ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE
Clinical safety rating: safe
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
Enalapril is an angiotensin-converting enzyme (ACE) inhibitor that inhibits the conversion of angiotensin I to angiotensin II, reducing vasoconstriction and aldosterone secretion, leading to decreased blood pressure. Hydrochlorothiazide is a thiazide diuretic that inhibits the sodium-chloride symporter in the distal convoluted tubule, increasing sodium, chloride, and water excretion, and reducing peripheral vascular resistance.
| Metabolism | Enalapril is metabolized primarily by the liver via ester hydrolysis to its active metabolite, enalaprilat; minor metabolism by CYP3A4. Hydrochlorothiazide is not extensively metabolized; majority excreted unchanged in urine. |
| Excretion | Enalapril: renal 60-80% (40-60% as enalaprilat, 20-40% as metabolites); fecal 20-40%. Hydrochlorothiazide: renal 95% (unchanged). |
| Half-life | Enalaprilat: terminal 11 hours (multiple doses), prolonged in renal impairment (creatinine clearance <30 mL/min: 30-40 h). Hydrochlorothiazide: terminal 6-15 hours (mean 10 h), prolonged in renal impairment. |
| Protein binding | Enalaprilat: 50-60% (primarily albumin). Hydrochlorothiazide: 40-68% (primarily albumin). |
| Volume of Distribution | Enalaprilat: ~1.7 L/kg (extensive extravascular distribution). Hydrochlorothiazide: ~0.8 L/kg (distributes into extracellular fluid). |
| Bioavailability | Enalapril: oral 60% (as enalaprilat, after hepatic hydrolysis). Hydrochlorothiazide: oral 65-75%. |
| Onset of Action | Enalapril: oral 1 hour (peak antihypertensive effect 4-6 h). Hydrochlorothiazide: oral 2 hours (peak diuresis 4-6 h). |
| Duration of Action | Enalapril: 24 hours (once-daily dosing). Hydrochlorothiazide: 12-24 hours (once-daily dosing). |
Oral: Initially enalapril 5 mg and HCTZ 12.5 mg once daily; titrate to maximum enalapril 20 mg / HCTZ 25 mg once daily.
| Dosage form | TABLET |
| Renal impairment | GFR 30-60 mL/min: Use with caution; maximum HCTZ 12.5 mg daily. GFR <30 mL/min: Not recommended (loop diuretic preferred). |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B or C: Use with caution; consider enalapril dose reduction due to reduced prodrug activation. |
| Pediatric use | Not recommended for pediatric patients; safety and efficacy not established. |
| Geriatric use | Start at enalapril 2.5 mg / HCTZ 12.5 mg daily; titrate slowly. Monitor renal function and electrolytes. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
| FDA category | Animal |
| Breastfeeding | Enalapril: Small amounts in breast milk; estimated infant dose <0.1% of maternal dose. Hydrochlorothiazide: Excreted in breast milk; may suppress lactation. M/P ratio not available for combination. Use with caution in breastfeeding; consider risk of neonatal electrolyte disturbance and hypotension. |
| Teratogenic Risk |
■ FDA Black Box Warning
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as pregnancy is detected.
| Common Effects | edema |
| Serious Effects |
["Hypersensitivity to enalapril, hydrochlorothiazide, or any other sulfonamide-derived drug","History of angioedema related to previous ACE inhibitor therapy","Anuria","Pregnancy (second and third trimesters)"]
| Precautions | ["Angioedema associated with ACE inhibitors; more common in black patients","Fetal/neonatal morbidity and mortality","Hypotension in volume-depleted patients","Renal impairment: monitor renal function","Electrolyte imbalances: hyperkalemia, hyponatremia, hypokalemia, hypomagnesemia","Exacerbation of gout","Systemic lupus erythematosus exacerbation","Sulfonamide allergy cross-sensitivity with hydrochlorothiazide"] |
Loading safety data…
| First trimester: ACE inhibitors have been associated with increased risk of congenital malformations (cardiovascular, renal) in some studies, though evidence is inconclusive. Second and third trimesters: Fetal and neonatal morbidity and mortality are well-documented, including oligohydramnios, fetal renal dysfunction, skull ossification defects, hypotension, and anuria. Hydrochlorothiazide crosses the placenta and has been associated with fetal or neonatal jaundice, thrombocytopenia, and electrolyte disturbances. |
| Fetal Monitoring | Monitor maternal blood pressure, renal function, and serum electrolytes (potassium, sodium) throughout pregnancy. Fetal ultrasound to assess amniotic fluid volume and fetal growth. Monitor for oligohydramnios if used in second or third trimester. Neonates should be observed for hypotension, hyperkalemia, and renal dysfunction. |
| Fertility Effects | No direct evidence of impaired fertility with enalapril or hydrochlorothiazide. However, ACE inhibitors may theoretically affect fertility through alterations in renin-angiotensin system; no clinical significance reported. Hydrochlorothiazide may cause erectile dysfunction but no known effect on female fertility. |