Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure

Abstract

To prevent drug accumulation and adverse effects the dose of hydrophilic angiotensin-converting enzyme (ACE) inhibitors, e.g. lisinopril, must be reduced in patients with renal failure. To obtain a rational basis for dose recommendations, we undertook a prospective clinical trial. After 15 days of lisinopril treatment pharmacokinetic and pharmacodynamic parameters were determined in patients with advanced renal failure (n = 8; endogenous creatinine clearance [CLCR]: 18 ml.min-1.1.73 m-2) and in healthy subjects with normal renal function (n = 16; CLCR: 107 ml.min-1.1.73 m-2). The volunteers received 10 mg lisinopril once daily, the daily dose in patients (1.1-2.2 mg) was adjusted to the individual CLCR according to the method of Dettli [13]. After 15 days of lisinopril treatment the mean maximal serum concentration (Cmax) in patients was lower than in volunteers (30.7 vs 40.7 ng.ml-1, while the mean area under the concentration-time curve (AUC0-24 h) was higher (525 vs 473 ng.h-1.ml-1). ACE activity on day 15 was almost completely inhibited in both groups. Plasma renin activity, angiotensin I and angiotensin II levels documented marked inhibition of converting enzyme in volunteers and patients. Furthermore, average mean arterial blood pressure in patients decreased by 5 mmHg and proteinuria from 3.9-2.7 g per 24 h after 15 days of treatment with the reduced dose of lisinopril. Adjustment of the dose of lisinopril prevents significant accumulation of the drug in patients with advanced renal failure during chronic therapy. Mean serum levels did not exceed this in subjects with normal renal function receiving a standard dose.(ABSTRACT TRUNCATED AT 250 WORDS)

How to improve drug dosing for patients with renal impairment in primary care - a cluster-randomized controlled trial

“…Benazepril was associated with a 52% reduction in the level of proteinuria and a 23% reduction in the rate of decline in renal function [31]. While lower doses may be sufficient to treat hypertension [32,33], dose escalation particularly in CKD may be beneficial due to a nephroprotective effect [31,34]. Although ACEI and ARB have a wide therapeutic margin, high doses bear a risk of hyperkalemia, hypotension, and acute deterioration of renal function [35].…”

Long-term changes of renal function in relation to ace inhibitor/angiotensin receptor blocker dosing in patients with heart failure and chronic kidney disease

“…As impaired renal function may adversely affect metabolism and elimination of ACEIs/ARBs (8)(9)(10)(11), trials of CHF generally excluded patients with severe CKD. Thus, surprisingly little is known about how to manage patients suffering from both CHF and CKD (12).…”

“…In contrast, guidelines for renal disease do not specify target doses of ACEIs/ARBs (16). Then again, there is a general recommendation that lower doses should be used in patients with CKD to prevent hyperkalemia and acute renal failure (8)(9)(10)(11).…”

“…Here, CKD is caused by sclerosis of the glomeruli, and ACEIs/ARBs improve renal function by lowering glomerular pressure (9)(10)(11). In CHF patients in contrast, renal venous congestion and a fall in the trans-renal pressure gradient mainly contribute to the development and progression of CKD (1).…”

Pro-active provision of drug information as a technique to address overdosing in intensive-care patients with renal insufficiency

“…In these cases, physicians justified dose selection by excellent tolerance of the drug, disregarding costs of potentially unnecessary doses. In the present study, only one intended overdose of an ACE inhibitor was detected; it was made in order to exploit the potential nephroprotective effects of doses exceeding those on the drug label [15][16][17].…”