Uncomplicated Mild Hypertension Research Articles

Transdermal Clonidine Therapy and Blood Pressure Nocturnal Fall in Mild Hypertensive Male Subjects

Treatment of mild hypertension with an antihypertensive drug administered by means of a transdermal therapeutic system (TTS) could produce favorable results, when compared with a traditional oral regimen. Purpose: Using 24-h ambulatory blood pressure (BP) monitoring (ABPM) in mild hypertensive male subjects, to analyze three aspects which have not been completely clarified: a) whether a latency in the antihypertensive effect may be present, recording BP already from the first day of application of the patch, b) the eventual hazardous enhancement of circadian nocturnal fall in BP values in treated mild hypertensive patients and, c) the possible overlapping of antihypertensive effect between the administration of two consecutive patches. Subjects and methods: In 12 caucasian male outpatients (yrs 55 ± 3 SEM) with uncomplicated essential mild hypertension, a patch containing placebo was applied for the first week (T 0 period). At the end of the T 0 period, a 5 mg TTS-2 clonidine patch was applied for one week, and, subsequently, a new patch of 5 mg TTS-2 clonidine was kept for another week. ABPM was performed on the last day of the placebo period (T 0) and on the 1st day (T1), the 7th day (T2) and the 14th day (T3) of transdermal clonidine therapy. Results: Both systolic and diastolic BP (24 h mean, day-night-time) decreased on the 1st, 7th and 14th day, when compared with T0. However, no significant differences were documented between the BP levels on the 1st and the 7th day of treatment. The incidence of nocturnal fall in systolic and diastolic BP was evaluated and no significant differences were found, when compared with night-time reference values. Conclusions: When compared with the placebo period, TTS-2 clonidine lowers SBP and DBP within the first 24 hours of application. The antihypertensive effect persists at the end of the first week, as well as after 14 days. The lowest values of systolic-diastolic BP documented were not below the levels reported in normotensive men. Therefore, TTS-2 clonidine seems to act as an antihypertensive agent rather than a hypotensive drug since it normalizes BP without lowering it below physiological levels.

Postural hypotension in elderly patients given carvedilol

First dose postural hypotension is commonly observed with antihypertensive drugs,1,2 but its incidence may be overstated in clinical trials because of protocol requirements, which may include frequent venesection, fasting, acute withdrawal from caffeine, and frequent changes in posture.1 The s blocker vasodilator drug carvedilol is associated with orthostatic hypotension, particularly in elderly people.*RF 234* We assessed the incidence of first dose hypotension in the absence of possible confounding factors linked to protocol. The study group comprised 16 elderly patients (nine men; mean (SD) age 70 (6) mean weight 73 (17) kg) with uncomplicated mild or moderate hypertension whose supine diastolic blood pressures were 90-110 mm Hg after one week's washout with placebo after antihypertensive treatment. Previous studies showed that a sample of 10-18 subjects would produce an 80% chance of detecting a difference in response of 10 mm Hg between treatments at the …

The place of combination therapy in the treatment of hypertension in 1993.

"Step Care" fell into disuse following the advent of the ACE inhibitors and calcium antagonists. This was partly because the potency of these agents encouraged their use in monotherapy, and partly because of dissatisfaction with ritual treatment using multiple drugs. However monotherapy too has its problems, not the least of which is ritual increase in the dose of the first drug prescribed, leading to prolonged treatment with high doses and hence an increase in side effects. It is therefore important to consider changing to an alternative drug rather than automatically increasing the dose, or adding a second drug. Combination therapy still has a major place in the treatment of hypertension. It is necessary in patients with severe hypertension, with clinical manifestations of target organ damage, or with associated conditions that often help the doctor to choose a rational combination. Even in patients with uncomplicated mild hypertension, the achievement of goal blood pressure requires combination therapy in around half the cases. By choosing two drugs from appropriate classes of agent, it is possible to add the primary actions of drugs acting through different mechanisms, while opposing the homeostatic compensations that limit the fall in blood pressure. Effective combinations therefore maximise hypotensive efficacy while minimising side effects. Effective combinations for the treatment of classical and of systolic hypertension, are discussed.

Guidelines for the treatment of mild hypertension.

Mild hypertension is defined as a state in which diastolic blood pressures ranging from 90 to 104 mm Hg are persistently observed. Systolic blood pressure is increasingly being recognised as a risk factor in its own right. Strictly speaking, the lessons learnt from the prospective trials in mild hypertension apply mainly to the stratum of mild diastolic hypertension. In this review, randomised placebo-controlled blind trials in uncomplicated mild hypertension (USPHS, ANBPS, MRC trials) will serve as the main data base from which to derive practical guidelines, in terms of benefits and risks, of early treatment.

Effects of Transdermal Clonidine in Young and Elderly Patients with Mild Hypertension

The efficiency of the clonidine transdermal therapeutic system was assessed in a group of patients under 35 years of age and in another group of patients over 60 years of age. The patients in both groups had mild uncomplicated hypertension. Blood pressure (BP) was measured by the three following methods: by the physician; by an automatic device at the outpatient clinic; and by the patient at home. Seventeen young patients (mean age, 26 years) and 18 elderly patients (mean age, 68.5 years) were included in a double-blind crossover study comprising four periods of 2 weeks each, during which patients were given, weekly, either placebo or one and then two transdermal clonidine patches containing 2.5 mg of the drug. In the younger group, the average systolic and diastolic BPs measured by the physician after administration of two clonidine patches were, respectively, 4.9 and 5.9 mm Hg lower than after placebo (p less than 0.05). The absolute drop was more significant in the older group (9.3 and 6.0 mm Hg; p less than 0.01). In the young group, placebo markedly reduced systolic BP (9.8 mm Hg; p less than 0.01), and comparison of the three methods of BP measurement demonstrated their great reactivity to the physician's presence. Nine young and eight elderly patients received clonidine treatment for an average duration of 9 +/- 5 months. Six cases of skin reactions occurred and limited the usefulness of the clonidine transdermal system used in this study.

Pharmacokinetics of ketanserin in patients with essential hypertension.

The pharmacokinetics of ketanserin and its main metabolite ketanserin-ol, and the antihypertensive effects of intravenous, single oral and chronic oral (40 mg once daily) administration of ketanserin, have been investigated in a single blind study of 10 patients with uncomplicated mild hypertension. Ketanserin had a terminal half-life of 29.2 h, a plasma clearance of 518 ml/min and a volume of distribution of 18.0 l/kg. Chronic oral intake of 40 mg ketanserin (tablet formulation) gave a peak concentration of unchanged ketanserin of 88 ng/ml after 1.1 h. Its absolute bioavailability was 48%. During chronic therapy the maximal concentration of ketanserin-ol was 208 ng/ml and its half-life of elimination was 35.0 h. As this metabolite can be oxidized back to ketanserin, it contributes to the prolonged half-life of unchanged ketanserin seen during chronic therapy. The blood pressure was reduced by approximately 15% by oral ketanserin. The maximal reduction in blood pressure coincided with the peak concentration of unchanged ketanserin. During chronic therapy with 40 mg once daily blood pressure was reduced over 24 h. The heart rate was slightly reduced and the cardiovascular responses and the plasma noradrenaline concentrations during isometric exercise were only slightly influenced by ketanserin therapy. Thus, unchanged ketanserin has a relatively long half-life during chronic oral therapy and its pharmacokinetics in middle-aged hypertensive patients is similar to that in normal young volunteers.

Value of echocardiographic measurement of left ventricular mass in predicting cardiovascular morbid events in hypertensive men.

To assess whether echocardiographic and electrocardiographic detection of left ventricular hypertrophy could predict cardiovascular morbid events in patients with uncomplicated essential hypertension, we followed 140 men for a mean of 4.8 years. Initial echocardiographic measurements of left ventricular mass were normal (less than 125 g/m2 body surface area) in 111 patients and revealed hypertrophy in 29 patients. Morbid events occurred in more patients with hypertrophy on echocardiography (7 of 29, 4.6/100 patient-years) than with normal ventricular mass (7 of 111, 1.4/100 patient-years; p less than 0.01). Electrocardiography showed hypertrophy in too few patients to be of predictive value. Multiple logistic regression analysis showed that left ventricular mass index had the highest independent relative risk for future events and that systolic and diastolic pressures and age had slightly lower relative risks. In men with mild uncomplicated hypertension, left ventricular hypertrophy detected by echocardiography identifies patients at high risk for cardiovascular morbid events and is a significant risk factor for future morbid events independent of age, blood pressure, or resting ventricular function.

Age related antihypertensive effect of nitrendipine, a new calcium entry blocking agent.

The effect of nitrendipine 20 mg o.d., a new calcium entry blocker similar in structure to nifedipine, on blood pressure has been evaluated in 14 patients (aged 24-62 years) with uncomplicated mild or moderate arterial hypertension. A significant decrease both in systolic (160 +/- 12 at baseline vs 141 +/- 8 mm Hg, p less than 0.001) and diastolic (106 +/- 8 vs 93 +/- 3 mm Hg, p less than 0.001) blood pressure was observed at the end of 8 weeks of nitrendipine treatment. An inverse correlation was found between age and the reduction in diastolic blood pressure (r = 0.772, p less than 0.001 as absolute reduction; r = 0.791, p less than 0.001 as percentage reduction versus baseline). This peculiar characteristic differentiates the effect of nitrendipine from that of other calcium entry blockers, which appear to be more effective in older patients.

Serum glucose levels during long-term observation of treated and untreated men with mild hypertension: The Oslo study

Serum glucose levels, triglyceride levels, and body weight are reported from a controlled drug trial in men, aged 40 to 49, with uncomplicated mild hypertension. The drug treatment started with hydrochlorothiazide alone, and methyldopa was added when necessary. If side effects occurred, methyldopa was replaced by propranolol. No detailed advice about diet, smoking, or weight reduction was given to any group. The untreated control subjects had a small increase in serum glucose levels during five years, from 6.08 to 6.21 mmol/liter. Those treated with hydrochlorothiazide alone and those treated with hydrochlorothiazide plus methyldopa had a small increase in serum glucose levels of the same order as that in the control subjects. However, those receiving the thiazide/propranolol combination experienced a sizeable increase in glucose levels, from 5.96 to 6.53 mmol/liter (p < 0.001). This increase was significantly greater than the increase in the other groups (p < 0.001). The thiazide/propranolol group also showed a significant increase in serum triglyceride levels (p < 0.05). There was no difference in serum potassium levels in the different drug groups. The results indicate that moderate thiazide doses do not have significant effects on serum glucose levels in this age group. Propranolol in combination with thiazide seems to increase the level of serum glucose.

Effects of labetalol on left ventricular mass and function in hypertension — An assessment by serial echocardiography

We determined echocardiographic (M-mode) indices of left ventricular mass and function serially at 1-month intervals in 10 patients with uncomplicated mild or moderate essential hypertension, before and after adequate control of blood pressure with labetalol, a combined alpha- and beta-receptor blocking agent. Seven patients had pretreatment echocardiographic evidence of left ventricular hypertrophy with disproportionate septal thickness in 4. Systolic blood pressure in the untreated state correlated well ( r = 0.96) with left ventricular mass but poorly ( r = 0.30) with diastolic pressure. Following a satisfactory blood pressure reduction, achieved in all patients, left ventricular mass decreased from 240.5 ± 71.1 g to 159.5 ± 40.7 g ( P < 0.01), interventricular septal thickness from 1.33 ± 0.3 cm to 0.92 ± 0.25 cm ( P < 0.01) and posterior wall thickness from 1.03 ± 0.23 cm to 0.93 ± 0.23 cm ( P < 0.05). While the maximum changes in left ventricular mass were noted by the end of first month ( P < 0.01) with insignificant changes thereafter, the correlation of fall in blood pressure with change in left ventricular mass was significant only after 2 months of treatment ( P < 0.05). Indices of left ventricular function (end-diastolic volume, ejection fraction, fractional diameter shortening, left atrial dimension and posterior aortic wall motion) were normal before treatment and remained unchanged during 3 months of treatment. In this short-term study, labetalol reduced left ventricular hypertrophy (expressed as left ventricular mass and wall thickness) without altering left ventricular function indices in patients with uncomplicated essential hypertension. This has important implications in the treatment of hypertensive patients.

Clonidine in the Elderly Hypertensive: Monotherapy and Therapy With a Diuretic

Forty-eight elderly patients with uncomplicated mild essential hypertension entered two drug regimens. In group 1, clonidine monotherapy (n = 15), clonidine was titrated to achieve goal blood pressure (less than 90 mm Hg diastolic) in dosages of 0.05 mg twice daily to 0.2 mg three times daily. Blood pressure decreased without major side effects (p less than 0.001). Three patients required small doses of diuretic after six months of clonidine monotherapy. In group 2, step-care therapy (n = 33), clonidine was added to chlorthalidone, 25 mg daily, for three weeks. Eight patients achieved the goal blood pressure with chlorthalidone, 25 required clonidine (0.1 mg to 0.3 mg twice daily) to achieve blood pressure control. Side effects of clonidine did not require discontinuation of therapy. Retrospective analysis of up to 2 1/2 years of clonidine plus diuretic (n = 51) showed a similar blood pressure reduction. Clonidine can be used effectively with or without a diuretic in the elderly hypertensive.

The role of salt in hypertension.

Epidemiological data indicate a weak but significant positive correlation between the level of salt intake and blood pressure. It is unclear how this relationship is mediated but some studies indicate that heredity for hypertension is associated with an increased sensitivity to salt. Decrease of the salt intake decreases blood pressure in established hypertension and should be used as a therapeutic adjuvant in mild uncomplicated hypertension much more often than is now the case. Increased salt intake in young subjects with or without heredity for hypertension does not seem to increase the blood pressure during a 4-12 week load. Increased salt intake in middle-aged men, on the other hand, seem to induce a blood pressure increase irrespective of the presence or absence of a positive family history. The sensitivity to a high salt intake might thus be associated with aging. Increase of the salt intake from the normal level seems to induce an increase in sympathetic nervous activity. The interplay between the level of salt intake and sympathetic nervous activity should be studied in more detail.

State-of-the-Art Review

The last few years have seen increasingly clear evidence appear that the treatment of mild uncomplicated hypertension can prevent the development of a variety of hypertension-related cardiovascular complications. A good case can now be made for preventive antihypertensive therapy in adults with casual Vth phase diastolic pressures of 95mm Hg or more. This realisation has produced a corresponding requirement for drugs with few side effects; agents such as guanethidine, reserpine, methyldopa and clonidine are less readily accepted in this context. Although neither β-blochers nor thiazides are free from unwanted effects, they most nearly answer these needs and the majority of physicians now employ them as initial therapy.

Situational variations of blood pressure in ambulatory hypertensive patients.

Blood pressure and heart rate were recorded at 15-min intervals for 24 hr in 60 untreated patients with uncomplicated mild essential hypertension using a new automatic noninvasive portable recorder. During the recording, the patients went about their normal daily routine, of which they kept a detailed record. The data were analyzed for five different recording situations: in the clinic, at work, at home, asleep, and average of the entire 24-hr period. Twenty-four hour readings were also compared with previously obtained casual readings. Clinic readings were correlated with the average 24-hr values, but for individual patients clinic pressures were relatively poor predictors of 24-hr pressures. Pressures recorded in the clinic were also greater than average 24-hr values. Similar degrees of correlation were found between clinic, home, work, and sleep pressures. Pressures recorded in the clinic were similar to pressures at work but higher than at home or asleep. In contrast, heart rate was similar in all conditions except during sleep, when it was lower. Previously measured casual pressures were also correlated with the clinic readings, with systolic values being similar, but diastolic values higher in the clinic during the 24-hr recording. For patients with clinic diastolic pressures in the range 90-104 mm Hg, 24-hr pressures varied from 75 to 100 mm Hg. We conclude that pressures measured casually in the clinic do not accurately reflect average 24-hr pressures and that ambulatory recording is helpful in the evaluation of mildly hypertensive patients.

9 The kinins and prostaglandins in hypertension

In the last decade, new approaches to the possible aetiology of human essential hypertension have been undertaken from the viewpoint of hypofunction of the depressor mechanism. There are many reports indicating that the kinin and the prostaglandin systems may contribute to the regulation of blood pressure by various mechanisms: direct vasodilation, opposing the vasoconstricting action of the renin—angiotensin—aldosterone system, autoregulation of renal blood flow, and modulation of salt—water excretion. Although urinary kallikrein excretion is not decreased in uncomplicated mild hypertension and is decreased in sustained hypertension, it seems likely that the renal kallikrein—kinin system and the renal prostaglandin system exert their effects in the early stage of hypertension to protect the development of hypertension and that hypertension increases because of reduced activity of the renal kallikrein and the prostaglandin systems in the face of normal and augmented pressor systems.

Exercise Performance in Mildly Hypertensive Patients: Impairment by Propranolol but not Oxprenolol

Beta blocking drugs are commonly used to treat hypertension. These agents can decrease exercise performance in normal subjects, but little is known of their effects on exercise capacity in hypertensive patients, although fatigue is one of the side effects of this therapy. We studied the effects of propranolol and oxprenolol, a beta-adrenergic blocking agent with intrinsic sympathomimetic activity, in 12 patients with uncomplicated mild essential hypertension. In six patients treated with oxprenolol for 13.7 ± 4.1 (SEM) weeks, exercise duration (upright bicycle exercise to symptomatic maximum) was insignificantly changed from 10.8 ± 0.9 to 10.5 ± 0.6 min and maximal O₂ consumption was also unchanged (21.5 ± 1.3 to 21.7 ± 1.8 ml/kg/min). In six other patients treated for 10.0 ± 3.4 weeks with propranolol, exercise duration fell from 13.2 ± 1.8 to 10.3 ± 1.0 min (<i>P</i><0.05) and maximal O2 consumption from 25.4 ± 1.8 to 20.9 ± 0.9 ml/kg/min (<i>P</i><0.05). There were no differences between groups in resting hemodynamics before or after beta-blockade. However, at peak exercise, propranolol reduced cardiac output by 1.74 ± 0.28 L/min (<i>P</i><0.02), while stroke volume was unchanged. Oxprenolol increased stroke volume by 22.3 ± 6.8 ml/beat at peak exercise, while not changing cardiac output. Both drugs similarly and significantly reduced heart rate and blood pressure at rest and during exercise. Thus, propranolol can reduce exercise capacity in hypertensive patients presumably by depressing the cardiac output response, while oxprenolol does neither, possibly because of its intrinsic agonist activity.

Effect of Adrenal Suppression with Dexamethasone in Essential Hypertension*

The 24-h integrated plasma concentration of aldosterone (IC-ALDO), PRA (IC-PRA), and cortisol (IC-F) were measured in 34 male patients with uncomplicated mild essential hypertension and 15 matched normal controls using a portable 24-h continuous nonthrombogenic blood withdrawal system. The hypertensive were subsequently given 0.5 mg dexamethasone three times per day, resulting in suppression of their urinary excretion of 17-hydroxycorticosteroids and free cortisol. The diastolic blood pressure of the hypertensives fell during adrenal suppression from 104 +/- 5 to 96 +/- 8 mm Hg (mean +/- 1 SD; P less than 0.0001). The systolic pressure fell from 150 +/- 16 to 148 +/- 17 (P greater than 0.01). Baseline values for IC-F, IC-ALDO, and IC-PRA were similar in hypertensive subjects and normal controls. After treatment with dexamethasone for 8 weeks, IC-F in the hypertensives decreased from 7.8 +/- 2.1 to 0.7 +/- 0.6 microgram/dl (P less than 0.0001). There was no associated change in IC-ALDO or IC-PRA. Thus, the fall in diastolic blood pressure in response to dexamethasone was associated with suppression of IC-F, without demonstrable changes in other endocrine or biochemical factors measured.

Serum triglycerides and serum uric acid in untreated and thiazide-treated patients with mild hypertension: The Oslo study

Levels of serum lipids, uric acid and body weight are reported from a controlled trial of drug treatment of middle-aged men with uncomplicated mild hypertension. The results come from 300 men after three years of follow up; 150 men in the treatment group and 150 men in the control group. The treatment has been standardized starting with hydrochlorothiazide alone and adding alpha methyldopa when necessary. In case of side effects, alpha methyldopa was replaced with propranolol. Pretreatment results demonstrated a strong covariation among body weight, uric acid and triglycerides. In the entire treatment group, there was no significant change in triglycerides after three years (increase from 1.85 to 2.02 mM/liter, P > 0.05). Cholesterol was also unchanged. Further analysis showed that certain patients reacted with an increase in triglycerides during treatment: those prone to a distinct increase in uric acid and those gaining weight. Those who needed combination therapy (having the highest pretreatment blood pressure) showed most of the Increase in triglyceride and uric acid. In the group treated with hydrochlorothiazide alone, the triglycerides were unchanged. However, those selected from this group with a distinct increase in uric acid also showed an increase in triglycerides. The treatment increased the pretreatment positive correlation between uric acid and triglycerides.