Edward D. Freis

SINGLE-DRUG THERAPY FOR HYPERTENSION IN MEN A Comparison of Six Antihypertensive Agents with Placebo

BACKGROUND Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents, but this clinically important issue has not been examined in sufficiently large trials, involving all standard treatments, to determine the effect of such factors. METHODS In a randomized, double-blind study at 15 clinics, we assigned 1292 men with diastolic blood pressures of 95 to 109 mm Hg, after a placebo washout period, to receive placebo or one of six drugs: hydrochlorothiazide (12.5 to 50 mg per day), atenolol (25 to 100 mg per day), captopril (25 to 100 mg per day), clonidine (0.2 to 0.6 mg per day), a sustained-release preparation of diltiazem (120 to 360 mg per day), or prazosin (4 to 20 mg per day). The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure, and the patients continued to receive therapy for at least one year. RESULTS The mean (+/- SD) age of the randomized patients was 59 +/- 10 years, and 48 percent were black. The average blood pressure at base line was 152 +/- 14/99 +/- 3 mm Hg. Diltiazem therapy had the highest rate of success: 59 percent of the treated patients had reached the blood-pressure goal at the end of the titration phase and had a diastolic blood pressure of less than 95 mm Hg at one year. Atenolol was successful by this definition in 51 percent of the patients, clonidine in 50 percent, hydrochlorothiazide in 46 percent, captopril in 42 percent, and prazosin in 42 percent; all these agents were superior to placebo (success rate, 25 percent). Diltiazem ranked first for younger blacks (< 60 years) and older blacks (> or = 60 years), among whom the success rate was 64 percent, captopril for younger whites (success rate, 55 percent), and atenolol for older whites (68 percent). Drug intolerance was more frequent with clonidine (14 percent) and prazosin (12 percent) than with the other drugs. CONCLUSIONS Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of a drug.

Salt, volume and the prevention of hypertension.

The evidence supporting the thesis that hypertension can be prevented by eliminating salt from the diet is based on four principal sources: (1) epidemiological studies in unacculturated peoples showing that the prevalence of hypertension is inversely correlated with the degree of salt intake; (2) hemodynamic studies suggesting that the development of chronic experimental hypertension is a homeostatic response to a maintained increase in extracellular fluid volume (ECF); (3) evidence that the ECF of “salt eaters” is expanded in comparison to that of “no-salt eaters”; and (4) investigations in hypertensive patients receiving either diets greatly restricted in salt or continuous diuretic therapy which correlate the fall in blood pressure with a reduction in ECF. Although this mechanism of essential hypertension is still obscure the evidence is very good if not conclusive that reduction of salt in the diet to below 2 g/day would result in the prevention of essential hypertension and its disappearance as a major public health problem.

Relationship Between Plasma and Extracellular Fluid Volume Depletion and the Antihypertensive Effect of Chlorothiazide

The importance of plasma and extracellular fluid volumes in the mechanism of the antihypertensive effect of chlorothiazide is disputed. The present investigation indicates that the lowering of blood pressure is accompanied by reductions in plasma and extracellular fluid volumes and in body weight. Furthermore, re-expansion of plasma volume with salt-free dextran reverses the antihypertensive effect. However, since gradual reaccumulation of extracellular fluid occurs during 1 year of continuous treatment, the late antihypertensive effects of chlorothiazide cannot be explained by the volume-depletion mechanism.

The Hemodynamic Effects of Hypotensive Drugs in Man IV. 1-Hydrazinophthalazine

Further data are presented concerning the unusual hemodynamic effects of 1-hydrazinophthalazine. Previous observations demonstrating a marked increase in cardiac output in normotensive subjects are confirmed in hypertensive patients. The splanchnic vascular bed is one of the sites of increased blood flow. The similarity between the hemodynamic effects of 1-hydrazinophthalazine and pyrogens is pointed out and the pharmacologic basis for the clinically observed additive effects of 1-hydrazinophthalazine and hexamethonium is discussed.

Informed consent: How much does the patient understand?

Comprehension and recall of the information contained in the informed consent statement was tested in clinically hypertensive patients entering a controlled trial comparing hydrochlorothiazide and propranolol. The consent statement was the primary vehicle for conveying the information to the patient. The average of correct answers to a multiple‐choice quiz was 71.6% at 2 hr and 61.2% at 3 mo after the consent procedure. The effectiveness of recall did not correlate with level of education. Patients exhibited greater comprehension of the action of the drugs than of their side effects. Nearly all patients indicated their belief that they would receive the best possible care. While 95% wanted to be informed about the trial, 75% stated they would have given their consent even without this information.

Treatment of hypertension in the elderly: II. Cognitive and behavioral function. Results of a Department of Veterans Affairs Cooperative Study.

This study was designed to determine whether blood pressure reduction, per se, causes adverse effects on cognitive and behavioral function in elderly hypertensive patients. Men with mild-to-moderate diastolic hypertension who had passed their 60th birthday were entered into the trial. After a placebo washout period, they were assigned in a randomized, double-blind manner to one of two groups receiving hydrochlorothiazide (either 25 mg once or twice daily or 50 mg once or twice daily). Responders entered a 1-year maintenance period. Nonresponders were randomly assigned to double-blind treatment with hydralazine, methyldopa, metoprolol, or reserpine added to the diuretic therapy. During the placebo and treatment periods, patients underwent a battery of psychometric tests designed to assess cognitive function, motor skills, memory, and affect. A separate questionnaire assessed the patients ability to perform activities of daily living. A subset of patients blindly being treated with placebo received the same battery of tests as a control for practice effect. The results showed that there was similar improvement on the psychometric tests between those patients whose blood pressure was successfully reduced and the placebo-treated control group. Therefore, the practice effect did not obscure a true deterioration in function. There were no substantive differences between the lower and higher doses of diuretic or among the four drugs added to the diuretic, although there were qualitative differences in side effects. We conclude that blood pressure reduction, per se, does not adversely affect cognitive and behavioral function in elderly hypertensive patients and that antihypertensive treatment is safe and effective in these patients.

Alteration of the Course of Hypertension in the Spontaneously Hypertensive Rat

The blood pressure of spontaneously hypertensive rats was controlled at low normotensive levels, using antihypertensive drugs for a 6-month period beginning when the rats were 3 months of age. Treatment was then withdrawn and the rats observed for an additional 4 months, until they were 13 months of age. Treatment with antihypertensive drugs arrested the progression of the hypertension and the secondary pathology for the duration of the treatment period. Following withdrawal of drugs the blood pressure did not rise to the level of the controls of a similar age, but rather it returned to the level that existed before treatment began and then progressed at the same rate that the controls exhibited when they were 3−7 months of age. Pathological changes were found only in controls. These results indicate that, although the tendency toward hypertension is inherited, its rate of development depends on environmental factors. The hypertension can be arrested by chemotherapeutic interventions and can be aggravated by excessive salt. The hypertension appears to be a progressive time-dependent process but is independent of biological processes associated with aging per se. Finally, control of blood pressure prevents end-organ damage.

Diuretic-Induced Hypokalemia in Uncomplicated Systemic Hypertension: Effect of Plasma Potassium Correction on Cardiac Arrhythmias

Sixteen patients with diuretic-induced hypokalemia underwent 24-hour ambulatory electrocardiographic monitoring during and after correction of hypokalemia. Plasma potassium averaged 2.83 +/- 0.08 mEq/liter before and 3.73 +/- 0.06 mEq/liter after correction with potassium chloride, triamterene or both. Premature atrial contractions decreased in 6 patients, increased in 6 and remained unchanged in 4. There was no improvement in ventricular ectopic activity after plasma potassium correction. Ventricular ectopic activity improved in 5 patients, worsened in 10 and remained unchanged in 1. Ventricular tachycardia was not observed in either phase. Plasma magnesium remained normal throughout. The investigators conclude that in patients with uncomplicated hypertension, correction of diuretic-induced hypokalemia does not significantly reduce the occurrence of spontaneous atrial or ventricular ectopic activity.

Minoxidil in Severe Hypertension with Renal Failure Effect of its Addition to Conventional Antihypertensive Drugs

Abstract Minoxidil, a new vasodilator antihypertensive compound, was given to 9 uremic patients with severe hypertension uncontrollable with currently available drugs. Addition of minoxidil in doses of 5 to 10 mg twice daily to their prior therapy, resulted in satisfactory control of blood pressure in all patients. Supine blood pressure fell from a control value of 200 ± 6/124 ± 3 to 164 ± 5/91 ± 2 mm Hg (mean and standard error) after administration of minoxidil, and no patient experienced orthostatic hypotension. Tachyphylaxis has not been seen during a follow-up period averaging 26 weeks. Side effects resulting from minoxidil have been limited to mild hypertrichosis in 2 patients, nausea in another 2 and fluid retention, which was readily controlled by either hemodialysis or furosemide. Minoxidil appears, therefore, to provide a means for controlling blood pressure in patients with severe hypertension resistant to all other antihypertensive drugs.

Comparison of effects of angiotensin and norepinephrine on pulmonary circulation, systemic arteries and veins, and systemic vascular capacity in the dog.

In dog experiments, angiotensin II and norepinephrine were compared in regard to some components of the generalized pressor response each of these agents produces. It was found that angiotensin II has no direct effect on pulmonary blood vessels, in contrast to the pulmonary vasoconstrictor effect of norepinephrine. Angiotensin II appeared to have no effects on veins or the systemic vascular capacity, while norepinephrine was a potent venoconstrictor with, therefore, a marked ability to reduce the systemic vascular capacity.