Current Pharmaceutical Design - Volume 21, Issue 6, 2015

Blood pressure (BP) is traditionally assessed, for centuries, at the brachial artery by cuff-based sphygmomanometric techniques. Technological and methodological innovations as well as emerging new findings from clinical studies and trials now provoke a re-consideration of traditional strategies for BP management. The existing knowledge regarding the occurring changes of BP over time (temporal variability) and the evident differences of BP levels between central and peripheral arteries (spatial variability) now pilots the progress in current therapeutic and diagnostic (“theranostic”) concepts and practices in hypertension. This special issue of Current Pharmaceutical Design covers current and intriguing topics regarding the technological, physiological, diagnostic, therapeutic and prognostic aspects of “spatio-temporal” assessment of BP variations. Moreover an in-depth analysis of other topics such as antihypertensive drugs metabolism and polypharmacy at the elderly are included.

The profound observations of William Harvey (1578-1657), in blood circulation and the progress of physical science laid the foundation for the development of the Iatrophysical School that contributed to the evolution of clinical sphygmomanometry. The pioneer work of Reverend Stephen Hales (1677-1761) demonstrated the dynamics of the vascular system. One century later the French physician Jean-Léonard-Marie Poiseuille (1797-1867) invented a U-tube mercury manometer and in 1860 the physiologist Etienne- Jules Marey (1830-1904) devised the first portable sphygmograph for recording the pulse wave. The non-invasive techniques of blood pressure measurement were completed by Scipione Riva-Rocci (1896-1937) sphygmomanometer and the description of “Korotkov sounds” by the Russian surgeon Nikolai- Sergeyevich Korotkov (1874-1920).

Hypertension provoked since the beginning of the 19th century a medical debate between physicians. The early antihypertensive agents were poorly tolerated. Progress towards more effective drugs, appeared after the 2nd World War. Thiocyanates, dehydrogenated alkaloids of ergot, barbiturates, bismuth and bromides, were soon replaced by phenoxbenzamine, hexamethonium, pentolinium, and mecamylamine. Thiazide diuretics were the biggest breakthrough during the early 1960's. Then Beta(β)-blockers and angiotensinconverting enzyme inhibitors heralded a new era, until 1995, when losartan, the first non-peptide anti-hypertensive drug, was introduced. The plethora of the antihypertensive drugs changed the relationship between physicians and patients, pushed medicine towards prevention, and altered the medical marketing forever.

While for years clinicians have used cuff pressure to assess patients’ cardiovascular risk, recent evidences has shown that aortic pressure, or more specifically aortic systolic and aortic pulse pressures, have a better prognostic value to predict cardiovascular events and mortality. This led to the emergence of multiple methods and devices to assess aortic pressure non-invasively. Some use scaled waveforms measured at the carotid level with tonometry, or ultrasounds. Others use transfer function or mathematical modelling from radial or brachial traces acquired from volume plethsymography or applanation tonometry. Not all these techniques are equivalent and most of them have the major flaw of using brachial cuff pressure to scale their results. The purpose of this review is to present the strengths and weaknesses of techniques and various commercial devices to estimate aortic systolic pressure.

Although the clinical relevance of brachial blood pressure (BP) measurement for cardiovascular (CV) risk stratification is nowadays widely accepted, this approach can nevertheless present several limitations. Pulse pressure (PP) amplification accounts for the notable increase in PP from central to peripheral arterial sites. Target organs are more greatly exposed to central hemodynamic changes than peripheral organs. The pathophysiological significance of local BP pulsatility, which has a role in the pathogenesis of target organ damage in both the macro- and the microcirculation, may therefore not be accurately captured by brachial BP as traditionally evaluated with cuff measurements. The predictive value of central systolic BP and PP over brachial BP for major clinical outcomes has been demonstrated in the general population, in elderly adults and in patients at high CV risk, irrespective of the invasive or non-invasive methods used to assess central BP. Aortic stiffness, timing and intensity of wave reflections, and cardiac performance appear as major factors influencing central PP. Great emphasis has been placed on the role of aortic stiffness, disturbed arterial wave reflections and their intercorrelation in the pathophysiological mechanisms of CV diseases as well as on their capacity to predict target organ damage and clinical events. Comorbidities and age-related changes, together with gender-related specificities of arterial and cardiac parameters, are known to affect the predictive ability of central hemodynamics on individual CV risk.

Reduction strategies of blood pressure, as a modifiable cardiovascular risk, are currently based on office assessment of brachial artery blood pressure. However, antihypertensive treatment based on brachial BP values reduces cardiovascular risk but cannot completely reverse the hypertension-induced risk of morbidity events. As is well known, BP varies in different arterial systems and invasive and non-invasive studies have demonstrated that brachial BP does not necessarily reflect central aortic BP. Emerging evidences now suggest that central pressure may predict cardiovascular diseases better than brachial BP; moreover, it may differently respond to certain antihypertensive drugs. The potential effects beyond peripheral BP control may be due to specific protective properties of different antihypertensive drugs in affecting central aortic pressure and arterial stiffness. Although data on direct cardiovascular benefit impact of central blood pressure treatment in randomized clinical trials are still lacking, it is likely that the improvement of quality of care and the individualized assessment of the hypertension-associated cardiovascular risk are achievable with the use of central hemodynamics. Therefore, basing antihypertensive treatment guidance on central pressures rather than on peripheral blood pressure may be the key for future antihypertensive strategies.

Differences in blood pressure measurements between arms are commonly encountered in clinical practice. If such differences are not excluded they can delay the diagnosis of hypertension and can lead to poorer control of blood pressure levels. Differences in blood pressure measurements between arms are associated cross sectionally with other signs of vascular disease such as peripheral arterial disease or cerebrovascular disease. Differences are also associated prospectively with increased cardiovascular mortality and morbidity and all cause mortality. Numbers of publications on inter-arm difference are rising year on year, indicating a growing interest in the phenomenon. The prevalence of an inter-arm difference varies widely between reports, and is correlated with the underlying cardiovascular risk of the population studied. Prevalence is also sensitive to the method of measurement used. This review discusses the prevalence of an inter-arm difference in different populations and addresses current best practice for the detection and the measurement of a difference. The evidence for clinical and for vascular associations of an inter-arm difference is presented in considering the emerging role of an inter-arm blood pressure difference as a novel risk factor for increased cardiovascular morbidity and mortality. Competing aetiological explanations for an inter-arm difference are explored, and gaps in our current understanding of this sign, along with areas in need of further research, are considered.

Blood pressure variability (BPV) is considered nowadays a novel risk factor for cardiovascular disease. Clinical evidences support that short-term and long-term BPV independently contribute to target organ damage, cardiovascular events and mortality in patients with hypertension or diabetes. Attenuation of excessive fluctuations of systolic and diastolic BPV has been suggested as an additional therapeutic target in cardiovascular prevention. A growing number of preclinical and clinical studies have focused in the assessment of drug effects or other interventions on the different types of BPV and their contribution in the prevention of cardiovascular events. Prospective clinical trials have shown that antihypertensive classes differ in their ability to control excessive BP fluctuations with an impact in clinical outcomes. Current evidences suggest that calcium channel blockers are more effective than other blood pressure lowering drugs for the reduction of short-term, mid-term and long-term BPV. In order to increase actual knowledge regarding the therapeutic significance of BPV in cardiovascular disease, there is a need for additional clinical studies specifically designed for the study of the relevance of short-term and long-term BPV control by antihypertensive drugs.

Elevated nighttime blood pressure (BP) and a reduced day-night BP fall ("nondipping" condition) are strong predictors of cardiovascular complications, both in hypertension and in the general population. A reduced or inverted nocturnal BP fall might also be theoretically used to define the most appropriate timing for drug administration. In a systematic review of the available evidence, we show that bedtime dosing of antihypertensive medication reduces nocturnal BP and increases day-night BP fall more than standard morning dosing. The effects of such an approach on average 24-hour BP are more modest and less univocal, with a considerable betweencenter heterogeneity. Admittedly, the mechanisms underlying non-dipping condition have not been fully understood yet, and it is still a matter of debate whether restorating a dipping pattern may reduce the cardiovascular risk associated with non-dipping independently from the effects on 24-hour BP. Under this regard, evidence from a single trial strongly suggests that bedtime dosing of antihypertensive medications may greatly reduce cardiovascular morbidity in hypertensive patients. The provocative results of that trial deserve to be explored further in larger intervention trials.

Recent findings indicate cardiovascular disease (CVD) risk is best predicted by asleep systolic blood pressure (SBP), and lowering it by scheduling ≥1 conventional long-acting hypertension medications, alone or in combination, at bedtime significantly lessens vascular-associated risks. Some 20 years ago, four controlled-onset extended-release drug-delivery systems incorporating a calcium channel or β-blocker, with the treatment goal specifically being attenuation of morning rather than asleep BP, were conceived as one type of bedtime hypertension chronotherapy. However, the CONVINCE outcomes trial failed to substantiate the merit of targeting morning and daytime BP to decrease CVD risk. The HOPE trial, entailing bedtime ramipril treatment for high CVD risk patients, showed substantial reduction of vascular-related events, theorized as the beneficial treatment-time-dependent strong asleep BP lowering. The MAPEC trial was the first prospective randomized treatment-time outcomes investigation to test the worthiness of bedtime hypertension chronotherapy entailing ≥1 conventional long-acting medications (BTCT), in comparison to the conventional morning-time therapeutic scheme for all medications (CMTT), to normalize asleep BP and diminish CVD risk. BTCT compared to CMTT significantly better lowered asleep BP and most importantly major CVD-associated morbidity and mortality, including myocardial infarction and ischemic and hemorrhagic stroke, by ~60%. CVD risk reduction was strongest when the BTCT included an angiotensin receptor blocker. The HOPE and MAPEC trials provide positive evidence of very significant CVD risk reduction by a BTCT strategy that specifically targets normalization of asleep BP, evidence that awaits conformation by the ongoing Hygia and other outcomes trials.

Clinical medicine faces many challenges, e.g. applying personalized medicine and genomics in daily practice; utilizing highly specialized diagnostic technologies; prescribing costly therapeutics. Today’s population is aging and patients are diagnosed with more co-morbid conditions than in the past. Co-morbidity makes management of the elderly difficult also in terms of pharmacotherapy. The high prevalence of hypertension and diabetes as co-morbidities is indicative of the complexities that can impact accuracy in diagnosis and treatment, with poly-pharmacy being a significant component. It is essential to apply analytic methods to evaluate retrospective data to understand real world patients and medical practice. This study applies social network analysis, a novel method, to administrative data to evaluate the scope and impact of poly-pharmacy and reveal potential problems in management of elderly patients with diabetes and hypertension. Social Network Analysis (SNA) enables the examination of large patient data sets to identify complex relationships that may exist and go undetected either because of infrequent observation or complexity of the interactions. The application of SNA identifies critical aspects derived from over-connected portions of the network. These criticalities mainly involve the high rate of poly-pharmacy that results from the observation of additional co-morbid conditions in the study population. The analysis identifies crucial factors for consideration in developing clinical guidelines to deal with real-world patient observations. The analysis of routine health data, as analyzed using SNA, can be further compared with the inclusion/exclusion criteria presented in the current guidelines and can additionally provide the basis for further enhancement of such criteria.

Drug discovery and development is a high-risk enterprise that requires significant investments in capital, time and scientific expertise. The studies of xenobiotic metabolism remain as one of the main topics in the research and development of drugs, cosmetics and nutritional supplements. Antihypertensive drugs are used for the treatment of high blood pressure, which is one the most frequent symptoms of the patients that undergo cardiovascular diseases such as myocardial infraction and strokes. In current cardiovascular disease pharmacology, four drug clusters - Angiotensin Converting Enzyme Inhibitors, Beta-Blockers, Calcium Channel Blockers and Diuretics - cover the major therapeutic characteristics of the most antihypertensive drugs. The pharmacokinetic and specifically the metabolic profile of the antihypertensive agents are intensively studied because of the broad inter-individual variability on plasma concentrations and the diversity on the efficacy response especially due to the P450 dependent metabolic status they present. Several computational methods have been developed with the aim to: (i) model and better understand the human drug metabolism; and (ii) enhance the experimental investigation of the metabolism of small xenobiotic molecules. The main predictive tools these methods employ are rule-based approaches, quantitative structure metabolism/activity relationships and docking approaches. This review paper provides detailed metabolic profiles of the major clusters of antihypertensive agents, including their metabolites and their metabolizing enzymes, and it also provides specific information concerning the computational approaches that have been used to predict the metabolic profile of several antihypertensive drugs.

High blood pressure (BP) is an important risk factor for stroke and ischaemic heart disease. Yet, despite the availability of effective drugs, it is generally poorly controlled. Partly this is because some patients do not adhere to treatment regimens and partly because clinicians either measure BP insufficiently frequently or are not rigorous in applying treatment guidelines. Additionally individual surgery measurements of BP provide a poor prediction of cardiovascular risk. Methods using multiple BP measures provide more accurate estimates of risk and response to treatment. Self-monitoring of blood pressure at home overcomes this problem, but alone has not been conclusively shown to lower BP. There is now strong evidence from several randomised controlled trials that using telemetry to communicate home BP measures to healthcare providers (telemonitoring) is associated with highly statistically and clinically significant reductions in BP. However the studies have been of relatively short duration and it is not known if these reductions would be sustained in the long term, nor have any of the studies been at large scale. While there are challenges to implementing telemonitoring at scale there is a need for large implementation trials over relatively prolonged periods to establish the efficacy of such an approach in routine care.