HYDRALAZINE HYDROCHLORIDE 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 arteriolar vasodilator that reduces peripheral vascular resistance via relaxation of vascular smooth muscle, possibly by interfering with calcium transport. Hydrochlorothiazide is a thiazide diuretic that inhibits the sodium-chloride symporter in the distal convoluted tubule, increasing excretion of sodium and water, and reducing plasma volume.
| Metabolism | Hydralazine: Hepatic acetylation (N-acetyltransferase 2, NAT2); Hydrochlorothiazide: Not extensively metabolized, largely excreted unchanged in urine. |
| Excretion | Hydralazine: 90% renal (primarily as metabolites, 10-15% unchanged); Hydrochlorothiazide: >95% renal (unchanged). Biliary/fecal: negligible for both. |
| Half-life | Hydralazine: 2-8 hours (terminal, prolonged in renal impairment; acetylator phenotype affects clearance; slow acetylators have 2-fold longer half-life). Hydrochlorothiazide: 6-15 hours (terminal, prolonged in renal impairment; clinically relevant for once-daily dosing). |
| Protein binding | Hydralazine: 85-90% (mainly albumin, alpha-1-acid glycoprotein). Hydrochlorothiazide: 40-70% (albumin). |
| Volume of Distribution | Hydralazine: 1.6 L/kg (wide distribution, high tissue binding; reflects extensive extravascular distribution). Hydrochlorothiazide: 3-4 L/kg (extensive distribution, accumulates in erythrocytes). |
| Bioavailability | Hydralazine: 30-50% (oral; extensive first-pass metabolism; bioavailability increased 2-3 fold with food; slow acetylators have higher bioavailability). Hydrochlorothiazide: 65-75% (oral; absorption reduced by food). |
| Onset of Action | Oral: Hydralazine vasodilatory effect within 20-30 minutes; Hydrochlorothiazide diuretic effect within 2 hours. Peak antihypertensive effect: 2-4 hours for hydralazine, 4-6 hours for HCTZ. |
| Duration of Action | Hydralazine: antihypertensive effect 6-12 hours (dose-dependent; tachyphylaxis possible with rapid acetylation). Hydrochlorothiazide: diuretic effect 6-12 hours; antihypertensive effect persists 12-24 hours with chronic dosing. |
Initially one capsule (25 mg hydralazine/25 mg hydrochlorothiazide, or 50 mg hydralazine/50 mg hydrochlorothiazide) twice daily, increase as needed to a maximum of 200 mg hydralazine/200 mg hydrochlorothiazide daily.
| Dosage form | CAPSULE |
| Renal impairment | Withhold if GFR <30 mL/min. For GFR 30-50 mL/min, reduce dose by 50% or extend interval. Hydrochlorothiazide is ineffective when CrCl <30 mL/min. |
| Liver impairment | Contraindicated in severe hepatic impairment. In Child-Pugh A/B, reduce hydralazine dose by 50% and monitor for hypotension. |
| Pediatric use | Not recommended due to fixed combination; hydralazine: 0.75-3 mg/kg/day PO divided q6h; hydrochlorothiazide: 1-2 mg/kg/day PO divided q12h. Max hydralazine 7.5 mg/kg/day. |
| Geriatric use | Start at lowest dose (25 mg hydralazine/25 mg hydrochlorothiazide) once daily; titrate slowly due to increased risk of hypotension and electrolyte disturbances; monitor 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 | Hydralazine is excreted into breast milk in small amounts (M/P ratio not established); unlikely to cause adverse effects in infants. Hydrochlorothiazide is also excreted in breast milk (low concentrations); may suppress lactation and cause electrolyte disturbances in infant. Use with caution; monitor infant for signs of dehydration, electrolyte imbalance. |
| Teratogenic Risk |
■ FDA Black Box Warning
None
| Common Effects | edema |
| Serious Effects |
["Hypersensitivity to hydralazine, hydrochlorothiazide, or sulfonamide-derived drugs.","Anuria (hydrochlorothiazide component).","Rheumatic heart disease affecting the mitral valve (hydralazine).","Addison's disease (adrenal insufficiency) relative to thiazides.","Hypersensitivity to thiazide diuretics."]
| Precautions | ["Hydralazine may cause a drug-induced lupus-like syndrome (positive ANA, arthralgia, rash); discontinue if symptoms develop.","Hydralazine may cause peripheral neuritis secondary to pyridoxine deficiency.","Use with caution in patients with coronary artery disease or mitral valve rheumatic heart disease (may cause anginal attacks or myocardial infarction).","Hydrochlorothiazide may cause electrolyte imbalances (hypokalemia, hyponatremia, hypomagnesemia), dehydration, and acute angle-closure glaucoma.","May exacerbate systemic lupus erythematosus.","Sulfonamide cross-reactivity possible (hydrochlorothiazide is a sulfonamide derivative).","Use with caution in hepatic impairment (hydralazine) and severe renal impairment (hydrochlorothiazide less effective and may accumulate)."] |
Loading safety data…
| First trimester: Limited human data; animal studies with hydralazine show no consistent teratogenicity, but high doses in rodents have been associated with skeletal anomalies. Hydrochlorothiazide is generally considered low risk, but may cause fetal electrolyte disturbances. Second/third trimester: Hydralazine is used for hypertension; risk of placental hypoperfusion with hypotension. Hydrochlorothiazide may cause fetal or neonatal jaundice, thrombocytopenia, and electrolyte imbalance. Avoid in pregnancy-induced hypertension due to decreased placental perfusion. |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, renal function, electrolytes (especially potassium), and signs of lupus-like syndrome. Fetal: ultrasound for growth, amniotic fluid index (hydrochlorothiazide may reduce amniotic fluid), and non-stress test in third trimester. Monitor newborn for jaundice, thrombocytopenia, and electrolyte abnormalities. |
| Fertility Effects | No known significant effects on fertility from either component. Hydralazine does not impair fertility in animal studies. Hydrochlorothiazide may cause transient reversible erectile dysfunction in males, but no direct impact on female fertility. |