The Haemodynamic and Neurohormonal Response to Initiation of Angiotensin Converting Enzyme Inhibitor Therapy in Heart Failure

The studies described in this thesis investigated the haemodynamic response to initiation of therapy with a number of angiotensin converting enzyme inhibitor agents in patients with heart failure. The studies were designed to: (i) define differences among agents in terms of the haemodynamic response to initiation of therapy (ii) investigate possible mechanisms for observed differences among agents in this regard (iii) investigate the relationship between plasma concentration of ACE inhibitor agent and the blood pressure response, and (iv) investigate the relationship between baseline clinical and physiological variables and the blood pressure response. Differences were observed among ACE inhibitor agents in terms of the blood pressure response to initiation of therapy. While similar blood pressure responses were observed to single oral doses of the ester prodrug ACE inhibitors enalapril and quinapril, the blood pressure response to oral perindopril did not differ from that seen with placebo. Two possible mechanisms, steric hindrance and "slow, tight binding", for the observed differences were explored using assay of both plasma ACE inhibition and relative concentrations of angiotensin I and angiotensin II. No evidence for either mechanism was gained from these studies. Using pharmacodynamic/pharmacokinetic modelling a direct linear relationship between the pharmacodynamic effect and plasma drug concentration was derived. Marked interindividual variability was apparent in the blood pressure response to oral initiation of ACE inhibitor therapy. The blood response was more consistent when interindividual pharmacokinetic differences were minimised by intravenous dosing. No consistent relationship could be identified between any single baseline physiological variable and the blood pressure response. The strongest relationship was with baseline mean arterial blood pressure. Forward stepwise regression analysis was used to identify the best combinations of predictive variables. The best of these, containing the variables, mean arterial pressure, plasma renin activity, 1/creatinine concentration, age and the ACE inhibitor agent, could explain approximately 25% of the variability in blood pressure response. In conclusion, differences in the individual blood pressure responses to initiation of ACE inhibitor therapy in CHF appear to be largely dependent upon interindividual pharmacokinetic differences. Accurate prediction of the blood pressure response to initiation of therapy is not possible using readily available laboratory and clinical criteria