RESERPINE, HYDRALAZINE HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE
Clinical safety rating: safe
MAOIs can cause excitability and hypertension Can cause depression and suicidal ideation.
Reserpine depletes catecholamines from adrenergic nerve endings by irreversibly inhibiting vesicular monoamine transporter 2 (VMAT2), reducing sympathetic outflow. Hydralazine directly relaxes arteriolar smooth muscle via unclear mechanism, possibly involving nitric oxide. Hydrochlorothiazide increases renal excretion of sodium and water by inhibiting Na+/Cl- symporter in distal convoluted tubule.
| Metabolism | Reserpine: hepatic metabolism (CYP3A4); Hydralazine: hepatic acetylation (N-acetyltransferase); Hydrochlorothiazide: not metabolized, excreted renally. |
| Excretion | Reserpine: renal (30% unchanged, remainder as metabolites); hydralazine: renal (80-90% as metabolites, <10% unchanged); hydrochlorothiazide: renal (95% unchanged via organic anion transporters). |
| Half-life | Reserpine: 33-50 hours (prolonged in renal impairment); hydralazine: 2-4 hours (rapid acetylators) to 4-8 hours (slow acetylators); hydrochlorothiazide: 6-15 hours (increased in renal impairment). |
| Protein binding | Reserpine: 96% (mainly to alpha1-acid glycoprotein and albumin); hydralazine: 87% (albumin); hydrochlorothiazide: 40-68% (albumin). |
| Volume of Distribution | Reserpine: 10-20 L/kg (extensive tissue binding); hydralazine: 1-2 L/kg; hydrochlorothiazide: 3.6-8.5 L/kg. |
| Bioavailability | Reserpine oral: 50%; hydralazine oral: 26-55% (influenced by acetylator status); hydrochlorothiazide oral: 65-75% (reduced with food). |
| Onset of Action | Reserpine oral: 3-6 days; hydralazine oral: 20-30 minutes; hydrochlorothiazide oral: 2 hours. |
| Duration of Action | Reserpine: 1-6 weeks (prolonged due to storage in adrenergic neurons); hydralazine: 6-12 hours; hydrochlorothiazide: 6-12 hours. |
| Molecular Weight | Reserpine: 608.68 Da; Hydralazine HCl: 196.64 Da; Hydrochlorothiazide: 297.74 Da |
Oral: 1 tablet (0.1 mg reserpine, 25 mg hydralazine, 15 mg hydrochlorothiazide) 1 to 4 times daily. Maximum: 2 tablets per dose (200 mg hydralazine equivalent) and 200 mg hydralazine/day.
| Dosage form | TABLET |
| Renal impairment | CrCl 30-50 mL/min: Reduce dose to 1 tablet daily or every other day. CrCl 15-29 mL/min: Use every other day or discontinue if not responding. CrCl <15 mL/min: Avoid use due to thiazide ineffectiveness and risk of azotemia. |
| Liver impairment | Child-Pugh Class A: No adjustment. Class B: Reduce dose by 50% (e.g., 1 tablet every other day). Class C: Avoid use due to accumulation of reserpine and hydralazine. |
| Pediatric use | Not recommended for children under 12 years. For adolescents >12 years: Same as adult dose adjusted for weight (0.1 mg reserpine, 25 mg hydralazine, 15 mg hydrochlorothiazide per tablet) starting at 0.5 to 1 tablet daily, titrate up to 2 tablets twice daily. |
| Geriatric use | Start at 0.5 tablet (0.05 mg reserpine, 12.5 mg hydralazine, 7.5 mg hydrochlorothiazide) once daily. Titrate slowly to 0.5 tablet twice daily. Maximum: 1 tablet twice daily. Monitor for orthostatic hypotension, electrolyte imbalance, and renal function. |
| 1st trimester | Crosses placenta. Risk of fetal abnormalities (e.g., neural tube defects) from reserpine? Limited human data. Hydralazine may cause maternal hypotension reducing placental perfusion. Hydrochlorothiazide associated with neonatal jaundice, thrombocytopenia; avoid in first trimester due to teratogenicity concerns. |
| 2nd trimester | Use only if benefit outweighs risk. Hydrochlorothiazide may cause electrolyte imbalances; monitor. Hydralazine and reserpine can cause fetal bradycardia, hypotension. Avoid during second trimester unless essential. |
| 3rd trimester | Contraindicated in third trimester: hydrochlorothiazide may cause fetal/neonatal electrolyte disturbances, jaundice, thrombocytopenia; reserpine and hydralazine can cause neonatal bradycardia, hypotension, respiratory depression. |
Clinical note
MAOIs can cause excitability and hypertension Can cause depression and suicidal ideation.
| FDA category | Animal |
| Placental transfer |
■ FDA Black Box Warning
None
| Common Effects | Depression |
| Serious Effects |
Hypersensitivity to reserpine, hydralazine, hydrochlorothiazide, sulfonamides or any componentActive peptic ulcer disease (reserpine)Ulcerative colitisMental depression (especially with reserpine)AnuriaSevere renal impairment (CrCl <30 mL/min)Electrolyte imbalance (hypokalemia, hyponatremia, hypercalcemia)Systemic lupus erythematosus (hydralazine)Sympathomimetic use (MAOI therapy or within 14 days)PheochromocytomaBradycardia or heart blockConcurrent use of MAOIs
| Precautions | Depression, suicidal ideation (reserpine), Lupus-like syndrome (hydralazine, especially in slow acetylators), Electrolyte disturbances, hypotension (hydrochlorothiazide), May cause acute angle-closure glaucoma, Avoid abrupt withdrawal (reserpine may cause severe hypertension) |
| Food/Dietary |
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| All three components cross the placenta. Reserpine and hydralazine reach fetal concentrations similar to maternal; hydrochlorothiazide crosses readily. Evidence of transfer in animal and human studies. |
| Breastfeeding | Reserpine and hydralazine are excreted into breast milk in small amounts; hydrochlorothiazide is excreted and may suppress lactation. Potential for infant hypotension, bradycardia, electrolyte disturbances. Not recommended during breastfeeding. If used, monitor infant for adverse effects. |
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | First trimester: Reserpine crosses placenta; animal studies show increased fetal abnormalities; human data limited. Hydralazine: no major teratogenic risk. HCTZ: risk of fetal/neonatal jaundice; use only if clearly needed. Second and third trimesters: HCTZ may cause electrolyte imbalance, thrombocytopenia; hydralazine and reserpine may cause neonatal hypotension, bradycardia, and respiratory depression. Avoid use for pregnancy-induced hypertension due to risk of decreased placental perfusion. |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, and electrolyte levels (especially potassium with HCTZ). Assess fetal growth and amniotic fluid volume via ultrasound. Neonatal monitoring for bradycardia, hypotension, extrapyramidal symptoms (reserpine), and thrombocytopenia (HCTZ). |
| Fertility Effects | Reserpine may decrease libido and cause gynecomastia in males; hydralazine and HCTZ have minimal reported effects on fertility. No significant impact on female fertility documented. |
| Avoid high-tyramine foods (aged cheeses, cured meats, fermented products) due to reserpine's monoamine oxidase inhibition potential. Avoid excessive salt intake; may reduce antihypertensive effect. Take with food to minimize GI upset. |
| Clinical Pearls | Combination product; avoid in patients with depression, peptic ulcer, or ulcerative colitis due to reserpine. Monitor for hydralazine-induced lupus-like syndrome (especially in slow acetylators) and reserpine-induced bradycardia/orthostasis. Hydrochlorothiazide may exacerbate hyperuricemia/gout. Do not use as first-line antihypertensive. |
| Patient Advice | Take exactly as prescribed; do not stop suddenly (risk of rebound hypertension). · Avoid activities requiring mental alertness if experiencing dizziness or drowsiness. · Report symptoms of depression, slow heart rate, unexplained fever, joint pains, or rash. · Limit alcohol intake; may increase hypotensive effects. · Rise slowly from sitting/lying to prevent falls. |