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.

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.

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.

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.

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.

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.

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.

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.

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.

Multiclinic comparison of labetalol to metoprolol in treatment of mild to moderate systemic hypertension.

The antihypertensive effects of oral labetalol, a new alpha- and beta-adrenergic blocking agent, and metoprolol, a relatively beta1 selective adrenergic blocker, were evaluated in 91 patients with mild to moderate hypertension (standing diastolic blood pressure of 90 to 115 mm Hg) in a double-blind parallel group multicenter clinical trial. The effects of the two drugs on plasma lipids and lipoprotein fractions were also assessed. Following a four-week placebo phase, 44 patients were randomized to receive labetalol and 47 metoprolol. During a four-week titration phase, the labetalol dose was increased from 100 mg twice daily to a maximum of 600 mg twice daily to achieve a standing diastolic blood pressure of 90 mm Hg that was decreased by 10 mm Hg or more. Metoprolol was titrated from 50 mg to 200 mg twice daily. An eight-week maintenance period followed during which hydrochlorothiazide could be added. At the end of the maintenance phase, the doses of labetalol and metoprolol were tapered over a two to four day period after which patients received a placebo for one week. Blood pressure in the supine and standing position was measured at each visit. Labetalol and metoprolol both significantly (p less than 0.01) lowered the supine and standing blood pressure from baseline with no significant difference found between the two treatment groups. Both drugs lowered the heart rate; however, the rate-lowering effect was significantly greater with metoprolol (p less than 0.01). There were no significant effects of either drug on plasma lipids or lipoprotein fractions. Fatigue was the most frequently reported complaint with both drugs. Dizziness, dyspepsia, and nausea were more common with labetalol; bradycardia was more common with metoprolol. There was no blood pressure "overshoot" after withdrawing drug treatment; however, a heart rate "overshoot" was seen after metoprolol was tapered off and stopped. Labetalol is as safe and effective as metoprolol in the treatment of patients with mild to moderate hypertension.

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.

Multicenter comparison of the nifedipine gastrointestinal therapeutic system and long-acting propranolol in patients with mild to moderate systemic hypertension receiving diuretics. A preliminary experience.

The efficacy and safety of nifedipine in a gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation was compared with long-acting propranolol in 49 patients with mild to moderate hypertension already receiving diuretics. Using a two-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 24) in doses of 30 mg, 60 mg, or 90 mg once daily; or long-acting propranolol (n = 25) in doses of 80, 160, or 240 mg once daily. Previous diuretic therapy was continued. Sitting and five-minute standing blood pressure and heart rate measurements were made 24 hours after dosing. At the endpoint of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p less than 0.001) in the sitting and standing positions. Nifedipine GITS was more effective in lowering standing systolic blood pressure than was propranolol (p less than 0.02). Propranolol caused a greater reduction in resting heart rate than did nifedipine GITS (p less than 0.003). Both drugs were well tolerated. Nifedipine GITS is an effective and safe once-daily drug for use in patients with hypertension who are already receiving diuretics, may be more effective than sustained-release propranolol, and may be better tolerated than conventional nifedipine capsules.

Influence of vegetation size on clinical outcome of right-sided infective endocarditis.

Endocarditis involving right-sided valvular structures is largely a disease of intravenous drug abusers. The majority of these patients respond to antibiotic therapy with clearing of their bacteremia and preservation of their hemodynamic status. This study evaluated the prognostic value of echocardiographically determined vegetation size in 23 episodes of right-sided valvular endocarditis in 21 patients. Right-sided vegetations were visualized in 19 of 23 episodes (83 percent). Of these, a vegetation of 1.0 cm or greater was found in 11. No patient with an echocardiographically determined vegetation size of less than 1.0 cm required surgery, whereas four of 11 (36 percent) of those episodes in which the vegetation size was 1.0 cm or greater required surgery for persistent pyrexia (p less than 0.05). In all patients requiring surgery, a bioprosthetic tricuspid valve was placed at the time of initial surgery and in no patient did early reinfection occur. This study reconfirms the benign prognosis of right-sided valvular endocarditis. Further, although vegetations of less than 1.0 cm identify those patients who will respond to medical therapy, echocardiographically documented vegetations of 1.0 cm or greater are associated with a significantly lower response rate to appropriate medical therapy. The association of fever that persists for more than three weeks in the absence of another source of infection with an echocardiographically demonstrable right-sided vegetation of 1 cm or more identifies those patients who will require surgical intervention. Finally, tricuspid valve replacement can be performed at the time of initial surgery without undue concern for early reinfection or valve dysfunction.

Multicenter clinical evaluation of long-term efficacy and safety of labetalol in treatment of hypertension.

The long-term efficacy and safety of labetalol, an antihypertensive agent with combined beta- and alpha-blocking activity, were evaluated alone (number = 193) and in combination with a diuretic (number = 144) in an open-label multicenter trial of 337 hypertensive patients aged 21 to 75 years, including initially 205 (61 percent) men and 219 (65 percent) Caucasians. There were 219 (65 percent) mild, 85 (25 percent) moderate, and 33 (10 percent) severe hypertensive patients. Labetalol (100 to 1,200 mg twice a day) alone or in combination with a diuretic reduced the mean standing blood pressure by 13/11 and 25/16 mm Hg to 135/88 and 130/91 mm Hg, respectively (p less than 0.01), and supine blood pressure by 6/7 and 18/13 mm Hg to 141/86 and 138/90 mm Hg (p less than 0.01), respectively. Blood pressure reductions observed at one month were maintained after one year; 206 (62 percent) patients had 10 mm Hg or greater reductions and 184 (56 percent) patients were maintained at diastolic blood pressures less than 90 mm Hg. Most frequently reported drug-related side effects included fatigue (14 percent), dizziness (12 percent), nausea (11 percent), nasal stuffiness (8 percent), headache (4 percent), and male sexual dysfunction (14 percent). Side effects were generally of mild to moderate intensity and often transient. In addition, in 27 (8 percent) patients reversible asymptomatic transaminase elevations to greater than twice normal developed at some time during the study. In 13 (4 percent) patients these alterations resolved during continued labetalol therapy, but in five (2 percent) patients these marked elevations led to discontinuation of the drug. A total of 32 (9.5 percent) patients were terminated prematurely due to side effects (most commonly genitourinary or gastrointestinal) possibly attributable to the drug. These findings indicate that labetalol with or without a diuretic is a potentially effective, safe, and relatively well-tolerated long-term antihypertensive therapy.

Pharmacokinetic optimisation of therapy with beta-adrenergic blocking agents.

beta-Adrenergic blockade has provided one of the major pharmacotherapeutic advances of this century. The drugs in this class have the common property of blocking the binding of catecholamines to beta-adrenergic receptor sites; however, there are pharmacodynamic and pharmacokinetic differences between the individual agents which are of clinical importance. Among these differences are the completeness of gastrointestinal absorption, degree of hepatic first-pass metabolism, lipid solubility, protein binding, brain penetration, concentration within cardiac tissue, rate of hepatic biotransformation, and renal clearance of drug and/or metabolites. Long-acting formulations of existing beta-blockers are currently in use, and ultrashort-acting agents are also available. The pharmacokinetics of beta-blocking drugs can also be influenced by race, age, cigarette smoking and concomitant drug therapy. The wide interpatient variability in plasma drug concentration observed with beta-blockers makes this parameter unreliable in routine patient management. Despite the pharmacokinetic differences among the beta-blockers, these drugs should always be titrated in the individual patient to achieve the desired clinical response.