Renin inhibitors - Australian Prescriber

Experimental and clinical pharmacologyRenin inhibitors – mechanisms of actionDuncan J Campbell, Senior Research Fellow, St Vincent's Institute of Medical Research andDepartment of Medicine, University of Melbourne, St Vincent's Hospital, MelbourneSummaryRenin inhibitors are antihypertensive drugs whichblock the first step in the renin-angiotensinsystem. Their mechanism of action differs fromthat of angiotensin converting enzyme inhibitorsand angiotensin receptor antagonists, but likethese drugs, renin inhibitors interrupt the negativefeedback effects of angiotensin II on reninsecretion. This increases renin concentrationswhich may attenuate the inhibition of the reninangiotensinsystem by these therapies. Renininhibitors may interfere with measurements ofrenin in plasma.Key words: aliskiren, antihypertensives, hypertension.(Aust Prescr 2009;32:132–5)IntroductionDrugs that inhibit the renin-angiotensin system, such asangiotensin converting enzyme (ACE) inhibitors and angiotensinreceptor antagonists, have proven value for the treatment ofhypertension, heart failure and renal disease. They reduce therates of death, myocardial infarction and stroke in a broad rangeof patients at high risk, but do not control the blood pressure inall cases. This led to research into inhibiting the renin-angiotensinsystem at its first step – the production of angiotensin I.PhysiologyRenin is an enzyme produced from the inactive protein,prorenin. The release of renin from the juxtaglomerular cells ofthe kidney is controlled by several mechanisms. These includethe sympathetic nervous system, salt and fluid balance, bloodpressure, and negative feedback by angiotensin II. Renin cleavescirculating angiotensinogen to form angiotensin I (Fig. 1).This inactive decapeptide is subsequently cleaved by ACE toproduce the octapeptide angiotensin II. Although other bioactiveangiotensin peptides are produced from angiotensin I and II,angiotensin II is the main bioactive angiotensin peptide.Two different receptors mediate the actions of angiotensin II.These are the type 1 (AT 1) and the type 2 (AT 2) receptors (Fig. 1).Stimulation of the AT 1receptor increases arterial tone andaldosterone secretion. Angiotensin II therefore plays an essentialrole in blood pressure, and fluid and electrolyte homeostasis.However, this role is much diminished in people consuming aWestern diet with an excessive salt content. In these people,even 'normal' concentrations of angiotensin II may play a role inhypertension and in cardiovascular and renal disease.Angiotensin-(1-7), a heptapeptide, is a metabolite ofangiotensins I and II. Both angiotensin-(1-7), acting through itsown receptor, and angiotensin II, acting on the AT 2receptor,may counterbalance some of the effects of angiotensin IIstimulating the AT 1receptor.The kidney is not the only organ which produces prorenin, anda receptor which binds renin and prorenin has been discovered.The physiological roles of the (pro)renin receptor are unknown,but high concentrations of prorenin predict microvascularcomplications of diabetes.Inhibitors of the renin-angiotensin systemThe therapeutic benefits of inhibiting the renin-angiotensinsystem are attributed primarily to reduced stimulation of the AT 1receptor. This can be achieved by either reducing angiotensin IIconcentrations or blocking the AT 1receptor, although othermechanisms may contribute (Table 1).Beta blockers inhibit renin release from the kidney and werethe original renin-angiotensin system inhibitors. Reduced reninrelease leads to reduced concentrations of angiotensin I and II,which may contribute to the benefits of beta blockade in heartfailure. 1In contrast to beta blockers, ACE inhibitors, angiotensin receptorantagonists and renin inhibitors cause an increase in reninrelease. This is because by reducing AT 1receptor stimulationthey interrupt the negative feedback-mediated regulation ofrenin release. The combination of an ACE inhibitor, angiotensinreceptor antagonist or renin inhibitor with another drug fromthese groups, or with a diuretic, markedly amplifies the increasein renin concentrations. The increase in renin concentrationsmay be as much as 100-fold, which then offsets the inhibition ofthe renin-angiotensin system by these antihypertensive drugs.This may attenuate any reduction in blood pressure.ACE inhibitors, angiotensin receptor antagonists and renininhibitors have different effects on the concentrations ofangiotensin peptides and bradykinin (a vasodilator) (Table 1).132 | Volume 32 | NUMBER 5 | OCTOBER 2009 www.australianprescriber.com

Fig. 1Mechanisms of action of renin inhibitorsRenin inhibitorBeta blockerAngiotensinogenReninKidneyKininogenKallikreinAngiotensin-(1-7)Angiotensin IBradykininACEACEinhibitorACEAngiotensin-(1-7) Angiotensin II MetabolitesARAAT 2receptorAT 1receptorVasodilationVasoconstrictionIncreased – aldosterone secretion– sodium and water retention– catecholamine release– stimulation of vascular and cardiac hypertrophy and fibrosisThe renin-angiotensin system can be inhibited by angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1receptor antagonists (ARA), renin inhibitors and beta blockers. Also shown is the role of ACE in bradykinin metabolism.ACE also metabolises angiotensin-(1-7).inhibitory actionTable 1Effects of renin-angiotensin system inhibitors on renin, angiotensin and bradykinin concentrations, and on AT 1and AT 2receptor stimulationBeta blocker ACE inhibitor ARA Renin inhibitorRenin concentrations ↓ ↑ ↑ ↑Renin activity ↓ ↑ ↑ ↓Angiotensin II concentrations ↓ ↓ ↑ ↓Angiotensin I concentrations ↓ ↑ ↑ ↓Angiotensin-(1-7) concentrations ↓ ↑ → ↓Bradykinin concentrations ? ↑ ↑ ?AT 1receptor stimulation ↓ ↓ ↓ ↓AT 2receptor stimulation ↓ ↓ ↑ ↓ACE angiotensin converting enzyme ↑ increase → no changeARA angiotensin II type 1 receptor antagonist ↓ decrease ? uncertainwww.australianprescriber.com| Volume 32 | NUMBER 5 | OCTOBER 2009 133

Renin inhibitors reduce the concentrations of all angiotensinpeptides, and their effect on bradykinin concentrations is underinvestigation.ACE inhibitors block the conversion of angiotensin I toangiotensin II and the metabolism of angiotensin-(1-7).They reduce angiotensin II concentrations and increase theconcentrations of angiotensin I and angiotensin-(1-7). Inaddition, because ACE contributes to bradykinin metabolism,ACE inhibitors increase bradykinin concentrations 2 , which maycontribute to the therapeutic benefits of ACE inhibition.Angiotensin receptor antagonist therapies block AT 1, butnot AT 2, receptors. This blockade leads to increased reninconcentrations and consequently increased angiotensin IIconcentrations. This causes increased stimulation of the AT 2receptor. Angiotensin receptor antagonists also increasebradykinin concentrations. 3 Stimulation of the AT 2receptorand increased bradykinin concentrations may contribute to theclinical effects of angiotensin receptor antagonist therapy.Renin inhibition differs from ACE inhibitor therapy because itreduces angiotensin I and angiotensin-(1-7) concentrations. Itdiffers from angiotensin receptor antagonist therapy becausethere is reduced stimulation of the AT 2receptor.Clinical pharmacology of renin inhibitorsSeveral renin inhibitors were abandoned because of problemsin development. Aliskiren is the first renin inhibitor for whichwe have extensive information about clinical pharmacology.Other renin inhibitors in clinical development are likely to havedifferent pharmacologies.Aliskiren is a competitive renin inhibitor which binds to theactive site of the enzyme. It is a rather hydrophilic moleculewith high aqueous solubility. 4 The distribution volume ofintravenously administered aliskiren is 135 L in normalvolunteers, indicating extensive tissue uptake of the drug. 5The absorbed fraction of orally administered aliskiren isapproximately 5%. This low oral bioavailability is compensatedfor by a long plasma half-life of 34–41 hours, and steady-stateplasma aliskiren concentrations are achieved after 5–8 daysof daily dosing. 6 Approximately 90% of the drug is excretedunchanged in the faeces. 7 The long plasma half-life and verylow urinary excretion (< 1%) 6,7 suggest extensive binding of thedrug to plasma proteins. 5Protein binding accounts for the discrepancy between theconcentration of aliskiren required for 50% inhibition ofpure renin and that for inhibition of renin in plasma. Theconcentration (IC 50) required was 0.6 nmol/L for pure reninversus 10–14 nmol/L for renin in human plasma. 5 This suggeststhat more than 90% of plasma aliskiren is bound to plasmaproteins. Extensive binding of aliskiren to plasma proteinsreduces the 'free' concentration of aliskiren available to inhibitrenin. This, together with the several-fold increase in reninconcentrations, accounts for the modest and transient reductionof plasma angiotensin concentrations during aliskiren therapy. 6Long-term therapy failed to significantly reduce plasmaaldosterone concentrations, although aliskiren did reduceurinary aldosterone excretion. 6Effect of renin inhibitors on renin measurementRenin is measured in the investigation of hypertension. Thereare two methods – activity assays and immunoassays. 5 Activityassays measure angiotensin I produced by renin cleavageof plasma angiotensinogen. Immunoassays measure reninconcentrations in plasma. Renin inhibitors have different effectson the two methods of renin measurement. Renin inhibitorsreduce plasma renin activity, although the reduction in plasmarenin activity is attenuated by the rise in renin concentrations.By contrast, renin immunoassay measures both active reninmolecules and renin molecules that are inhibited by the renininhibitor. Consequently, renin immunoassay shows increasedrenin concentrations because of the increased release of reninthat occurs during treatment with a renin inhibitor.Renin inhibitor therapy can interfere with renin activity assaysand immunoassays in other ways. The renin activity assaymay overestimate renin inhibition because displacement ofthe inhibitor from plasma proteins during the assay causesgreater inhibition of renin activity in vitro than was presentin vivo. During immunoassay, renin inhibitors may cause anartefactual increase in the amount of renin molecules measuredas the drug binds to, and causes unfolding of, the prosegmentof plasma prorenin. This unfolding causes prorenin to berecognised by the renin immunoassay.The clinician who wishes to screen for primary aldosteronismor who wishes to investigate hypertensive conditions with highrenin concentrations such as renal artery stenosis, in a patientreceiving renin inhibitor therapy, needs to cease this therapyfor at least two weeks. This allows for clearance of the renininhibitor before samples are taken for measurement by eitheractivity assay or immunoassay.ConclusionRenin inhibitors represent an alternative strategy for inhibitingthe renin-angiotensin system. They have a mechanism of actiondifferent from that of ACE inhibitors and angiotensin receptorantagonists. Whether renin inhibitors offer therapeutic benefitsbeyond those provided by ACE inhibitor and angiotensinreceptor antagonist therapies will require their directcomparison in clinical outcome studies.References1. Campbell DJ, Aggarwal A, Esler M, Kaye D. Beta-blockers,angiotensin II, and ACE inhibitors in patients with heartfailure. Lancet 2001;358:1609-10.134 | Volume 32 | NUMBER 5 | OCTOBER 2009 www.australianprescriber.com

2. Zeitz CJ, Campbell DJ, Horowitz JD. Myocardial uptake andbiochemical and hemodynamic effects of ACE inhibitors inhumans. Hypertension 2003;41:482-7.3. Campbell DJ, Krum H, Esler MD. Losartan increasesbradykinin levels in hypertensive humans. Circulation2005;111:315-20.4. Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC,Rasetti V, et al. Structure-based design of aliskiren, a novelorally effective renin inhibitor. Biochem Biophys ResCommun 2003;308:698-705.5. Campbell DJ. Interpretation of plasma renin concentrationin patients receiving aliskiren therapy. Hypertension2008;51:15-8.6. Nussberger J, Wuerzner G, Jensen C, Brunner HR.Angiotensin II suppression in humans by the orally activerenin inhibitor aliskiren (SPP100): comparison with enalapril.Hypertension 2002;39:E1-8.7. Waldmeier F, Glaenzel U, Wirz B, Oberer L, Schmid D,Seiberling M, et al. Absorption, distribution, metabolism,and elimination of the direct renin inhibitor aliskiren inhealthy volunteers. Drug Metab Dispos 2007;35:1418-28.Dr Campbell holds a Senior Research Fellowship from theNational Health and Medical Research Council (NHMRC), andhas received research grants from the NHMRC and the NationalHeart Foundation. He has had research contracts with Solvay andNovartis and has been on an advisory board for Novartis.Self-test questionsThe following statements are either true or false(answers on page 143)5. Renin inhibitors act at angiotensin II receptors.6. Renin inhibitors increase the plasma concentrationof renin.Experimental and clinical pharmacologyClinical implications of renin inhibitorsKaren Duggan, Chair, National Blood Pressure and Vascular Disease Advisory Committee, andformerly Director, Hypertension Service, Sydney South West Area Health ServiceSummaryDirect renin inhibition lowers blood pressure byan effective blockade of the renin-angiotensinsystem. Aliskiren is the first renin inhibitor to bemarketed for the treatment of hypertension. Atcurrently available doses it lowers blood pressureto a similar degree as other antihypertensive drugs.Used in combination with thiazides, angiotensinconverting enzyme inhibitors, angiotensin receptorantagonists or calcium channel blockers, aliskirenhas improved blood pressure control with noappreciable increase in adverse events. Aliskirenhas an adverse effect profile comparable toplacebo, but its long-term effects are unknown.Key words: aliskiren, antihypertensives, hypertension.(Aust Prescr 2009;32:135–8)IntroductionHypertension is one of the commonest reasons for generalpractitioner attendances. Less than 25% of those who arediagnosed attain their recommended blood pressure targets,while some studies place this figure as low as 7%. Althoughmuch of this failure to control blood pressure can be attributedto therapeutic inertia, the adverse effects of antihypertensivedrugs also contribute. These adverse effects often limit the dosesat which antihypertensive drugs can be used. This problem hasprompted the ongoing search for more efficacious drugs withfewer adverse effects. One such group of drugs is the directrenin inhibitors which are currently undergoing clinical trials.The first of the drugs to be marketed is aliskiren.Prorenin and the renin receptorThe discovery of the renin receptor provided a new rolefor renin, that of a profibrotic agent in its own right. It wassubsequently found that the renin receptor also bindswww.australianprescriber.com| Volume 32 | NUMBER 5 | OCTOBER 2009 135