ZESTORETIC
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZESTORETIC (ZESTORETIC).
Combination of lisinopril (ACE inhibitor) and hydrochlorothiazide (thiazide diuretic). Lisinopril inhibits angiotensin-converting enzyme, reducing angiotensin II formation, decreasing vasoconstriction and aldosterone secretion. Hydrochlorothiazide inhibits sodium reabsorption in distal convoluted tubule, increasing diuresis and reducing plasma volume.
| Metabolism | Lisinopril: Not metabolized; excreted unchanged in urine. Hydrochlorothiazide: Not extensively metabolized; small amount metabolized via unknown pathways. |
| Excretion | Lisinopril is excreted unchanged in urine; 100% renal elimination. Hydrochlorothiazide is excreted primarily by the kidney (≥95% as unchanged drug) via tubular secretion. |
| Half-life | Lisinopril: terminal half-life approximately 12 hours (accumulation half-life 13.8 hours in patients with normal renal function). Hydrochlorothiazide: terminal half-life 5.6–14.8 hours (mean 9.6 hours). |
| Protein binding | Lisinopril: 25% bound to plasma proteins. Hydrochlorothiazide: 40–68% bound to albumin. |
| Volume of Distribution | Lisinopril: Vd approximately 1.8 L/kg (suggests extensive extravascular distribution). Hydrochlorothiazide: Vd 0.8–1.0 L/kg. |
| Bioavailability | Lisinopril: oral bioavailability 25% (range 6–60%). Hydrochlorothiazide: oral bioavailability 65–75%. |
| Onset of Action | Lisinopril: onset of antihypertensive effect within 1 hour after oral administration. Hydrochlorothiazide: diuresis begins within 2 hours. |
| Duration of Action | Lisinopril: duration of antihypertensive effect is 24 hours. Hydrochlorothiazide: diuretic effect lasts 6–12 hours. |
| Molecular Weight | Lis: 441.53 Da; HCTZ: 297.74 Da. Combination: average not applicable. |
Zestoretic (lisinopril/hydrochlorothiazide) is available in fixed-dose combinations. Typical adult dose: 10 mg/12.5 mg, 20 mg/12.5 mg, or 20 mg/25 mg orally once daily. Maximum dose: lisinopril 80 mg/day, hydrochlorothiazide 50 mg/day.
| Dosage form | TABLET |
| Renal impairment | For GFR 30-60 mL/min/1.73 m²: use lower initial doses and titrate cautiously. For GFR <30 mL/min/1.73 m²: contraindicated (hydrochlorothiazide ineffective). Avoid if creatinine clearance <30 mL/min. |
| Liver impairment | Child-Pugh Class A or B: no specific dose adjustment recommended; use with caution. Child-Pugh Class C: contraindicated (hydrochlorothiazide may precipitate hepatic encephalopathy). No specific Child-Pugh based dosing guidelines established. |
| Pediatric use | Not recommended for pediatric patients under 18 years due to lack of safety and efficacy data. For hypertension in children, individual components may be used: lisinopril starting 0.07 mg/kg once daily (max 5 mg) titrated to 0.6 mg/kg/day (max 40 mg); hydrochlorothiazide 1-2 mg/kg/day in 1-2 divided doses (max 50 mg/day). |
| Geriatric use | Start with the lowest available strength (10 mg/12.5 mg) once daily; titrate slowly. Monitor renal function and electrolytes closely. Due to age-related decreased renal function, consider initial dose reduction and careful titration. |
| 1st trimester | Avoid in first trimester due to risk of fetotoxicity and teratogenicity (ACE inhibitors associated with oligohydramnios, renal dysplasia, and skull ossification defects). |
| 2nd trimester | Contraindicated in second trimester; risk of oligohydramnios, fetal renal impairment, and hypotension. |
| 3rd trimester | Contraindicated in third trimester; risk of neonatal renal failure, oligohydramnios, and hypotension. |
Clinical note
Comprehensive clinical and safety monograph for ZESTORETIC (ZESTORETIC).
| Placental transfer | Significant placental transfer; both lisinopril and hydrochlorothiazide cross the placenta and can cause fetal harm. |
| Breastfeeding | Excreted into breast milk in low amounts; however, due to potential for adverse effects in nursing infants (e.g., hypotension, renal impairment), use is generally not recommended. Monitor infant for hypotension and renal function if used. |
■ FDA Black Box Warning
Fetal toxicity: Drugs acting directly on the renin-angiotensin-aldosterone system can cause injury and death to the developing fetus. Discontinue as soon as possible when pregnancy is detected.
| Serious Effects |
Pregnancy (all trimesters)History of angioedema related to ACE inhibitor useAnuria (due to HCTZ component)Hypersensitivity to lisinopril, hydrochlorothiazide, or sulfonamide-derived drugsCo-administration with aliskiren in patients with diabetes or renal impairment (GFR <60 mL/min)
| Precautions | Anaphylactoid reactions (including angioedema) in patients with or without prior ACE inhibitor therapy, Hepatic failure, Neutropenia/agranulocytosis, Impaired renal function (especially in renal artery stenosis), Electrolyte disturbances (hypokalemia, hyperkalemia, hyponatremia), Hypotension (volume-depleted patients), Cough (ACE inhibitor-related), Sulfonamide sensitivity (hydrochlorothiazide), Acute angle-closure glaucoma (hydrochlorothiazide), Exacerbation or activation of systemic lupus erythematosus (thiazides) |
| Food/Dietary | Avoid high-potassium foods (e.g., bananas, oranges, spinach) in large amounts. Limit alcohol intake as it may potentiate hypotension. Avoid salt substitutes containing potassium chloride. Maintain adequate fluid intake to prevent dehydration. |
Loading safety data…
| Lactation Rating | L4 (Possibly Hazardous; similar to ACE inhibitors) |
| Teratogenic Risk | First trimester: Limited data suggest potential risk of congenital malformations (renal, cardiac) with ACE inhibitors, but absolute risk is low. Second and third trimesters: Known to cause fetal renal dysfunction, oligohydramnios, skull ossification deficits, hypotension, and anuria; risk of fetal/neonatal death. Contraindicated in second and third trimesters. |
| Fetal Monitoring | Monitor maternal blood pressure, renal function, serum electrolytes. Fetal ultrasound for amniotic fluid volume and renal function (especially in second/third trimester exposure). Neonatal monitoring for hypotension, hyperkalemia, and renal function if exposed in utero. |
| Fertility Effects | No known direct effects on fertility. ACE inhibitors may theoretically impact reproductive function via renin-angiotensin system modulation, but clinical data insufficient. |
| Clinical Pearls | Zestoretic is a fixed-dose combination of lisinopril (ACE inhibitor) and hydrochlorothiazide (thiazide diuretic). Monitor renal function and serum electrolytes (especially potassium and sodium) at baseline and periodically. Avoid use in pregnancy (category D). Adjust dose in renal impairment (CrCl <30 mL/min). Can cause angioedema; counsel patients to report swelling of face, lips, or throat. |
| Patient Advice | Take exactly as prescribed, usually once daily. Do not skip doses or double up. · Report any signs of swelling of the face, lips, tongue, or difficulty breathing immediately. · Avoid salt substitutes containing potassium without consulting your doctor. · May cause dizziness or lightheadedness; rise slowly from sitting or lying down. · Use effective contraception during treatment and notify your doctor if you become pregnant. · Stay hydrated unless otherwise instructed, especially in hot weather or exercise. |