HYDRALAZINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE AND RESERPINE
Clinical safety rating: safe
MAOIs can cause excitability and hypertension Can cause depression and suicidal ideation.
Hydralazine is a direct-acting vasodilator that relaxes arterial smooth muscle, reducing peripheral vascular resistance. Hydrochlorothiazide is a thiazide diuretic that inhibits sodium and chloride reabsorption in the distal convoluted tubule, decreasing plasma volume and cardiac output. Reserpine depletes catecholamines from adrenergic nerve endings, reducing sympathetic tone and lowering blood pressure.
| Metabolism | Hydralazine: N-acetylation (hepatic, NAT2); Hydrochlorothiazide: minimal hepatic metabolism, mostly excreted unchanged; Reserpine: extensive hepatic metabolism (CYP3A4, CYP2D6). |
| Excretion | Hydralazine: 90% renal (as metabolites, 5-10% unchanged), 10% fecal. Hydrochlorothiazide: >95% renal (unchanged). Reserpine: 30-50% renal (as metabolites), 40-60% fecal (unchanged and metabolites). |
| Half-life | Hydralazine: 3-7 hours (terminal; prolonged in renal impairment; acetylator phenotype affects clearance; slow acetylators have higher AUC). Hydrochlorothiazide: 6-15 hours (terminal; prolonged in renal impairment, up to 24 h in severe dysfunction). Reserpine: 50-100 hours (terminal; biphasic with α-phase 4.5 h; prolonged in liver disease). |
| Protein binding | Hydralazine: 85-90% (albumin; binding reduced in uremia). Hydrochlorothiazide: 65-70% (albumin). Reserpine: 96% (albumin and lipoproteins). |
| Volume of Distribution | Hydralazine: 1.6 L/kg (large due to tissue binding; penetrates vascular smooth muscle). Hydrochlorothiazide: 0.8 L/kg (restricted to extracellular fluid). Reserpine: 10-15 L/kg (extensive tissue distribution; accumulates in adipose and brain). |
| Bioavailability | Hydralazine: Oral 40-60% (first-pass metabolism; slow acetylators have higher bioavailability). Hydrochlorothiazide: Oral 65-75% (food may increase). Reserpine: Oral 30-50% (extensive gut and liver metabolism). |
| Onset of Action | Hydralazine: Oral 20-30 min (peak effect 1-2 h). Hydrochlorothiazide: Oral 2 h (peak diuresis 4-6 h). Reserpine: Oral 3-6 days (cumulative effect; full antihypertensive effect weeks). |
| Duration of Action | Hydralazine: 6-8 h (immediate-release; extended-release up to 12 h). Hydrochlorothiazide: 6-12 h (diuretic); antihypertensive effect lasts 24 h. Reserpine: 1-6 weeks (prolonged due to irreversible neuronal uptake inhibition; effects persist after discontinuation). |
Oral: 1 tablet (containing 25 mg hydralazine hydrochloride, 25 mg hydrochlorothiazide, and 0.1 mg reserpine) twice daily. Maximum dose: 2 tablets twice daily.
| Dosage form | TABLET |
| Renal impairment | GFR 30-59 mL/min: Reduce dose by 50% or extend interval to every 12-24 hours. GFR 15-29 mL/min: Use with caution, reduce dose by 75% or extend interval to every 24-48 hours. GFR <15 mL/min: Avoid use due to accumulation of active metabolites. |
| Liver impairment | Child-Pugh Class A: No adjustment necessary. Child-Pugh Class B: Reduce dose by 50%. Child-Pugh Class C: Avoid use. |
| Pediatric use | Not recommended for use in pediatric patients due to lack of safety and efficacy data. |
| Geriatric use | Initiate at the lowest available dose (e.g., 1 tablet once daily) and titrate slowly due to increased risk of hypotension, electrolyte disturbances, and central nervous system effects. Monitor renal function and electrolytes closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
MAOIs can cause excitability and hypertension Can cause depression and suicidal ideation.
| FDA category | Animal |
| Breastfeeding | Hydralazine and hydrochlorothiazide are excreted in breast milk in low concentrations; reserpine is excreted in breast milk and may cause adverse effects in neonates, including respiratory depression and bradycardia. M/P ratio not available. The combination is not recommended during breastfeeding. |
| Teratogenic Risk | First trimester: Inadequate human data; animal studies not available. Second and third trimesters: Hydralazine and hydrochlorothiazide are associated with decreased placental perfusion; reserpine has been associated with neonatal respiratory depression, bradycardia, and hypothermia. Hydrochlorothiazide may cause neonatal jaundice, thrombocytopenia, and electrolyte disturbances. |
■ FDA Black Box Warning
None explicitly listed for this combination; however, reserpine carries a warning about increased risk of depression and suicide.
| Common Effects | Depression |
| Serious Effects |
["Hypersensitivity to any component","Aortic dissection","Mitral valvular rheumatic heart disease (hydralazine)","Anuria (hydrochlorothiazide)","Active peptic ulcer disease","Ulcerative colitis","Electroconvulsive therapy within 7 days","History of depression or suicidal ideation (reserpine)"]
| Precautions | ["Hydralazine: May induce a lupus-like syndrome, especially in slow acetylators; monitor for fever, arthralgia, rash.","Hydrochlorothiazide: May cause hypokalemia, hyponatremia, dehydration; monitor electrolytes; can exacerbate renal impairment.","Reserpine: May cause depression, suicidal ideation; avoid in patients with history of depression; may cause bradycardia, nasal congestion."] |
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| Fetal Monitoring | Monitor maternal blood pressure, heart rate, and electrolyte levels (especially potassium, sodium, chloride). Assess fetal growth and amniotic fluid volume via ultrasound. Monitor for signs of neonatal depression (e.g., respiratory rate, heart rate) at birth. |
| Fertility Effects | No well-controlled studies on fertility. Hydralazine and hydrochlorothiazide have no known direct effects on fertility. Reserpine may cause gynecomastia or menstrual irregularities in females and decreased libido in males, potentially affecting fertility. |