Issues in hypertension: drug tolerability and special populations.

Improvements in the death rate from coronary heart disease and in the control of hypertension have leveled off in recent years, reversing a trend toward steady improvement that began in 1972. Of the roughly 20% of Americans who suffer from hypertension, only 29% achieve adequate control (<140/90 mm Hg) with treatment and nearly half receive no treatment at all. Poor adherence to therapy doubtless plays a key role in this failure. As a major cause of poor adherence, tolerability becomes an extremely important element in any discussion of effective antihypertensive treatment. Despite their efficacy in treating hypertension, diuretics, beta-blockers, and calcium channel blockers have all been associated with numerous side effects, including increased serum lipid levels, insulin resistance, and edema. With the introduction of the angiotensin converting enzyme (ACE) inhibitors, patients were able to achieve blood pressure goals with fewer side effects. These agents, however, cause an irritating cough in up to 19% of patients. A newer class of drugs, the angiotensin receptor blockers (ARB), have similar effects to the ACE inhibitors, but their highly selective nature produces even fewer side effects. Eprosartan is a structurally unique ARB. Like the other ARB, this promising new agent has a side effect profile similar to placebo, and its response rate rivals or exceeds that of enalapril. Although it remains to be seen whether the ARB can significantly reduce morbidity and mortality from cardiovascular disease, preliminary data from the Evaluation of Losartan in the Elderly (ELITE) trial appear to be promising.

The angiotensin II type 1 receptor blocker losartan in clinical practice: a review.

Blockade of angiotensin II receptors was first achieved in the 1970s using a peptide, saralasin acetate. Although it was effective in lowering blood pressure, it required parenteral administration and had a short duration of action and partial agonist activity. These disadvantages are absent with losartan, a selective, orally administered, nonpeptide blocker of the angiotensin II type 1 receptor that recently became available for clinical use. Losartan has a sustained duration of action, permitting once-daily dosing in many patients, and lacks partial agonist activity. More than 3300 hypertensive patients have received losartan in Phase III, controlled clinical trials. Losartan given concomitantly with a low dose (12.5 mg) of hydrochlorothiazide further reduces blood pressure. Its overall incidence of adverse experiences is similar to that of placebo. Because of its efficacy, specificity, duration of action, and safety profile, losartan should be considered as first-line therapy for the treatment of patients with hypertension.

Prior exercise potentiates the thermic effect of a carbohydrate load.

It is unclear whether dietary-induced thermogenesis (DIT) is increased after exercise. To test this possibility, six healthy volunteers, male and female, exercised for 45 minutes at 70% of maximal aerobic capacity (VO2 max) in the morning after an overnight fast. Two hours after the end of the exercise, by which time VO2 had returned to near baseline levels, subjects ingested a 100-g glucose load. Blood samples and respiratory gas exchange data were collected over the next three hours. On a separate day on which the subjects did not exercise, the test procedure was repeated. Glucose tolerance and the insulin response to the glucose load were not significantly different between the two trials; however, VO2 increased by 15.5% over baseline on the exercise day, compared with only 8.9% when exercise was not performed. The net increase in energy expenditure for the three-hour period following glucose ingestion was 15 kcal/180 min greater on the exercise than on the control day, with increases upwards of 20 kcal/180 min in several individuals. No correlation was found between the magnitude of exercise-enhanced DIT and VO2 max, suggesting that this effect is independent of the state of training. The results indicate that the thermic effect of exogenous carbohydrate can be potentiated by prior exercise.

Impact of captopril on hemodynamic and hormonal effects of nitroprusside.

The impact of oral captopril, 2 mg . kg-1, on the dose and on the hemodynamic and hormonal effects of nitroprusside was studied in seven patients (Group II). A comparable group (Group I, n = 7) received nitroprusside alone. In both groups, nitroprusside produced comparable decreases in mean arterial pressure, systemic vascular resistance, and right atrial pressure; cardiac output increased because of a significant change in heart rate. Although plasma renin activity increased significantly (compared with control values) in both groups, it was greater (p = 0.01) through the operative period in patients pretreated with captopril. Plasma aldosterone concentration increased in Group I (p = 0.01) but decreased in Group II (p = 0.01). Plasma catecholamine concentrations increased (p = 0.01) with nitroprusside alone but were unchanged in captopril-treated patients. Plasma converting enzyme activity was markedly inhibited (p = 0.001) by captopril. Following cessation of nitroprusside infusion in Group I, rebound hypertension occurred in conjunction with a significant (p = 0.01) increase in systemic vascular resistance; it was associated with elevated plasma renin activity, catecholamines, and aldosterone concentrations. In contrast, captopril-treated patients showed no rebound hemodynamic changes. Nitroprusside dose was less (p = 0.01) with captopril pretreatment (2.1 +/- 0.3 vs. 4.8 +/- 0.9 microgram . kg-1 . min-1). Thus, captopril is a useful adjunct to nitroprusside-induced hypotension.

A cooperative multicenter study of captopril in congestive heart failure: hemodynamic effects and long-term response.

The acute hemodynamic effects, long-term clinical efficacy, and safety of the oral angiotensin-converting enzyme inhibitor, captopril, were assessed in a multicenter cooperative study of 124 patients with heart failure resistant to digitalis and diuretics. The cardiac status of most patients was deteriorating prior to the study. Favorable acute hemodynamic effects consistently occurred with captopril. Maximal mean percentage increases in cardiac index, stroke index, and stroke work index were, respectively, 35%, 44%, and 34%. Systemic and pulmonary vascular resistances were each decreased by approximately 40%, as were the filling pressures of the right and left heart. Infusion of nitroprusside in some of the same patients to an end point of a pulmonary capillary wedge pressure of 12 to 18 mm Hg (equivalent to that after captopril) revealed no significant difference in the effect of either drug on the other hemodynamic parameters. Recatheterization after 8 weeks of captopril therapy revealed sustained hemodynamic changes. Significant and sustained improvements in clinical status were observed in most patients as measured by changes in New York Heart Association (NYHA) functional classification and exercise tolerance times. Seventy-nine percent of patients for whom there were adequate NYHA class data improved. Twenty percent remained unchanged and 1% deteriorated. Those patients who had both pretreatment and post-treatment exercise stress testing exhibited a highly significant mean increase in exercise tolerance times of 34% (317 +/- 32 seconds pretreatment to 425 +/- 34 seconds, final measurement). There was no evidence of tachyphylaxis over an 18-month period.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonarrhythmogenicity of diuretic-induced hypokalemia. Its evidence in patients with uncomplicated hypertension.

Twenty patients aged 33 to 69 years with uncomplicated hypertension, no heart disease, and normal stress test results underwent ambulatory ECG monitoring a month after receiving placebo and two and four weeks after hydrochlorothiazide therapy. Serum potassium level (+/- SEM) averaged 4.4 +/- 0.09 mEq/L after the placebo trial and 3.4 +/- 0.07 and 3.0 +/- 0.06 mEq/L after two and four weeks of therapy, respectively. Sixteen patients had no arrhythmias. Four patients had 329 +/- 140 premature ventricular beats (PVBs) while receiving placebo and 341 +/- 203 and 315 +/- 158 PVBs per 24 hours after two and four weeks of therapy, respectively. Thus, patients with uncomplicated hypertension and no arrhythmias before diuretic therapy did not experience arrhythmias as a result of diuretic-induced hypokalemia of one month's duration. Patients with low-grade ventricular ectopy (VE) before therapy did not progress to higher grades of VE after diuretic treatment for four weeks.

Prediction of sustained antihypertensive efficacy of chronic captopril therapy: relationships to immediate blood pressure response and control plasma renin activity.

The blood pressure (BP) lowering effect of the orally active angiotensin converting enzyme inhibitor, captopril (SQ14225), was studied in 59 hypertensive patients maintained on a constant sodium intake. Within 2 hours of the first dose of captopril BP fell from 171/107 to a maximum low of 142/92 mm Hg (p less than 0.001), and after 4 to 8 days to treatment BP averaged 145/94 mm Hg (p less than 0.001). The magnitude of BP drop induced by captopril was significantly correlated to baseline plasma renin activity (PRA) both during the acute phase (r = -0.38, p less than 0.01) and after the 4 to 8-day interval (r = -0.33, p less than 0.01). Because of considerable scatter in individual data, renin profiling was not precisely predictive of the immediate or delayed BP response of separate patients. However, the BP levels achieved following the initial dose of captopril were closely correlated to BP measured after 4 to 8 days of therapy, and appeared to have greater predictive value than control PRA of the long-term efficacy of chronic captopril therapy despite marked BP changes occurring in some patients during the intermediate period. Because of these intermediate BP changes, addition of a diuretic to enhance antihypertensive effectiveness of angiotensin blockade should be restrained for several days after initiation of captopril therapy.