Carvedilol in hypertension treatment

REVIEW Carvedilol in hypertension treatment Panagiotis C Stafylas Pantelis A Sarafidis 1st Department of Medicine, AHEPA University Hospital, Aristotle University, Thessaloniki, Greece Abstract: Although β-blockers have been previously shown to effectively reduce blood pressure (BP) and have been used for hypertension treatment for over 40 years, their effect on cardiovascular morbidity and mortality in hypertensive patients remains controversial and its use in uncomplicated hypertension is currently under debate. However, data on the above field derive mainly from studies which were conducted with older agents, such as atenolol and metoprolol, while considerable pharamacokinetic and pharmacodynamic heterogeneity is present within the class of β-blockers. Carvedilol, a vasodilating non-cardioselective β-blocker, is a compound that seems to give the opportunity to the clinician to use a cardioprotective agent without the concerning hemodynamic and metabolic actions of traditional β-blocker therapy. In contrast with conventional β-blockers, carvedilol maintains cardiac output, has a less extended effect on heart rate and reduces BP by decreasing vascular resistance. Further, several studies has shown that carvedilol has a beneficial or at least neutral effect on metabolic parameters, such as glycemic control, insulin sensitivity, and lipid metabolism, suggesting that they could be used in subjects with the metabolic syndrome or diabetes without negative consequences. This article summarizes the distinct pharmacologic, hemodynamic, and metabolic properties of carvedilol in relation to conventional β-blockers, attempting to examine the potential use of this agent for hypertension treatment. Keywords: carvedilol, β-blockers, hypertension treatment Introduction Correspondence: Pantelis A Sarafidis 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, Thessaloniki, Greece Tel/Fax +30 2310 994616 Email: Hypertension represents the most common cardiovascular risk factor. Its prevalence is continuously rising, affecting more than 25% of the adult population in developed societies (Wolf-Maier et al 2004; Sarafidis et al 2004; Sarafidis and Bakris 2008). On the other hand, several previous studies have clearly shown longitudinal associations between hypertension and coronary artery disease, myocardial infarction, stroke, congestive heart failure, and peripheral vascular disease (MacMahon et al 1990; Stamler et al 1993) and lowering blood pressure (BP) significantly reduces the cardiovascular morbidity and mortality (Collins et al 1990; MacMahon et al 1997). However, control rates of hypertension is currently inappropriate and the majority of the hypertensive patients will require two or more antihypertensive agents to reach target BP goals (Chobanian et al 2003; ESH-ESC Guidelines Committee 2003; Mancia et al 2007). Beta-blockers have been used for more than 40 years to treat hypertension (Sarafidis and Bakris 2006b). Data from clinical trials that used these agents to manage BP have demonstrated reductions in cardiovascular mortality and this has resulted in recommendations of β-blockers as first- or second-line antihypertensive agents in the most recent guidelines of the European Society of Hypertension/European Society of Cardiology (Mancia et al 2007) and the Joint National Committee (JNC 7) on the Prevention, Detection and Treatment of High Blood Pressure (Chobanian et al 2003). All of the β-blocker compounds now available for use have been approved for the treatment of hypertension Vascular Health and Risk Management 2008:4(1) 23–30 © 2008 Dove Medical Press Limited. All rights reserved 23 Stafylas and Sarafidis (Opie and Yusuf 2005). Despite the above and the wide use of β-blockers for the management of hypertension, their use in patients with uncomplicated hypertension has become increasingly controversial over the past few years (Sarafidis and Bakris 2006c; Black and Sica 2007). This was in part due to the results of recent meta-analyses showing no difference between atenolol and placebo in risk reduction for mortality, myocardial infarction, or stroke (Carlberg et al 2004) and an increased risk of mortality and stroke with atenolol or propranolol in comparison to other antihypertensive drug classes, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calciumchannel blockers (CCBs) (Carlberg et al 2004; Lindholm et al 2005). The recently updated National Institute for Health and Clinical Excellence guidelines in Great Britain reflected this concern, having changed the indication for β-blockers from use as first-line agents for hypertension treatment to consideration as a fourth-line add-on therapy in patients requiring multiple drugs (Williams et al 2004; National Collaborating Centre for Chronic Conditions 2006). In the most recent guidelines, the European Society of Hypertension / European Society of Cardiology (Mancia et al 2007) recommend that β-blockers should not be preferred in hypertensives with multiple metabolic risk factors including metabolic syndrome, abdominal obesity, high normal or impaired fasting glucose, and impaired glucose tolerance, conditions that make the risk of incident diabetes higher. Although the above data on β-blockers and CVD risk reduction cannot be overlooked, one must always bear in mind that most of the studies on the field included “traditional” agents (such as propranolol and atenolol). This notion is of great importance, since, although a class effect is possible for certain facets of β-blocker action, many effects of the various β-blockers differ greatly between the various compounds, according to the individual physicochemical and pharmacological properties of each of them (Williams et al 2004). Several head-to-head studies have convincingly shown that non-selective agents, such as atenolol, have a negative effect on myocardial contractility, vascular resistance (Man et al 1988), and carbohydrate and lipid metabolism (Sarafidis and Bakris 2007), while newer agents with vasodilating properties, such as carvedilol and nebivolol, have a hemodynamic and metabolic profile that is much better than that of older compounds (Sarafidis and Bakris 2006b; Weiss 2006; Sica 2007). The present review summarizes the current data on the pharmacologic, hemodynamic, and metabolic properties of carvedilol in comparison with conventional β-blocking compounds, in an attempt to 24 examine whether this particular agent could be still useful in the treatment of hypertension. Pharmacologic properties of β-blockers First generation β-blockers, such as propranolol, block both β1- and β2-receptors. Through β1-receptor blocking these compounds induce the well known inhibitory effects on the function of the sinus and atrioventricular nodes and on myocardial contraction (negative chronotropic, dromotropic, and inotropic effect). By blocking the β2-receptors, (...truncated)