Angiotensin converting enzyme inhibitors. ATC code:
Lisinopril (ZESTRIL) is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion. The latter decrease may result in an increase in serum potassium concentration.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodilatory peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated.
The effect of Lisinopril (ZESTRIL) on mortality and morbidity in congestive heart failure has been studied by comparing a high dose (32.5 mg or 35 mg once daily) with a low dose (2.5 mg or 5 mg once daily). In a study of 3164 patients, with a median follow up period of 46 months for surviving patients, high dose Lisinopril (ZESTRIL) produced a 12% risk reduction in the combined endpoint of all-cause mortality and all-cause hospitalization (p = 0.002) and an 8% risk reduction in all-cause mortality and cardiovascular hospitalization (p = 0.036) compared with low dose. Risk reductions for all-cause mortality (8%; p = 0.128) and cardiovascular mortality (10%; p = 0.073) were observed. In a post-hoc analysis, the number of hospitalizations for heart failure was reduced by 24% (p = 0.002) in patients treated with high-dose Lisinopril (ZESTRIL) compared with low dose. Symptomatic benefits were similar in patients treated with high and low doses of Lisinopril (ZESTRIL).
The results of the study showed that the overall adverse event profiles for patients treated with high or low dose Lisinopril (ZESTRIL) were similar in both nature and number. Predictable events resulting from ACE inhibition, such as hypotension or altered renal function, were manageable and rarely led to treatment withdrawal. Cough was less frequent in patients treated with high dose Lisinopril (ZESTRIL) compared with low dose.
In the GISSI-3 trial, which used a 2 x 2 factorial design to compare the effects of Lisinopril (ZESTRIL) and glyceryl trinitrate given alone or in combination for 6 weeks versus control in 19,394, patients who were administered the treatment within 24 hours of an acute myocardial infarction, Lisinopril (ZESTRIL) produced a statistically significant risk reduction in mortality of 11% versus control (2p = 0.03). The risk reduction with glyceryl trinitrate was not significant but the combination of Lisinopril (ZESTRIL) and glyceryl trinitrate produced a significant risk reduction in mortality of 17% versus control (2p = 0.02). In the sub-groups of elderly (age > 70 years) and females, pre-defined as patients at high risk of mortality, significant benefit was observed for a combined endpoint of mortality and cardiac function. The combined endpoint for all patients, as well as the high-risk sub-groups, at 6 months also showed significant benefit for those treated with Lisinopril (ZESTRIL) or Lisinopril (ZESTRIL) plus glyceryl trinitrate for 6 weeks, indicating a prevention effect for Lisinopril (ZESTRIL). As would be expected from any vasodilator treatment, increased incidences of hypotension and renal dysfunction were associated with Lisinopril (ZESTRIL) treatment but these were not associated with a proportional increase in mortality.
In a double-blind, randomized, multicentre trial which compared Lisinopril (ZESTRIL) with a calcium channel blocker in 335 hypertensive Type 2 diabetes mellitus subjects with incipient nephropathy characterized by microalbuminuria, Lisinopril (ZESTRIL) 10 mg to 20 mg administered once daily for 12 months, reduced systolic/diastolic blood pressure by 13/10 mmHg and urinary albumin excretion rate by 40%. When compared with the calcium channel blocker, which produced a similar reduction in blood pressure, those treated with Lisinopril (ZESTRIL) showed a significantly greater reduction in urinary albumin excretion rate, providing evidence that the ACE inhibitory action of Lisinopril (ZESTRIL) reduced microalbuminuria by a direct mechanism on renal tissues in addition to its blood pressure lowering effect.
ACE is known to be present in the endothelium and increased ACE activity in diabetic patients which results in the formation of angiotensin II and destruction of bradykinin, potentiates the damage to the endothelium caused by hyperglycemia. ACE inhibitors, including lisinopril, inhibit the formation of angiotensin II and breakdown of bradykinin and hence ameliorate endothelial dysfunction.
The effects of Lisinopril on urinary albumin excretion rate in diabetic patients is mediated by a reduction in blood pressure as well as a direct mechanism on the renal and retinal tissues.
In a clinical study involving 115 hypertensive pediatric patients aged 6 to 16 years, patients who weighed less than 50 kg received either 0.625 mg, 2.5 mg or 20 mg of Lisinopril (ZESTRIL) once a day, and patients who weighed 50 kg or more received either 1.25 mg, 5 mg or 40 mg of Lisinopril (ZESTRIL) once a day. At the end of 2 weeks, Lisinopril (ZESTRIL) administered once daily lowered trough blood pressure in a dose-dependent manner with a consistent antihypertensive efficacy demonstrated at doses greater than 1.25 mg.
This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mm Hg more in patients randomized to placebo that it did in patients who were randomized to remain on the middle and high doses of Lisinopril. The dose-dependent antihypertensive effect of Lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, and race.
Lisinopril is an orally active non-sulphydryl-containing ACE inhibitor.
Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with inter-patient variability 6-60% over the dose range studied (5-80 mg). The absolute bioavailability is reduced to approximately 16% in patients with heart failure. Lisinopril absorption is not affected by the presence of food.
Lisinopril does not appear to be bound to serum proteins other than to circulating angiotensin converting enzyme (ACE). Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.
Lisinopril does not undergo metabolism and is excreted entirely unchanged into the urine. On multiple dosing lisinopril has an effective half-life of accumulation of 12.6 hours. The clearance of lisinopril in healthy subjects is approximately 50 mL/min. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose.
Impairment of hepatic function in cirrhotic patients resulted in a decrease in lisinopril absorption (about 30% as determined by urinary recovery) but an increase in exposure (approximately 50%) compared to healthy subjects due to decreased clearance.
Impaired renal function decreases elimination of lisinopril, which is excreted via the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. (See Table 1.)
Click on icon to see table/diagram/image
With a creatinine clearance of 30-80 mL/min, mean AUC was increased by 13% only, while a 4-5 fold increase in mean AUC was observed with a creatinine clearance of 5-30 mL/min.
Lisinopril can be removed by dialysis. During 4 hours of hemodialysis, plasma lisinopril concentrations decreased on average by 60%, with a dialysis clearance between 40 and 55 mL/min.
Patients with heart failure have a greater exposure of lisinopril when compared to healthy subjects (an increase in AUC on average of 125%), but based on the urinary recovery of lisinopril, there is reduced absorption of approximately 16% compared to healthy subjects.
Older patients have higher blood levels and higher values for the area under the plasma concentration time curve (increased approximately 60%) compared with younger subjects.
The pharmacokinetic profile of Lisinopril was studied in 29 pediatric hypertensive patients, aged between 6 and 16 years, with a GFR above 30 mL/min/1.73m2
. 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 101/h, which increases in proportion to renal function.
AUC and Cmax
values in children in this study were consistent with those observed in adults.
Toxicology: Preclinical safety data:
Lisinopril is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Prescribing Information.