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Initial evidence of the existence of renin (angiotensinogenase enzyme secreted by the kidney) was presented to the medical community more than 100 years ago. Nevertheless, the significance of renin in the regulation of arterial blood pressure and the role of renin–angiotensin system in cardiovascular diseases was not fully grasped until the 1970s.
Today we know that the renin-angiotensin system has a fundamental role in hypertension development, mediating its effects via the peptide hormone angiotensin II which increases arterial tone, activates sympathetic neurotransmission, stimulates aldosterone release, and promotes renal sodium reabsorption. Therefore over activation of this system contributes to hypertension and associated end-organ damage.
The inhibition of renin and renin-angiotensin system can be achieved at various points: angiotensin-converting enzyme (ACE) inhibitors reduce the conversion of angiotensin I to angiotensin II, angiotensin receptor blockers (ARBs) antagonize the interaction of angiotensin II with the type-1 angiotensin II receptor, whereas direct renin inhibitors block the proximal step in the conversion of angiotensinogen to angiotensin I by directly inhibiting the action of renin.
The development of the first class of ACE inhibitors stemmed from the observation that different polypeptides isolated from the venom of the Brazilian snake Bothrops jararacacould potentiate bradykinin (an endogenous vasodilator nonapeptide) and inhibit angiotensin-converting enzyme. The discovery of ARBs followed after researchers found that simple benzylimidazoles act as weak antagonists of angiotensin II receptors.
Within a few years after their introduction in the clinical practice, the ACE inhibitors became established as highly effective therapeutic agents for all grades of hypertension and congestive heart failure. The clinical uses for angiotensin receptor blockers include the aforementioned two indications, but they are also useful in the treatment of stroke and diabetic nephropathy.
Still, both ACE inhibitors and ARBs reduce the downstream effects of angiotensin II and do not have a direct influence on renin. The advent of computational molecular modeling made the effective renin inhibitors a reality and a valuable addition to the medical techniques available to medical practitioners, of antihypertensive drugs.
Aliskiren represents a first drug in the class of the orally active and direct renin inhibitors for the treatment of hypertension. This is a novel compound that was developed using both X-ray crystallography of the active site of renin and computational modelling. The non-peptide structure of the drug overcame certain difficulties of previous attempts to develop efficacious renin inhibitors.
The major characteristic of direct renin inhibitor is that it blocks the rate-limiting step in the renin-angiotensin system, which in turn decreases angiotensin I and II production, increases plasma renin concentration (akin to ACE inhibitors and ARBs), but unlike other drugs, plasma renin activity is decreased when this drug is used.
The systemic availability of aliskiren is limited, as less than 3% of the drug is being absorbed. Still, its half-life of approximately 40 hours allows effective once-daily dosing, with steady-state plasma concentrations achieved after 5-8 days. The main route of elimination is biliary excretion and subsequent fecal elimination.
The largest clinical studies to date with aliskiren have investigated the use of doses of up to 600 milligrams per day, and indicated effective blood pressure lowering in patients with hypertension. Long-term adverse effects have not been studied, as reported trials have been primarily short-term.
The favorable effect of aliskiren on plasma renin activity implies that if the drug is used in the combination with antihypertensive agents that otherwise increase renin activity, the end-effect should be more beneficial than if used as a monotherapy. Combinations with hydrocholorthiazide, ramipril and ibesartan were investigated in open studies with improved blood pressure control as a result.
Taking into account the public health importance and pervasive use of antihypertensive agents, it is important to understand their comparative effects on clinical outcomes. In 2012, a report from Healthcare Research and Quality (AHRQ) of the US Department of Health and Human Services identified the future research of comparative effectiveness between ACE inhibitors, ARBs and direct renin inhibitors as one of the priorities in the field.