The role of alpha 1-blockers in combination therapy for hypertension

Antihypertensive monotherapy provides adequate blood pressure control in less than 50% of patients with hypertension (BP > 140/90 mmHg), especially those with stage 2-3 disease. This article reviews clinical studies that demonstrate that add-on therapy with an alpha1-blocker (doxazosin, terazosin or prazosin) is an effective and well-tolerated regimen for improving blood pressure control in patients with inadequately controlled hypertension. Furthermore, alpha1-blockers have therapeutic benefits that go beyond blood pressure management. They have a small but positive effect on the serum lipid profile and they have favourable or benign effects on conditions that frequently coexist with hypertension, such as type 2 diabetes mellitus and benign prostatic hyperplasia.     

Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension

Recent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact “lower is better,” with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of β-blockers and renin-angiotensin-aldosterone system inhibitors have previously been deemed “less effective,” based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating β₁-selective blocker and β₃- adrenoceptor agonist; β₃-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other β-blockers, and will further support the pharmacological advantages of this particular combination.     

Drug treatment of essential hypertension: the case for initial combination therapy

Essential hypertension is a major cause of cardiovascular morbidity and mortality in the Western world, yet it remains poorly controlled. Single drug-antihypertensive therapy is unsuccessful in up to half of all patients with hypertension; although lack of adherence may account for a proportion of this, there is evidence of considerable variation in the response of different hypertensive patients to different drug classes. A number of algorithms have been proposed in the literature, with a view to predicting an individual's response to different antihypertensive agents. However, even using such algorithms, hypertension control remains problematic, and they are frequently difficult to apply in everyday clinical practice. Initiation of treatment with low-dose combination antihypertensive therapy, using a drug which reduces total body sodium and/or volume in combination with a drug which blocks the renin-angiotensin system, provides an effective and easily applicable means to improve hypertension control in the primary care setting.     

Arterial hypertension and hemorheology: the effects of triamterene and hydrochlorothiazide

Ten patients with arterial hypertension and chronic heart failure (stages NYHA I and II) were treated in a pilot study with a combination of 50 mg triamteren and 25 mg of hydrochlorothiazide for 20 days under clinical conditions. The purpose of this investigation was to determine hemorheological alterations in comparison with initial data after treatment with a common diuretic combination. The influence of the therapy on hematocrit, number of leucocytes and thrombocytes as well as fibrinogen-mediated hemorheological parameters was not significant. Statistically significant (p = 0.0215) was the improvement of erythrocyte-fluidity, which indicates a positive influence of the diuretic combination on the erythrocyte membrane. Furthermore a very effective, statistically significant (p less than 0.05) decrease of blood pressure appeared, even down to a normal standard. Discussions on negative effects of diuretic therapy on hemoconcentration hitherto reported in literature are not attempted by this investigation.     

Fixed-dose combination therapy of candesartan cilexetil and amlodipine besilate for the treatment of hypertension in Japan

Hypertension is one of the most prevalent disorders and the largest contributor to global mortality. The aim of antihypertensive treatment is to reduce the risk of cardiovascular morbidity and mortality by lowering increased blood pressure (BP) to target levels. Despite progress in antihypertensive drug development, BP control remains suboptimal. Accumulating evidence has shown that fixed-dose combination therapy is better in terms of BP control than increasing the dose of one drug or its corresponding combination. Fixed-dose combinations of an angiotensin receptor blocker, candesartan cilexetil, and a calcium channel blocker, amlodipine besilate (candesartan/amlodipine 8/2.5 or 8/5 mg), were approved in Japan for once-daily oral administration in hypertensive patients. Recent data showed that a fixed-dose combination of candesartan and amlodipine lowered BP safely and rapidly, providing a potential opportunity to improve the rate of BP control. Further studies are needed to determine whether this will lead to improvements in long-term clinical outcomes.     

Treatment of arterial hypertension with ketanserin in mono- and combination therapy

We evaluated the long-term antihypertensive effects of ketanserin, a selective serotonin2-receptor blocker with weak adrenergic receptor blocker properties. Ketanserin was given alone, 40 mg o.d. or b.i.d., for 2 years to 12 patients with essential hypertension. Systolic and diastolic blood pressures (BPs) were significantly reduced 14 days after the start of therapy and remained lowered during the 2-year follow-up period. In a larger group of patients who received ketanserin monotherapy for 2 to 3 months, the response to therapy varied considerably between subjects, with an overall response rate (BP less than 165/95 mm Hg) of 60% to 75%. During steady-state conditions, the maximum and minimum ketanserin plasma concentrations varied from threefold to fourfold between subjects and did not correlate with individual reductions in BP, but for each individual there was a positive correlation between BP reduction and ketanserin plasma concentration throughout a study day. In combination with beta-blockers, ketanserin effectively reduced BP in the supine and standing positions. The plasma concentration profile was not altered as much during combination therapy as when ketanserin was given alone. Side effects were few and tolerable. Ketanserin effectively reduces BP both alone and in combination with beta-blockers and may be still another drug useful in the treatment of essential hypertension.     

Aliskiren-hydrochlorothiazide combination for the treatment of hypertension

Hypertension is a major risk factor for cardiovascular morbidity and mortality and currently has been estimated at 30% of the US population. Of these, only 36.8% have their blood pressure reduced to recommended levels of lower than 140/90 mmHg for uncomplicated hypertension, or less than 130/80 mmHg for patients with diabetes mellitus or renal disease. Since monotherapy controls blood pressure in less than 50% of treated hypertensive patients, combination therapy is often required to bring blood pressure to the recommended levels of the 7th Joint National Committee report. One of the most effective and widely used combinations is the combination of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with hydrochlorothiazide (HCTZ). Aliskiren, a new blocker of the renin-angiotensin system has been developed and approved by the US FDA on 18th January 2008 for the treatment of hypertension. Aliskiren is a direct inhibitor of renin, the rate-limiting enzyme for the production of angiotensin II, a powerful vasoconstrictive peptide. Several randomized clinical trials have demonstrated that aliskiren administered in single daily doses of 150, 300 or 600 mg alone and in combination with HCTZ 12.5 and 25 mg is effective in lowering blood pressure, and is safe and well tolerated. In this article, the pharmacokinetic and pharmacodynamic profile and the clinical application of aliskiren alone and in combination with HCTZ will be discussed.     

Combined therapy with amlodipin and lisinopril in arterial hypertension: efficacy of a low-dose combination

AIM: To assess antihypertensive efficacy of a low-dose combination of amlodipin with lisinopril in the treatment of patients with arterial hypertension (AH) of the second degree. MATERIAL AND METHODS: A total of 42 patients with the second degree of AH (16 males, 26 females, mean age 55-9 +/- 1.9 years) entered an open, comparative and controlled trial. They were divided into three groups by the treatment. Group 1 (n = 14) received amlodipin (normodipin, Gedeon Richter) monotherapy in a mean dose 8.9 +/- 0.6 mg/day, group 2 (n = 12) - lisinopril (diroton, Gedeon Richter) in a mean dose 17.5 +/- 1.4 mg/day, group 3 (n = 16) was given combined therapy with amlodipin+lisinopril in a dose 6.8 +/- 0.7 and 8.7 +/- 0.6 mg/day, respectively. The drugs were given for 12 weeks. The efficacy of the treatment was assessed by the results of 24-h monitoring of blood pressure, echocardiography, endothelium-related vasodilatation of the brachial artery (ERVD), dopplerographic investigation of circulation in the middle cerebral artery (MCA), heart rate and cost-effect estimation. RESULTS: Combined low-dose treatment with amlodipin and lisinopril for 12 weeks allowed achievement of target blood pressure in more patients and lower systolic and diastolic blood pressure than monotherapy with each of the drugs. There was also a positive effect on E/A index, ERVD, MCA circulation. CONCLUSION: Low-dose combined treatment with lisinopril and amlodipin is more effective and cost-efficient. Moreover, lisinopril addition to amlodipin corrects side effects of amlodipin on central nervous system.     

Capozide-50 alone and in combination with melatonin in therapy of hypertension

Monotherapy with caposide-50 (C-50) was compared to combined therapy C-50 + melatonin in 22 patients with essential hypertension stage II (mean age 60 years). The patients were divided into two groups. Group 1 received C-50 at 8.00 a.m., group 2 received C-50 at 8.00 a.m. and melatonin at 10.00 p.m. in a dose 3 mg. Before the treatment and 14 days after it echo-CG was made to assess hemodynamics. Also, 24-h monitoring of arterial pressure was performed. The findings were analysed with variance statistics and cosinor-analysis. Group 1 achieved a moderate hypotensive effect. Circadian rhythm of systolic blood pressure was abnormal. Group 2 patients achieved more pronounced decline of systolic, diastolic and mean arterial pressures. Circadian rhythm of these pressure did not return to normal.     

Effect of triamterene on urinary excretion of immunoreactive prostaglandin E in essential hypertension

The effect of triamterene on urinary excretion of prostaglandin E was studied, and the results were compared with those obtained with spironolactone. Urinary excretion of immunoreactive prostaglandin E was measured radioimmunologically. Triamterene was administered in a dose of 100 mg/day for 8 days to 7 patients with essential hypertension. Following the administration of triamterene, urinary prostaglandin E tended to increase. However, the increment was not significant. The lack of significant increase in urinary prostaglandin E excretion during the administration of triamterene contrasted with our previous finding with spironolactone, in which a significant increase in prostaglandin E excretion was observed on the first day of spironolactone administration. Urinary Na excretion and urinary Na/K ratio were significantly increased and urine volume also tended to increase following the administration of triamterene. Plasma renin activity and plasma aldosterone concentration were increased in all cases. However, there was no significant correlation between these parameters and urinary prostaglandin E. These results suggest that the effect of triamterene on renal prostaglandin E synthesis is different from that of spironolactone and that the change in urinary prostaglandin E after the administration of triamterene is not the reflection of the change in the renin-angiotensin-aldosterone system.     

Barnidipine monotherapy and combination therapy in older patients with essential hypertension: a long-term study

The long-term (2 year) safety and efficacy of barnidipine was assessed in an open-label, dose-titration, multicentre study of 236 patients aged > or = 75 years with a sitting diastolic blood pressure (DBP) > or = 95 mmHg. All eligible patients started treatment with barnidipine 10 mg once daily. After at least 4 weeks treatment, the dose of barnidipine was titrated upwards to 20 mg daily in patients who did not achieve normalisation of blood pressure (sitting DBP < 90 mmHg). After at least another 4 weeks of treatment an ACE inhibitor or diuretic was added if necessary. Barnidipine monotherapy was the final treatment in 74% of patients in the ITT population (50% barnidipine 10 mg, 24% barnidipine 20 mg). The overall response rate was 84.1% at endpoint. Overall mean sitting DBP decreased by 18.4 mmHg from 102.1 mmHg at baseline to 83.7 mmHg at endpoint. Although a total of 82.2% of patients reported at least one adverse event, only 37.4% of patients experienced an adverse event that was possibly or probably related to the study medication. Many patients experienced adverse events associated with co-existing diseases common in older people. It can be concluded that barnidipine as monotherapy or in combination with ACE inhibitors or diuretics is safe and effective in older patients with essential hypertension.