RESERPINE, HYDROCHLOROTHIAZIDE, AND HYDRALAZINE HYDROCHLORIDE
Clinical safety rating: safe
MAOIs can cause excitability and hypertension Can cause depression and suicidal ideation.
Reserpine irreversibly inhibits the vesicular monoamine transporter (VMAT), depleting catecholamines and serotonin in peripheral sympathetic neurons. Hydrochlorothiazide inhibits the Na+/Cl- cotransporter in the distal convoluted tubule, reducing sodium and water reabsorption. Hydralazine directly vasodilates arterioles by relaxing vascular smooth muscle, possibly via nitric oxide-mediated guanylate cyclase activation.
| Metabolism | Reserpine: extensively metabolized in the liver via CYP enzymes (unknown specific isoenzymes). Hydrochlorothiazide: not metabolized; eliminated unchanged renally. Hydralazine: metabolized by hepatic N-acetyltransferase (NAT2); acetylation polymorphism. |
| Excretion | Reserpine: renal (60-70% as metabolites, <1% unchanged) and fecal (10-30%). Hydrochlorothiazide: renal (≥95% unchanged via tubular secretion). Hydralazine: renal (80-90% as metabolites, including acetylation products, and 10-15% unchanged). |
| Half-life | Reserpine: 50-100 hours (long, allows once-daily dosing; cumulative effects may persist after discontinuation). Hydrochlorothiazide: 6-15 hours (prolonged in renal impairment). Hydralazine: fast acetylators 2-4 hours, slow acetylators 4-8 hours (variable; justifies twice-daily dosing). |
| Protein binding | Reserpine: 95-96% (mainly albumin). Hydrochlorothiazide: 40-68% (albumin). Hydralazine: 85-90% (albumin and α1-acid glycoprotein). |
| Volume of Distribution | Reserpine: 1.6-3.4 L/kg (extensive tissue binding). Hydrochlorothiazide: 0.83-1.4 L/kg (not extensively distributed). Hydralazine: 0.5-0.8 L/kg (slow acetylators have lower Vd due to slower clearance). |
| Bioavailability | Reserpine: oral 50-60% (extensive first-pass metabolism). Hydrochlorothiazide: oral 65-75% (absorption reduced by food). Hydralazine: oral 30-50% (fast acetylators lower due to high first-pass acetylation; slow acetylators 30-50%). |
| Onset of Action | Oral: Reserpine 3-6 days (antihypertensive effect), Hydrochlorothiazide 2 hours (diuresis), Hydralazine 30-60 minutes (vasodilation). |
| Duration of Action | Reserpine: 6-24 hours (antihypertensive effect may persist up to weeks after cessation). Hydrochlorothiazide: 6-12 hours (diuresis). Hydralazine: 6-12 hours (antihypertensive effect; duration may be shorter in fast acetylators). |
Each tablet contains reserpine 0.1 mg, hydrochlorothiazide 25 mg, and hydralazine hydrochloride 25 mg. One tablet orally once or twice daily, not to exceed 2 tablets per day.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in anuria or severe renal impairment (CrCl <30 mL/min). For CrCl 30-60 mL/min, reduce dose by 50% (maximum 1 tablet daily). Monitor electrolytes and renal function. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). For Child-Pugh class B, reduce dose by 50% and monitor for signs of hepatic encephalopathy. For Child-Pugh class A, no adjustment needed but caution advised. |
| Pediatric use | Not recommended for pediatric use due to lack of safety and efficacy data. |
| Geriatric use | Initiate at half the standard dose (0.5 tablet daily) due to increased sensitivity, risk of hypotension, electrolyte imbalance, and impaired renal function. Monitor blood pressure 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 | Reserpine excreted in breast milk (M/P ratio unknown); may cause galactorrhea, neonatal respiratory depression, bradycardia. Hydrochlorothiazide excreted in low amounts (M/P ratio ~0.1-0.6); may suppress lactation, cause electrolyte abnormalities. Hydralazine excreted in small amounts (M/P ratio ~0.5-1.0); limited data. Avoid breastfeeding due to potential adverse effects on infant, especially reserpine. |
| Teratogenic Risk |
■ FDA Black Box Warning
None.
| Common Effects | Depression |
| Serious Effects |
Hypersensitivity to any component; reserpine: active peptic ulcer, ulcerative colitis, or electroconvulsive therapy; hydrochlorothiazide: anuria, renal failure; hydralazine: severe coronary artery disease, mitral valvular rheumatic heart disease.
| Precautions | Reserpine: risk of depression, peptic ulcer, and extrapyramidal symptoms; avoid in patients with a history of depression. Hydrochlorothiazide: electrolyte disturbances (hypokalemia, hyponatremia), hyperuricemia, hyperglycemia; may exacerbate renal insufficiency. Hydralazine: drug-induced lupus-like syndrome, peripheral neuritis (pyridoxine deficiency), tachycardia, and angina; use with caution in coronary artery disease. |
Loading safety data…
| First trimester: Reserpine crosses placenta; limited human data but animal studies show no teratogenicity; may cause respiratory depression, bradycardia, hypothermia in neonate. Hydrochlorothiazide: not associated with major malformations but may cause electrolyte disturbances, thrombocytopenia, jaundice. Hydralazine: no evidence of teratogenicity in humans. Second and third trimesters: Reserpine may cause neonatal respiratory depression, bradycardia; hydrochlorothiazide may cause fetal/neonatal jaundice, thrombocytopenia, electrolyte imbalance; hydralazine may cause neonatal thrombocytopenia, lupus-like syndrome. Overall, use only if benefit outweighs risk; avoid in preeclampsia due to potential maternal hypotension. |
| Fetal Monitoring | Maternal: Blood pressure, heart rate, serum electrolytes (potassium, sodium), renal function, complete blood count, signs of lupus-like syndrome (hydralazine), depression (reserpine). Fetal: Ultrasound for growth and amniotic fluid volume (hydrochlorothiazide may cause oligohydramnios), fetal heart rate monitoring in third trimester. |
| Fertility Effects | Reserpine: may cause menstrual irregularities, galactorrhea, decreased libido in females; gynecomastia in males. Hydrochlorothiazide: no known direct effect on fertility. Hydralazine: no known direct effect on fertility. Limited data on combination drug. Potential reversible impact on spermatogenesis (reserpine). |