HYDRALAZINE, HYDROCHLOROTHIAZIDE W/ RESERPINE
Clinical safety rating: safe
MAOIs can cause excitability and hypertension Can cause depression and suicidal ideation.
Hydralazine: direct vasodilation of arterioles, decreasing peripheral resistance. Hydrochlorothiazide: thiazide diuretic inhibiting NaCl reabsorption in distal convoluted tubule. Reserpine: depletes catecholamines from postganglionic sympathetic nerve endings.
| Metabolism | Hydralazine: N-acetylation (NAT2), CYP450 (minor). Hydrochlorothiazide: not metabolized. Reserpine: extensive hepatic metabolism. |
| Excretion | Hydralazine: 86% renal (48% unchanged, 38% metabolites); Hydrochlorothiazide: >95% renal (unchanged); Reserpine: 30% renal (metabolites), 60% fecal. |
| Half-life | Hydralazine: 2-4 hours (fast acetylators), 4-8 hours (slow acetylators); Hydrochlorothiazide: 6-15 hours; Reserpine: 50-100 hours (biphasic, terminal). Clinical context: hydralazine dosing adjusted by acetylator status; hydrochlorothiazide once daily covers 24h; reserpine accumulates with repeated dosing. |
| Protein binding | Hydralazine: 85-90% (albumin); Hydrochlorothiazide: 40-68% (albumin); Reserpine: 96% (albumin and lipoproteins). |
| Volume of Distribution | Hydralazine: 1.5-1.8 L/kg (extensive tissue distribution); Hydrochlorothiazide: 3-15 L (approx 0.2 L/kg, limited to extracellular fluid); Reserpine: 20-35 L/kg (large, extensive tissue binding, especially brain). |
| Bioavailability | Hydralazine: oral 26-55% (first-pass metabolism, variable for acetylator status); Hydrochlorothiazide: oral 65-75% (food increases); Reserpine: oral 30-50% (first-pass). |
| Onset of Action | Oral: Hydralazine 20-30 min, Hydrochlorothiazide 2 hours, Reserpine 3-6 days (delayed due to catecholamine depletion). IV: Hydralazine 5-20 min; other components not available IV. |
| Duration of Action | Hydralazine: 2-6 hours (dose-dependent); Hydrochlorothiazide: 12-16 hours; Reserpine: 2-6 weeks (prolonged effect on norepinephrine stores). Note: combination may require QD to BID dosing. |
| Molecular Weight | Hydralazine HCl: 160.18 Da; Hydrochlorothiazide: 297.74 Da; Reserpine: 608.68 Da |
1 tablet (Hydralazine 25 mg / Hydrochlorothiazide 25 mg / Reserpine 0.1 mg) orally 2 to 4 times daily. Max dose: Hydralazine 200 mg/day, Hydrochlorothiazide 50 mg/day, Reserpine 0.25 mg/day.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in anuria. For CrCl <30 mL/min: avoid hydrochlorothiazide; adjust hydralazine dose based on response. For CrCl 30-60 mL/min: use with caution, consider reducing dose or extending interval. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce hydralazine dose by 50% (start 12.5 mg component) and monitor. Child-Pugh Class C: contraindicated due to risk of hepatic coma from reserpine and impaired hydralazine metabolism. |
| Pediatric use | Not recommended for children. No established safety and efficacy. If used: hydralazine 0.75-3 mg/kg/day in 3-4 divided doses; hydrochlorothiazide 1-2 mg/kg/day; reserpine 0.005-0.02 mg/kg/day (max 0.25 mg/day). |
| Geriatric use | Initiate at low dose (e.g., half tablet) due to increased sensitivity to hypotension and electrolyte disturbances. Monitor renal function, avoid in CrCl <30 mL/min. Use cautiously with high risk of depression and bradycardia from reserpine. |
| 1st trimester | Avoid; teratogenic risk (neural tube defects, cardiac malformations) in animal studies; reserpine crosses placenta and may cause CNS depression. |
| 2nd trimester | Avoid; risk of fetal bradycardia, hypotension, and electrolyte imbalance from HCTZ; reserpine may deplete fetal catecholamines. |
| 3rd trimester | Avoid; risk of neonatal hypotension, bradycardia, and electrolyte disturbances; HCTZ may cause neonatal thrombocytopenia. |
Clinical note
MAOIs can cause excitability and hypertension Can cause depression and suicidal ideation.
| FDA category | Animal |
| Placental transfer | All components cross the placenta. Hydralazine and HCTZ show measurable fetal concentrations; reserpine accumulates in fetal tissues and depletes fetal catecholamines. |
■ FDA Black Box Warning
None
| Common Effects | Depression |
| Serious Effects |
Hypersensitivity to any componentActive peptic ulcer or ulcerative colitis (reserpine)Electroconvulsive therapy (reserpine)Parkinson's disease (reserpine)Overt heart failure or cor pulmonale (reserpine)Anuria (HCTZ)Severe renal impairment (CrCl <30 mL/min) (HCTZ)Systemic lupus erythematosus (hydralazine)Severe tachycardia or high-output heart failure (hydralazine)
| Precautions | Lupus-like syndrome (hydralazine), Orthostatic hypotension (reserpine), Electrolyte imbalance (hydrochlorothiazide), Depression (reserpine), Sulfonamide allergy cross-reactivity (hydrochlorothiazide) |
| Food/Dietary | Avoid high-sodium foods as they may reduce antihypertensive effect. Limit alcohol intake (increases risk of hypotension and drowsiness). Maintain potassium intake; hydrochlorothiazide may cause hypokalemia; consider potassium-rich foods or supplements if needed. Grapefruit juice may increase hydralazine absorption; avoid excessive consumption. |
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| Breastfeeding |
| Hydralazine and reserpine are excreted into breast milk. Reserpine may cause galactorrhea and CNS effects in infant. HCTZ may suppress lactation. Avoid breastfeeding due to potential for adverse effects in nursing infant. |
| Lactation Rating | L5 |
| Teratogenic Risk | First trimester: Reserpine may cause respiratory depression, nasal congestion, and hypothermia in neonates; limited human data for hydralazine and hydrochlorothiazide, but animal studies suggest low teratogenic risk. Second and third trimesters: Hydralazine is associated with maternal hypotension, potentially reducing uteroplacental perfusion; hydrochlorothiazide may cause electrolyte imbalance, jaundice, thrombocytopenia; reserpine may increase risk of neonatal respiratory depression. Avoid in pregnancy unless essential. |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, electrolytes, and renal function. Fetal monitoring: assess growth and amniotic fluid volume, especially with hydrochlorothiazide. Neonatal: observe for respiratory depression, nasal congestion, electrolyte disturbances. |
| Fertility Effects | Hydralazine may cause systemic lupus erythematosus-like syndrome affecting fertility. Hydrochlorothiazide may cause electrolyte imbalances impacting reproductive function. Reserpine can lead to hyperprolactinemia, amenorrhea, and impaired fertility. Overall, potential for negative impact on fertility. |
| Clinical Pearls | Monitor for first-dose syncope; start at lowest dose and titrate slowly. Avoid in patients with severe renal impairment (CrCl <30 mL/min) due to hydrochlorothiazide. Reserpine may cause depression; screen for history of depression. Hydralazine can induce lupus-like syndrome; check ANA at baseline and if symptoms develop. Combination may cause orthostatic hypotension, especially in elderly. |
| Patient Advice | Take this medication exactly as prescribed; do not skip doses or stop abruptly without consulting your doctor. · Rise slowly from sitting or lying down to prevent dizziness or fainting. · You may experience drowsiness or fatigue; avoid driving or operating heavy machinery until you know how this drug affects you. · Report any signs of depression (e.g., mood changes, insomnia, loss of interest) or joint pain, fever, or rash (possible lupus-like reaction). · Limit alcohol consumption as it can worsen side effects. · Use sun protection as hydrochlorothiazide increases sensitivity to sunlight. · Maintain adequate hydration to prevent dehydration and electrolyte imbalances. |