HYDRALAZINE HYDROCHLORIDE-HYDROCHLOROTHIAZIDE-RESERPINE
Clinical safety rating: safe
MAOIs can cause excitability and hypertension Can cause depression and suicidal ideation.
Hydralazine directly relaxes arteriolar smooth muscle by unclear mechanism, possibly interfering with calcium movements; hydrochlorothiazide inhibits the Na+/Cl- cotransporter in distal convoluted tubules, reducing reabsorption of sodium and chloride; reserpine depletes catecholamines from adrenergic nerve endings by inhibiting vesicular monoamine transporter (VMAT), reducing sympathetic outflow.
| Metabolism | Hydralazine: N-acetylation (NAT2), hydrolysis; Hydrochlorothiazide: limited metabolism (<10%); Reserpine: extensive hepatic metabolism via CYP2D6 and other enzymes |
| Excretion | Hydralazine: 80% renal, 5% fecal; Hydrochlorothiazide: >95% renal; Reserpine: 60% renal, 40% fecal. |
| Half-life | Hydralazine: 3-7 h (slow acetylators) or 1-2 h (rapid acetylators); Hydrochlorothiazide: 6-15 h; Reserpine: 50-100 h (biphasic, terminal half-life). |
| Protein binding | Hydralazine: 87% bound to plasma proteins; Hydrochlorothiazide: 40-68% bound to albumin; Reserpine: 96% bound to plasma proteins. |
| Volume of Distribution | Hydralazine: 0.3-0.7 L/kg; Hydrochlorothiazide: 0.2-0.5 L/kg; Reserpine: 3-9 L/kg (large Vd due to tissue binding). |
| Bioavailability | Hydralazine: oral 30-50% (extensive first-pass metabolism); Hydrochlorothiazide: oral 70%; Reserpine: oral 50-60%. |
| Onset of Action | Hydralazine: oral 20-30 min, IV 5-20 min; Hydrochlorothiazide: oral 2 h; Reserpine: oral several days to weeks for full antihypertensive effect. |
| Duration of Action | Hydralazine: oral 2-6 h, IV 2-4 h; Hydrochlorothiazide: oral 6-12 h; Reserpine: oral 1-6 weeks (cumulative effect). |
| Molecular Weight | Hydralazine HCl: 196.64 Da; Hydrochlorothiazide: 297.74 Da; Reserpine: 608.68 Da. Combination product: not applicable. |
1 tablet (25 mg hydralazine / 25 mg hydrochlorothiazide / 0.1 mg reserpine) orally once daily, increased to 2 tablets daily if needed.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in severe renal impairment (CrCl <30 mL/min). For CrCl 30-50 mL/min: reduce dose by 50% or extend interval. For hydralazine: CrCl <30 mL/min: decrease dose to 25 mg/day. |
| Liver impairment | Contraindicated in Child-Pugh class B or C. Use with caution in mild hepatic impairment; reduce hydralazine dose by 50%. |
| Pediatric use | Not recommended for children under 12 years. For adolescents (≥12 years): initiate at 0.75 mg/kg/day hydralazine component orally in 2 divided doses, maximum 2.5 mg/kg/day or 200 mg/day. |
| Geriatric use | Initiate at lowest dose (1 tablet daily). Monitor for hypotension (especially orthostatic), electrolyte imbalance, and CNS depression. Avoid in patients with history of depression or parkinsonism. |
| 1st trimester | Reserpine and hydrochlorothiazide are associated with adverse fetal effects; hydralazine has limited safety data. Avoid unless essential. |
| 2nd trimester | Risk of fetal bradycardia and electrolyte imbalance; hydralazine may cause maternal hypotension and placental hypoperfusion. Use only if clearly needed. |
| 3rd trimester | Reserpine can cause neonatal respiratory depression, bradycardia, and hypothermia; hydrochlorothiazide may cause fetal electrolyte disturbances. Avoid near term. |
Clinical note
MAOIs can cause excitability and hypertension Can cause depression and suicidal ideation.
| FDA category | Animal |
| Placental transfer | All three components cross the placenta. Reserpine has high placental transfer; hydralazine and hydrochlorothiazide have moderate transfer. |
■ FDA Black Box Warning
None
| Common Effects | Depression |
| Serious Effects |
Active peptic ulcer disease (reserpine increases gastric acid)Ulcerative colitis (reserpine may exacerbate)Electroconvulsive therapy within 1 weekHypersensitivity to any componentSevere hepatic impairmentSevere renal impairment (CrCl <30 mL/min) (hydrochlorothiazide)Anuria (hydrochlorothiazide)Concurrent MAOI therapy (reserpine potentiates hypotensive effects)
| Precautions | Hydralazine: Drug-induced lupus (especially slow acetylators), hypotension, myocardial infarction precipitation; Hydrochlorothiazide: Electrolyte disturbances, hyperuricemia, photosensitivity; Reserpine: Mental depression (active or history), peptic ulcer, paradoxical anxiety, extrapyramidal symptoms |
| Food/Dietary | Avoid high-sodium foods to enhance antihypertensive effect. Do not consume large amounts of potassium-rich foods unless directed. Limit alcohol intake as it may exacerbate hypotension and side effects. |
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| Breastfeeding |
| Hydralazine and hydrochlorothiazide are excreted in breast milk in low amounts; reserpine also excreted and may cause adverse effects in nursing infants (e.g., nasal congestion, depression). Use caution; consider alternative antihypertensives. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | First trimester: Hydralazine and hydrochlorothiazide are not associated with major malformations; reserpine has limited data but may cross placenta. Second/third trimester: Hydralazine may cause maternal hypotension and fetal distress; hydrochlorothiazide may cause fetal electrolyte disturbances, thrombocytopenia; reserpine may cause neonatal bradycardia, respiratory depression, hypothermia, and lethargy. Overall risk: FDA category C for hydralazine, D for hydrochlorothiazide (based on maternal benefit), and C for reserpine. |
| Fetal Monitoring | Monitor maternal blood pressure (avoid hypotension), serum electrolytes (especially potassium due to hydrochlorothiazide), and renal function. Fetal monitoring includes growth scans, amniotic fluid volume (hydrochlorothiazide risk of oligohydramnios), and neonatal monitoring for electrolyte imbalance, bradycardia, and respiratory depression. |
| Fertility Effects | Hydralazine may rarely cause reversible lupus-like syndrome affecting fertility; hydrochlorothiazide and reserpine have no established effects on fertility. However, reserpine can cause gynecomastia and menstrual irregularities. |
| Clinical Pearls | Monitor for lupus-like syndrome with hydralazine (especially slow acetylators). Reserpine can cause depression and nasal congestion. Hydrochlorothiazide may worsen gout and cause hypokalemia. Use with caution in renal impairment. Avoid abrupt discontinuation to prevent rebound hypertension. |
| Patient Advice | Take exactly as prescribed; do not stop suddenly. · Report symptoms like joint pain, fever, or rash (lupus-like syndrome). · Avoid alcohol and excessive salt intake. · May cause dizziness; rise slowly from sitting/lying. · Monitor for unusual tiredness, depression, or nasal stuffiness. · Do not use over-the-counter cold or appetite suppressants without consulting doctor. |