Adverse metabolic effects of antihypertensive drugs. Implications for treatment.

Adverse metabolic effects have been associated with drugs used in the therapy of hypertension, especially diuretics and beta-blockers. These effects include electrolyte, glucose/insulin, lipid and uric acid disturbances. This may explain, at least in part, why early trials examining the impact of antihypertensive pharmacotherapy with diuretics and beta-blockers showed beneficial effects on coronary artery disease that fell disappointingly short of the predicted effect. Among therapeutic drugs, diuretics cause disturbances in electrolyte homeostasis, e.g. hypokalaemia, hypomagnesaemia, and hyponatraemia. In contrast, ACE inhibitors cause hyperkalaemia under certain circumstances. Both diuretics and beta-blockers, especially nonselective beta-blockers that lack intrinsic sympathomimetic capabilities, have been associated with disturbances in glucose/insulin metabolism and can cause deleterious alterations in the profile of circulating plasma lipids. Hyperuricaemia, associated with diuretic use, appears to be a problem only in those patients who are predisposed to high circulating levels of uric acid.

Beyond controlling blood pressure in the black patient: metabolic considerations.

Hypertension is highly prevalent among African Americans, who are also more likely than whites to develop end-organ complications of hypertension. Traditional diuretic-based stepcare therapy has successfully reduced such complications of hypertension as stroke, congestive heart failure, and premature death in all populations tested. Prevention of coronary deaths has been less successful. Potentially adverse metabolic effects of thiazide diuretics and some beta-blockers may partially explain the less successful cardiac outcomes. Use of antihypertensive agents lacking adverse metabolic effects but still achieving effective blood pressure control could improve cardiac outcomes while maintaining the benefits achieved with older forms of therapy. Achievement of improved cardiac outcomes is now one of the principal goals of hypertension research and treatment.

The expanding role of angiotensin converting enzyme inhibitors in the management of hypertension.

Angiotensin converting enzyme (ACE) inhibitors are increasingly important in antihypertensive therapy because of their efficacy, tolerability, and specific benefits in subsets of patients. They are pharmacologically diverse. Whereas most benefits have been proven with older agents (captopril, enalopril), newer agents, such as benazepril, quinapril, and ramipril, offer potential advantages that remain to be proven.

First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension.

This 30-center, randomized, double-blind, placebo-controlled, parallel-group study was designed to (1) establish that 6.25 mg of hydrochlorothiazide (HCTZ) given once daily with 5 mg of bisoprolol fumarate can contribute to antihypertensive effectiveness in patients with stage I and stage II (mild to moderate) systemic hypertension; and (2) assess whether this formulation was more effective or possessed a safety advantage over standard monotherapy with bisoprolol or 25 mg of HCTZ. Results showed that HCTZ 6.25 mg contributed significantly to the antihypertensive effectiveness of bisoprolol 5 mg. Bisoprolol 5 mg/HCTZ 6.25 mg (B5/H6.25) produced significantly greater mean reductions from baseline in sitting systolic and diastolic blood pressure (-15.8 mm Hg/-12.6 mm Hg) than bisoprolol 5 mg alone (-10.0 mm Hg/-10.5 mm Hg) and HCTZ 25 mg alone (-10.2 mm Hg/-8.5 mm Hg). A 73% response rate was achieved with the low-dose formulation compared with 61% for the bisoprolol 5 mg (B5) group and 47% for the HCTZ 25 mg (H25) group. B5/H6.25 was found to be significantly more effective than B5 or H25 in all subgroups of patients, regardless of gender, race, age, or smoking history. Antihypertensive effects were maintained during the 24-hour dosing interval. The incremental effectiveness of B5/H6.25 was not accompanied by an increase in the frequency or severity of adverse experiences; the incidence of adverse experiences in the B5/H6.25 group was comparable to that in the placebo group. B5/H6.25 was shown to provide safety advantages over H25, as shown by less hypokalemia (< 1% with B5/H6.25 versus 6.5% with H25).(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind comparison of amlodipine and hydrochlorothiazide in patients with mild to moderate hypertension.

In the final analysis of this study at Week 26, 26% of the patients randomized to receive amlodipine attained blood pressure control with amlodipine alone compared with 33% of the patients allocated to hydrochlorothiazide (HCTZ). Neither amlodipine nor HCTZ produced clinically significant changes in pulse rate or in the electrocardiogram. Amlodipine treatment did not appear to produce clinically significant changes in blood lipids; HCTZ, however, produced an increase in total plasma cholesterol (delta 22.9 +/- 8.6 mg/dl). The incidence of side effects and the rate of patient withdrawal in the amlodipine and HCTZ groups were comparable. As expected, HCTZ therapy caused well-recognized biochemical alterations in cholesterol and potassium levels, whereas amlodipine was metabolically neutral.

The effect of amlodipine on ambulatory blood pressure in hypertensive patients.

Certain high-risk populations, such as diabetics and blacks, have sustained elevation in blood pressure and heart rate throughout the day and night, with blunting of the usual diurnal variability pattern. This may contribute to their higher incidence of left ventricular hypertrophy (blacks) and cardiovascular complications (diabetics). Hypertensives who maintain a diurnal pattern of blood pressure variation still exhibit higher daytime and nocturnal blood pressure levels than normotensives. Thus, to achieve maximum effectiveness in treating hypertension, 24-hour control of blood pressure is necessary. Antihypertensive agents should effectively reduce blood pressure consistently throughout a 24-hour period. The objective of this study was to assess the effects of amlodipine, 5 mg once daily, on blood pressure measured by 24-hour ambulatory monitoring in a randomized, double-blind, placebo-controlled single-site study. Patients with mild-to-moderate essential hypertension were randomized to receive amlodipine (n = 11) or placebo (n = 5) in a 2:1 ratio. A 4-week single-blind placebo run-in period was followed by a 4-week double-blind phase. Ambulatory monitoring of blood pressure was carried out for 24 hours at the end of each 4-week phase. Patients receiving amlodipine had significantly lower blood pressure compared with placebo 24 hours after the last dose (supine blood pressure -25.1/-10.1 mm Hg; standing blood pressure -21.2/-9.7 mm Hg) after 4 weeks of treatment. This effect was clearly demonstrated by the 24-hour postdose measurement and the mean blood pressure over the 24-hour interval as measured by ambulatory recordings.(ABSTRACT TRUNCATED AT 250 WORDS)

The USA experience with the clonidine transdermal therapeutic system.

Cardiovascular diseases are the leading causes of death in the United States, with hypertension being amongst the most prevalent of the cardiovascular risk factors. Improvement of hypertension management has, in consequence, received much attention. Extensive pre- and post-marketing experience with the transdermal formulation of clonidine marketed in the USA in the mid-1980s has now been accumulated. Transdermal clonidine is effective as monotherapy in mild-moderate hypertension, and in combination with diuretics, calcium antagonists and ACE inhibitors in more resistant cases. It controls blood pressure throughout the 24-h circadian cycle. It is effective and generally well-tolerated in adolescents, the elderly, blacks, diabetics, and subjects with chronic renal insufficiency. It has been used perioperatively and for suppression of adrenergic symptoms in subjects withdrawing from addicting substances. In comparison with oral clonidine, transdermal clonidine reduces the incidence and severity of such symptomatic side-effects as dry mouth, drowsiness, and sexual dysfunction. Minor skin reactions occur at the site of application of the transdermal patch with moderate frequency. Adherence to transdermal clonidine therapy is high, and patients commonly prefer it to oral therapy. Transdermal administration of clonidine is a useful therapeutic advance in the long-term management of hypertension.

Beta-blockers, dyslipidemia, and coronary artery disease. A reassessment.

Despite the strong association between hypertension and accelerated atherosclerosis, and the known beneficial clinical effects of beta-blockers in patients with coronary artery disease, antihypertensive trials of beta-blockers have shown only modest protection against fatal and nonfatal myocardial infarction. This review explores the explanations put forth for this apparent failure of beta-blockers. It also examines the clinical relevance of the metabolic effects of beta-blockers within the framework of the heterogeneity of this class of drugs. Recent evidence indicates that long-term treatment of hypertension with beta-blockers that do not possess intrinsic sympathomimetic activity reduces the occurrence of cardiac complications of hypertension. There are no data to show a quantified effect on clinical outcome of the lipid and glucose changes associated with beta-blocker therapy. The metabolic influence of these drugs varies considerably within the class and may be of little clinical relevance. Unless it is contraindicated, an appropriate beta-blocker should be considered for the treatment of hypertension in patients who have coronary artery disease or who are at high risk for coronary artery disease.

Hypertension: a review with emphasis on therapeutics with ACE inhibitors.

Hypertension, more prevalent with aging, is a major risk factor for cardiovascular disorders. Accordingly, it is important to decrease blood pressure and maintain it in an acceptable range to lessen morbidity and mortality. When nonpharmacological therapy fails, drug therapy should be instituted. The ideal drugs lower blood pressure, have few adverse side effects, and may have additional benefits on coexisting maladies. ACE (angiotensin-converting enzyme) inhibitors are excellent first-line drugs because they have few adverse effects and may have additional benefits on cardiac and renal status. This overview discusses many aspects of hypertension and its therapy, but emphasizes use of ACE inhibitors in the elderly.

Lessons learned with ambulatory blood pressure monitoring: a focus on ramipril.

Ambulatory blood pressure monitoring (ABPM) has been available since the mid-1970s. Widespread use of ABPM in research settings has led to an appreciation of its advantages and disadvantages. ABPM is a valuable research tool because of its ability to evaluate the duration and consistency of action with new antihypertensive agents. It has also been used to exclude patients who have white-coat hypertension from pharmacotherapy. Past and current clinical studies are reviewed to illustrate the role of this technique in the development of a new angiotensin converting enzyme inhibitor, ramipril. The studies involve administering a single daily dose of ramipril to lower blood pressure and ABPM. Three double-blinded, randomized studies and one placebo-controlled, crossover study are reviewed. In these studies of patients with essential hypertension, once-daily ramipril controlled blood pressure, reduced systolic/diastolic blood pressure throughout a 24-hour period, and did not interfere with normal circadian blood pressure patterns. Lessons learned from research suggest that ABPM will find a niche in clinical practice.