Source: Health Products Regulatory Authority (ZA) Publisher: Ranbaxy Pharmaceuticals (Pty) Ltd, 14 Lautre Road, Stormill Ext. 1, Roodepoort, 1724, South Africa
A7.1.3 Other hypotensives
Pharmacotherapeutic group: Angiotensin-converting enzyme inhibitors
ATC code: C09AA03
Lisinopril 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 also antihypertensive 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.
In patients with diabetes mellitus who have microalbuminuria,, lisinopril reduces the urinary albumin excretion.
Following oral administration, peak serum concentrations occur within 6 to 8 hours, although there is a trend to a small delay in time taken to reach peak plasma concentrations in acute myocardial infarction patients. The extent of absorption of lisinopril is approximately 25%, with interpatient variability (6-60%) at all doses tested (5-80 mg).
The absolute bioavailability is reduced 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).
Lisinopril is excreted unchanged in the urine. The clearance of lisinopril In healthy subjects is approximately 50 ml/min. Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12,6 hours.
Declining serum concentrations exhibits 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.
Pharmacokinetic parameters of Lisinopril to different groups of renal patients after administration of a multiple 5 mg dose:
| Renal function measured by creatinine clearance | n | Cmax (ng/ml) | Tmax (hr) | AUC~(0-24 hrs)~ (ng/hr/ml) | T½ (hr) |
|---|---|---|---|---|---|
| >80 ml/min | 6 | 40,3 | 6 | 492 ± 172 | 6,0± 1,1 |
| 30-80 ml/min | 6 | 36,6 | 8 | 555 ± 364 | 11,8 ± 1,9 |
| 5-30 ml/min | 6 | 106,7 | 8 | 2228 ± 938 | 19,5 ± 5,2 |
Lisinopril can be removed by dialysis.
During 4 hours of haemodialysis, 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 %) than younger patients.
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