It is amply recognized that blood pressure (BP) control remains far away from the goals recommended by the guidelines set forth by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) and the European Society of Hypertension-European Society of Cardiology (ESH-ESC) [1
]. In clinical practice, a percentage of control above 30% (for a goal inferior to 140/90 mmHg) is rarely seen [3
]. For a similar BP goal, control values above 40% have been described in hospital-based hypertension units [4
], and the percentage has been as high as 60% in some clinical studies, such as that in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [5
]. However, in the last two instances, if a goal lower than 130/80 mmHg had been considered according to the guidelines-for example, when associated clinical conditions (ACC), diabetes, or chronic kidney disease are present-the adequate BP control seen would be less than 20% in hypertension units [4
] and the same would probably be applicable for most clinical trials. All these facts have led to the conclusion that attaining an adequate BP goal, especially that of systolic BP, is really difficult.
Calcium channel blockers (CCBs) have been used for more than one quarter of a century and are among the most widely prescribed drugs for the treatment of hypertension because of their well-established antihypertensive efficacy [6
] and their favorable impact on cardiovascular (CV) morbidity and mortality in hypertensive patients [7
]. These findings have been incorporated into the guidelines for hypertension management [1
], and they also have forced the consideration that the achievement of an adequate BP control could be an elusive target in daily clinical practice [8
]. The aim of this monograph is to review the usefulness of dihydropyridine CCBs, focusing on barnidipine, attaining a better BP control in daily clinical practice.
WHEN TO INITIATE PHARMACOLOGICAL INTERVENTION
Threshold blood pressure revisited
Both the level of BP and its consequences rise continuously if arterial hypertension is not adequately treated. Progression from prehypertension into established hypertension is well known . Later on and if hypertension is not controlled, it progresses to more advanced stages and causes the wellknown increase in CV and renal damage . Defining the most adequate threshold BP to start pharmacological intervention would impede the evolution of arterial hypertension, thus avoiding the progression of CV disease. A direct pharmacological intervention, accompanied by lifestyle changes, is contemplated if BP levels are above the limit defining stage 2 in arterial hypertension (>160/100 mmHg). In the remaining cases, threshold BP is defined by the persistence of BP values >140/90 mmHg after a period of adequately performed lifestyle changes. In comparison, both JNC-7 and ESH-ESC guidelines [1,2] recognize the existence of compelling indications that suggest starting treatment even when BP levels are in the range of prehypertension. This is the case when target organ damage (TOD) or ACC are present. However, in daily clinical practice the threshold BP to start pharmacological therapy differs, and intervention frequently takes place when BP levels are clearly above the levels recommended by the guidelines. In addition, once pharmacological therapy is started, clinical inertia  greatly contributes to facilitating the absence of a good BP control due to the acceptance by physicians of elevated BP levels as adequate for the patient.
Arterial hypertension prevention through pharmacological intervention
The possibility of preventing arterial hypertension with a healthy lifestyle, particularly if obesity is corrected, has been demonstrated . Pharmacological intervention directed at preventing arterial hypertension (BP >140/90 mmHg) has been recently suggested . The Trial Of Preventing Hypertension (TROPHY) tested the hypothesis that pharmacological treatment of prehypertension prevents or postpones stage 1 hypertension. Active therapy decreased the risk to develop stage 1 hypertension by 66.3% (p <.001) during the first 2 years. At the end of the study, the risk was still reduced by 15.6% (p <.007) in those patients who had received the active medication .
The transition from prehypertension into established hypertension reflects, in part, ongoing changes such as arteriolar hypertrophy  and endothelial dysfunction . In this sense, prehypertension is characterized by the existence of elevations in plasma norepinephrine and plasma renin concentrations [16,17] that could promote growth and endothelial dysfunction. These data stress the consideration that an earlier intervention with drugs in daily clinical practice could facilitate the attainment of a much better BP control due to the regression of the vascular changes accompanying the increase in BP since the initial stages of the process.
Conversely, BP within the range of prehypertension is associated with an elevated risk of CV disease [18,19] beyond that attributable to accompanying situations such as diabetes, TOD, or established CV disease and is partly attributable to the association of prehypertension with other CV risk factors [20,21]. Early pharmacological intervention in arterial hypertension must then be contemplated in order to diminish the early development of CV disease.
HOW TO INITIATE PHARMACOLOGICAL THERAPY
An apparent discrepancy for the choice of the first drug exists between JNC-7  and recently published ESH-ESC  guidelines. JNC-7 defends the use of diuretics in most people as a first-step therapy to significantly diminish the great risk that accompanies elevated BP and suggests doing it at the lowest cost. In contrast, the ESH-ESC guidelines defend the need for individual therapy in each patient, admitting that any drug available can be considered as adequate for first-step therapy. The demonstration that arterial hypertension is the number one risk factor in promoting death in developed, as well as in developing, countries  agrees with the premise of JNC-7. However, that prehypertension nowadays correlates particularly well with insulin resistance  forces the consideration that the benefit of simply lowering BP could at medium term not be enough to correct the risk of elevated BP. In fact, targeting prediabetes in hypertensive patients  represents a situation frequently seen in clinical practice, in which the choice of the antihypertensive drug is relevant to promote, prevent, or retard the development of diabetes.
CCBs are widely used in the treatment of hypertension, both as monotherapy and in combination with other antihypertensive drugs, and are well established as first-line treatments . Barnidipine is a new 1,4-dihydropyridine derivative and is the first drug of this class to be composed of a single optical isomer [25-27]. Like other members of these drugs, barnidipine is selective for L-type calcium channels, with a high affinity for smooth muscles, leading to the marked vasodilation of peripheral and coronary arteries . Its antihypertensive action may also be partly due to its significant natriuretic effect . It is available in a modified-release formulation for once-daily oral administration in the treatment of patients with mild-to-moderate hypertension . In these patients, a starting dose of 10 mg barnidipine once daily, with a doubling of the dose to 20 mg once daily, was associated with rates of response among 41 to 44% and 49 to 57%, respectively . It has been demonstrated that these effects are maintained for 24 h , both in patients with isolated clinical hypertension and in those with a nondipping pattern of circadian BP variation . Moreover, barnidipine is as efficacious and safe as other CCBs, such as felodipine , nitrendipine , or amlodipine , in the treatment of essential hypertension, or other antihypertensive drugs, such as atenolol  or benazepril in patients with renal parenchymal hypertension . Furthermore, the efficacy and tolerability of barnidipine monotherapy are maintained for at least 2 years .
When to use combination therapy?
It is also true that the discussion on which monotherapy is most adequate seems insufficient if we consider the elevated percentage of patients requiring combination therapy to obtain an acceptable BP control. Only 22 to 24% of people in clinical trials actually achieve BP goals with monotherapy. In fact, unwanted metabolic effects of some antihypertensive drugs are attenuated when used in combination with members of other classes of antihypertensive agents, in particular with drugs that suppress the renin-angiotensin system (RAS) .
The possibility of using a combination, either free or fixed, since the beginning of pharmacological therapy in hypertensive patients is contemplated in both guidelines [1,2]. Implementing this possibility probably will contribute to improved BP control due to the higher capacity of the combination to lower BP. In this sense, barnidipine, when added to atenolol in nonresponder hypertensive patients, produced a further mean reduction of 11.3 mmHg in systolic and 5.5 mmHg in diastolic BP . Moreover, in mild essential hypertension, the addition of enalapril produced a response in 57% of patients not responding to barnidipine monotherapy .
Is there a different response to therapy depending on age?
A new version of the British Society of Hypertension Guidelines  has been published . The recommended choice of the first antihypertensive drug is based on the fact that hypertensives can be broadly classified as "high renin" and "low renin." Drugs can be divided, according to their effects on the RAS, into those with the capacity to inhibit angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (A) or beta-blockers (B) and those without effects on the system, calcium antagonists (C), and diuretics (D). As can be seen in Figure 1, patients aged <55 years, with the highest activity of the RAS, require as their first drug one included in group A or B, while those >55 years of age should receive one in group C or D. Combination therapy cab be started by adding a drug from the other group (C or D for A or B and vice versa). If three drugs are required, A+ C+ D should be the ideal combination.
Figure 1. Recommendations for blood-pressure-lowering drug combinations (AB/CD rule).
In this sense, barnidipine is a safe and effective antihypertensive agent to use in the long term in patients aged ≥75 years with essential hypertension, either as monotherapy or in combination with ACE inhibitors or diuretics [40,41].
PREDICTORS OF A POOR RESPONSE TO ANTIHYPERTENSIVE THERAPY
The greater the cardiovascular damage, the poorer the response to drug treatment
Several factors have been identified as potential impediments for the attainment of an adequate BP control. Some of them are related to an unhealthy lifestyle: in particular, a diet containing an excessive amount of salt, alcohol intake, calories facilitating an increase in body weight, or a low intake of fruit and vegetables (Table 1). Other factors are related to inadequate doses of antihypertensive drugs or combinations, or accompanying therapies interfering with antihypertensive therapy. However, there is an important predictor of the need for multiple antihypertensive therapies, the degree of CV and renal involvement as a consequence of the increase in BP. The presence of ACC or advanced TOD precludes a more difficult control of BP and the need for more medication to achieve it . An aggressive attitude is required in the treatment of these patients because maintaining an adequate level of BP control is inferior to having a BP value of 130/80 mmHg.
|TABLE 1. Lifestyle modifications and effects on blood pressure
High-risk conditions benefited by the use of CCBs include high coronary disease risk and diabetes (particularly in combination with other agents) . Conditions favoring the choice of a dihydropyridine CCB for hypertension include advanced age, isolated systolic hypertension, angina pectoris, peripheral vascular disease, carotid atherosclerosis, and pregnancy .
Poor long-term adherence as a relevant cause of poor blood pressure control
Many patients do not take their prescribed medications. In most surveys, 25 to 50% of patients have abandoned their antihypertensive drugs 1 year after starting therapy . It is also true that many physicians do not prescribe all the required medications necessary to control BP in their patients . The reasons for a low compliance and for such a poor long-term adherence are diverse, but in particular poor tolerability has been claimed as one of the most important. Table 2 summarizes the guidelines directed to improve maintenance of antihypertensive therapy .
||TABLE 2. Guidelines to improve maintenance of antihypertensive therapy
Whereas the new long-acting dihydropyridine CCBs and the slow-release preparations of nifedipine do not exhibit reflex tachycardia, they still evoke an increase in sympathetic nerve activity . Further limitations to the use of this class of drugs are side effects such as ankle edema, headache, and flushing . Adverse events reported with the use of barnidipine are similar to those with nitrendipine and amlodipine in multicenter, double-blind studies . Edema was less frequent with the use of barnidipine than it was with nitrendipine (2.1 vs 10.9%, respectively) and amlodipine (3.8 vs 5.4%, respectively). Adverse events such as palpitations, rash, and diarrhea that occurred in patients receiving amlodipine were not observed with the use of barnidipine .
IF AN EARLIER INTERVENTION IS REQUIRED, WHO SHOULD RECEIVE THE MESSAGE?
CV and renal disease have been described as a continuum  starting with the detection of CV and renal risk factors, followed by the detection of TOD and, finally, by ACC and eventually death. It is apparent that lifestyle interventions can clearly delay development of hypertension as well as reduce CV risk (Table 1). Nevertheless, the achievement of adequate BP control and an integral protection of the increased global CV risk are mandatory in patients with established essential hypertension. In most cases, it will be necessary to combine two or more antihypertensive drugs, and CCBs will be one of the most frequent components of this combination. Newer long-acting CCBs, such as barnidipine, provide similar benefits to those currently seen with existing agents within the CCB class with a more favorable tolerability profile, most notably a reduction in peripheral edema.
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