Current Clinical Pharmacology - Volume 8, Issue 3, 2013

Despite the well documented and very effective non pharmacologic and pharmacologic therapies, hypertension remains often poorly controlled. There is still room for improvements in blood pressure control and recent technological advances have generated a regained interest in the physiopathology of renal sympathetic innervation in hypertension. In this article we review the evidence that renal sympathetic activity is increased in essential hypertension. The postganglionic sympathetic fibers are directed to the afferent and efferent renal arterioles, the juxtaglomerular apparatus, the proximal renal tubule, the loop of Henle, as well as the distal renal tubule and are under the control of many reflex loops, which are summarized in a most comprehensive manner for an unfamiliar reader within this field of research. Studies on renal denervation have provided further insights on the role of the sympathetic system in the kidneys, however their proper interpretation requires a special attention to the experimental protocols, as is explained in the text. Last, the possibility of kidney reinnervation is discussed, as well as the emerging evidence that the kidney is also a sensory organ. In summary, this review article provides a strong scientific background to understand not only the mechanisms of the hypotensive effects, but also those of possible pitfalls, of renal denervation.

The present paper reviews the techniques allowing to assess sympathetic activity in humans, highlighting their advantages and limitations. While plasma noradrenaline measurement represents a useful and widely used method to evaluate sympathetic neural function, new approaches, developed starting from the seventies, like direct recording of sympathetic nerve traffic and noradrenaline spillover. These approaches have largely supplanted the plasma noradrenaline approach due to the precise estimation of the behavior of regional sympathetic neural function. The paper in particular will focus the microneurographic technique, considered as the gold standard, and on the new clinical evidences obtained with this technique.

The sympathetic nervous system has a profound effect on the kidney’s ability to regulate blood pressure and, vice versa, the kidney has an important effect on the overall sympathetic tone. As a result, renal sympathetic nerves are crucial for initiation and the maintenance of systemic hypertension. It is fairly well established that efferent renal sympathetic nerve activity contributes significantly to homeostatic regulation of renal blood flow, glomerular filtration rate, renal tubular epithelial cell solute and water transport, and hormonal release. The afferent nerves from the kidney activate central sympathetic nervous system activity, participate in a reflex control system via reno-renal reflexes and are involved in cardiovascular regulation and pathogenesis of hypertension in CKD patients whose kidney ischemia also seems to play a key role. Sympathetic nerve modulation in hypertension had been considered as a therapeutic strategy long before the advent of modern pharmacological therapies. Renal sympathetic denervation with a percutaneous, catheter-based approach results in significant and sustained blood pressure reduction in patients with resistant hypertension. This procedure has also beneficial effects in multiple organs function. However, renal physiology and the long term observed benefits with the use of renal sympathetic denervation have not completely elucidated.

The kidney has been shown to be critically involved as both trigger and target of sympathetic nervous system overactivity in both experimental and clinical studies. Renal injury and ischemia, activation of renin angiotensin system and dysfunction of nitric oxide system have been implicated in adrenergic activation from kidney. Conversely, several lines of evidence suggest that sympathetic overactivity, through functional and morphological alterations in renal physiology and structure, may contribute to kidney injury and chronic kidney disease progression. Pharmacologic modulation of sympathetic nervous system activity has been found to have a blood pressure independent renoprotective effect. The inadequate normalization of sympathoexcitation by pharmacologic treatment asks for novel treatment options. Catheter based renal denervation targets selectively both efferent and afferent renal nerves and functionally denervates the kidney providing blood pressure reduction in clinical trials and renoprotection in experimental models by ameliorating the effects of excessive renal sympathetic drive. This review will focus on the role of sympathetic overactivity in the pathogenesis of kidney injury and CKD progression and will speculate on the effect of renal denervation to these conditions.

In the present review article we address the issue of the potential effect of renal sympathetic denervation (RSD) on metabolic states associated with resistant hypertension. So far, there is an established pathophysiological background denoting that abnormalities in glucose metabolism especially in obese patients and in those with sleep apnea are constantly accompanied by increased sympathetic firing, as assessed by markers of sympathetic activity. Since resistant hypertension is also characterized by enhanced sympathetic activity, it seems logical and biologically plausible, that RSD might favorably influence impaired glucose metabolism, sleep disorders and increased body adiposity beyond BP lowering. Despite the limited evidence from clinical trials, there are promising data suggesting that RSD indeed ameliorates glucose metabolism-related measures in resistant hypertension. Well-designed randomized trials recruiting a larger number of patients with hypertension, and focused on metabolic parameters, may refine the role of RSD as a potential intervention to treat dysmetabolic states associated with hypertension.

Resistant hypertension is frequently encountered and remains challenging in everyday clinical practice despite the availability of numerous effective antihypertensive drugs. Existing limitations in drug therapy renders renal nerve ablation (RNA) an attractive alternative for the management of resistant hypertension. RNA has been proven so far both effective and safe in small clinical studies. However, every novel technique raises several questions that need to be answered before the wide application of this approach. Likewise, existing data with RNA leave some unanswered questions, which among others include: the heterogeneity in blood pressure response, the identification of response predictors, the extent of RNA, the association between office and ambulatory blood pressure reduction, the long-term efficacy and safety of the procedure, the time-course of blood pressure response, and the effects on renal function in the long-term. This review aims to discuss these issues since RNA represents one of the hottest topics in hypertension and research directions are urgently needed.

Percutaneous catheter-based transluminal renal nerve ablation (RNA) by delivery of radiofrequency energy constitutes a novel therapeutic strategy for the treatment of resistant hypertension. The sympathetic nervous activation to the kidney and the sensory afferent signals to the central nervous system represent the targets of RNA. In this review we summarize current recommendations for appropriate patient selection for RNA and multimodal strategies in order to optimize pharmacological treatment for resistant hypertension. The safety and efficacy of the RNA based on published trials are also presented. Furthermore, a detailed description of the periprocedural management, the methodology of the RNA procedure and appropriate follow-up are provided. In conclusion, in order to improve the overall clinical outcome and achieve optimal management of resistant hypertensive patients before and after the RNA, experienced and certified centers are of major importance.

The metabolic syndrome is a constellation of risk factors for cardiovascular diseases including: abdominal obesity, a decreased ability to metabolize glucose (increased blood glucose levels and/or presence of insulin resistance), dyslipidemia, and hypertension. Patients who have developed this syndrome have been shown to be at an increased risk of developing cardiovascular disease and/or type 2 diabetes. Genetic factors and the environment both are important in the development of the metabolic syndrome, influencing all single components of this syndrome. The goals of therapy are to treat the underlying cause of the syndrome, to reduce morbidity, and to prevent complications, including premature death. Lifestyle modification is the preferred first-step treatment of the metabolic syndrome. There is no single effective drug treatment affecting all components of the syndrome equally known yet. However, each component of metabolic syndrome has independent goals to be achieved, so miscellaneous types of drugs are used in the treatment of this syndrome, including weight losing drugs, antidiabetics, antihypertensives, antilipemic and anticlothing drugs etc. This article provides a brief insight into contemporary drug treatment of components the metabolic syndrome.

The amount of body fat is precisely regulated in the overall process of energy homeostasis. Multiple organ systems participate in the regulatory process. Key regulatory signals reach the brain from the blood and control food intake and energy expenditure. The hypothalamus region integrates neurohormonal signaling from gut and adipose tissue. Morbid obesity is also associated with low grade systemic inflammation and immune activation. It can be at least in part regarded as an inflammatory disease. The anti-ghrelin vaccine decreases food intake, decreases hypothalamic orexigenic signals and increases energy expenditure and therefore might become an alternative treatment tool.

Obesity is a worldwide health problem associated with substantial morbidity and cost. Lifestyle modification and pharmacotherapy for obesity have limited benefit. Bariatric surgery is effective but with substantial risks, considerable cost and limited patient applicability. Endoscopic approach to obesity has evolved as a result of an attempt to replicate some of the anatomical manipulations and the physiological effects of the traditional weight loss surgery in a minimally invasive manner. Endoscopic interventions performed entirely through the GI tract offer the potential for an ambulatory weight loss procedure that is more cost-effective compared with current surgical approaches. There are two main endoscopic weight loss modalities - restrictive and malabsorptive. Restrictive procedures act to decrease gastric volume by space-occupying prosthesis and/or by suturing or stapling devices that alter gastric anatomy while malabsorptive procedures tend to create malabsorption by preventing food contact with the duodenum and proximal jejunum. Restrictive endoscopic procedures include intragastric balloon treatment, endoluminal vertical gastroplasty, transoral gastroplasty (TOGA) and transoral endoscopic restrictive implant system (TERIS). The duodenojejunal bypass sleeve (DJBS) is a malabsorptive device that mimics such surgical procedure. Gastroduodenojejunal bypass sleeve is a combination of both procedures. Except for intragastric balloon all mentioned procedures are rather novel, tested on a small number of subjects and with limited knowledge on safety and long-term efficacy. Owing to evolving field of evidence-based medicine with demand for rigorous evaluation of the scientific evidence these therapies need to be carefully tested in a randomized controlled manner to determine their safety and efficacy in the short and long-term. This review is aimed to compare endoscopic bariatric interventions with each other and with other weight loss modalities including conventional treatment and surgical procedures.

Orally administered drugs are generally absorbed by the small intestine and transported either to the lymphatic system or to the hepatic portal system. In general, lipid soluble drugs and vitamins are transported by the small intestine to the lymphatics, and water-soluble drugs are transported to the hepatic portal system. By avoiding the early hepatic first pass effect, the lymphatic transport system may increase drug bioavailability. In addition to its transport systems, the small intestine may affect drug bioavailability through drug uptake, intestinal first pass effect, recruitment of drugs by chylomicrons, formation and secretion of chylomicrons, and enterohepatic circulation. All of these factors should be considered when formulating orally administered lipophilic drugs. Our data also suggest that Caco-2 cells may serve as a valuable in vitro model to study the intestinal transport of orally administered drugs.

Schizophrenia is a chronic, severe and recurrent brain disorder that requires continuous, long-term treatment with antipsychotic medication to minimize relapse and provide clinical benefit to patients. For patients with schizophrenia, non-adherence to medication is a major risk factor for relapse and re-hospitalization. Long-acting injectable formulations of second-generation antipsychotics (SGAs-LAIs) provide constant medication delivery and the potential for improved adherence. Currently, three drugs are available for the treatment of schizophrenia, risperidone longacting injectable, olanzapine pamoate and paliperidone palmitate. Several studies have also demonstrated efficacy and safety of such drugs in patients with acute schizophrenia. In the present paper the literature on LAI atypical antipsychotics will be reviewed and practical advice will be given concerning the use of these drugs in the clinical practice.