Angiotensin-converting enzyme inhibitors. Relationship between pharmacodynamics and pharmacokinetics.

The inter-relationship between the pharmacokinetic and pharmacodynamic behaviour of ACE inhibitors is reviewed. First, some of the methods which have been used to assess the pharmacodynamics of ACE inhibitors in humans are presented. They include humoral assays (e.g. ACE activity in plasma, renin activity, etc.), haemodynamic changes (blood pressure, total peripheral resistance, etc.) and agonist challenges (angiotensin I infusions). Subsequently a pharmacokinetic-dynamic model is described, based on biochemical processes obtained after ACE inhibition, which seems to be useful for the interpretation of the complex processes. The various correlations between plasma drug concentration on the one hand and plasma ACE activity, angiotensin II concentration in plasma or blood pressure on the other, are discussed on the basis of this model. From the model obtained it becomes obvious that under many circumstances the release of the inhibitor from ACE binding is the step which in fact determines the pharmacodynamically relevant elimination rate of the drug at low concentrations, whereas at high concentrations the elimination of the drug is mainly dependent on kidney (and/or liver) elimination rate. The dynamic-kinetic correlations are then presented for some ACE inhibitors in various disease states: arterial hypertension, heart failure, old age, renal failure, liver disease. In a final section the kinetic and dynamic relevance of interactions of ACE inhibitors with food and other drugs is described (e.g. prostaglandin inhibitors, diuretics, digoxin and cimetidine). Despite the great body of literature which deals with the kinetic and/or dynamic properties of ACE inhibitors, precise knowledge of the relationship between their kinetic and dynamic behaviour is rather limited and there is a clear need for further studies to elucidate this complex topic, thereby improving therapeutic possibilities with these useful new compounds.