Therapeutic inhibition of the renin angiotensin aldosterone system

Background: Inhibitors of the renin angiotensin aldosterone system (RAAS) represent some of the most widely prescribed, successful and well-tolerated therapeutics of recent times and are of proven worth in the management/prevention of cardiovascular disease and diabetic nephropathy. However, as knowledge has grown about the RAAS and its manifold alternate pathways, loci of action and dynamic response to inhibition, so has the clinical debate as how to best use existing therapeutics as well as how best to conceptualise and design RAAS inhibitors of the future. Objective: To provide an overview of the several points of therapeutic anti-RAAS intervention, many of which have already been exploited from 'upstream' renin inhibition to 'midstream' ACE inhibition to 'downstream' angiotensin AT1 receptor blockade. Methods: A search of patents for RAAS inhibitors recorded in 2008 was conducted along with a relevant literature search. Results/conclusion: Each intervention has merits and demerits with implications for RAAS 'escape' phenomena, 'dual inhibition' therapy, long-term clinical efficacy and adverse drug reactions. Renin inhibitors offer the most complete RAAS inhibition, but more downstream interventions are likely to recruit supplementary anti-RAAS mediators and receptor signalling pathways. Furthermore, managing hyperkalaemia-stimulated aldosterone escape during combined ACE inhibitor and angiotensin receptor blocker treatment may realise the full clinical potential of dual inhibition therapy.