Diazoxide in the Treatment CLARENCE L. GANTT, M.D. which suggest that diazoxide may be the. drug of choice in the treatment of all forms

Transcription

1 Intravenous Use o;f Diazoxide in the Treatment of Severe Hypertension By WILLIAM M. HAMBY, M.D., GERALD J. JANKOWSKI, M.D., J. MAURICE POUGET, M.D., GEORGE DUNEA, M.D., AND CLARENCE L. GANTT, M.D. SUMMARY Thirty-three patients with severe hypertension were treated with rapidly injected intravenous diazoxide. Renal function was measured in nine patients and four underwent cardiac catheterization during renal function studies. Diazoxide had a rapid, profound hypotensive effect. Average decrease in mean arterial pressure was 26%, with an average duration of 16 hours. Drug resistance was not observed. Renal function was not impaired despite maintenance of arterial pressure at or near normal levels. Decreased mean arterial pressure was associated with a decrease in systemic vascular resistance and left ventricular end-diastolic pressure while an increase in cardiac index and heart rate occurred. Urine volume was unchanged, whereas the glomerular filtration rate and the effective renal plasma flow increased but urinary sodium excretion decreased markedly. Intravenous diazoxide is a practical effective agent for treatment of all forms of severe hypertension. Additional Indexing Words: Kidney function tests Cardiovascular system Cardiac catheterization THE PRESENTLY available hypotensive agents are generally effective in the treatment of severe hypertension. However, the reduction of systemic pressure is usually accompanied by decreased renal perfusion and glomerular filtration rate. In the presence of previous renal damage these changes may result in progressive azotemia. Since hypotensive agents that do not alter renal function would be extremely useful, the properties of diazoxide, a nonsaluretic benzothiadiazine, were reinvestigated. This drug when given orally produces marked hyperglycemia, which precludes its use in the long-term management of hypertension." 2 Intravenous diazox- From the Departments of Medicine, V. A. West Side Hospital, Cook County Hospital, The University of Illinois Research and Educational Hospitals and The Clinical Research Center of the University of Illinois College of Medicine, Chicago, Illinois. Renal vascular disease ide, however, is a remarkably effective drug that may be lifesaving in patients who are refractory to other hypotensive agents.3 The present report extends previous clinical observations and presents hemodynamic data which suggest that diazoxide may be the drug of choice in the treatment of all forms of severe hypertension.6 8 Methods Thirty-three patients with severe or malignant hypertension were studied. All patients had sustained diastolic blood pressures of 120 mm Hg or more. The patients were separated into two groups. Group 1 consisted of 24 patients, age 10 months to 57 years, who were studied clinically. Many had severe renal disease. Mean blood urea nitrogenwas 82 mg% and mean serum creatinine was 7.7 mg%. The patients were given 300 mg of diazoxide intravenously by the rapid-injection technique described by Finnerty and associates.4 The injections were repeated at appropriate intervals to maintain control of arterial pressures. 169

2 170 HAMBY ET AL. Group 2 was comprised of nine patients, age 33 to 49 years, who were investigated extensively and in whom a diagnosis of essential hypertension was made by exclusion. Mean blood urea nitrogen was 41 mg% and mean serum creatinine was 4.2 mg%. Standard priming and sustaining infusions for measurement of effective renal plasma flow (ERPF;CPAH) and glomerular filtration rate (GFR; Cin) were given. Renal function measurements weremade before the initial diazoxide injection and were repeated at 10-minute intervals after the injection until urinary volumes were stable for 30 minutes or until an increasing urine volume was observed. Thereafter, renal function was monitored for 1 hour. Diazoxide injections were given every 15 to 30 minutes until the mean blood pressure (diastolic pressure plus one third of the pulse pressure) was 107 mm Hg or less. In each of these instances of multiple injection the mean blood pressure prior to each diazoxide injection was used as a new control blood pressure. In addition to these measurements, the final four patients underwent cardiac catheterization studies during their renal function studies. During cardiac catheterization the intra-aortic blood pressure and the electrocardiograms were monitored constantly, and the standard measurements of cardiac function were made before and after the rapid intravenous injection of diazoxide. with a range from 0.5 to 72 hours. The effect of repeated intravenous injections over a 1to 15-day period is shown in table 1. Repeated doses were not associated with the development of drug resistance or tachyphylaxis, since the response to the last injection was similar to that of the first injection (table 1). The sustained average decrease in mean arterial pressure following rapid intravenous injection was 31% in group 1 and 23% in group 2 (table 1). No significant changes occurred in the gross measures of renal function during such sustained lowering of mean arterial pressure (table 2). The more finite measurements of renal function are presented as acute changes (occurring within 20 minutes after each intravenous injection) and delayed changes (occurring 1 to 2 hours after the final injection). These data are summarized in table 3. An Results One to 3 minutes following the initial diazoxide the mean blood pressure had decreased by 25 to 27% (table 1). A typical, acute response following 300 mg of intravenous diazoxide is shown in figure 1. The average duration of drug action was 16 hours, Figure 1 The intra-aortic systolic, diastolic, and mean blood pressure, before, during, and after rapid intravenous injection of 300 mg of diazoxide. Table 1 Average Mean Blood Pressure Response per Injection of Diazoxide Group 1 Group 2 Injection no. N* CtDf N* ct D: Mean *N = Number of injections given. tcontrol. *After diazoxide. Per cent decrease in mean blood pressure calculated as per cent of the control value. Mean blood pressure is diastolic plus one-third pulse pressure.

3 INTRAVENOUS USE OF DIAZOXIDE 171 Table 2 Chemical Changes Secondary to Treatment Group 1 Group 2 Age 31.5 yr (1-57) 39 yr (33-49) Weight 141 lb (17-230) 172 lb ( ) Height* 65 inches (60-72) 69 inches (65-72) Control Diazoxide Control Diazoxide BUN (mg%) (16-189) (25-155) (21-101) (12-76) Cr (mg %) ( ) ( ) ( ) ( ) Sodium (meq/l) ( ) ( ) ( ) ( ) Potassium (meq/l) ( ) ( ) ( ) ( ) Ranges are in parentheses. *These results do not include the infant. Table 3 Summary of Renal Function Measurements* Volume GFR ERPF Na excretion Mean BP (ml / min) (ml/min) (ml min) (meq /min) Ct D* C D C D C D C D Acute % Increase 4 % Decrease Delayed % Increase % Decrease *Corrected to 1.73 m2 body surface area. tcontrol. tafter diazoxide. Mean BP = Diastolic pressure + 1/3 pulse pressure. Control BP for the acute studies include all pressures taken just prior to injection of diazoxide. Control BP for the delayed studies are those taken prior to the initial injection of diazoxide. acute 20% decrease in mean arterial pressure was associated with a 7% decrease in GFR, a 17% decrease in ERPF, and no significant change in urine volume. The delayed renal function measurements indicate that in spite of a 36% decrease in mean arterial pressure the acute decreases in GFR and ERPF are reversed rapidly. The over-all effect of a 36% decrease in mean arterial pressure was accompanied by a 7% increase in GFR and a 31% increase in ERPF. In the presence of these increases in filtration and plasma flow there was a striking decrease in urinary sodium excretion. The measured 71% decrease in sodium excretion must be an underestimate of the increase in tubular reabsorption because of the necessary increase in the sodium load presented to the tubule cells by an increased GFR in the presence of a stable serum sodium.9 Table 4 presents the hemodynamic changes that occurred within 15 to 30 minutes after intravenous diazoxide. There was a marked increase in cardiac index (76%) and heart rate (37%), whereas there was a significant decrease in systemic vascular resistance

4 172 HAMBY ET AL. Table 4 Summary of Hemodynamic Alterations after Diazoxide Therapy CI Aortic P LVEDP Heart (L/min/m2) SVR rate (mm Hg) (mm Hg) (beats /min) C D C D C D C D C D M % Increase % Decrease Range Low High Abbreviations: Cardiac index; systemic vascular resistance (dynes-sec cm-5); mean aortic pressure; left ventricular end-diastolic pressure; C, control; D, after diazoxide. (55%), mean aortic pressure (25%), and left ventricular end-diastolic pressure (46%). Side Effects of Diazoxide In four patients small amounts of drug inadvertently leaked into the subcutaneous tissues. This caused a severe burning sensation that persisted for approximately 2 hours but no tissue sloughing occurred. Two patients developed severe anginal syndromes with T- wave inversion on their electrocardiograms but no change in serum enzymes (LDH and SGOT). The electrocardiographic changes were transient in one and persisted in the other patient. One patient had a tonic-clonic seizure after a marked fall in arterial pressure. No neurological abnormalities were noted after the seizure, and there was no recurrence of seizure activity with repeated injections. Significant orthostatic hypotension occurred in four patients who were receiving diazoxide alone and in six patients who received diazoxide combined with other hypotensive agents. Significant hyperglycemia was not observed except in one patient with diabetes mellitus. Discussion The present studies confirn earlier reports that diazoxide is a potent hypotensive agent that reduces arterial pressure without a significant incidence of side effects. Initially its use was restricted to patients with severe hypertension who were refractory to large doses of reserpine, ganglionic blockers, and hydralazine, and who previously would have been treated with sodium nitroprusside. The use of diazoxide was extended subsequently to include patients who were partially responsive to other agents. Good responses with minimal side effects were observed in these patients. Neither sodium retention nor hyperglycemia was troublesome. Only one of the diabetic patients had a significant rise in blood glucose levels. This was controlled easily with oral hypoglycemic agents, which did not alter his responsiveness to diazoxide.y' In contrast to other hypotensive agents the administration of intravenous diazoxide was not associated with decreased renal function or cardiac output. A marked reduction in blood pressure with a simultaneous increase in cardiac index and heart rate and decrease in systemic vascular resistance and left ventricular end-diastolic pressure was produced. These changes in heart rate, aortic pressure, and left ventricular pressure were associated with an acute decrease in GFR and ERPF, which was reversed after 1 to 2 hours to an increase of 37% for GFR and 31% for ERPF. The cardiac hemodynamics at the time of the latter renal function measurements have not been evaluated. However, the data suggest that the changes persist since there was no significant change in serum urea, creatinine or electrolytes in patients who received repeated injections of the drug or in whom the agent had a prolonged hypotensive effect. Diazoxide therapy was accompanied by a marked decrease in sodium excretion, the mechanism of which is unclear. The delayed renal function measurements suggest that it is due to increased tubular reabsorption of Circulation, Volurne XXXVII, February 1968

5 INTRAVENOUS USE OF DIAZOXIDE sodium, since it persists in spite of a significant increase in the filtered load of sodium. The increase in sodium reabsorption did not result in increases in serum sodium nor were there any significant changes in body weight in the patients studied (group 2). The exact mechanism of the hypotensive effect of this agent is not understood. Chemically, diazoxide resembles chlorothiazide but pharmacologically it is quite different. Chlorothiazide is a saluretic agent that decreases cardiac output, has a delayed, mild hypotensive effect and increases urinary output while decreasing GFR and ERPF. Intravenous diazoxide is a sodium-retaining agent that increases cardiac output, has a marked, immediate hypotensive effect, and increases urinary output, GFR, and ERPF. The reason why the speed of injection determines the magnitude and duration of the hypotensive effect is unknown. Diazoxide, to be effective, must be given within 30 seconds. Only a short, mild, hypotensive response occurs if the injection time is prolonged to 1 minute; no effect is observed if the drug is given over 1 to 4 minutes. An occasional patient will fail to respond to a single, rapid intravenous injection of 300 mg of this agent but will respond to a second injection given 15 to 30 minutes later. The only patient who failed to respond to a second injection responded to a third injection given 30 minutes later. Because of this some patients were given 600-mg doses as a single, second injection and, therefore, the second-injection results from these patients were not included in this report. No explanation can be given for the failure of the initial injection nor for the success of the repeated injections. The four patients in this study who had cardiac catheterization were studied because their hypertension could not be adequately controlled with oral agents. They had severe hypertension but no papilledema or encephalopathy. Daily therapy had consisted of chlorothiazide, 1 g; hydralazine, 200 mg; reserpine, 0.5 mg; alpha-methyldopa, 2 to 4 g; and guanethidine, 100 to 300 mg. Control of 173 arterial pressure in these patients for periods of 4 to 11 days was obtained with diazoxide in combination with diuretic agents. The patients were then discharged from hospital and the three who have been followed for more than 2 months have mean arterial pressures of 107 mm Hg or less while taking only alpha-methyldopa, 2 g, and chlorothiazide, 1 g, daily. This pattern of response is known to occur in patients with malignant hypertension following adequate control of their blood pressure for a period of time. These results suggest that this concept may be extended to patients who require large doses of hypotensive agents but do not have the characteristic manifestations of malignant hypertension.1' The marked sodium retention following intravenously administered diazoxide caused no clinical problems in the studied patients. However, since sodium retention could be hazardous in some patients, concomitant administration of a diuretic may be desirable in patients receiving multiple injections of diazoxide. These results suggest that intravenously administered diazoxide is a useful agent for the treatment of severe hypertension. Its advantages include an immediate onset of action which accomplishes the goal of therapy rapidly; lack of resistance to repeated injections; increased cardiac output which decreases the danger of collapse secondary to a marked decrease in peripheral vascular resistance; maintenance of effective renal plasma flow and glomerular filtration rate, which militates against progressive azotemia, and allows the arterial pressure to be lowered to the desired levels. References 1. LocKWOOD, C. H., NICHOLLS, D. M., TROOP, V. L., AND LEWIS, J. A.: Diazoxide therapy in hypertension. Amer J Med Sci 246: 312, OKuN, R., WILSON, W. R., AND GELFAND, M. D.: Hyperglycemic effect of hypotensive drugs. J Chronic Dis 17: 31, DUNEA, G., AND GANTT, C. L.: Diazoxide in hypertensive crisis. Lancet 2: 638, 1966.

6 FINNERTY, F. A., JR., KAKAVIATOS, N., TucKMAN, J., AND MAGILL, J.: Clinical evaluation of diazoxide: New treatment for acute hypertension. Circulation 28: 203, FINNERTY, F. A., JR., KAKAVIATOS, N., CHUP- KOVICH, V., TUCKMAN, J., AND MARSHALL, J.: Value of diazoxide administered intravenously in acute hypertension. Circulation 28: 719, FINNERTY, F. A., JR.: Newer antihypertensive drugs. Med Clin N Amer 48: 329, FINNERTY, F. A., JR.: Hypertensive emergencies. Amer J Cardiol 17: 652, HAMBY ET AL. 8. WILSON, W. R., AND OKUN, R.: Acute hemodynamic effects of diazoxide in man. Circulation 28: 89, TAYLOR, R. M.: Renal aspects of certain antihypertensive agents. Angiologia 14: 79, WALES, J. K., GRANT, A. M., AND WOLFF, F. W.: Reversal of diazoxide effects by tolbutamide. Lancet 1: 1137, FINNERTY, F. A., JR., DAvmov, M., AND KAKA- VIATOS, N.: Hypertensive vascular disease: Long term effect of rapid repeated reductions of arterial pressure with diazoxide. Amer J Cardiol 19: 377, Excellence by Association Scientific Genealogies So, above all, attitudes rather than knowledge are conveyed by the distinguished teacher. Technical skills can be learned from many teachers and, like a modicum of intelligence, are, of course, prerequisites for successful research. What is critical is the use of skills, how to assess their potentialities and their limitations; how to improve, to rejuvenate, to supplement them. But perhaps the most important element of attitude is humility, because from it flows a self-critical mind and the continuous effort to learn and to improve. Also of great importance is the enthusiasm conveyed from teacher to pupil: it is the root of a large capacity for work; it makes the research worker look on research not as work but as a hobby and it also induces him to say "No" when he is faced with tempting diversions leading him to the "corridors of power" or travel on innumerable trips abroad.-h. A. KREBS: The Making of a Scientist. Nature 215: 1445, 1967.