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). |
| Molecular Weight | 376.47 |
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 | Avoid. ACE inhibitors are associated with increased risk of major congenital malformations, particularly cardiovascular and central nervous system defects, when used during the first trimester. |
| 2nd trimester | Contraindicated. ACE inhibitors can cause fetal and neonatal morbidity and death when used during the second and third trimesters, including oligohydramnios, fetal renal dysfunction, skull hypoplasia, and hypotension. |
| 3rd trimester | Contraindicated. Same risks as second trimester, including oligohydramnios and neonatal renal failure. |
Clinical note
Other antihypertensive drugs can have additive effects Lithium levels may be increased Can cause hypokalemia and hyponatremia.
| FDA category | Animal |
| Placental transfer | Both enalapril (as enalaprilat) and hydrochlorothiazide cross the placenta. Enalaprilat levels in cord blood are approximately 50% of maternal levels. Hydrochlorothiazide reaches fetal serum concentrations similar to maternal. |
■ 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 |
History of angioedema related to previous ACE inhibitor therapyHereditary or idiopathic angioedemaAnuriaHypersensitivity to enalapril, hydrochlorothiazide, or sulfonamide-derived drugsPregnancy (especially second and third trimesters)Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²)
| 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 |
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| Breastfeeding | Enalapril is excreted into breast milk in low concentrations (about 2% of maternal weight-adjusted dose). Hydrochlorothiazide is also excreted but may suppress lactation and cause neonatal electrolyte disturbances. Use with caution, especially in preterm infants or those with impaired renal function. |
| Lactation Rating | L3 - Moderately Safe |
| Teratogenic Risk | 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. |
| Food/Dietary |
| Avoid excessive intake of high-potassium foods (bananas, oranges, tomatoes, potatoes with skin, avocados, spinach, and salt substitutes containing potassium) due to risk of hyperkalemia from enalapril. Limit sodium intake (processed foods, canned soups, fast food) to enhance antihypertensive effect. Alcohol may increase hypotensive effects; limit to moderate consumption. Do not use potassium-containing salt substitutes without medical approval. |
| Clinical Pearls | Monitor serum potassium, creatinine, and blood urea nitrogen (BUN) 2-4 weeks after initiation or dose increase due to risk of electrolyte imbalances and renal impairment. Start with lowest dose to avoid first-dose hypotension, especially in volume-depleted patients. Caution in renal artery stenosis: can cause acute renal failure. Avoid use in pregnancy (ACE inhibitors cause fetal toxicity; thiazides cause neonatal electrolyte disturbances). |
| Patient Advice | Take exactly as prescribed, usually once daily with food to reduce stomach upset. · Avoid potassium supplements or salt substitutes containing potassium unless advised by your doctor. · Report persistent cough, swelling of face/lips/tongue (angioedema), or difficulty breathing immediately. · You may feel dizzy or lightheaded when starting treatment; rise slowly from sitting or lying down. · Do not stop taking this medication without consulting your doctor, even if you feel well. · Drink adequate fluids to prevent dehydration, especially during hot weather or exercise. · This drug can cause gout flares; avoid excessive alcohol and high-purine foods. · Use effective contraception if you are of childbearing potential; seek immediate medical advice if you become pregnant. |