Pathophysiology and medical management of systemic hypertension and pre-eclampsia in pregnancy.

Hypertension in pregnancy includes a group of distinct disorders that require special consideration in both prevention and pharmacological treatment. In recent years, there have been few advances regarding the pathophysiology and prevention of pre-eclampsia, however there have been some promising studies regarding possible modes of screening women for preeclampsia before clinical signs and symptoms are apparent. The recommendations for first-line drug therapy for the hypertensive complications of pre-eclampsia, and the recommendations for pharmacological treatment of women with chronic hypertension antedating pregnancy, have changed little primarily because first-line medications have the advantage of having had more extensive research experience. Recent clinical trials have demonstrated the efficacy and safety of various second-line drugs for the hypertensive disorders of pregnancy; whether these therapies can eventually replace the standard recommended medications will require more extensive long-term investigation.

Cardiovascular disease in the elderly. Clinical assessment.

The elderly patient with suspected cardiovascular disease poses a diagnostic challenge to the clinician. In many elderly patients the frequent unreliability of the history and the presence of multiple concurrent diseases and medications complicate accurate assessment of the patient's cardiac problem. Clinical laboratory and noninvasive cardiac techniques are now available that enhance the accuracy of cardiac diagnosis and aid in the evaluation of left ventricular function.

Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The Zatebradine Study Group.

OBJECTIVES: We examined the antianginal and anti-ischemic effects of oral zatebradine, a direct sinus node inhibitor that has no blood pressure-lowering or negative inotropic effects in patients with chronic stable angina pectoris taking extended-release nifedipine. BACKGROUND: Heart rate reduction is considered an important pharmacologic mechanism for providing anginal pain relief and anti-ischemic action in patients with chronic stable angina, suggesting a benefit for sinus node-inhibiting drugs. METHODS: In a single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once a day) were randomized to receive zatebradine (5 mg twice a day [n = 64]) or placebo (n = 60). All subjects had reproducible treadmill exercise-induced angina at baseline, and after randomization they performed a serial exercise test 3 h after each dose for 4 weeks. RESULTS: Zatebradine reduced rest heart rate both at 4 weeks ([mean +/- SEM] 12.9 +/- 1.23 vs. 2.3 +/- 1.6 [placebo] beats/min, p < 0.0001) and at the end of comparable stages of Bruce exercise (16.7 +/- 1.2 vs. 3.4 +/- 1.2 [placebo] beats/min, p < 0.0001). Despite the significant effects on heart rate at rest and exercise, there were no additional benefits of zatebradine from placebo baseline in measurements of total exercise duration, time to 1-mm ST segment depression or time to onset of angina. Subjects taking zatebradine also had more visual disturbances as adverse reactions. CONCLUSIONS: Zatebradine seems to provide no additional antianginal benefit to patients already receiving nifedipine, and it raises questions regarding the benefit of heart rate reduction alone as an antianginal approach to patients with chronic stable angina.

Verapamil in treatment of chronic stable angina.

Verapamil, a calcium-entry blocking drug, is now available in the United States for the treatment of chronic stable angina. The effectiveness of the drug in obstructive coronary disease is dependent on a complex interplay of its direct actions and the reflex phenomena that they elicit. Clinical trials have demonstrated that the efficacy and safety of verapamil in treating patients with effort-related angina compares favorably with that seen with other antianginal agents. Relative contraindications to the use of verapamil include left ventricular dysfunction and sinus node and atrioventricular conduction disease. Combination therapy of beta-blockers with verapamil can provide important therapeutic benefits for many patients but it carries with it the potential for serious adverse reactions and, thereby, patients need to be carefully selected for such therapy. Verapamil is proving to be an important addition to existing drug regimens available for the treatment of stable angina pectoris.

Lipids, vascular disease, and dementia with advancing age. Epidemiologic considerations.

Elevated plasma lipid and lipoprotein levels are associated with an increased risk of cardiovascular disease in middle-aged men and women. It is still not clear, however, whether lipid and lipoprotein abnormalities continue to be risk factors for cardiovascular disease in the elderly population. It is not even clear what normal lipid values are in the elderly, and whether diet or drug therapy should be advised on the basis of lipid values established in middle-aged populations. Ischemic heart disease does remain the leading cause of death in the elderly, and there is now preliminary evidence from epidemiologic studies that relative elevations of levels of lipid and lipoprotein fractions in an elderly population might be associated with an independent and increased risk of coronary heart disease, stroke, and possibly dementia. Intervention studies are about to begin that will assess various lipid-and lipoprotein-modifying therapies and their ability to reduce vascular disease risk in the elderly.

Calcium channel blockers in myocardial infarction.

Calcium channel blockers are currently approved for use in patients with arrhythmias, stable and unstable angina pectoris, and systemic hypertension. The hemodynamic and electrophysiologic properties of these agents suggest that their use would be appropriate in both the immediate and the long-term management of patients who suffered a myocardial infarction. Some experimental evidence accumulated from animal models supports the ability of these drugs to reduce both myocardial infarct size and the incidence of ventricular arrhythmias. The clinical trials with these drugs, however, have yielded disappointing results. Some data suggest a role of diltiazem therapy in reducing the incidence of transmural wall infarction and angina in those patients sustaining non-Q-wave myocardial infarctions. In the setting of Q-wave infarction, calcium channel blockers seem to be less effective than beta-blockade both for acute and long-term management. Finally, calcium channel blockers appear to be contraindicated in patients who have suffered a myocardial infarction and who have concomitant left ventricular dysfunction.

Herbal medicine for the treatment of cardiovascular disease: clinical considerations.

Herbs have been used as medical treatments since the beginning of civilization and some derivatives (eg, aspirin, reserpine, and digitalis) have become mainstays of human pharmacotherapy. For cardiovascular diseases, herbal treatments have been used in patients with congestive heart failure, systolic hypertension, angina pectoris, atherosclerosis, cerebral insufficiency, venous insufficiency, and arrhythmia. However, many herbal remedies used today have not undergone careful scientific assessment, and some have the potential to cause serious toxic effects and major drug-to-drug interactions. With the high prevalence of herbal use in the United States today, clinicians must inquire about such health practices for cardiac disease and be informed about the potential for benefit and harm. Continuing research is necessary to elucidate the pharmacological activities of the many herbal remedies now being used to treat cardiovascular diseases.

Dementia. Age-dependent incidence, prevalence, and mortality in the old old.

Age has been reported as a strong risk factor for dementia. Supporting data have been derived mainly from prevalence studies, which had varied criteria and sample compositions that precluded direct comparisons, especially among those aged 85 years and older. Data regarding rates of dementia are presented based on 85 incident cases in the Bronx (NY) Aging Study, a prospective study of 488 initially nondemented, old old persons (mean age on entry, 79 years). Overall, the incidence rate over 8 years of follow-up for all-cause dementia was 3.4 per 100 per year (43% Alzheimer's disease, 30% mixed Alzheimer's and vascular, and 27% other). Incidence rose significantly, irrespective of gender, as subjects were followed up through three age intervals--ages 75 to 79 years (1.3/100 per year), 80 to 84 years (3.5), and 85 years and older (6.0). The comparable age-associated prevalence rates of dementia were 3.7%, 12.2%, and 23.9%, respectively, with an overall period prevalence of 22.8%. Additionally, there was a threefold greater mortality associated with dementia. In conclusion, despite the shortened life expectancy of demented persons, dementia is a highly prevalent condition among those aged 85 years and older. Public policy attention is warranted, since this group is the fastest growing population subgroup.

Prognostic factors in acute pulmonary edema.

Over a six-month period, 106 admissions of 94 patients for acute pulmonary edema were identified and their charts were reviewed. Precipitating factors for acute pulmonary edema included progressively worsening congestive heart failure in 25.5% of cases, coronary insufficiency in 20.8%, subendocardial myocardial infarction in 16.0%, acute transmural myocardial infarction in 10.4%, arrhythmia in 8.5%, medical noncompliance in 6.6%, and other causes in 12.6%. In-hospital mortality was 17.0% (16 patients). Of those patients discharged from the hospital, an additional 27 (39.7%) were dead at one year, giving an overall one-year mortality of 51.2%. We found that patients with progressively worsening congestive heart failure have a better prognosis than patients with other precipitants. Also, patients with an initial systolic blood pressure in the emergency room of 160 mm Hg or higher had an improved survival over patients with an initial systolic blood pressure under 160 mm Hg. No other in-hospital or long-term prognostic factors were identified.

Twice-daily administration of oral verapamil in the treatment of essential hypertension.

The antihypertensive effect of twice-daily administration of verapamil hydrochloride was evaluated in 21 adult patients with mild to moderate essential hypertension. Following four weeks of placebo therapy, verapamil was given for four weeks with a treatment goal of sitting diastolic blood pressure (BP) of less than 90 mm Hg, or to a maximum dose of 160 mg twice daily. Sitting and standing BPs, heart rate, and verapamil plasma levels were determined weekly, ten to 12 hours post dose. At the maximal dose (mean, 154 +/- 19.2 mg), heart rate was not affected, side effects were minimal, and sitting diastolic BP was significantly reduced from placebo baseline, with 12 of 21 patients having a fall in sitting diastolic BP of 10 mm Hg or more or less than 90 mm Hg. A trough verapamil plasma level of greater than 80 ng/mL was associated with a good hypotensive response. These data indicate the safety and utility of twice-daily verapamil administration for the treatment of essential hypertension and suggest the value of obtaining verapamil plasma levels as a guide to dosage determination.

A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide.

BACKGROUND: The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide. METHODS: A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial. RESULTS: The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo. CONCLUSIONS: The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension.

Beta-adrenergic receptor blockers. Adverse effects and drug interactions.

Adverse effects of beta-adrenergic receptor blocking drugs can be divided into two categories: 1) those that result from known pharmacological consequences of beta-adrenergic receptor blockade; and 2) other reactions that do not appear to result from beta-adrenergic receptor blockade. Adverse effects of the first type include bronchospasm, heart failure, prolonged hypoglycemia, bradycardia, heart block, intermittent claudication, and Raynaud's phenomenon. Neurological reactions include depression, fatigue, and nightmares. It is not yet proven whether the beta 1-selective adrenergic blockers or those with partial agonist activity reduce the overall frequency of adverse reactions seen with propranolol. Patient age does not appear, in itself, to be associated with more beta-blocker side effects. Side effects of the second category are rare. They include an unusual oculomucocutaneous reaction and the possibility of oncogenesis. There are also many drugs that interact with beta-blockers, which may increase toxicity. Finally, there are specific patient characteristics where one beta-blocker may be more effective and safer than another.

Influence of oral verapamil on glucoregulatory hormones in man.

We evaluated the effect of treatment with placebo or verapamil (320 mg/day) for 2 weeks on glucose-induced insulin secretion and hypoglycemia-stimulated counterregulatory hormone secretion in hypertensive patients. Verapamil treatment was associated with a significant reduction in diastolic blood pressure (P = 0.02 vs. placebo). During a hyperglycemic clamp (plasma glucose raised 125 mg/dl above basal level) maintained for 90 min, plasma insulin increased 4- to 5-fold (early) and then to values 8- to 10-fold above baseline (late). These increments were identical during placebo or verapamil treatment. The rates of glucose metabolized during each study also were similar, suggesting that no significant change in insulin action occurred during drug treatment. When plasma glucose was allowed to decline precipitously from hyperglycemic levels (220 mg/dl) to nadirs ranging from 42-77 mg/dl, plasma concentrations of glucagon, cortisol, epinephrine, and norepinephrine all increased; however, no consistent differences in the counter-regulatory hormone responses could be attributed to verapamil therapy. We conclude that physiologically effective drug concentrations of verapamil capable of influencing blood pressure do not have a significant effect on secretion of glucoregulatory hormones in man.

Dynamic responses to continuous use of prazosin and hydralazine in patients with refractory heart failure.

The hemodynamic effects of oral doses of prazosin and hydralazine were studied in the same group of patients with chronic congestive heart failure. Prazosin, 3 to 10 mg, and hydralazine, 75 to 100 mg, were given by mouth every 6 hr and the responses to the first and the fifth consecutive dose were compared. The first dose of prazosin was followed by a predominant effect of left ventricular filling pressure and concomitantly by reduction of left ventricular afterload. Hydralazine acted primarily on left ventricular afterload with no significant effect on the filling pressure. A marked difference was noted in respect to the dynamic responses to continuous therapy with these two drugs. While the initial hemodynamic effect of prazosin was markedly attenuated in most of the cases after the fifth consecutive oral dose, the response to hydralazine was augmented by continuous therapy. These findings suggest that the reported hemodynamic tachyphylaxis seen with prazosin does not occur with hydralazine when given to the same patients with chronic congestive heart failure. Our study also indicates the importance of prolonged monitoring for the assessment of the hemodynamic effect of prazosin and hydralazine in patients with severe chronic congestive heart failure.

Women, myocardial infarction, and dementia in the very old.

Dementia is a major public health problem among the very old. Available information on incidence and prevalence is sparse and variable; however, there appears to be a higher prevalence among very old women. We present data from a prospective study of initially nondemented community-residing elderly. There were 75 incident dementia cases (up to 7 years of follow-up) of which at least 47% were probable Alzheimer's disease. Based on a proportional hazards analysis, women were over 3 times more likely to develop dementia than men despite controlling for baseline demographic, psychosocial, and medical history variables. Poor word fluency and a high normal Blessed test score at baseline were also strong predictors of dementia. We did not find age, head trauma, thyroid disease, or family history of dementia to be risk factors. A new finding is that history of myocardial infarction (MI) is associated with dementia, such that women with a history of MI were 5 times more prone to dementia than those without a history. This observation was not true for men.

Epidemiology, pathophysiology, and management of isolated systolic hypertension in the elderly.

Isolated systolic hypertension (ISH) is a common disorder in the elderly, carrying with it a high risk of cardiovascular morbidity and mortality. Environmental and age-related factors believed to contribute to ISH include obesity, declining physical activity, stress, and such dietary changes as increased salt intake and decreased intake of calcium and potassium. Increased rigidity of the aorta resulting in reduced compliance is an important hemodynamic feature, but factors that increase peripheral resistance also appear to play a role. Antihypertensive drugs have been shown to effectively and safely lower the systolic blood pressure elevations characteristic of ISH. To date, use of low drug doses and careful titration of dosage have avoided significant orthostatic hypotension and undue lowering of the diastolic pressure. Studies of relatively small groups of patients suggest that antihypertensive drugs can lower the risk of cardiovascular morbidity/mortality associated with ISH but the definitive answer awaits results of the ongoing large-scale Systolic Hypertension in the Elderly Program trial. In the interim, management should begin with conservative measures such as weight loss, salt restriction and, possibly, calcium supplementation. If this fails, drug therapy should be considered in patients with systolic blood pressures above 180 mm Hg and in those with systolic readings between 160 and 180 mm Hg who have concomitant cardiovascular risk factors. To date, no controlled trials of sufficient size have demonstrated that one drug class is more effective than another in treating ISH. Drug therapy should be tailored to the individual patient, starting with a low dose of a single drug and, if necessary, slowly increasing dosage until a systolic blood pressure under 160 mm Hg is attained.

Biologic markers as predictors of cardiovascular disease.

Epidemiologic data obtained over the past 30 years suggest that a number of new biologic markers are associated with increased risk for cardiovascular disease. These include indices related to (1) altered glucose metabolism, particularly insulin resistance; (2) hyperlipidemia; (3) elevated levels of lipoprotein(a) and homocysteine; (4) increased levels of molecules reflecting decreased fibrinolysis and increased activation of the coagulation cascade; (5) elevations in cell adhesion molecules and other markers of endothelial function; and (6) elevations in molecules associated with infection, inflammation, and vascular remodeling. Changes in molecules associated with increased risk usually occur in clusters. This clustering suggests that effective treatment of one marker may have positive effects on multiple markers. Indeed, several studies have demonstrated that therapies designed to reduce hyperlipidemia may also lower the plasma levels of factors associated with increased coagulation and reduced fibrinolysis. Thus, careful assessment of patient risk factors, and the development of therapies directed toward chains of markers associated with increased risk, may significantly alter the course of cardiovascular disease.

Hormonal and metabolic effects of calcium channel antagonists in man.

Calcium is a component of many metabolic reactions. By blocking calcium transport across cell membranes, calcium channel antagonists can therefore theoretically affect numerous metabolic and hormonal processes. In vitro studies have often documented just such an effect. Because of the expanding use and prevalence of calcium antagonists in clinical practice, a review of their in vivo effects on hormones and metabolism is warranted. The effect on glucoregulatory hormones, calcium regulatory hormones, anterior and posterior pituitary secretion, the renin-angiotensin axis, plasma catecholamines, and plasma lipids and lipoproteins is herein reviewed. The various calcium antagonists, by virtue of their distinct chemical structures, influence metabolism in their own unique manner. Despite the widespread involvement of calcium in hormone action, however, calcium channel antagonists have little dramatic impact on hormone regulation. This is, in part, due to the drug dosage used in clinical practice and to the inherent compensatory mechanisms built into normal endocrine function. The development of agents with greater and more potent metabolic specificity, however, coupled with the ability to target drug action, holds promise for expanded therapeutic application in the future.

Beta-adrenergic blockade and the gastrointestinal system.

As beta-adrenergic blockers grow increasingly popular for the therapy of a wide variety of disorders, it becomes increasingly important to appreciate the spectrum of physiologic effects on the gastrointestinal system and the potential hazards associated with use of these agents. This review details the effects of the beta-adrenergic blocking agents on the gastrointestinal tract.

Calcium entry blockers for the treatment of severe hypertension and hypertensive crisis.

Calcium entry blockers (diltiazem, nifedipine, and verapamil) are currently indicated for the treatment of patients with vasospastic and chronic stable angina pectoris. The calcium entry blocking actions of these drugs cause potent peripheral vasodilatory and antihypertensive effects in human subjects. The drugs have proved beneficial in the treatment of patients with severe hypertension and hypertensive emergencies. Single oral, sublingual, and intravenous doses of these drugs have been shown to rapidly and smoothly reduce blood pressure in adults and children, without significant untoward effects. The absolute reduction in blood pressure with treatment appears to be inversely correlated with the pretreatment blood pressure level, and few episodes of hypotension have been reported. Combinations of calcium entry blockers with other antihypertensive regimens have also proved effective. Some patients experience a mild increase in heart rate with nifedipine, an effect that appears to be inversely related to age. Side effects are minimal and not life-threatening. Continuous hemodynamic monitoring of patients does not seem necessary in most cases. The role of calcium entry blockade in the treatment of hypertensive emergencies still needs to be established in relation to other available approved drug regimens for this condition.