Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of ¹⁴C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.

Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive patients between 6 years and 16 years with glomerular filtration rate >30 mL/min/1.73 m². After doses of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours and the extent of absorption based on urinary recovery was about 28%. These values are similar to those obtained previously in adults. The typical value of lisinopril oral clearance (systemic clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to renal function.

Pharmacodynamics and Clinical Effects

Hypertension

Adult Patients: Administration of PRINIVIL to patients with hypertension results in a reduction of supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients. (See WARNINGS.) When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive.

In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of PRINIVIL, with peak reduction of blood pressure achieved by six hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was six hours after dosing.

In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy.

The antihypertensive effects of PRINIVIL are maintained during long-term therapy. Abrupt withdrawal of PRINIVIL has not been associated with a rapid increase in blood pressure or a significant increase in blood pressure compared to pretreatment levels.

Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20, or 80 mg of PRINIVIL. In controlled clinical studies, PRINIVIL 20-80 mg has been compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-500 mg; and in patients with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic blood pressure in a population that was ¾Caucasian. PRINIVIL was approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure and had somewhat greater effects on systolic blood pressure.

PRINIVIL had similar effectiveness and adverse effects in younger and older (>65 years) patients. It was less effective in Blacks than in Caucasians.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of PRINIVIL, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of PRINIVIL on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and effective in controlling blood pressure (see PRECAUTIONS).

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