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Redalyc.Renin Inhibitors As Antihypertensive Agents Revista Latinoamericana de Hipertensión ISSN: 1856-4550 [email protected] Sociedad Latinoamericana de Hipertensión Organismo Internacional Israili, Zafar H. Renin inhibitors as antihypertensive agents Revista Latinoamericana de Hipertensión, vol. 3, núm. 4, mayo-junio, 2008, pp. 98-112 Sociedad Latinoamericana de Hipertensión Caracas, Organismo Internacional Available in: http://www.redalyc.org/articulo.oa?id=170217040002 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative Revista Latinoamericana de Hipertensión. Vol. 3 N° 4,2008 enin inhibitors as antihypertensive agents Zafar H. Israili, Department ofMedicine, Emory University School ofMedicine, Atlanta, Georgia USA [email protected] Recibido: 15/06/2008 Aceptado: 07/07/2008 espite numerous advances in the phar­ Food reduces peak levels by 81 % and area under the macologic treatment of high blood curve by 62%, but inhibition of plasma renin activ­ pressure (BP) and the availability of ity is not affected; absorption is further reduced by seven c1asses of antihypertensive drugs, a significant high-fat mea!. The protein binding is about 50% and proportion of treated hypertensive patients still have the apparent volume of distribution is 135 L. The ter­ uncontrolled high Bp, and thus, face serious morbidity minal T'12 is about 24 hr (range 16-40 hr), suggest­ and mortality. Therefore, new therapeutic modalities ing 2- to 3-fold accumulation after multiple dosing; have to be developed to achieve optimum BP control steady-state is reached in 7 days of repeated dosing. as well as treat all the cardiovascular (CV) risk factors, Aliskiren does not have pharmacokinetic interactions, prevent end-organ damage and other hypertension when co-administered with allopurinol, celecoxib, ci­ (HTN) related pathologies. The renin-angiotensin-al­ metidine, lovastatin, atenolol, or warfarin. dosterone system (RAAS) is a major physiological reg­ ulator of body fluid volume, electrolyte balance, arte­ In patients with HTN, aliskiren produces dose-de­ rial Bp, and adrenal functions. Dysregulation of RAAS pendent BP reduction and 24-hr BP control up to a has been shown to be a major underlying cause of maximum dose of 300 mg given once daily; at this HTN, heart failure, renal disease, and related CV dis­ dose, aliskiren shows placebo-Iike tolerability. Its orders. Increasing evidence indicates that inhibition of antihypertensive potency is approximately equiva­ the RAAS is an effective way to control high BP and lent to that of ACE inhibitors, ARBs, calcium chan­ intervene in the pathogenesis of CV disorders, dia­ nel blockers, or diuretics. No dosage adjustment is betic kidney disease and atherogenesis. Blockade of necessary in the elderly or in patients with hepatic the RAAS with angiotensin converting enzyme (ACE) dysfunction or with mild-to-moderate renal impair­ inhibitors, angiotensin 11 AT, receptor blockers (ARBs) ment. However, the dose in patients with severe re­ does not result in complete suppression of RAAS. nal impairment has not been established. Aliskiren Blockade of renin at the initial, rate-limiting step in has favorable effect on left ventricular hypertrophy the renin cascade would favor more complete block­ and proteinuria. No ethnic difference was observed ade of the system, and may be more effective in af­ in the efficacy and tolerability of aliskiren. The drug fording greater protection from complications of high can be safely administered to obese, diabetic and/ BP. In that respect, orally active direct renin inhibitors, or elderly patients. In combination therapy, aliskiren such as aliskiren, ciprokiren, enalkiren, remikiren, ter­ further decreases BP when combined with either hy­ lakiren, zernikiren, etc., have been developed. Only drochlorothiazide, amlodipine, irbesartan or ramipril, Aliskiren has been approved for the treatment of possibly by a synergistic action both in terms of ef­ HTN. The renin inhibitors bind to the active site of re­ ficacy and tolerability. nin resulting in the inhibition of conversion of angio­ The major adverse effects (in 1% to 10% of patients), tensinogen to angiotensin I (Ang which results in 1), include malaise, palpitation, dizziness, rash, hyperkale­ the suppression of plasma renin activity (PRA), levels mia, diarrhea, nocturia, and increase in creatinine. Hy­ of Ang 1. Ang 11, and aldosterone. potension may also occur in patients with an activat­ ed RAAS, such as in volume or salt depleted patients, The renin inhibitors have low oral bioavailabilty, and such as in patients on diuretics. It is contraindicated most have short half life (T'I2)' Aliskiren has a bio­ in patients with a history of idiopathic or hereditary availability of 2.6%; peak levels are achieved in 1­ angioedema, or ACE inhibitor- related angioedema, 4 hr following oral administration. Single oral doses bilateral renal artery stenosis, and pregnancy. of aliskiren (160 mg) produce plasma concentrations (24 ± 7 ng/mL) greater than 50 times the reported Renin inhibition has potential therapeutic benefit in 50% inhibitory concentration value for human renin. the treatment of renovascular HTN and congestive heart failure. These drugs may prevent end organ Renin-angiotensin-aldosterone system damage, especially the kidney and the heart, or at The renin-angiotensin-aldosterone system (RAAS) least slow the progression of damage. These drugs (Figure 1) is a major physiological regulator of body may also be useful in conditions such as stroke, myo­ fluid volume, electrolyte balance, arterial blood pres­ cardial infarction, scleroderma, renal trauma, and sure, tissue perfusion, and adrenal functions. How­ acute c10sure of renal artery grafts, which are associ­ ever, dysregulation of RAAS, such as by chronic RAAS ated with high plasma renin levels. activation, has been shown to be a major underly­ ing cause of hypertension, heart failure, renal dis­ Potential limitations of renin inhibitors include mod­ ease, and related CV disorders. Increasing evidence est levels of BP reduction that are equivalent to but indicates that inhibition of the RAAS is an effective not greater than produced by ARBs or ACE inhibi­ way to control high BP and intervene in the patho­ tors, flat-dose-response curve, reduced gastrointes­ genesis of CV disorders, diabetic kidney disease and tinal absorption with a high-fat meal, considerable atherogenesis (Dzau, 2005; Sepehrdad et aL, 2007). first-pass effect limiting oral bioavailability, short Although, blockade of the RAAS with angiotensin plasma T'12 and duration of action for most renin in­ converting enzyme (ACE) inhibitors, angiotensin 11 hibitors, and the large reactive increases in renin se­ AT1 receptor blockers (ARBs) or a combination of cretion. Furthermore, development of tolerance, due these drugs has become one of the most success­ to renin hypersecretion, may result in the reduction fui therapeutic approaches in medicine (Wuerzner in the antihypertensive effect of some renin inhibi­ and Azizi, 2008), the ACE inhibitors and ARBs do tors, especially in salt-replete hypertensive patients. not completely suppress the RAAS, beca use of the In addition, combination therapy (renin inhibitors compensatory rise in plasma renin activity (Li et aL, with ARBs or ACE inhibitors) is expected to increase 2007). Based on studies using very high-dose ARB the incidence of si de effects, such as hyperkalemia or combination therapy with ACE inhibitor and ARB, and acute renal insufficiency. it has been suggested that more complete blockade In conclusion, despite some reservations, renin inhib­ would lead to improved c1inical outcomes (Hollen­ itors may be a useful addition to the armamentarium berg, 2008). Blockade of renin, the most upstream of antihypertensive agents, especially when used in point of RAAS, that is, at the initial, rate-limiting step combination with other antihypertensive agents, in the renin cascade would also favor more complete such as diuretics, ACE inhibitors, ARBs or calcium blockade of the system than with the existing agents, channel, blockers. and therefore, may be more effective in affording Key words: Antihypertensive agents; Renin inhibi­ greater protection from hypertensive complications (Hollenberg, 2007; Shafiq et aL, 2008). tors; Renin-Angiotensin-Aldosterone System; Aliski­ ren; Pharmacokinetics; Pharmacodynamics Figure 1. Renin-angiotensin-aldosterone system _______~idnev Angiotensinogen l¡l- 1 I I 1 Adrenergic 1 ..................... 1 blockers 1 1 Reninq~~~ Cathepsin o, Tonins ~ .. ~~~.~~~~~.¡.~...J r---- I Renin L_Inhibltors I ypertension, a serious disease affect­ ing almost a billion people (25% of adults) worldwide, is a major modi­ fiable risk factor for cardiovascular (CV) and renal disease (Kearney et aL, 2005). Despite numerous advances in the pharmacologic treatment of high blood pressure (BP) and availability of seven c1asses of antihypertensive drugs to treat hypertension, a significant proportion of treated hypertensive pa­ tients still have uncontrolled high Bp, and thus, face serious morbidity and mortality. Furthermore, it is • Smoot1l mu,c;." ¡;ontn~n c.asoeon&triction) ·Atter-.d"I\II~mb 'Mocl"lItlonof not sufficient to aim for optimum BP control, but to IdecrNMCI blOGd fIow. iIIR,t1'.IIC4IlIul ... inc,..Md ,(MI um uptllka' m¡¡tTb: treat all CV risk factors,
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