The antihypertensive potential of flavonoids from Chinese Herbal Medicine: A review.

With the coming of the era of the aging population, hypertension has become a global health burden to be dealt with. Although there are multiple drugs and procedures to control the symptoms of hypertension, the management of it is still a long-term process, and the side effects of conventional drugs pose a burden on patients. Flavonoids, common compounds found in fruits and vegetables as secondary metabolites, are active components in Chinese Herbal Medicine. The flavonoids are proved to have cardiovascular benefits based on a plethora of animal experiments over the last decade. Thus, the flavonoids or flavonoid-rich plant extracts endowed with anti-hypertension activities and probable mechanisms were reviewed. It has been found that flavonoids may affect blood pressure in various ways. Moreover, despite the substantial evidence of the potential for flavonoids in the control of hypertension, it is not sufficient to support the clinical application of flavonoids as an adjuvant or core drug. So the synergistic effects of flavonoids with other drugs, pharmacokinetic studies, clinical trials and the safety of flavonoids are also incorporated in the discussion. It is believed that more breakthrough studies are needed. Overall, this review may shed some new light on the explicit recognition of the mechanisms of anti-hypertension actions of flavonoids, pointing out the limitations of relevant research at the current stage and the aspects that should be strengthened in future researches.

Adherence to Antihypertensive Medication and Incident Cardiovascular Events in Young Adults With Hypertension.

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Translating research evidence into clinical practice: a reminder of important clinical lessons in management of resistant hypertension through a case study in general practice.

A case of a 59-year-old man with resistant hypertension, despite 8 months of non-pharmacological and pharmacological management up to maximal doses of triple antihypertensive therapy. Review of the literature found a study that reported improved blood pressure control with bedtime dosing of antihypertensive treatment. Changing to bedtime dosage of antihypertensives resulted in significant improvement in blood pressure control to below target levels. This highlights the importance of the clinicians' awareness and implementation of research findings and hence delivery of best evidence-based care.

An overview of the preclinical toxicity and potential carcinogenicity of sitaxentan (Thelin®), a potent endothelin receptor antagonist developed for pulmonary arterial hypertension.

Sitaxentan (Thelin®), an endothelin receptor antagonist with a long duration of action and high specificity for the endothelin receptor A subtype, was used to treat pulmonary arterial hypertension. It was withdrawn from the market due to an idiosyncratic risk of drug-induced liver injury identified from emerging clinical trial data and clinical case reports. The preclinical safety profile of sitaxentan is presented, including single- and repeat-dose toxicity in mice, rats, and dogs and carcinogenicity in mice and rats. Sitaxentan-related adverse effects included coagulopathy in rats and dogs, increased serum alkaline phosphatase activity in mice and dogs, and hepatic hypertrophy in all species. Decreased albumin, erythrocyte count, hemoglobin concentration and hematocrit, and increased coagulation times and liver weight were also noted. These effects generally occurred at systemic exposures (AUC(0-24)) that were substantially greater than those seen in humans. Twice-daily (vs. once daily) dosing resulted in increased toxicity, which correlated with increased trough plasma sitaxentan concentrations. Sitaxentan appeared to have a low potential for testicular and hepatic toxicity and was not carcinogenic. These studies suggested that sitaxentan would have a reasonable margin of safety when used as directed in humans and supported a positive benefit:risk assessment at the time of marketing approval.

Description of antihypertensive use in patients with resistant hypertension prescribed four or more agents.

Data describing the use of recommended antihypertensive agents in the resistant hypertension population are limited. Treatment recommendations for resistant hypertension include maximizing diuretic therapy by using chlorthalidone and/or adding an aldosterone antagonist. Additional recommendations include combining antihypertensive agents from different drug classes. This retrospective cohort study describes antihypertensive use in patients with resistant hypertension defined as the concurrent use of ≥4 antihypertensive agents. Claims data from the Medstat MarketScan Commercial Claims and Encounter database were used to identify patients with resistant hypertension based on International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes and National Drug Codes between May 1, 2008 and June 30, 2009. Of the 5 442 410 patients with hypertension in the database, 140 126 met study criteria. The most frequently prescribed antihypertensive classes were angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (96.2%), diuretics (93.2%), calcium channel blockers (83.6%), and ß-blockers (80.0%). Only 3.0% and 5.9% of patients were on chlorthalidone or an aldosterone antagonist, respectively. A total of 15.6% of patients were treated with angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker. Our findings demonstrate that frequently prescribed antihypertensive agents for the treatment of resistant hypertension included guideline-recommended first-line agents. However, evidence-based and recommended agents, such as chlorthalidone and aldosterone antagonists, were underused. Moreover, minimally efficacious combinations, such as an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker, were prescribed at higher rates than evidence-based and recommended agents.

Discrepancies between prescribed and defined daily doses: a matter of patients or drug classes?

PURPOSE: Defined daily doses (DDD) are used for the measurement of drug utilisation. The aim of the study was to analyse whether differences between DDD and prescribed daily doses (PDD) exist for relevant drug classes such as antihypertensive drugs and, if so, whether they primarily depend on drug classes or patient-related factors. METHODS: Using the data of a large German statutory health insurance scheme, we analysed continuous prescriptions for the following antihypertensive drug classes: thiazide diuretics, beta-blockers, dihydropyridine calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs). We summed the doses of all dispensed drugs per person during a defined time frame. We calculated the PDD (= total dose divided by the number of days) and expressed them as the PDD:DDD ratio (= amount of DDD per day and person). RESULTS: During the study period, 149,704 patients continuously received an antihypertensive medication. The average PDD:DDD ratio ranged from 0.84 (beta-blockers) to 1.88 (ARBs) and 2.17 (ACEIs). The average prescribed dosage of each drug class remained unchanged, even if the patients had previously received another antihypertensive drug with another PDD:DDD ratio. For example, if patients were switched from a beta-blocker to an ACEI, the PDD:DDD ratio increased, on average, from 0.79 to 2.17. Vice versa, the ratio decreased for patients with a drug change from an ACEI to a beta-blocker from 2.06 to 0.75. CONCLUSIONS: Even large differences between DDD and PDD seem to be a matter of drug classes and not primarily of patient characteristics.

Special considerations for antihypertensive agents in dialysis patients.

Hypertension is present in most patients with end-stage renal disease and likely contributes to the premature cardiovascular disease in dialysis patients. Previous practice guidelines have recommended that, in patients on chronic dialysis, blood pressure (BP) should be reduced below 130/80 mm Hg. This is based on opinions but not strong evidence, since no concrete information exists about which BP values should be the parameter to follow and which should be the target BP values. The majority of the antihypertensive agents can be used in this population, but the pharmacokinetics altered by the impaired kidney function and dialyzability influence the appropriate dosage as well as the time and frequency of administration. Combination therapy using multiple agents is often necessary. Because of the prevalence of overactivity of the renin-angiotensin-aldosterone system and sympathetic tone as well as the high calcium influx in vascular smooth muscle cells in dialysis patients, drugs acting in these three specific systems may potentially have additional cardioprotective benefits beyond their BP-lowering effect. Thus, antihypertensive regimens should preferably be based on these classes of drugs, alone or in combination. Other antihypertensive drug classes can play a complementary role.

[Therapeutic novelties in the management of arterial hypertension]. / Novedades terapéuticas en el manejo de la HTA.

Arterial hypertension is one of the major risk factors for the development of cardiovascular diseases such as heart failure, ischemic heart disease, chronic kidney disease and cerebrovascular events. Adequate blood pressure control is vital for the management of patients with vascular disease. New therapeutic alternatives are appearing on the horizon to improve the degree of blood pressure control in these patients, such as direct renin inhibitors, beta-blockers with additional properties, carotid receptor- stimulating devices and vaccination against arterial hypertension. Direct renin inhibitors are a new family of antihypertensive drugs that have so far shown a good antihypertensive effect and an additive effect on reduction of proteinuria in patients with diabetic nephropathy. Recent meta-analyses suggest that betablockers used as first-line treatment for uncomplicated arterial hypertension could have a less beneficial effect on the development of cardiovascular disease than other antihypertensive drugs. However, the emergence of new subtypes of beta-blockers with other hemodynamic and metabolic properties could change this conception. Carotid receptor-stimulating devices and vaccination against arterial hypertension, although not totally new therapies, are being revitalized, with preliminary results that suggest that they could be used for the treatment of arterial hypertension in patients with a specific profile. Although scientifically stimulating, the long-term beneficial effects of these new therapeutic alternatives on target-organ protection still need to be confirmed.

Combined therapy with a calcium channel blocker and an angiotensin II type 1 receptor blocker.

Fixed-dosed combination regimens consisting of a calcium channel blocker and an angiotensin II type 1 receptor blocker represent a new addition to the available antihypertensive treatment options. Clinical trials demonstrate that both the dihydropyridine calcium channel blocker amlodipine and angiotensin II receptor blockers are effective agents for the management of hypertension in individuals with or without cardiovascular disease. When combined, these 2 classes of agents have complementary effects on blood pressure, as each targets separate signaling pathways in the vasculature pivotal to the regulation of vascular function. In clinical trials this combination has demonstrated better efficacy, defined by time to reach blood pressure targets as well as levels of blood pressure achieved, compared with the individual agents. In a comparative trial, a combination of amlodipine plus valsartan (an angiotensin II receptor blocker) also produced greater reductions in blood pressure compared with a combination of lisinopril (an angiotensin-converting enzyme inhibitor) and hydrochlorothiazide. The combination of amlodipine and an angiotensin II receptor blocker is well tolerated, including in patients with stage 2 hypertension and the elderly.

[Potential of using pattern diagnosis of traditional Chinese medicine to improve the clinical use of antihypertensive agents].

Despite the availability of six classes of antihypertensive agents, control of blood pressure and improving patients' quality of life remain far from ideal. There is a wide variability in terms of the hypotensive effect and side effect profile for the same antihypertensive agent used in different patients. How to select the right agent to provide the most beneficial results in terms of efficacy and improvement of quality of life as well as to decrease clinical symptoms and minimize adverse reactions is an important therapeutic challenge. It has been suggested that clinical usage of pattern (Zheng) diagnosis of traditional Chinese medicine may improve the accuracy in selecting the right antihypertensive agents with improved efficacy and deceased adverse effects. Limited research in this area suggested the calcium channel blocker may work better in treating phlegmatic damp excess pattern and blood stasis pattern while beta-blockers may be more beneficial in the liver yang rising pattern. On the other hand, angiotensin converting enzyme inhibitors may be more suitable in a yin deficiency and yang hyperactivity pattern as well as combined liver and kidney yin deficiency pattern. More research studies using this innovative approach in improving the selection of antihypertensive agents including mechanistic studies are urgently needed.

[Sex-specific antihypertensive drug therapy]. / Geschlechtsspezifische medikamentöse Therapie der Hypertonie.

BACKGROUND: Hypertension is a leading cause of cardiovascular diseases. To evaluate sex-specific differences in the prescription pattern of antihypertensive therapy, registry data from the regional health insurance fund "Burgenländische Gebietskrankenkasse" (BGKK) were analyzed. MATERIAL AND METHODS: In a retrospective cross sectional cohort study data from 41499 individuals covered by the BGKK in 2003, and who had been treated with cardiovascular drugs were analyzed. Data were evaluated according to drug classifications. RESULTS: Among subjects treated with cardiovascular medication 38.3 % were males and 61.7 % females. The drug classes acting on the renin-angiotensin-system were prescribed more frequently than beta-blockers, calcium channel blockers, diuretics and antihypertensives. Women were treated more often with diuretics and beta-blockers, whereas men received more antihypertensives and drugs acting on the renin angiotensin system (p < 0.01 between groups of sexes). CONCLUSION: Sex-specific differences exist regarding the prevalence of antihypertensive drug prescriptions between men and women. Further, the prescription pattern of equivalently effective medications differs between sexes.

["Coffee swallowing syncope"]. / "Kaffeesynkope".

HISTORY: A 38-year-old man was admitted with recurrent syncope. Remarkably the patient had lost consciousness after drinking hot coffee. A vasovagal syncope was considered as the most likely diagnosis. INVESTIGATIONS AND DIAGNOSIS: Following various investigations no pathological findings were revealed. Event-monitoring (R-test) showed high grade atrioventricular block (2 Mobitz and 3 ) induced by swallowing with subsequent syncope. TREATMENT AND COURSE: A two-chamber pacemaker was implanted and the antihypertensive therapy was changed from a beta-blocker to an AT II receptor antagonist. CONCLUSION: Typical vasovagal symptoms during or shortly after meals followed by syncope should point towards an oesophago-cardia reflex mechanism; including a cardiac arrhythmia. Known to be usually triggered by cold meals, vasovagal reflex after hot meals is rare.

Inadequate control of blood pressure in Nigerians with diabetes.

To observe the extent to which blood pressure (BP) was reduced to below 140/90 mm Hg in Nigerians with diabetes (DM), data were collected using structured questionnaire, standard sphygmomanometer, and measurement of fasting blood glucose (FBG). Two hundred forty-four subjects (85 males) aged 17-84 years with a mean duration of DM of 7.9 years and who regularly attended the clinic for diabetes at least monthly for no less than 6 months were involved. Eleven percent, 13 of the 115 treated hypertensives, had BP controlled to levels below 140/90 mm Hg. Nifedipine was the most frequently prescribed antihypertensive (44.30%), followed by alpha-methyldopa (15.7%) and then the angiotensin-converting enzyme inhibitors (ACEIs) captopril and lisinopril (11.3%). Thiazides (9.7%) or thiazide-based fixed combination tablets were prescribed in about 25% of the patients. Eighteen percent were on more than one antihypertensive concurrently and dosages were often at threshold. The majority of the hypertensives with BP below 140/90 mm Hg were on thiazide-based medications. In 152 participants, the presence of hypertension did not affect glycemic control (chi2 = 4.41, df = 2, P = .1) observed and 60% of the entire population had FBC < or = 7.9 mmol/L. Lack of access to care does not explain these findings and suggests an area for improvement. Fortunately, the data also show that thiazides were associated with better control of BP at a cost that was affordable without jeopardizing diabetic control.

Abordaje diagnóstico y terapéutico de las crisis hipertensivas / Diagnostic and therapeutic hypertensive crisis management

Las crisis hipertensivas constituyen una causa de consulta frecuente en los servicios de Urgencias. Existe alguna dificultad para establecer un diagnóstico diferencial entre lo que supone una emergencia o una urgencia hipertensiva. El abordaje terapéutico difiere en función de cuál sea la presentación de la crisis (urgencia o emergencia), por lo que es importante establecer un diagnóstico correcto. La finalidad primordial del tratamiento es evitar el daño que se está produciendo sobre el órgano diana afectado y no llevar de manera obligada las cifras de tensión arterial (TA) a valores normales. Tanto la velocidad como el grado de descenso de las cifras de TA depende del tipo de emergencia hipertensiva que presente el paciente. Existe un gran número de fármacos para el manejo de esta patología, aunque no hay estudios comparativos para determinar cuál está más indicado en cada tipo de emergencia. En función de las características individuales de cada uno de los fármacos se pueden hacer recomendaciones particulares para su uso. (AU)

Efficacy of different drug classes used to initiate antihypertensive treatment in black subjects: results of a randomized trial in Johannesburg, South Africa.

BACKGROUND: Thiazides are recommended to initiate antihypertensive drug treatment in black subjects. OBJECTIVE: To test the efficacy of this recommendation in a South African black cohort. METHODS: Men and women (N = 409), aged 18 to 70 years, with a mean ambulatory daytime diastolic blood pressure between 90 and 114 mm Hg, were randomized to 13 months of open-label treatment starting with the nifedipine gastrointestinal therapeutic system (30 mg/d, n = 233), sustained-release verapamil hydrochloride (240 mg/d, n = 58), hydrochlorothiazide (12.5 mg/d, n = 58), or enalapril maleate (10 mg/d, n = 60). If the target of reducing daytime diastolic blood pressure below 90 mm Hg was not attained, the first-line drugs were titrated up and after 2 months other medications were added to the regimen. RESULTS: While receiving monotherapy (2 months, n = 366), the patients' systolic and diastolic decreases in daytime blood pressure averaged 22/14 mm Hg for nifedipine, 17/11 mm Hg for verapamil, 12/8 mm Hg for hydrochlorothiazide, and 5/3 mm Hg for enalapril. At 2 months the blood pressure of more patients treated with nifedipine was controlled: 133 (63.3%, P

Use of calcium channel blockers in hypertension.

During the past 20 years the number of subclasses of calcium channel blockers has increased from one to four. Three classes have only a single clinically approved compound: verapamil, diltiazem, and mibefradil. The fourth class, dihydropyridines, contains numerous compounds. All agents are effective in lowering blood pressure in short-term studies, and side effects that trouble the patient are infrequent. Long-term studies in hypertensive patients are limited. Short-acting agents such as nifedipine have been associated with an increased cardiovascular risk in some, but not all studies. These agents also probably create a compliance problem for hypertensive patients because of the need for multiple daily doses and their unpleasant side effects, e.g., ankle edema, palpitations, and flushing. Therefore, they are not useful or indicated for the treatment of hypertensive patients. No data have suggested that long-acting dihydropyridines or nondihydropyridine calcium channel blockers share the same fate. Indeed, several lines of evidence suggest the opposite: they have a cardioprotective effect. However, definitive information will require the completion of several long-term trials, including ALLHAT, CONVINCE, HOT, INSIGHT and NORDIL. Finally, it is important to reflect on the lessons learned from the controversy associated with the potential risks of calcium channel blockers. First, disagreements are common when one uses case-controlled studies and are reflective of the poor precision of the methods used. What is statistically relevant in one study may not hold true for another and may have no clinical relevance, particularly if the relative risk is less than 2. Investigators need to temper their enthusiasm to reflect this reality. Second, at the cutting edge of science there is probably relatively little agreement about what is correct among equally competent scientists. All have bias in their positions and should both recognize and admit so to themselves and their colleagues. Inferring that those who disagree have an unstated secondary agenda that will bring personal financial rewards or government accolades is inappropriate and counterproductive. Third, the randomized clinical trial, despite all its imperfections, is still the best tool to establish common ground on controversial issues. Finally, what may seem best from the public health perspective may not be in the best interest of the individual patient--a possibility that physicians have to constantly consider. For example, no public health benefit occurs if patients remain hypertensive because they fail to take their medications, no matter what the medication.

How should we treat hypertensive women with cardiac and renal impairment?

Arterial hypertension is the most common chronic medical condition requiring office visits to physicians and is a major contributing factor to the development of myocardial infarction and stroke. Its importance as a cardiovascular risk factor is at least as significant in women as in men; however, the ever-growing literature on hypertension shows surprisingly little data concerning sex differences. Large clinical trials of antihypertensive treatment have not clearly demonstrated gender differences in blood pressure response and outcome, but the majority of patients in these trials were men. Even so, some evidence indicates that white women treated for hypertension obtain less benefit than men. The pathophysiology of hypertension in men and women is similar in many aspects, but important gender differences are now emerging. Studies designed to clarify these differences are required, as a better knowledge of the underlying mechanisms will allow for a more precise stratification of risk and a more accurate approach to both nonpharmacologic and pharmacologic treatment.

Who is using antihypertensive drugs? A prescription analysis from Finland.

OBJECTIVE: To analyse the prescribing of antihypertensives in Finland in 1993. DESIGN: A descriptive three-month follow-up study of reimbursed prescriptions for chronic hypertension dispensed in Finnish pharmacies. SETTING: The nationwide prescription data base of the Social Insurance Institution covering 80% of Finnish pharmacies. Material--The study material consisted of 479 744 antihypertensive prescriptions from ATC-groups hypotensives (C02), diuretics (C03), beta blocking agents (C07), and potassium (A12B) for 279 435 hypertensive patients. RESULTS: Of all the prescriptions (excluding potassium supplements), 30% were for beta blocking agents, 24% for diuretics, 22% for calcium channel blocking agents, 20% for ACE inhibitors or ACE inhibitor + diuretic combinations, and 4% for other hypotensives. Two thirds of the men received a drug from a hypotensive group, nearly half were prescribed a beta blocking agent, and 27% a diuretic. Among women the distribution of the different drug groups was more even: more than half the women (55%) were prescribed hypotensives while beta blocking agents and diuretics were prescribed for 43% and 44%, respectively. Due to the different treatment profile between men and women the expenses of treatment also differed. The cost of prescriptions for female patients was, on average, 17% less than that for male patients. CONCLUSION: The choice of antihypertensive drugs depends on the age and sex of a patient. Prescribing antihypertensive drugs does not fully meet national recommendations. New drugs are gaining ground in the treatment of hypertension. An increase in the cost of treatment will result from this development.