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. |
| Molecular Weight | Hydralazine HCl 196.64 Da, Hydrochlorothiazide 297.74 Da |
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 | Contraindicated due to teratogenicity (first trimester). Hydralazine may cause maternal hypotension and reduced placental perfusion; hydrochlorothiazide is Associated with fetal/neonatal adverse effects including jaundice, electrolyte disturbances, and possible teratogenicity. |
| 2nd trimester | Use only if clearly needed. Hydralazine may cause maternal hypotension; hydrochlorothiazide can cause fetal/neonatal electrolyte imbalances and jaundice. |
| 3rd trimester | Use only if clearly needed. Hydrochlorothiazide can cause neonatal thrombocytopenia, jaundice, and electrolyte disturbances; hydralazine may cause maternal hypotension affecting placental perfusion. |
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 components cross the placenta. Hydrochlorothiazide extensively; hydralazine moderately. |
■ FDA Black Box Warning
None
| Common Effects | edema |
| Serious Effects |
AnuriaSulfonamide allergy (cross-sensitivity with hydrochlorothiazide)Hypersensitivity to hydralazine, hydrochlorothiazide, or any componentCoronary artery disease (severe)Mitral valvular rheumatic heart diseaseDissecting aortic aneurysmSystemic lupus erythematosus (SLE) or history of drug-induced lupus
| 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). |
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| Breastfeeding | Hydralazine is excreted into breast milk in low amounts; hydrochlorothiazide also passes into breast milk. The combination may suppress lactation. Monitor infant for signs of hypotension and electrolyte disturbances. |
| Lactation Rating | L3 (Moderately Safe) - Consider risks vs benefits; avoid if possible, especially in neonates with compromised renal function. |
| Teratogenic Risk | 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. |
| Food/Dietary | Avoid excessive intake of potassium-rich foods (e.g., bananas, oranges, potatoes, tomatoes) or potassium supplements as hydrochlorothiazide can cause hyperkalemia when combined with ACE inhibitors or ARBs but hypokalemia alone. Limit sodium to control blood pressure. Avoid alcohol as it may potentiate hypotension. Grapefruit juice may increase hydralazine absorption; avoid excessive consumption. Magnesium supplements may increase hypotension risk. |
| Clinical Pearls | Monitor for lupus-like syndrome (arthralgias, rash, fever) with hydralazine, especially in slow acetylators and doses >200 mg/day. Hydrochlorothiazide may cause hypokalemia, which can be exacerbated by hydralazine-induced reflex tachycardia. Check electrolytes and renal function at baseline and periodically. Use with caution in patients with severe renal impairment (CrCl <30 mL/min) as thiazides are ineffective. Avoid in patients with coronary artery disease or mitral valve rheumatic heart disease due to reflex sympathetic activation. |
| Patient Advice | Take this medication exactly as prescribed, usually twice daily with or without food. · If you miss a dose, take it as soon as you remember unless it is almost time for the next dose; do not double the dose. · Notify your doctor immediately if you experience joint pain, muscle aches, rash, fever, or unexplained bruising (possible lupus-like reaction). · Avoid sudden standing to prevent dizziness from low blood pressure; rise slowly from sitting or lying down. · This medication may increase sensitivity to sun; use sunscreen and protective clothing. · Do not take any other antihypertensives or diuretics unless prescribed by your doctor. · Report symptoms of low potassium (muscle weakness, cramps, irregular heartbeat) or high sugar (excessive thirst, frequent urination). |