Calcium Channel Blockers and Hypertension

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<ul><li><p></p><p>Journal of Cardiovascular Pharmacology and</p><p> online version of this article can be found at:</p><p> DOI: 10.1177/1074248414555403</p><p> published online 14 November 2014J CARDIOVASC PHARMACOL THERMassimo Volpe</p><p>Giuliano Tocci, Allegra Battistoni, Jasmine Passerini, Maria Beatrice Musumeci, Pietro Francia, Andrea Ferrucci andCalcium Channel Blockers and Hypertension</p><p>Published by:</p><p></p><p> can be found at:Journal of Cardiovascular Pharmacology and TherapeuticsAdditional services and information for </p><p> Alerts: </p><p> </p><p> </p><p> </p><p> What is This? </p><p>- Nov 14, 2014OnlineFirst Version of Record &gt;&gt; </p><p> at UCSF LIBRARY &amp; CKM on November 27, 2014cpt.sagepub.comDownloaded from at UCSF LIBRARY &amp; CKM on November 27, 2014cpt.sagepub.comDownloaded from </p><p></p></li><li><p>Calcium Channel Blockers and Hypertension</p><p>Giuliano Tocci, MD, PhD1,2, Allegra Battistoni, MD1,Jasmine Passerini, MD1, Maria Beatrice Musumeci, MD1,Pietro Francia, MD1, Andrea Ferrucci, MD1,and Massimo Volpe, MD, FAHA, FESC1,2</p><p>AbstractEffective treatment of high blood pressure (BP) represents a key strategy for reducing the burden of hypertension-related cardio-vascular and renal diseases. In spite of these well-established concepts, hypertension remains poorly controlled worldwide. In orderto improve BP control in patients with hypertension, several interventions have been proposed, among which (1) preferred use ofmore effective, sustained, and well-tolerated antihypertensive drug aimed to ensure adherence to prescribed medications and (2)extensive use of rational, integrated, and synergistic combination therapies, even as first-line strategy, aimed to achieve the recom-mended BP targets. Within the possible antihypertensive drug classes currently available for the clinical management of hypertension,both in monotherapy and in combination therapy, drugs inhibiting the reninangiotensin system and calcium channel blockers(CCBs) have demonstrated to be effective and safe in lowering BP levels and achieving the recommended BP targets with a goodtolerability profile. In particular, CCBs have been one of the most widely used classes of antihypertensive agents in the last 20 years,based on their effectiveness in reducing BP levels, good tolerability, and abundant evidence on reducing cardiovascular and renalconsequences of hypertension. This article provides an updated overview of the evidence supporting the use of CCBs-based anti-hypertensive regimen, both in monotherapy and in combination therapies with different classes of antihypertensive drugs.</p><p>Keywordshypertension, blood pressure control, antihypertensive therapy, combination therapy, calcium channel blockers, calciumantagonists</p><p>Introduction</p><p>Hypertension is a major modifiable risk factor, which signifi-</p><p>cantly and independently increases the risk of developing major</p><p>cardiovascular, cerebrovascular, and renal complications.1 On</p><p>the other hand, an effective treatment of hypertension substan-</p><p>tially reduces the risk of developing such complications and</p><p>improves cardiovascular prognosis.2 However, the control of</p><p>blood pressure (BP) remains largely unsatisfactory world-</p><p>wide.3,4 In particular, analyses of data collected across different</p><p>Western countries on BP control rates have consistently and</p><p>independently confirmed that only 20% to 30% of treatedpatients with hypertension achieve the recommended BP tar-</p><p>gets.5-8 Inadequate BP control increases the risk of developing</p><p>hypertension-related cardiovascular diseases, including myo-</p><p>cardial infarction, ischemic stroke, end-stage renal disease, and</p><p>congestive heart failure, and explains the persistently high bur-</p><p>den of cardiovascular death related to hypertension.9</p><p>Current recommendations from international guidelines</p><p>stated that in all patients with hypertension, it is important to</p><p>reduce BP until systolic and diastolic BP values below 140/</p><p>90 mm Hg are achieved.10,11 These BP goals are recommended</p><p>for all adult patients with hypertension, regardless of gender,</p><p>age, ethnicity, or other concomitant clinical conditions.10,11</p><p>Results of large, randomized, controlled clinical trials demon-</p><p>strated that it is possible to reach these BP targets in large pro-</p><p>portions of treated patients with hypertension having different</p><p>cardiovascular risk profiles.12-14 Indeed, the design of these</p><p>clinical trials systematically included antihypertensive thera-</p><p>pies based on drugs inhibiting the reninangiotensin system</p><p>(RAS) and calcium channel blockers (CCBs) compared to</p><p>b-blockers and diuretics.12-14 On the basis of these findings,a preferred use of these antihypertensive drug classes have been</p><p>pursued by recent hypertension guidelines, in order to bridge</p><p>the gap between the attained and expected BP control rates,</p><p>1 Division of Cardiology, Department of Clinical and Molecular Medicine,</p><p>Faculty of Medicine and Psychology, University of Rome Sapienza, SantAndrea</p><p>Hospital, Rome2 IRCCS Neuromed, Pozzilli (IS), Italy</p><p>Manuscript submitted: June 10, 2014; accepted: August 8, 2014.</p><p>Corresponding Author:</p><p>Massimo Volpe, Division of Cardiology, Department of Clinical and Molecular</p><p>Medicine, Faculty of Medicine, University of Rome Sapienza, SantAndrea</p><p>Hospital, Rome, Via di Grottarossa 1035-39, 00189 Rome, Italy.</p><p>Email:</p><p>Journal of CardiovascularPharmacology and Therapeutics1-10 The Author(s) 2014Reprints and 10.1177/</p><p> at UCSF LIBRARY &amp; CKM on November 27, 2014cpt.sagepub.comDownloaded from </p><p></p></li><li><p>to ensure adequate adherence and persistence to prescribed</p><p>medications and to improve cardiovascular outcomes in treated</p><p>patients with hypertension.10,11</p><p>Being the vast majority of these evidence based on the use of</p><p>dihydropyridinic CCBs, these drugs are now recommended</p><p>both as first-line therapy and as an ideal partner for dual or tri-</p><p>ple combination therapies for the clinical management of</p><p>hypertension and hypertension-related comorbidities.10,11</p><p>The aim of this article is to provide an updated overview of</p><p>the evidence supporting the use of CCBs-based antihyperten-</p><p>sive regimen, both in monotherapy and in combination thera-</p><p>pies with different classes of antihypertensive drugs.</p><p>General Considerations on CCBs</p><p>Within the drug class, CCBs showed several important differ-</p><p>ences from the pharmacokinetic15 and pharmacodynamic16</p><p>point of views as well as for selectivity and duration of pharma-</p><p>cological action,17-19 although sharing the same ability to inter-</p><p>act with L-type voltage-dependent transmembrane calcium</p><p>channels (Figure 1). As expected, these differences impact both</p><p>clinical and therapeutic effectiveness as well as tolerability and</p><p>safety profile in different clinical settings.</p><p>Several classifications have been proposed to distinguish dif-</p><p>ferent compounds within this drug class. Among these, CCBs</p><p>may be classified into 3 groups according to their selectivity for</p><p>interactions with either cardiac or vascular (or both) L-type</p><p>voltage-dependent transmembrane calcium channels,20,21 as</p><p>reported in Table 1. According to this classification, CCBs may</p><p>be stratified into 3 groups, namely (1) dihydropyridinic agents,</p><p>which mostly act as dilating agents at peripheral vessel level,</p><p>(2) phenilalchilaminic agents, which predominantly act as nega-</p><p>tive inotropes and chronotropes at cardiac level, and (3) ben-</p><p>zothiazepinic agents, which have an intermediate profile.</p><p>The first generation of the compounds of these 3 groups</p><p>included nifedipine, verapamil, and diltiazem, respectively.</p><p>They were characterized by short-acting therapeutic actions,</p><p>which have limited their clinical effectiveness due to potential</p><p>risk of drug-related adverse reactions (eg, peripheral edema,</p><p>reflex tachycardia, skin reactions). Following the availability</p><p>of the first-generation molecules, over the years several other</p><p>compounds have been developed for widespread use in treat-</p><p>ing hypertension and cardiovascular diseases. In particular,</p><p>among dihydropyridinic agents, second-generation CCBs,</p><p>including manidipine,22,23 felodipine,24,25 and nicardipine,26</p><p>and third-generation CCBs, including lacidipine,27 lercanidi-</p><p>pine28 barnidipine,29 and amlodipine,30 were characterized by</p><p>high selection for vascular calcium channels and favorable</p><p>pharmacokinetic and pharmacodynamic profile.</p><p>From a clinical point of view, dihydropyridinic CCBs are</p><p>considered one of the first-line therapeutic options to treat</p><p>hypertension and reduce hypertension-related cardiovascular</p><p>morbidity and mortality.10,11</p><p>According to the recommendations from the European</p><p>guidelines,10 all CCBs can be effectively and safely used for</p><p>the treatment of hypertension, both in monotherapy and in</p><p>combination therapies (Figure 2). In particular, according</p><p>with the compelling indications (Table 2), they are now</p><p>Figure 1. Schematic representation to explain the molecular mechanisms of actions of calcium channel blockers (CCBs).</p><p>2 Journal of Cardiovascular Pharmacology and Therapeutics</p><p> at UCSF LIBRARY &amp; CKM on November 27, 2014cpt.sagepub.comDownloaded from </p><p></p></li><li><p>recommended for lowering BP levels in black individuals,</p><p>elderly patients with isolated systolic hypertension as well as</p><p>in patients with hypertension having metabolic syndrome, car-</p><p>diac (left ventricular hypertrophy) or vascular (atherosclerosis)</p><p>organ damage, previous stroke, or peripheral artery disease. In</p><p>addition, nondihydropyridinic CCBs are also recommended for</p><p>treating patients with hypertension having angina pectoris and</p><p>for those with atrial fibrillation, with the aim of achieving ven-</p><p>tricular rate control.10 Finally, they are recommended for treat-</p><p>ing gestational hypertension or for preventing eclampsya.10 On</p><p>the other hand, dihydropyridinic CCBs are contraindicated for</p><p>those patients with hypertension having tachycardia or conges-</p><p>tive heart failure, while nondihydropyridinic CCBs are contrain-</p><p>dicated for those patients with hypertension having grade 2 to 3</p><p>atrioventricular block, severe left ventricular dysfunction, or</p><p>congestive heart failure.</p><p>According to the recommendations from the evidence-based</p><p>guidelines in the United States,11 some selected dihydropyridi-</p><p>nic CCBs (ie, amlodipine 2.5-10 mg and nitrendipine 10-20</p><p>mg) and only 1 nondihydropyridinic CCB (diltiazem extended</p><p>release120-360 mg) may be used for lowering BP levels and</p><p>reducing incidence of hypertension-related cardiovascular</p><p>Table 1. Classification of Different Compounds Within the CCB Drug Class, According to Their Selectivity for Interactions With EitherCardiac or Vascular (or Both) L-Type Voltage-Dependent Transmembrane Calcium Channels.a</p><p>GroupFirst Generation(Original Formulations)</p><p>Second Generation(Extended-Release Formulations)</p><p>Third Generation(New Formulations)</p><p>Dihydropiridinic Nifedipine Nifedipine SR/GITSFelodipine ERNicardipine SR</p><p>NicardipineIsradipineManidipineNilvadipineNimodipineNisoldipineNitrendipineAmlodipineFelodipineLacidipineBarnidipine</p><p>Benzotiazepinic Diltiazem Diltiazem SRFenilalchilaminic Verapamil Verapamil SR</p><p>Abbreviations: SR, slow release; GITS, gastrointestinal-transport system; ER, extended release.a Derived from Reference20,21.</p><p>Figure 2. Schematic representation illustrating the different therapeutic options (monotherapy vs combination therapy) for the clinicalmanagement of hypertension, according to current European guidelines.10</p><p>Tocci et al 3</p><p> at UCSF LIBRARY &amp; CKM on November 27, 2014cpt.sagepub.comDownloaded from </p><p></p></li><li><p>events. With the only exception of renal diseases, in which</p><p>RAS-blocking agents should be preferred, CCBs are now rec-</p><p>ommended as first-line therapy in all stages of hypertension,</p><p>independent of age, gender, race, and other comorbidities</p><p>(Figure 3). They may be used both in monotherapy and in com-</p><p>bination therapies with either angiotensin-converting enzyme</p><p>(ACE) inhibitors or angiotensin receptor blockers (ARBs) or</p><p>thiazide diuretics.11</p><p>Table 2. Compelling Indications and Contraindications for Using CCBs in the Clinical Management of Hypertension, According to CurrentEuropean Guidelines.10</p><p>Compelling Indications CCB Other Drugs</p><p>Asymptomatic organ damageLVH Dihydropyridinic CCB ACE inhibitor, ARBAsymptomatic atherosclerosis Dihydropyridinic CCB ACE inhibitor</p><p>Clinical CV eventPrevious stroke Any agent effectively lowering BP, including CCBAngina pectoris Dihydropyridinic CCB BBAtrial fibrillation, ventricular rate control Non-dihydropyridinic CCB BBPeripheral artery disease Dihydropyridinic CCB ACE inhibitor</p><p>Other conditionsISH (elderly) Dihydropyridinic CCB DiureticMetabolic syndrome Dihydropyridinic CCB ACE inhibitor, ARBPregnancy Dihydropyridinic CCB Methyldopa, BBBlacks Dihydropyridinic CCB Diuretic</p><p>ContraindicationsTachycardia Dihydropyridinic CCBCongestive heart failure Dihydropyridinic CCBAV block (grade 2 or 3, trifascicular block) non-dihydropyridinic CCB (verapamil, diltiazem)Severe LV dysfunction Nondihydropyridinic CCB (verapamil, diltiazem)Heart failure Nondihydropyridinic CCB (verapamil, diltiazem)</p><p>Abbreviations: CCBs, calcium-channel blockers; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; BB, b-blockers, LVH, left ventricularhypertrophy; CV, cardiovascular, ISH, isolated systolic hypertension; AV, atrioventricular.</p><p>Figure 3. Schematic representation illustrating the different therapeutic options (monotherapy vs combination therapy) for the clinical man-agement of hypertension, according to current United States guidelines.11</p><p>4 Journal of Cardiovascular Pharmacology and Therapeutics</p><p> at UCSF LIBRARY &amp; CKM on November 27, 2014cpt.sagepub.comDownloaded from </p><p></p></li><li><p>Current Recommendations for HypertensionTreatment and Control</p><p>In view of the documented equivalence in terms of antihyper-</p><p>tensive efficacy and in terms of reducing the risk of major car-</p><p>diovascular events, it is now possible to choose among 5</p><p>antihypertensive drug classes, including ACE inhibitors,</p><p>ARBs, b-blockers, CCBs, and diuretics, for starting and main-taining antihypertensive treatment in monotherapy.10</p><p>In the selection of the first-choice antihypertensive drug class,</p><p>however, it should be noted that, even in the presence of a s...</p></li></ul>