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. |
| Molecular Weight | Hydralazine: 160.18 Da. Hydrochlorothiazide: 297.74 Da. Combined: average or note separate weights. |
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 | Hypertension in pregnancy: cautious use due to potential teratogenicity (hydralazine associated with congenital defects in animal studies, thiazides cross placenta and may cause fetal/neonatal effects). Avoid as first-line. Use only if benefits outweigh risks for severe hypertension. |
| 2nd trimester | Hydralazine may cause maternal hypotension and placental hypoperfusion. Thiazides can cause electrolyte disturbances. Use with caution, monitor maternal blood pressure and fetal well-being. |
| 3rd trimester | Hydralazine may cause maternal hypotension and placental hypoperfusion. Thiazides can cause neonatal thrombocytopenia, electrolyte imbalances, and hypoglycemia. Use only if clearly needed and monitor neonate after delivery. |
Clinical note
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
| FDA category | Animal |
| Placental transfer |
■ FDA Black Box Warning
None
| Common Effects | edema |
| Serious Effects |
AnuriaHypersensitivity to thiazides, sulfonamides, or hydralazineDissecting aortic aneurysmSevere systemic lupus erythematosus (hydralazine-induced)Coronary artery disease (hydralazine may exacerbate angina)
| 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 |
| Food/Dietary | Avoid excessive intake of potassium-rich foods (e.g., bananas, oranges, spinach) as thiazides may cause hypokalemia, but hydralazine does not significantly affect potassium; however, monitor potassium levels. Limit salt and high-sodium foods. Grapefruit juice may interact with hydralazine; avoid concurrent use. Alcohol may potentiate hypotensive effects. |
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| Both agents cross the placenta. Hydralazine reaches fetal plasma levels similar to maternal; hydrochlorothiazide crosses readily and accumulates in amniotic fluid. |
| Breastfeeding | Both hydralazine and hydrochlorothiazide are excreted into breast milk in low amounts. Hydralazine milk levels are negligible, while thiazide diuretics may suppress lactation and cause neonatal electrolyte disturbances. Caution is advised, especially with high maternal doses. |
| Lactation Rating | L3 (Moderately Safe) for hydralazine; hydrochlorothiazide is classified as L3 for short-term use; combined product not well studied, use with caution. |
| 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. |
| Clinical Pearls | Monitor for hypotension, especially orthostatic; may require dose adjustment of hydralazine. Assess renal function and electrolytes (potassium, sodium, magnesium) before and during therapy. Hydralazine can cause drug-induced lupus-like syndrome; monitor for symptoms (arthralgias, rash, fever). Use with caution in patients with coronary artery disease as hydralazine may cause reflex tachycardia. Thiazides may exacerbate gout; monitor uric acid levels. |
| Patient Advice | Take exactly as prescribed; do not stop without consulting your doctor. · This medication may cause dizziness upon standing; rise slowly from sitting or lying positions. · Avoid alcohol as it can worsen dizziness and lightheadedness. · Report any joint pain, rash, fever, or unusual bruising to your healthcare provider. · Limit salt intake to help control blood pressure. · Take in the morning to avoid nighttime urination. · Monitor weight daily and report sudden weight gain or swelling. |