The expanding role of angiotensin receptor blockers in the management of the elderly hypertensive

SUMMARY

The world faces the challenge of an ageing population, and for developed countries, the particular challenge is the increasing number of very old people, over 80 years of age. Hypertension is a condition associated with increasing age, but elderly patients with hypertension are often difficult to manage. Nevertheless, treatment of hypertension is of greatest value in older patients who often have additional risk factors or cardiovascular disease. Older patients have generally tolerated antihypertensive therapy well in randomised, placebo-controlled trials. The tolerability of angiotensin receptor blockers (ARBs) is better than that of many other classes of drugs currently used for the management of hypertension and these drugs have virtually no contraindications. Thus, ARBs have a bright future in the management of hypertension and in the treatment of stroke and cognitive decline in the elderly.     

Vascular benefits of angiotensin receptor blockers

There is convincing evidence that angiotensin II, through activation of the angiotensin II type 1 (AT1) receptor, is involved in the atherosclerotic process. Similarly, angiotensin receptor blockers decrease vascular inflammation, hypertrophy and thrombosis, which are the key components of the progression of atherosclerosis. In addition, in several animal models, angiotensin receptor blockade was able to inhibit atherosclerosis. However, the effects of angiotensin receptor blockers on clinical outcome in cardiovascular patients remains to be established. Contradictory results have been found on the reduction of the risk on myocardial infarctions and in-stent restenosis, although there is solid evidence for cerebroprotective effects of these receptor blockers. These differences may be related to the role of the AT2 receptor. This review discusses the role of angiotensin II and angiotensin receptor blockers in the atherosclerotic process and its translation into clinical practice.     

Vascular benefits of angiotensin receptor blockers

There is convincing evidence that angiotensin II, through activation of the angiotensin II type 1 (AT1) receptor, is involved in the atherosclerotic process. Similarly, angiotensin receptor blockers decrease vascular inflammation, hypertrophy and thrombosis, which are the key components of the progression of atherosclerosis. In addition, in several animal models, angiotensin receptor blockade was able to inhibit atherosclerosis. However, the effects of angiotensin receptor blockers on clinical outcome in cardiovascular patients remains to be established. Contradictory results have been found on the reduction of the risk on myocardial infarctions and in-stent restenosis, although there is solid evidence for cerebroprotective effects of these receptor blockers. These differences may be related to the role of the AT2 receptor. This review discusses the role of angiotensin II and angiotensin receptor blockers in the atherosclerotic process and its translation into clinical practice.     

Drug interactions with angiotensin receptor blockers

Many patients with high blood pressure receive multiple medications for hypertension and other conditions, placing them at risk for adverse drug interactions. Additionally, as the prevalence of hypertension increases with age, factors like greater frailty, comorbidity of the elderly requiring polypharmacy, and reduced hepatic and renal clearance rates for the elimination of drugs increase the likelihood of drug interactions. Angiotensin receptor blockers (ARBs) are the most recent class of agents for the treatment of hypertension. Due to a favourable side effect profile, this class of drugs deserves increased attention. This article reviews drug interactions of ARBs and suggests measures for reducing the risk of adverse events when drugs are co-administered. MEDLINE, EMBASE, Cochrane library, and CINAHL were searched. Reported and likely clinical relevant interactions of ARBs with concomitantly given drugs are summarised in Table 2 and 3. Compared to other classes of antihypertensive agents, the ARBs appear to have a low potential for drug interactions; however, interactions with this class occur and variations within the class have been detected, mainly due to different affinities for cytochrome P450 isoenzymes.     

Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.     

Therapeutic potential of angiotensin receptor blockers in hypertension

The renin-angiotensin-aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin II receptor blockers (ARBs) inhibit angiotensin II type 1 receptors and large clinical trials have shown that they are effective in many cardiovascular diseases including hypertension, heart failure, myocardial infarction and diabetic nephropathy. They lower blood pressure effectively, are very well tolerated and can be used as monotherapy or in combination with other drug classes for the treatment of hypertension. ARBs are particularly suitable for hypertensive patients with co-morbidities such as diabetes, microalbuminuria, proteinuria, left ventricular hypertrophy and heart failure. Unlike angiotensin-converting enzyme inhibitors, ARBs do not cause persistent dry cough. For patients in whom angiotensin-converting enzyme inhibitors are indicated but not tolerated, an ARB should be considered. Periodic monitoring of renal function and electrolytes is required in patients treated with an ARB.     

Therapeutic potential of angiotensin receptor blockers in hypertension

The renin–angiotensin–aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin II receptor blockers (ARBs) inhibit angiotensin II type 1 receptors and large clinical trials have shown that they are effective in many cardiovascular diseases including hypertension, heart failure, myocardial infarction and diabetic nephropathy. They lower blood pressure effectively, are very well tolerated and can be used as monotherapy or in combination with other drug classes for the treatment of hypertension. ARBs are particularly suitable for hypertensive patients with co-morbities such as diabetes, microalbuminuria, proteinuria, left ventricular hypertrophy and heart failure. Unlike angiotensin-converting enzyme inhibitors, ARBs do not cause persistent dry cough. For patients in whom angiotensin-converting enzyme inhibitors are indicated but not tolerated, an ARB should be considered. Periodic monitoring of renal function and electrolytes is required in patients treated with an ARB.     

The role of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in the management of diabetic complications

Evidence suggests that ACE inhibitors can be advantageous for prevention and halting progression of both micro- and macrovascular complications in patients with diabetes mellitus. ACE inhibitors are useful antihypertensive agents in both type 1 and type 2 diabetes; however, ACE inhibitor therapy often needs to be supplemented with calcium channel antagonists, beta-blockers or diuretics to achieve good blood pressure control. ACE inhibitors are also indicated in non-hypertensive patients with type 1 and type 2 diabetes who have micro- or macroalbuminuria. The effect of ACE inhibitors in halting the development and progression of retinopathy and, potentially, neuropathy needs further proof in large-scale studies. More recently, angiotensin II receptor antagonists are emerging as drugs with the potential to be successfully included in the management of diabetic complications, especially when ACE inhibitors are not suitable because of adverse effects.     

我院血管紧张素Ⅱ受体拮抗剂的用药分析

目的:分析血管紧张素Ⅱ受体拮抗剂(ARB)的临床用药情况。方法:分别统计ARB药品用药频度(DDDs)、销售金额和平均日费用;比较2004-2006年ARB与血管紧张素转化酶抑制药(ACEI)的使用情况。结果:2001-2003年ARB平均日费用为7.66元,2004-2006年为6.81元,下降9.79%。ARB类药物每年销售总金额和DDDs均在增长,但增长速度逐年减弱,2004-2006年期间缬沙坦、厄贝沙坦2药的DDDs占总ARB类药物的DDDs的百分比分别为81.20%,82.05%,80.08%。平均日费用ARB类药物是ACEI的1.85倍。结论:ARB作为新型降压药,发展潜力巨大,但其日均费用较高,影响了临床使用。     

The use of angiotensin receptor blockers in the treatment of chronic heart failure

Angiotensin receptor blockers (ARBs) have a pharmacological role in the treatment of heart failure through their blockade of the effects of angiotensin II. ARBs, however, lack the potential benefits of inhibiting the breakdown of bradykinin that is seen with ACE-Is. Historically, the medical literature assessing ARBs in the treatment of chronic heart failure have been short in duration and primarily focused on surrogate markers of disease severity. Recent, well-designed clinical trials have shed new light on the potential roles of ARBs in the treatment of chronic heart failure and their effects on mortality in this patient population. In comparison to captopril, losartan has been shown to have similar benefits in cardiovascular mortality and morbidity. In patients with systolic dysfunction who are intolerant to ACE-Is, candesartan has been shown to reduce cardiovascular mortality and hospital admissions for heart failure. In combination with ACE-Is, candesartan and valsartan have been shown to improve heart failure morbidity and, with candesartan, reduced cardiovascular mortality in those with systolic dysfunction. These 2 trials show conflicting mortality information regarding the use of triple therapy with ACE-Is, ARBs, and beta-blockers for systolic dysfunction. In patients with heart failure but preserved systolic dysfunction, candesartan showed no effects on mortality and only modest effects on morbidity.     

The role of angiotensin II type 1 receptor antagonists in elderly patients with hypertension

Hypertension is a major risk factor for stroke and coronary events in elderly people and clinical trials have shown that treatment of hypertension with various drugs can result in a substantial reduction in cerebrovascular and cardiovascular events. The angiotensin II type 1 (AT1) receptor antagonists are the newest class of antihypertensive agents to be used widely in clinical practice. AT1 receptor antagonists can generally be given once-daily. They are also extremely well tolerated with minimal first-dose hypotension and an incidence of adverse effects similar to that seen with placebo. Adverse event rates are significantly lower than with other classes of antihypertensive drugs including ACE inhibitors. These factors result in improved compliance and increased rates of continuance on therapy. AT1 receptor antagonists show similar efficacy in lowering blood pressure to other classes of antihypertensive agents and their antihypertensive effect is potentiated when they are given concomitantly with low-dose thiazide diuretics. AT1 receptor antagonists are eliminated predominantly by the hepatic route but most are not subject to extensive metabolism and interactions with other drugs are uncommon. This is an advantage in the elderly, who are often receiving multiple medications which increases the risk for adverse drug interactions. Dose adjustments are not usually required in the elderly unless there is plasma volume depletion. Although plasma AT1 receptor antagonist concentrations are generally higher in the elderly than in younger subjects, this pharmacokinetic difference may be balanced by decreased activation of the circulating renin-angiotensin-aldosterone system in the elderly. Recent clinical studies in high-risk hypertensive patients with left ventricular hypertrophy or in patients with diabetic nephropathy or heart failure have demonstrated that AT1 receptor antagonists can improve clinical outcomes to a similar or sometimes greater extent than other antihypertensive agents. Many of these studies have included large numbers of older patients and have confirmed the excellent tolerability profile of these drugs. Thus, AT1 receptor antagonists should be considered as a possible first-line treatment or as a component of combination therapy in patients with type 2 diabetes mellitus and microalbuminuria or nephropathy and as an alternative or additional treatment to ACE inhibitors in patients with heart failure or left ventricular dysfunction. AT1 receptor antagonists also appear to reduce the onset of new diabetes compared with some other antihypertensive drugs. The benefits in terms of organ protection have mainly been seen in studies using higher doses of particular AT1 receptor antagonists and it is not certain at present whether these results can be extrapolated to other members of the class. As the elderly are more likely to have developed organ damage related to hypertension or to have heart failure or diabetes as concomitant conditions, AT1 receptor antagonists represent an appropriate option for many elderly patients. The main disadvantage of these drugs is the cost of the medication but this may be offset by their improved tolerability with fewer adverse reactions and thus increased compliance, resulting in better blood pressure control and fewer clinical events. Overall, AT1 receptor antagonists are well tolerated and efficacious for blood pressure-lowering when given as a single daily dose in elderly patients and have many potential benefits in high-risk hypertensive subjects.     

血管紧张素受体拮抗剂在慢性肾脏病中的应用

目前,已经公认血管紧张素Ⅱ(AngiotensinⅡ,AngⅡ)与许多肾脏疾病的发展过程密切相关。随着对肾素-血管紧张素系统(ReninAngiotensinSystem,RAS)的主要效应因子AngⅡ及血管紧张素受体的深入研究,血管紧张素受体拮抗剂(Angiotensin Receptor Blockers,ARB)因能更完全地阻断RAS,因此,在肾脏疾病的治疗中逐步得到应用。本文对近年来ARB药物的特点、在治疗肾脏疾病中的应用等问题做一介绍。     

Comparison between the antiproteinuric effects of the calcium channel blockers benidipine and cilnidipine in combination with angiotensin receptor blockers in hypertensive patients with chronic kidney disease

Aims: Benidipine, an L-/T-type calcium channel blocker, dilates renal efferent and afferent arterioles and reduces glomerular pressure; therefore, it may exert renoprotective effects. We conducted an open-labeled randomized trial to compare the effects of benidipine with cilnidipine in hypertensive patients with chronic kidney disease (CKD).

Methods: The patients who were already being treated with angiotensin receptor blockers (ARBs) received one of the following treatment regimens: benidipine at a dose of 2 mg/day that was increased up to a dose of 8 mg/day (benidipine group; n = 118) or cilnidipine at a dose of 5 mg/day that was increased up to a dose of 20 mg/day (cilnidipine group; n = 115).

Results: After 12 months of treatment, we observed a significant and comparable reduction in the systolic and diastolic blood pressure in both groups. The urinary protein:creatinine ratio was significantly decreased in both groups after 3 months of treatment and thereafter; however, the difference between both groups was not significant after 12 months of treatment. Benidipine exerted an antiproteinuric effect to a greater extent than cilnidipine in patients with diabetes.

Conclusion: The addition of benidipine as well as cilnidipine reduces urinary protein excretion in hypertensive patients with CKD who are already being administered ARBs.     

Effects of angiotensin receptor blockers on endothelial nitric oxide release: the role of eNOS variants

AIM

Angiotensin II receptor blockers (ARBs) improve endothelial cell (EC)-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide (NO) synthase (eNOS) function. To investigate this question, we tested the effects of various ARBs on NO release in ECs from multiple donors, including those with eNOS genetic variants linked to higher cardiovascular risk.

METHODS

The effects of ARBs (losartan, olmesartan, telmisartan, valsartan), at 1 µm, on NO release were measured with nanosensors in human umbilical vein ECs obtained from 18 donors. NO release was stimulated with calcium ionophore (1 µm) and its maximal concentration was correlated with eNOS variants. The eNOS variants were determined by a single nucleotide polymorphism in the promoter region (T-786C) and in the exon 7 (G894T), linked to changes in NO metabolism.

RESULTS

All of the ARBs caused an increase in NO release as compared with untreated samples (P < 0.01, n = 4–5 in all eNOS variants). However, maximal NO production was differentially influenced by eNOS genotype. Olmesartan increased maximal NO release by 30%, which was significantly greater (P < 0.01, n = 4–5 in all eNOS variants) than increases observed with other ARBs.

CONCLUSIONS

The ARBs differentially enhanced NO release in ECs in a manner influenced by eNOS single nucleotide polymorphisms. These findings provide new insights into the effects of ARBs on EC-dependent vasodilation and eNOS function.     

The therapeutic potential of angiotensin II receptor blockers in the treatment of heart failure

Background: Epidemiological data link erectile dysfunction (ED) and lower urinary tract symptoms (LUTS), two highly prevalent conditions in men, assuming a common pathophysiology. Preliminary data showed that phosphodiesterase type 5 inhibitors (PDE5i) might be a promising class of drugs also for LUTS. Objective: The aim of this review is to provide an overview of current knowledge on the association between ED and LUTS with a particular focus on PDE5i as a viable treatment option for LUTS. Methods: A Medline search was completed using the Medical Subject Headings (MESH^® keywords) ‘erectile dysfunction’ and the expression ‘lower urinary tract symptoms’ in all fields of the database. This search revealed 122 relevant references (all Medline database until 31 October 2008). Results/conclusions: LUTS are an independent risk factor for ED. Although the pathophysiological link between these conditions is not clear, several theories have been described with various levels of supporting data. Current data show that PDE5i reduce obstructive and irritative voiding symptoms but have no effect in uroflowmetry parameters of postvoid residual volume. The combination with α-adrenergic antagonists may be another treatment option for LUTS. However, further research is needed to establish efficacy and safety of PDE5i in the treatment of LUTS.     

The therapeutic potential of angiotensin II receptor blockers in the treatment of heart failure

In clinical heart failure (HF) the renin-angiotensin-aldosterone system is an important component of neurohormonal activation. Angiotensin-converting enzyme inhibitors have been shown to be of great clinical benefit in reducing the production of angiotensin II. However, they do not fully suppress angiotensin II production in HF because there are other pathways through which angiotensin II can be produced. Theoretically, angiotensin II receptor blockers (ARBs) have great potential because of their ability to directly block angiotensin II produced through any pathway. A large body of literature has accumulated examining the effects of ARBs in HF. The earlier, smaller studies examined outcomes such as symptoms, neurohormonal concentrations and cardiac function. More recent, larger studies have examined the effects of ARBs on mortality and morbidity. This paper reviews the data defining the role of ARBs in the treatment of HF patients, focusing more on the large randomised clinical outcome trials.