Angiotensin II receptor antagonists role in arterial hypertension.

Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT(1) receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT(1) receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan, irbesartan, telmisartan, candesartan, eprosartan and others on current investigation. All these drugs have the common properties of blockading the AT(1) receptor thereby relaxing vascular smooth muscle, increase salt excretion, decrease cellular hypertrophy and induce antihypertensive effect without modifying heart rate or cardiac output. Most of the AT(1) receptor blockers in use controlled blood pressure during the 24 h with a once-daily dose, without evidence of producing tolerance to the antihypertensive effect and being with low incidence of side effects even at long term use. Monotherapy in mild-to-moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of thiazide diuretic is added, 60-70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium antagonists and beta-blocking agents. AT(1) receptor blockers are specially indicated in patients with hypertension who are being treated with ACE inhibitors and developed side effects such as, cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted and seem promising.

Update on the use of calcium antagonists on hypertension.

Calcium antagonists represent an important group of drugs for the treatment of hypertension; they are effective in the whole range of severity of the disease. Dihy- dropyridine derivatives are most frequently used, and can be used in association with other antihypertensive drugs; meanwhile phenylalkylamines and benzothiazepines are contraindicated in association with beta-blocker drugs. Calcium antagonists with slow starting effect and long duration of action are the choice for use in long-term antihypertensive treatment. This group of drugs is specially indicated in elderly patients, in those with diabetes mellitus and in patients with coronary heart disease. Phenylalkylamines and benzothiazepine derivatives are also used in patients with supraventricular arrhythmias. This group of agents is as safe as diuretics, angiotensin-converting enzyme-inhibitors and beta-blocking drugs in the long-term treatment of hypertension.

Comparison of two nimodipine formulations in healthy volunteers.

The objective of this study was to assess the pharmacokientic parameters of regular nimodipine (Bayer), 30 mg, given every 6 h and nimodipine AP (nimodipine in micro particles with programmed action contained in tablets, developed by Biocontrolled-Leti Group Laboratories), 120 mg, given every 24 h. Subjects (19 healthy volunteers, five female; 14 male: age: 21 +/- 0.7 years) received one formulation over 5 days. Then, after a washout period of 7 days, the other formulation was given. The analyst was blinded to the relationship in formulation received. Antecubital blood samples were taken before the first tablet was taken and after 15, 45, 60 min and 2, 4, 6, 8, 12, 13, 18 and 24 h on day 1 and five of each formulation. Nimodipine blood levels were analysed by HPLC. At steady-state regular nimodipine reached a C-max of 10.208 +/- 0.317 ng/ml, at a t-max of 1 h; minimum concentration 6 h after dosage was 1.2929 +/- 0.411 ng/ml, half-life was estimated in 2.9 h. Meanwhile nimodipine AP 120 mg reach a C-max of 11.885 +/- 0.403 ng/ml; a t-max of 1 h with a minimum concentration 24 h after the last dose of 4.2387 +/- 0.353 ng/ml (P < 0.001). Apparent half-life was calculated in 17.8 h (P < 0.001). Area under the curve for the 24 h period was 143.76 ng/ml/min for regular nimodipine and 183.7 ng/ml/min for nimodipine AP 120 mg (P < 0.001), indicating better bioavailability. In conclusion nimodipine in AP formulation 120 mg produced similar peak plasma levels (C-max) than regular nimodipine, but with higher trough (C-min) values and stable plasma levels with one administration every 24 h. This formulation would be more suitable when nimodipine chronic therapy is indicated.

Semipersonalized psychological evaluation of quality of life in hypertensive patients during a trial with two calcium antagonists: a multicenter Latin-American Study (LASTLHY).

OBJECTIVE: The main objective of this study was to evaluate well-being and physical activity of 248 hypertensive patients, including 177 females, who had previously been included in the Latin-American Study on Lacidipine in Hypertension (LASTLHY). SUBJECTS, MATERIALS AND METHODS: This open study was carried out in 12 clinical centers in Argentina, Brazil, Colombia, Mexico and Venezuela, to compare, over a period of 16 weeks, the antihypertensive action of a fixed-dose, once daily of 4 mg lacidipine administered orally to 120 patients and 30 mg nifedipine GITS (Gastro-Intestinal Therapeutic System) administered to 128 patients, aged between 40 and 65 years. All patients had mild to moderate hypertension and treatment was begun at the end of a one-week placebo run-in period (end of week -1). Well-being and physical activity were assessed by means of single questionnaire, which reflected the physical and cultural diversities amongst the clinical centers and patients. The questionnaire included 13 multiple-choice and 8 contingent open questions. The score of each question was multiplied by a coefficient related to the importance of each question to the patient (semipersonalization); the coefficient was obtained from cultural and socioeconomic data collected at the time of enrollment. The semipersonalization was carried out by a blind psychological study with respect to the medication and had a high repeatability in the assignment of personalized coefficients to the score of each question. The scores of each question were added to obtain an overall well-being and activity scoring. The possible theoretical range for the overall scoring in this study was 10 - 124. RESULTS: See Table 1. CONCLUSION: The study revealed that the administration of calcium channel blockers such as lacidipine and nifedipine GITS, and lacidipine in particular, produced low incidence of side effects, and lacidipine in particular induced significant improvement in the quality of life.

Comparative effects of amlodipine and nifedipine GITS during treatment and after missing two doses.

OBJECTIVE: To compare the antihypertensive efficacy of amlodipine and nifedipine gastrointestinal therapeutic system (GITS) measured by office and ambulatory blood pressure monitoring (ABPM) during treatment and, after patients have missed two doses. METHOD: After a single blind run-in 4-week placebo period, 58 patients were randomly allocated to amlodipine (5mg/daily, n=30) or nifedipine GITS (30mg/daily; n=28) in a double-blind, double dummy fashion. Patients received active medication for 4 weeks. Then, to simulate failure of compliance, patients received two single blinded doses of placebo. Ambulatory blood pressure monitoring was carried out at the end of run-in placebo phase, the first day, the last day of active treatment and up to 72h after the last active dose. RESULTS: Diastolic blood pressure was controlled in 61.9% patients on amlodipine and 52.9% on nifedipine GITS. Reductions in blood pressure were similar in both groups. ABPM showed significant reduction in blood pressure from the first day in the nifedipine GITS group, while amlodipine group had marginal effect. Peak reduction in systolic/diastolic blood pressure was 26/15mmHg at 5-6h after ingestion of amlodipine tablets. The trough reduction was 22/13mmHg; with a trough-to-peak ratio of 84.61% for systolic and 86.67% for diastolic blood pressure. Peak reduction in systolic/diastolic blood pressure with nifedipine GITS was 19/15mmHg and the trough reduction was 21/17mmHg, giving a trough-to-peak ratio of 100% for both systolic and diastolic blood pressure. When patients received placebo after 4 weeks of active treatment, simulating a compliance failure, amlodipine maintained reduction in systolic and diastolic blood pressure for at least up to 72h after the last active dose, maintaining 57.71% of the effect for systolic blood pressure and 60.00% for diastolic blood pressure. In contrast, nifedipine GITS effect was rapidly lost during this study phase, with a reduction in systolic and diastolic blood pressure of only 14-16%, 72h after the last active dose. CONCLUSION: This study showed that amlodipine and nifedipine GITS reduce blood pressure to about the same extent during chronic treatment. In the case of compliance failure, such as missing one or two doses, amlodipine maintained significant and important antihypertensive effect with the trough-to-peak ratio still over 50% 72h after the last active dose. On the other hand, the coverage of nifedipine GITS was limited to about 36h after the last active dose.

Hypertension and cardiovascular health in Venezuela and Latin American countries.

Since 1950 all countries of the Latin-American subcontinent have experienced very important changes in several health indicators, in the demographic, epidemiological, socio-cultural and way of living profiles. The proportion of the population over 65 years old tend to be low in the Latin American countries in contrast to developed countries. Cardiovascular diseases are the main cause of death in most of the Latin American countries at a similar rate to that of the developed world. As infectious diseases are reduced, cardiovascular diseases takes their place as the main cause of death in Latin American countries. Prevalence of hypertension in different reports show variations from 40 to 8% in the adult population, but on average 20 to 23% of the adult population have elevated blood pressure. This prevalence is similar to reports in the developed world. However there is considerable variability in each country and its regions so it is important that local studies of prevalence and local factors in the development of hypertension are investigated. The degree of awareness, treatment and control of hypertension is lower than that reported in the developed world, and it is important to establish programmes to attend to this public health problem, from prevention to treatment, from primary care to higher levels of attention.

Angiotensin II receptor antagonists in arterial hypertension.

Angiotensin II receptor antagonists (AT-1) represent a new group of orally active antihypertensive agents. Activation on AT-1 receptor leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone with production of thirst, and promote growth of vascular and cardiac muscle; these effects are blocked by AT-1 antagonist agents. The first chemically useful, orally active AT-1 receptor antagonist was losartan, followed by other agents currently in clinical use, such as: valsartan, eprosartan, irbesartan, telmisartan, candesartan, and many others under investigation. AT-1 receptor antagonists are effective in reducing high blood pressure in hypertensive patients. Monotherapy in mild to moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of a thiazide diuretic is added, 60 to 70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme inhibitors, diuretics, calcium antagonists and beta-blocking agents. Tolerability has been reported to be very good. AT-1 receptor antagonists would be a drug of choice in otherwise well-controlled hypertensive patients treated with angiotensin-converting enzyme inhibitors who developed cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted.

Effect of lacidipine and nifedipine GITS on platelet function in patients with essential hypertension.

With the aim of evaluating the effects on blood pressure, platelet function and insulin sensitivity of the dihydropiridines lacidipine and nifedipine GITS, a parallel double-blind study was carried out in a group of 20 patients with mild to moderate essential hypertension. They received a placebo for 4 weeks; then were divided at random into two groups of 10 patients each. Nifedipine GITS, 30 mg and lacidipine, 4 mg, were given during 16 weeks of active treatment. Blood pressure and heart rate were measured at the clinic in supine, sitting and standing positions, 24 +/- 1 h after the last dose. After the placebo and active phases were carried out, a platelet aggregation test was performed to determine platelet malondialdehyde production and a tolerance to 100 g of glucose by measuring glucaemia and plasma insulin. Both drugs reduced systolic and diastolic blood pressure at the same level, however there were observable differences in the rate of reduction. The nifedipine GITS reduced supine systolic blood pressure by 25 mm Hg in the first week, while the lacidipine did so by 11 mm Hg. At the end of the study period nifedipine reduced supine systolic blood pressure by 28 mm Hg and lacidipine by 20 mm Hg. Heart rate was increased slightly but significantly in the nifedipine GITS group only in the standing position. Both drugs reduced platelet aggregation ex vivo only marginally but they modified the malondialdehyde production, indicating an action on the arachidonic acid metabolic pathway.

Effects of amlodipine and enalapril on platelet function in patients with mild to moderate hypertension.

OBJECTIVE: The aim of this study was to compare the effect of amlodipine and enalapril on platelet aggregation, and platelet production of malondialdehyde in patients with mild to moderate arterial hypertension. PATIENTS AND METHODS: A parallel, double-blind, placebo-controlled study was carried out in 24 patients (2 groups of 12 patients each). Initially all patients received placebo for four weeks; then amlodipine, 5 mg daily or enalapril 20 mg daily taken once a day at 7 am. Dosage was doubled after 4 weeks when diastolic blood pressure was > 90 mmHg in sitting position, the treatment was continued for 12 weeks. At the end of placebo and active phases a platelet aggregation test, using adenosine diphosphate, collagen and adrenaline, and a platelet malondialdehyde production test, either in basal conditions (MDA-basal) and after the stimulation of arachidonic acid pathway by adding ethylmaleimide (MDA-activated) were carried out. RESULTS: Blood pressure was reduced by both agents, enalapril and amlodipine. Enalapril controlled 58.3% of hypertensive patients with an average dosage of 31.7 mg/daily. Amlodipine controlled 75% of patients with a dosage of 7.1 mg/daily. Platelet aggregation was reduced by amlodipine in 15.9% for ADP (10 microM); 17.4% for collagen (2 microg/ml) and 19.9% for adrenaline (2 microM) (p < 0.025). Meanwhile enalapril slightly increased platelet aggregation by 6.7%, 1.3% and 5.6% for the three agents, respectively (p > 0.05, ns). Malondialdehyde was reduced by amlodipine in 45.33% (p < 0.05) for MDA-basal; 3.76% (p > 0.05) for MDA-activated; and the ratio MDA-basal:MDA-activated in 36.79% (p < 0.005). Meanwhile enalapril increased MDA-basal in 2.89%; MDA-activated in 3.58% and reduced the ratio MDA-basal:MDA-activated, in 10.34% (p > 0.05). CONCLUSION: Both agents, enalapril and amlodipine, reduced blood pressure, but only amlodipine reduced platelet aggregation and platelet production of malondialdehyde, indicating its action on the arachidonic acid metabolic pathway.

The prevalence of hypertension and the state of cardiovascular health in Venezuela and surrounding nations.

This review summarizes the prevalence of hypertension and the state of cardiovascular health in Venezuela and surrounding nations. First, the review discusses the fact that cardiovascular disease (CVD) is the main cause of death in Venezuela, Colombia, Brazil, and Trinidad and Tobago, accounting for 20% to 35% of all deaths. These data are similar to data from the developed world. Second, prevalence of hypertension in this region varies from 8% to 40% in the adult population, and, on average, 22% of the adult population of this region has an elevated blood pressure. However, prevalence rates vary considerably from country to country and within regions of the same country. Although mortality from hypertension as the main cause of death accounts for 1% to 4% of all deaths, mortality from stroke, mainly caused by hypertension, accounts for 10% of all deaths, indicating a failure in the treatment of hypertension. In most Latin American countries, the degree of awareness, treatment and control of hypertension is low, necessitating the establishment of programs to prevent, detect and effectively treat hypertension and decrease CVD risk factors.

[Platelet aggregation in arterial hypertension]. / Agregación plaquetaria en hipertensión arterial.

Hypertension is a major risk factor for stroke/myocardial infarction as expression of the atherogenic process. Platelets play a fundamental role in all these disease processes. In physiological conditions there is an equilibrium between pro aggregating and anti aggregating factors. In pathological situations this equilibrium is broken and pro aggregating factors are predominant . Patients with hypertension have an state of hyper-aggregation and dysequilibrium in the production of eicosanoids. Some antihypertensive drugs tend to not only reduce blood pressure to control levels but to reduce platelet aggregation and re-establish the broken equilibrium in eicosanoid production.

Terazosin: ex vivo and in vitro platelet aggregation effects in patients with arterial hypertension.

Antihypertensive effect, platelet aggregation, and plasma lipid profile were studied in a group of 14 hypertensive patients with diastolic blood pressure between 96 and 116 mm Hg during placebo and terazosin phases. Terazosin, an alpha 1-adrenergic blocking agent, was given initially at the dosage of 1 mg daily. Then it was continued at a dosage of 2 mg daily and 5 mg daily respectively, each dosage for 4 weeks. Blood pressure was taken every 2 weeks. Ex vivo platelet aggregation induced by epinephrine, collagen, and adenosine diphosphate (ADP) were carried out twice during the first placebo phase, once at the end of each terazosin dosage, and once in the second placebo phase. Total cholesterol, HDL cholesterol, and triglycerides were measured at the end of first placebo and terazosin phases. Blood from eight patients was taken during the second placebo phase to carry out in vitro response of platelet aggregation induced by ADP, collagen, and epinephrine before and after incubation with terazosin (1, 2 and 5 micrograms/L or doxazosin (100, 200, and 500 micrograms/L for 5 min. Terazosin induced a statistically significant decrease in 14.2/8.0 mm Hg, 26.1/13.4 mm Hg, and 33.9/16.5 mm Hg in the supine position for 1, 2, and 5 mg/daily, respectively. No changes in heart rate were observed. Terazosin inhibited significant ex vivo platelet aggregation induced by epinephrine, collagen, and ADP in a range from 20% to 45% for different concentrations of inducers. Reductions in platelet aggregation seemed not to be dose dependent, as reductions were statistically equivalent for dosages of 1, 2, and 5 mg daily. Terazosin significantly reduced the level of total cholesterol (8.71%) and triglycerides (14.31%), and increased (although not significantly) levels of HDL cholesterol (3.91%). In vitro platelet aggregation was inhibited by doxazosin to a significant extent but not by terazosin.

Cumplimiento de la terapia antihipertensiva / Antihypertensive therapy compliance

El cumplimiento en el tratamiento antihipertensivo es muy importante para proteger al paciente de las complicaciones cardíacas y cerebrovasculares de la hipertensión. Con el régimen de dos veces al día, el 50 por ciento toman la medicación prescripta el 90 por ciento de los días de observación, comparado con el 70 por ciento cuando los pacientes cumplen la medicación una vez al día. la acción antihipertensiva de la amlodipina y el enalapril ha sido publicada recientemente por nuestro grupo de investigación, en un estudio controlado, paralelo, doble ciego y al azar. Después de cuatro semanas de recibir placebo en forma ciego-simple, los pacientes fueron asignados a recibir 20 mg de enalapril (15 pacientes) o 5 mg de amlodipina (15 pacientes) una vez al día. En la cuarta semana de medicación activa la dosis fue duplicada, en caso que la presión arterial diastólica en posición sentada fuera superior a 90 mmHg. Un monitoreo ambulatorio de presión arterial fue realizado al final de la etapa placebo por un período de 24 horas y al final de la semana 12 de tratamiento activo por un período de 48 horas. Las reducciones en la presión arterial fueron mayores en el grupo amlodipina

Cumplimiento de la terapia antihipertensiva / Antihypertensive therapy compliance

El cumplimiento en el tratamiento antihipertensivo es muy importante para proteger al paciente de las complicaciones cardíacas y cerebrovasculares de la hipertensión. Con el régimen de dos veces al día, el 50 por ciento toman la medicación prescripta el 90 por ciento de los días de observación, comparado con el 70 por ciento cuando los pacientes cumplen la medicación una vez al día. la acción antihipertensiva de la amlodipina y el enalapril ha sido publicada recientemente por nuestro grupo de investigación, en un estudio controlado, paralelo, doble ciego y al azar. Después de cuatro semanas de recibir placebo en forma ciego-simple, los pacientes fueron asignados a recibir 20 mg de enalapril (15 pacientes) o 5 mg de amlodipina (15 pacientes) una vez al día. En la cuarta semana de medicación activa la dosis fue duplicada, en caso que la presión arterial diastólica en posición sentada fuera superior a 90 mmHg. Un monitoreo ambulatorio de presión arterial fue realizado al final de la etapa placebo por un período de 24 horas y al final de la semana 12 de tratamiento activo por un período de 48 horas. Las reducciones en la presión arterial fueron mayores en el grupo amlodipina (AU)

Effects of amlodipine on platelet aggregation and blood pressure in patients with essential hypertension.

Ten patients (mean age, 46 years) with mild to moderate hypertension received 5 mg of amlodipine daily for 12 weeks. The amlodipine dose was increased to 10 mg daily in 4 patients whose blood pressure remained > or = 90 mmHg during the first 8 weeks. After 8 and 12 weeks of treatment, mean blood pressures in the supine, sitting, and standing positions and after exercise were reduced significantly. Heart rate did not change significantly from before to after treatment. Six hours after amlodipine administration, however, slight but significant increases in heart rate were noted at rest and after exercise. Platelet aggregation induced by adenosine diphosphate or collagen was significantly reduced 6 hours after amlodipine. One patient reported headache after the 10-mg dose of amlodipine. No other side effects were noted. It is concluded that 10 mg of amlodipine once daily is safe and effective in the treatment of mild to moderate hypertension.

Amlodipine in hypertension: its effects on platelet aggregation and dynamic exercise.

The antihypertensive efficacy and safety of once-daily amlodipine (5-10 mg) were studied in patients with essential hypertension. The study also included an assessment of the effects of single doses of amlodipine on platelet aggregation. Ten patients received amlodipine (mean daily dose of 7 mg) for 12 weeks in an open chronic study preceded by a 4-week placebo run-in period. Amlodipine significantly reduced the mean dorsal supine (-31/-20 mm Hg), sitting (-34/-23 mm Hg), standing (-34/ -23 mm Hg), and postexercise (-30/-20 mm Hg) blood pressures (BPs) at the end of 12 weeks of treatment compared with the placebo run-in period (p < 0.005), with no significant change in heart rate. At the end of a 4-week placebo washout phase following the chronic study, nine of the patients received an acute single 10-mg dose of amlodipine. Exercise testing before and 6 h after dosing showed that an acute 10 mg dose of amlodipine reduced BP without modifying the physiologic response to dynamic exercise. Amlodipine significantly reduced the degree of platelet aggregation in these patients (p < 0.005) induced by either collagen or ADP. This study demonstrated that amlodipine once daily was an effective antihypertensive agent and significantly inhibited platelet aggregation.

The effect of doxazosin on platelet aggregation in normotensive subjects and patients with hypertension: an in vitro study.

An in vitro assay was used to investigate the effects of doxazosin on the platelet aggregation induced by epinephrine, collagen, and adenosine diphosphate. Platelet-rich plasma from normotensive subjects and patients with hypertension was compared. Doxazosin produced a concentration-dependent inhibition of platelet aggregation in both groups, but significantly lower concentrations were required to inhibit platelet aggregation in plasma taken from patients with hypertension. The concentrations of doxazosin that inhibited platelet aggregation in vitro were similar to those that are used clinically to control blood pressure in patients with hypertension.

Evidence of an antiplatelet aggregation action of doxazosin in patients with hypertension: an ex vivo study.

Eighteen patients with a mean age of 54.7 years were included in the study. All patients had a diagnosis of mild or moderate essential hypertension (sitting diastolic blood pressure of 96 to 114 mm Hg). The study design was single blind and in two phases: phase I, placebo (4 weeks), and phase II, the active treatment (8 weeks) with increasing doses, if needed, of doxazosin every 2 weeks (1, 2, 4, and 8 mg/day). Results show that doxazosin has an antihypertensive effect that is dose dependent. Systolic, diastolic, and mean blood pressures were decreased significantly, and no effect on heart rate was observed. Doxazosin significantly inhibited the platelet aggregation induced by epinephrine, adenosine diphosphate, and collagen in a dose-dependent manner. In addition, treatment with doxazosin lowered total serum cholesterol and triglyceride levels, without changing other standard biochemical parameters. This indicates that doxazosin could offer a distinct therapeutic advantage in the modulation of atherogenic and thromboembolic factors associated with coronary heart disease.

The effects of the calcium antagonist amlodipine on blood pressure and platelet aggregation in hypertensive patients.

This study examined the antihypertensive efficacy of open-label amlodipine in once-daily doses of 5-10 mg for 12 weeks. Efficacy was assessed by measurement of blood pressure and heart rate in the supine, seated and standing positions and after exercise periodically during the study. Blood pressure was significantly reduced throughout the study with no change in heart rate. During a placebo-washout phase after the 12-week active treatment phase of the study, blood pressure returned to baseline values. After the 4-week placebo-washout phase some patients received a single 10-mg dose of amlodipine followed by an exercise test 6 h later, which showed that amlodipine lowered blood pressure without blunting the normal physiological response to exercise. In these patients amlodipine also significantly reduced ex vivo platelet aggregation induced by collagen or ADP.