Antihypertensive therapy: special focus on drug interactions

Today, the lifetime risk of patients aged 55-65 years to receive antihypertensive drugs approaches 60%. Yet, recent trials suggest that hypertension is not adequately controlled in the majority of patients. The prevalence of hypertension increases with advancing age, as does the prevalence of comorbid conditions and the total number of medications taken. Multi-drug therapy, advancing age and comorbid conditions are also key risk factors for adverse drug reactions and drug interactions. In this review, the authors evaluate the most frequently used antihypertensive drugs (diuretics, beta-adrenergic blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotensin II receptor Type 1 blockers and alpha-adrenergic blockers) with special reference to pharmacodynamic and pharmacokinetic drug interactions. As the spectrum of drugs prescribed is constantly changing, safety yesterday does not imply safety today and safety today does not imply safety tomorrow. Furthermore, therapeutic efficacy should not be neglected over concerns regarding drug interactions. Many patients are at risk of clinically relevant drug interactions involving antihypertensive drugs but, presently, even more patients may be at risk of suffering from the consequences of their inadequately treated hypertension. In this respect, the authors discuss controversial viewpoints on the overall clinical relevance of drug interactions occurring at the level of cytochrome P450 metabolism.     

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.     

常用降压药物的相互作用

高血压是心脑血管疾病的主要危险因素之一,安全和有效的控制血压是降低心脑血管疾病风险必不可少的措施。本文简单介绍了常用的5种降压药物（利尿剂、钙拮抗剂、β肾上腺素受体阻滞剂、血管紧张素转换酶抑制剂、血管紧张素Ⅱ受体阻滞剂）联合应用的原则,重点介绍这5种降压药物联合应用时可能产生的药物相互作用,以及与其它非降压药物联合应用时可能产生的药物相互作用。旨在引起临床关注联合治疗中药物的相互作用和对用药安全产生的影响。     

Antihypertensive agents acting on the renin–angiotensin system and the risk of sepsis

AimsIn response to safety concerns from two large randomized controlled trials, we investigated whether the use of telmisartan, an angiotensin receptor blocker (ARB), ARBs as a class and angiotensin-converting enzyme inhibitors (ACEIs) increase the risk of sepsis, sepsis-associated mortality and renal failure in hypertensive patients.MethodsWe performed a nested case–control study from a retrospective cohort of adults with hypertension from the UK General Practice Research Database diagnosed between 1 January 2000 and 30 June 2009. All subjects hospitalized with sepsis during follow-up were matched for age, sex, practice and duration of follow-up with 10 control subjects. Exposure was defined as current use of antihypertensive drugs.ResultsFrom the cohort of 550 436 hypertensive patients, 1965 were hospitalized with sepsis during follow-up (rate 6.9 per 10 000 per year), of whom 824 died and 346 developed acute renal failure within 30 days. Compared with use of β-blockers, calcium-channel blockers or diuretics, use of ARBs, including telmisartan, was not associated with an elevated risk of sepsis (relative risk 1.09; 95% confidence interval 0.83–1.43); but use ACEIs was (relative risk 1.65; 95% confidence interval 1.42–1.93). Users of ARBs, β-blockers, calcium-channel blockers or diuretics, but not users of ACEIs, had lower rates of hospitalization for sepsis compared with untreated hypertensive patients. Findings were similar for sepsis-related 30 day mortality and renal failure.ConclusionsHypertensive patients treated with ARBs, including telmisartan, do not appear to be at increased risk of sepsis or sepsis-related 30 day mortality or renal failure. On the contrary, users of ACEIs may have an increased risk.     

Non‐adherence to antihypertensive medication and impaired cognition: which comes first?

Objective Antihypertensive medications are important in the prevention of serious consequences of hypertension, such as stroke and heart failure. Up to one‐third of elderly hypertensive patients, however, do not adhere to their medication. Adherence to medication decreases with increasing age, and with decreasing cognitive ability, thus elderly, cognitively‐impaired patients have poorer control of blood pressure. Good control of blood pressure is associated with decreased prevalence of dementia and Alzheimer's disease. This study assessed the evidence that antihypertensive medications have effects on the prevalence or severity of mild cognitive impairment, dementia or Alzheimer's disease. Methods The ISI Web of Knowledge database was searched; including replicates, the nine searches identified 14 400 publications since 1952, of which 9.9% had been published in 2009. This review considers the 18 studies meeting the set criteria published in 2009 or later. Key findings Not all antihypertensive medications are equivalent in their positive cognitive effects, with brain‐penetrating angiotensin‐converting‐enzyme inhibitors and possibly angiotensin receptor antagonists being the most effective. Conclusions Based on evidence of blood‐pressure control and cost, UK National Institute for Health and Clinical Excellence guidelines recommend calcium‐channel blockers or thiazide‐type diuretics for the treatment of hypertension in patients over 55 years. These guidelines take no account of the potential cognitive effects of the antihypertensive therapies, consideration of which might lead to a review. There may be benefit in stressing that adherence to antihypertensive medication not only decreases the risk of cardiovascular disease and death, but may also decrease the risk or severity of mild cognitive impairment, dementia and Alzheimer's disease.     

某高校社区门诊离退休教工抗高血压药的使用分析

目的了解和分析某社区门诊离退休教工抗高血压药的使用情况。方法抽查1 264例(2011年3月)门诊离退休高血压患者处方,详细统计及分析。结果 5大类抗高血压药中,钙拮抗药(CCB)使用率最高,达到51.91%,β-肾上腺素受体阻滞药(β-阻滞药)占14.49%,血管紧张素转化酶抑制药(ACEI)占9.22%,血管紧张素Ⅱ受体抑制药(ARB)占11.33%,利尿药占1.45%。采用单种抗高血压药治疗1 018例(占80.54%),联合使用2种或2种以上抗高血压药246例(占19.46%),利尿药联合使用率占13.82%。结论该社区门诊抗高血压药的种类及联合用药符合《中国高血压防治指南》的要求,基本合理规范,但抗高血压药物联合应用较少、利尿药的使用率偏低。     

Hypertension management and control in primary care: a study of 20 practices in 14 states

STUDY OBJECTIVE: To describe the management and control of hypertension in primary care practice. DESIGN: Retrospective medical record review. SETTING: Twenty primary care practices in 14 states. PATIENTS: Thirteen thousand forty-seven patients with hypertension. MEASUREMENTS AND MAIN RESULTS: Diagnoses, drugs prescribed, and blood pressure readings were extracted from the electronic medical record at each practice in the study. For patients with hypertension and comorbid diagnoses, the most recent blood pressure and antihypertensive drugs prescribed were determined. Analyses assessed the blood pressure control rates and the association between control and demographic variables, frequency of visits to the practice site, and pharmacologic treatment patterns. Among the 20 practices in the study, 13,047 patients had received a diagnosis of hypertension and their blood pressures had been measured within the previous 12 months. One third of the patients had comorbid coronary heart disease, diabetes mellitus, heart failure, and/or renal insufficiency. The most recent blood pressure reading was below 140/90 in half the patients. Control was associated with age 60 years or younger, female sex, more than one visit to the practice, more than one comorbidity, and type of practice (p<0.01, logistic regression). Wide variability was noted among practices in the use of multiagent antihypertensive therapy, and in antihypertensive therapy by drug class. Among patients without comorbidity treated with one drug, systolic blood pressure did not differ significantly by drug class. Diastolic blood pressure was slightly lower in patients prescribed thiazide diuretics than in those prescribed angiotensin receptor blockers (p=0.03, analysis of covariance). CONCLUSION: Blood pressure control in primary care practice can be much better than reports usually indicate. Good control in this study was not due to specific drug choice, but instead may have been due to regular monitoring of blood pressure and motivation of the practice to improve patient care.     

Antihypertensive efficacy of olmesartan medoxomil alone and in combination with hydrochlorothiazide

Angiotensin receptor blockers (ARBs) are highly effective antihypertensive agents with excellent safety profiles. ARBs have been shown to improve cardiovascular morbidity and mortality in hypertensive patients with heart failure or diabetic nephropathy. For this later class of patients, the American Diabetes Association recommends ARBs as the primary treatment option. The ARBs function by blocking the binding of angiotensin-II (A-II) to its receptor, thereby inhibiting the action of A-II. Unlike the angiotensin-converting enzyme (ACE) inhibitors, which block the production of A-II through the ACE pathway, the ARBs effectively inhibit A-II regardless of whether it is produced through ACE or some alternate enzyme pathway. This difference in action offers a distinct advantage of ARBs over ACE inhibitors. Olmesartan medoxomil, the latest addition to the ARB class, is a long-acting, safe and well-tolerated antihypertensive drug. The combination of olmesartan medoxomil with a low-dose diuretic, potentiates the blood pressure lowering effect of either agent alone and is highly effective in achieving the recommended blood pressure goals in the majority of patients treated.     

A complicated role for the renin–angiotensin system during pregnancy: highlighting the importance of drug discovery

Introduction: Blood pressure management is recommended to avoid maternal cerebrovascular or cardiovascular compromise during pregnancy. Current antihypertensive treatment during pregnancy with positive safety profiles includes labetalol, hydralazine, methyldopa and nifedipine.

Areas covered: Many earlier animal and human studies indicate that angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are associated with fetopathy; therefore, these drugs are contraindicated during pregnancy, especially if these medications were taken during the second and third trimesters. The role of the RAS is quite complex, with fetal development heavily dependent on its appropriate expression and function. New findings indicate that the placental unit expresses its own RAS in order to regulate angiogenesis. Multiple studies have shown that women with abnormal uterine doppler sonography produce an agonistic autoantibody to the angiotensin I receptor, implicating a role for RAS function and regulation in abnormal pregnancies. Importantly, interruption of a normal RAS compromises fetal development.

Expert opinion: Traditional medications that inhibit components of RAS for long-term hypertension control are not appropriate for use before or during pregnancy. Further study and drug discovery are needed to find alternative pathways for treatment of hypertensive disorders when pregnancy is present or a possibility.     

Eprosartan for the treatment of hypertension

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT₁) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT₁ receptors (postsynaptically) and at presynaptic AT₁ receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.     

Targeting angiotensin II type I receptors to reduce the risk of stroke in patients with hypertension

The incidence of stroke is rising among the elderly population. Hypertension is the single most important contributor to stroke, and hypertension treatment and control is the most important intervention to prevent it. Blood pressure reduction by any means will substantially reduce the risk of stroke. However, accumulating evidence indicates that angiotensin receptor blocker-based regimens may provide additional benefits in the prevention of stroke. This effect seems to be particularly prominent in high-risk patients and patients with isolated systolic hypertension. The pathophysiological mechanisms have not been clearly delineated, but favourable remodelling of the left atrium and reduction of the risk of atrial fibrillation has been suggested. In addition, blockade of the central AT1 receptors and stimulation of AT2 receptors and/or preferential reduction of central pressure by angiotensin receptor blockers may account for the beneficial protective effect.     

Atrial natriuretic peptide contributes to the antihypertensive action of many drugs.

Data derived from a 10 years research program of our team demonstrate that many categories of antihypertensive drugs like beta-adrenergic blockers, alpha1-adrenergic blockers, ACE inhibitors, AT1-receptor antagonists and calcium-entry blockers increase plasma atrial natriuretic peptide (ANP) levels after a medium-term treatment of patients suffering from moderate essential hypertension. ANP always increases despite the drop of the arterial pressure and the fact that the left atrial and ventricular diameters remain unchanged or slightly reduced. These findings indicate that the increase of ANP plasma levels is not the result of a mechanical overload in the left cardiac chambers but the result of a pharmacological action. In conclusion, ANP is a universal factor contributing to the antihypertensive action of many drugs.     

33 398例次肾移植术后高血压患者降血压药物利用分析

目的 分析2015-2018年全国5个城市肾移植术后高血压患者特征及降血压药物使用情况,为临床合理用药提供参考.方法 基于《医院处方分析合作项目》随机抽取的多中心处方大数据,采用世界卫生组织(WHO)推荐的药物利用分析方法,对降血压药物的使用情况进行分析.结果 抽取5个城市共40家三级医院(不含军队医院)共计33 39...     

Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives.

The ever-increasing introduction of new therapeutic agents means that the potential for drug interactions is likely to escalate. Numerous different classes of drugs are currently used to treat hypertension. The angiotensin receptor blockers offer one of the newest approaches to the management of patients with high blood pressure. Compared with other classes of antihypertensive agents, the angiotensin receptor blockers appear overall to have a low potential for drug interactions, but variations within the class have been detected. Losartan and irbesartan have a greater affinity for cytochrome p450 (CYP) isoenzymes and, thus, are more likely to be implicated in drug interactions. There is pharmacokinetic evidence to suggest that such interactions could have a clinical impact. Candesartan cilexetil, valsartan and eprosartan have variable but generally modest affinity and telmisartan has no affinity for any of the CYP isoenzymes. In vitro studies and pharmacokinetic/pharmacodynamic evaluation can provide evidence for some interactions, but only a relatively small number of drug combinations are usually studied in this way. The absence of any pharmacokinetic evidence of drug interaction, however, should not lead to complacency. Patients should be made aware of possible interactions, especially involving the concurrent use of over-the-counter products, and it may be prudent for all patients receiving antihypertensive treatment to be monitored for possible drug interactions at their regular check-ups. The physician can help by prescribing agents with a low potential for interaction, such as angiotensin receptor blockers.     

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.     

Calcium channel blockers in the spectrum of antihypertensive agents

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. Through blood pressure reduction, and possibly other mechanisms such as antioxidative effects, they may play a role in diminishing the risk for a variety of cardiovascular outcomes. The combination of CCBs with other newer antihypertensive agents such, as ACE inhibitors and angiotensin receptor blockers, may provide complementary effects on risk reduction in cardiovascular adverse events and renal disease. Although the efficacy of CCBs as antihypertensive agents has been adequately demonstrated, there have been concerns regarding the use of short acting dihydropyridines after acute myocardial infarction. There have also been questions about the role of CCBs with regards to other antihypertensive agents in renal disease. For example, differential effects of dihydropyridine and non-dihydropyridine CCBs may affect progression of renal disease and risk for diabetes. Certain precautions involving drug interactions are needed because of the effects of CCBs on the CYP450 enzyme systems.     

Focal adhesion kinase in cancer

The metabolic syndrome (MetS) is a strong predictor of cardiovascular morbidity and mortality, as well as new Type 2 diabetes. MetS consists of visceral obesity, elevated blood pressure, impaired glucose metabolism, atherogenic dyslipidaemia (elevated triglycerides and low levels of high-density lipoprotein cholesterol), as well as other metabolic abnormalities. The underlying pathophysiology seems to be largely, but not uniquely, attributable to insulin resistance. Existing antihypertensive drugs were designed to lower blood pressure rather than to modify the metabolic abnormalities associated with hypertension. This review considers the role of renin–angiotensin system inhibition and especially the use of angiotensin receptor blockers (ARBs) in the treatment of hypertension in MetS. There are differences among ARBs. Among them is the uricosuric effect of losartan. Furthermore, telmisartan may function as a partial agonist of the peroxisome proliferator-activated receptor-γ (PPAR-γ).     

Combination therapy for hypertension: focus on high-dose olmesartan medoxomil (40 mg) plus hydrochlorothiazide

Importance of the field: Cardiovascular disease is a major cause of premature death and disability worldwide, and effective blood pressure (BP) control is crucial for the reduction of cardiovascular risk in patients with hypertension. Despite this, many will fail to attain recommended BP goals. A reappraisal of European guidelines led to revised recommendations for BP reduction to values within the SBP/DBP range of 130 – 139/80 – 85 mmHg in all patients with hypertension, including higher-risk groups such as those with diabetes.

Areas covered in this review: The majority of hypertensive patients will require the enhanced blood-pressure-lowering effects of at least two antihypertensive drugs with complementary mechanisms of action to achieve these goals.

What the reader will gain: The angiotensin II receptor blocker (ARB) olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide (HCTZ) provide greater antihypertensive efficacy when used in combination than as monotherapy with either component, with a similar tolerability profile. In addition, there is evidence that higher doses of olmesartan may prolong the antihypertensive effect of this ARB, and a number of US ‘treat-to-target’ and European add-on clinical trials have been conducted to assess the efficacy and safety of high-dose olmesartan plus HCTZ in a wide range of patients with mild-to-severe hypertension.

Take home message: Combination therapy with olmesartan, including the high 40-mg dose, plus HCTZ is an effective and safe treatment option for controlling BP in patients with mild-to-severe hypertension, particularly those who fail to achieve recommended BP goals with monotherapy.     

降压新药血管紧张素Ⅱ受体拮抗剂的研究

高血压会严重损害心脏、大脑和肾脏等靶器官。血管紧张素Ⅱ受体拮抗剂(angiotensinⅡre-ceptor blockers,ARB)是继血管紧张素转换酶抑制剂(angiotension converting enzyme inhibitors,ACEI)后发展起来的一类新型降压药,其降压作用显著,效果持久,能够逆转高血压引起的靶器官损害,并有效降低心血管疾病发生的几率,每天服用一次可以24 h良好控制血压。此外,它克服了ACEI具有的致咳、血管性水肿等不良反应,是目前临床应用的一线降压药。本文对近年来文献报道的活性较高的ARB进行了介绍,并对其分子设计和构效关系进行了阐述,同时介绍了计算机辅助设计在该类药物研发中的应用。