Nikos Kakaviatos

Clinical Evaluation of Diazoxide A New Treatment for Acute Hypertension

Forty-six hypertensive patients have received diazoxide intravenously. Three hundredmilligrams (one ampule) administered rapidly undiluted resulted in a 27 per cent average reduction in mean arterial pressure in 1 to 2 minutes. During the next 3 to 5 minutes the arterial pressure increased gradually to a 15 per cent average reduction as compared to the control. The average duration of diazoxide in these patients was 4.7 ± 1.7 hours. No signs of postural hypotension, cerebral ischemia, or collapse were noted. At the peak of hypotensive action there was a 41 per cent average reduction in total peripheral resistance.Repeated doses of diazoxide in both nonpregnant patients with acute hypertension and pregnant patients with toxemia adequately controlled the arterial pressure and were not associatetd with the development of drug resistance. The standard dosage of 300 mg. (one ampule), the immediate onset of action and the moderately long duration of action, the maintenance of cardiac output, the lack of significant side effects, and the fact that it can be administered repeatedly without the development of drug resistance make diazoxide administered intravenously the ideal therapy for acute hypertension.

The antihypertensive effects of an imidazoline compound

The antihypertensive properties of a new imidazoline compound, ST 155, were examined in man. Oral administration of 75 to 150 mcg. consistently produced an average fall of about 15 per cent in mean arterial pressure within one hour. Repeated administration was associated with drug resistance which was prevented by the simultaneous use of thiazide diuretics. The combination of ST 155 in a dosage of 450 mcg. with a diuretic in patients with moderately severe hypertension resulted in an average fall in mean arterial pressure of about 25 per cent. The only side effects were dryness of the mouth and sedation, whichdecreased after the first month of therapy.

Antihypertensive Properties of Furosemide

The antihypertensive properties of single doses of furosemide were evaluated in 113 patients. Doses over 120 mg consistently produced a fall in arterial pressure whereas smaller doses did not. Thus 20 of 22 patients (90%) who received more than 120 mg had a 26 ± 6% average reduction in mean arterial pressure. The hypotensive action began in 30 to 45 minutes, the nadir of the decrease occurred between 2 and 2½ hours, and the hypotension usually lasted 10 to 12 hours. Repeated weekly doses of furosemide over a 2-month period in six patients were not associated with development of drug resistance. The antihypertensive properties of doses of furosemide of more than 120 mg seemed to be of about the same potency as ethacrynic acid. The antihypertensive effect of high doses of furosemide did not seem to be related to the diuretic effect or to the decrease in plasma volume.These studies have demonstrated that doses of furosemide of more than 120 mg consistently decreased arterial pressure. The usefulness of this agent in the long-term management of hypertension remains to be determined.

Hypertensive vascular disease: The long term effect of rapid repeated reductions of arterial pressure with diazoxide∗

Abstract The long term effect of repeated acute reductions of arterial pressure has been evaluated in 16 patients with severe hypertension who had become unresponsive to antihypertensive therapy. During a 20 day period, 300 mg. of diazoxide was administered intravenously and repeated on a daily basis as often as necessary to keep the arterial pressure more than 20 per cent below control levels. At the end of the 20 day period diazoxide had been successful in reducing the arterial pressure in 14 of 16 patients. In addition, retinopathy had cleared in 2, cardiac size significantly decreased in 4 and congestive heart failure had lessened in 4 and completely cleared in one patient. All 14 patients were then restarted on a combination of chlorthalidone and reserpine. Cardiovascular-renal function continued to improve with this therapy over a 30 month period in 7 patients. In the remaining 7 patients the addition of hydralazine or methyldopa administered in one-half the previous effective dose was needed to maintain the beneficial effect. Thirty months after the rapid reduction of arterial pressure, the average mean arterial pressure in the 14 patients was 123 + 6.7, compared to 112.5 ± 11.7 mm. Hg immediately after diazoxide. Retinopathy and congestive heart failure had cleared, and heart size was reduced in all patients. Since rapid reduction of arterial pressure with diazoxide was accomplished effectively, safely and in a short period of time, and since, at least in 14 of 16 patients studied here, beneficial effects were observed as long as 30 months it would seem: (1) that such aggressive therapy might be incorporated into the routine of treating patients with severe hypertension, and (2) the usefulness of such an approach might be evaluated in the therapy of patients with less severe types of hypertension.

Preliminary Observations on the Value of Diazoxide Administered Intravenously in Man

become available, all of which reduce arterial pressure, enhance the effect of other antihypertensive agents and cause a prompt diuresis and natriuresis. The mode of their antihypertensive action is still obscure. Recent studies indicate that the immediate antihypertensive effects of the thiazides do not depend upon their saluretic or diuretic properties,’ while it is also agreed that after prolonged use of thiazides the fall in arterial pressure is due to other factors than natriuresis or reduction of plasma volume .2, 3 These and other findings4 led to a further exploration of the benzothiadiazine compounds in

Value of Chlorthalidone Plus Reserpine in Moderately Severe and Severe Hypertension A Two-Year Study

One hundred nine patients with moderately severe hypertension and 12 patients with severe hypertension received the combination of 50 mg. of chlorthalidone plus 0.25 mg. of reserpine combined in a single tablet (Regroton) administered once daily for an average duration of 2 years.The ease of administration (one tablet daily), the effectiveness (78-per cent good response), the lack of development of drug resistance over a 2-year period, and the small incidence of side effects would seem to make the combination of 50 mg. of chlorthalidone plus 0.25 mg. of reserpine the ideal treatment for most patients with hypertension. If a more rapid reduction in arterial pressure is indicated, as in patients with severe hypertension, or if a satisfactory therapeutic response has not been observed in 3 to 4 months in patients with moderately severe hypertension, suboptimal doses of other antihypertensive agents may be added.

Comparison of chlorthalidone, a long-acting antihypertensive and diuretic agent, with chlorothiazide. Analysis of one hundred twenty-three cases.

Abstract Thirty-two patients with chronic hypertensive vascular disease received alternate 6 week courses of 50 mg. of chlorthalidone daily, 100 mg. of chlorthalidone daily and 500 mg. of chlorothiazide twice daily. Serial studies demonstrated (1) that 50 to 100 mg. of chlorthalidone daily caused at least as great a reduction in arterial pressure as 500 mg. of chlorothiazide administered twice daily, (2) neither dose of chlorthalidone or chlorothiazide caused any change in the level of serum sodium, and (3) the reduction in serum potassium was similar following both diuretics. Ninety-one pregnant patients with edema received chlorthalidone in dosages varying between 50 mg. daily and 100 mg. every other day. It was found (1) that a single daily dose of 50 mg. of chlorthalidone was followed by at least as good a reduction in arterial pressure and frequently a greater diuresis than 500 mg. of chlorothiazide administered twice daily, and (2) continuous administration of chlorthalidone was not associated with the development of drug resistance.

Comparison of alpha-methyldopa with standard antihypertensive therapy in man

Abstract Fifty-seven patients with moderately severe or severe hypertension received alpha-methyldopa plus hydrochlorothiazide for an average of nine months. The daily dose of alpha-methyldopa varied between 500 to 3,000 mg., and the daily dose of hydrochlorothiazide was 100 mg. The therapeutic response was either extremely good or very disappointing. The combination produced an excellent response in 22 patients, a good response in 16 and a poor response in 19. Alpha-methyldopa plus hydrochlorothiazide produced at least as good and frequently a better therapeutic response than prior standard antihypertensive therapy in 68 per cent of patients. Nine of the patients who demonstrated an excellent response were patients who did poorly on previous antihypertensive therapy. Although the individual patients response could not be predicted prior to therapy, the data presented indicate that there is a 3 to 1 chance that alpha-methyldopa will produce at least a good response in the patient with moderately severe or severe hypertension. Another effective method of lowering the arterial pressure is, therefore, available to the physician. Drug toxicity which occurred in only 9 patients consisted of postural dizziness, drowsiness and weakness. Although other investigators have reported drug fever and abnormal liver function tests following alpha-methyldopa therapy, serious side effects have not been observed here. Until further clinical experience has been obtained, it would seem wise to restrict the use of alpha-methyldopa to those hypertensive patients who are either not doing well or are developing serious side effects to conventional antihypertensive therapy.