Update on the role of candesartan in the optimal management of hypertension and cardiovascular risk reduction

Integrated Blood Pressure Control Dovepress open access to scientific and medical research Review Integrated Blood Pressure Control downloaded from https://www.dovepress.com/ by 5.135.254.153 on 12-Jul-2018 For personal use only. Open Access Full Text Article Update on the role of candesartan in the optimal management of hypertension and cardiovascular risk reduction This article was published in the following Dove Press journal: Integrated Blood Pressure Control 26 May 2010 Number of times this article has been viewed Ikechi G Okpechi Brian L Rayner Department of Medicine, Division of Nephrology and Hypertension, Groote Schuur Hospital and University of Cape Town, Observatory, Cape Town 7925, South Africa Introduction to hypertension management and CV risk reduction Correspondence: Ikechi G Okpechi Department of Medicine, Division of Nephrology and Hypertension, Groote Schuur Hospital and University of Cape Town, Observatory, Cape Town 7925, South Africa Tel +27214042292 Fax +27215312855 Email submit your manuscript | www.dovepress.com Dovepress 9963 Powered by TCPDF (www.tcpdf.org) Abstract: Hypertension is the most prevalent cardiovascular disease of adults and is a major risk factor for cardiovascular (CV) and cerebrovascular morbidity and mortality worldwide. Treatment of hypertension leads to reduction of CV morbidity and mortality through blood pressure reduction. The role of renin–angiotensin–aldosterone system (RAAS) in the pathophysiology of hypertension is mainly through generation of potent vasoconstrictor angiotensin II, stimulation of aldosterone secretion, and increase in sympathetic activation. Angiotensin II receptor blockers such as candesartan, a long-acting agent, alter this system by blocking the activation of angiotensin I receptors. Several important clinical trials have tested the efficacy of candesartan with placebo, antihypertensive agents, or other agents that block the RAAS for the control of hypertension and reduction of key CV risk factors such as microalbuminuria, heart failure, retinopathy, and carotid intima medial thickness. Candesartan has been shown to be a welltolerated and effective antihypertensive agent with positive metabolic characteristics and additional benefits on CV and cerebrovascular outcomes. The aim of this review is to discuss the pharmacology, efficacy, and safety of candesartan, with an overview of key hypertension and CV studies involving candesartan. Keywords: ACE inhibitor, ARB, blood pressure, treatment, heart Hypertension is the most prevalent cardiovascular disease (CVD) of adults and is a major risk factor for both cardiovascular (CV) and cerebrovascular morbidity and mortality worldwide.1 Although the results of several cross-sectional or cohort epidemiological studies have shown that the prevalence of hypertension varies significantly,2–7 essential hypertension is estimated to affect 30% of adults8,9 and to account for up to 30% of all deaths.1 The relationship between blood pressure (BP) and CV risk is continuous such that every 20 mmHg increase in systolic BP (SBP) or 10 mmHg increase in diastolic BP (DBP) doubles the risk of CVD.10 The main objective of hypertension treatment is to reduce CV morbidity and mortality by reducing BP.11 Inameta-analysis of placebo-controlled hypertension studies, for every 12/6 mmHg reduction in BP, there was a 35%–40% reduction in stroke, 20%–25% reduction in myocardial infarction, and .50% in heart failure (HF) and prevention of CVD-related death rates.11 An estimated one-third of all hypertensive patients still remain untreated despite the level of awareness of hypertension worldwide, and over half of those treated have uncontrolled hypertension.12 The increased mortality and morbidity associated with uncon- Integrated Blood Pressure Control 2010:3 45–55 45 © 2010 Okpechi and Rayner, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Dovepress Integrated Blood Pressure Control downloaded from https://www.dovepress.com/ by 5.135.254.153 on 12-Jul-2018 For personal use only. Okpechi and Rayner trolled hypertension results in a substantial economic burden. Antihypertensives that are effective and well tolerated are important for persistence with therapy and hence control of BP. The role of renin–angiotensin–aldosterone system (RAAS) in the pathophysiology of hypertension is pivotal mainly through the generation of powerful vasoconstrictor angiotensin II, which significantly contributes to hypertension through vasoconstriction, stimulation of aldosterone secretion, and increase in sympathetic activation. Angiotensin II receptor blockers (ARBs), therefore, modulate the RAAS by blocking the activation of angiotensin I (AT1) receptors, resulting in vasodilatation, reduced sympathetic activation, and reduced salt and water retention. ARBs also block angiotensin II production irrespective of whether it is generated by AT1 through angiotensin converting enzyme (ACE) pathway or through alternative pathways such as chymase. This article reviews the pharmacology, efficacy, and safety of candesartan (an ARB), with an overview of key hypertension and CV studies involving candesartan. Pharmacology of candesartan After oral administration, candesartan cilexetil is rapidly converted to candesartan (an active drug) by hydrolysis in the gastrointestinal tract, with an average absolute bioavailability of candesartan of approximately 40%. Candesartan is highly bound to plasma protein (.99%).13 The serum concentration (AUC) of candesartan is not significantly affected by food intake, and Tmax is reached within 3–5 hours after oral administration.13 The AUC of candesartan has shown dose linearity with increasing doses in the therapeutic dose range.14 Elimination of the drug is largely via urine and bile in an unchanged form, and only an insignificant amount of the drug is inactivated by hepatic metabolism. an oral dose of candesartan, about 20%–30% is excreted in urine and 60%–70% is excreted in feces. The apparent volume of distribution of candesartan is 0.1 L/kg. The terminal half-life of candesartan is 5–9 hours, and no significant accumulation after multiple doses was observed (plasma concentrations +3% to +17%).14 Total plasma clearance of candesartan is about 0.37 mL/min/kg, with a renal clearance of about 0.19 mL/min/kg. Candesartan has high selectivity for AT1 receptors, with tight binding to and slow dissociation from the receptor.15 In displacement studies using rabbit aortic membranes, candesartan’s affinity for the AT1 receptor was found to be 80 times higher than that of losartan.16 Due to candesartan’s tight binding to and slow dissociation from the AT1 receptors, candesartan cilexetil provides a dose-related and long-lasting antihypertensive effect.15,17 46 Powered by TCPDF (www.tcpdf.org) submit your manuscript | www.dovepress.com Dovepres (...truncated)