Development Process of ACE Inhibitors in Hypertension

Because of the heterogeneity of hypertension, the blood pressure response to blockade of the RAS is quite variable from one patient to another, which complicates the search for the optimal daily dose of ACE inhibitors and the optimal dosage interval. Many factors influence the magnitude and the duration of the blood pressure response to ACE inhibition (230)  

The multiple difficulties encountered in the quantification of ACE inhibitor blood pressure effects have importantly contributed to a general improvement in the antihypertensive drug development process leading up to registration by health authorities (234, 235). Definition of the dose-range that is effective in blood pressure lowering has become more and more precise with time (236). It became obvious that a placebo-controlled investigation of the effect of ACE inhibitors on 

As to the use of crossover designs, with all their weaknesses they can be suitable for testing different doses in the same individual. They require an extremely precise methodology and placebo periods and treatment periods of sufficient duration (246-248). They also need to be used with a constant sodium diet (249). 

Finally, the use of factorial designs, concluded by a response-surface analysis, is the latest approach used to select the most appropriate combination doses of two classes of drugs that allows complete pharmacological manipulation of the RAS, namely diuretics and ACE inhibitors (250, 251). 

It is important to realize how difficult it is to define the in vivo inhibition of ACE. The enzyme may be explored for its N-terminal active sites by measurement of a constant and maximally increased level of N-acetyl SDKP in plasma and urine (211), but the residual activity of the C-ter-minal sites is probably not being measured. The methods for in vitro measurement of plasma ACE, except perhaps that described by Nuss-berger et al. (256), do not appropriately quantify global ACE inhibition. Moreover, the consequences of enzyme blockade are modified by secondary activation of the RAS (233). Residual amounts of angiotensin II secondary to a reactive rise in renin and angiotensin I may explain why the administration of an angiotensin II antagonist still has an additive effect on blood pressure and possibly on the heart, the vessels, and the kidney when added to certain doses of ACE inhibitors (228, 229, 257). 

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