart rate monitoring. Neonatal: Platelet count, bilirubin, electrolytes. |
| Fertility Effects | Hydralazine: No reported direct fertility effects. Hydrochlorothiazide: May cause mild glucose intolerance; no direct impact on fertility. Combined: Limited data, but no major impairment expected. |
| Avoid high-sodium foods to maximize antihypertensive effect. Limit alcohol. Hydrochlorothiazide may cause hypokalemia, so maintain adequate dietary potassium unless contraindicated. Dose with caution in gout patients (thiazides increase uric acid). |
| Clinical Pearls | Monitor for first-dose hypotension; titrate hydralazine gradually to avoid reflex tachycardia. Check serum potassium and renal function during thiazide therapy. Caution in rapid acetylators (higher hydralazine dose needed). Avoid use in severe renal impairment (CrCl <30 mL/min). |
| Patient Advice | Take exactly as prescribed; do not skip doses or double up. · Rise slowly from sitting or lying to prevent dizziness. · Notify your doctor if you experience joint pain, fever, rash, or unexplained fatigue (lupus-like syndrome). · Avoid excessive sun exposure; hydrochlorothiazide increases photosensitivity. · Limit alcohol intake as it may worsen side effects. |