Large dose furosemide therapy for hypertension

REPORTS ON THERAPY

Large Dose Furosemide Therapy for Hypertension Long-Term Use in 22 Patients

WILLIAM J. MROCZEK, MD MICHAEL DAVIDOV, MD FRANK

A.

Washington,

FINNERTY,

Jr.,

MD,

FACC

D. C.

A retrospective study of 22 hypertensive patients receiving large oral doses of furosemide (80 to 840 mg daily for 32 f 7 months) and standard antihypertensive therapy was performed. All patients had moderately severe or severe hypertension. The substitution of furosemide for the previous diuretic agents resulted in a 22 percent average reduction in arterial pressure and significant improvement in the clinical status of 15 patients. The addition of furosemide allowed a reduction in the dose of antihypertensive medication in four patients. Besides preventing the sodium retention and extracellular fluid volume expansion associated with standard antihypertensive agents, large doses of furosemide may have exerted an additional antihypertensive effect. The combination of orally administered furosemide and standard antihypertensive therapy permitted better control of arterial pressure than that obtained with previous diuretic-antihypertensive combinations in the patients studied. The overall safety of large dose furosemide therapy for extended periods of time appears to be relatively good.

Studies from this laboratory have demonstrated the effectiveness of intravenously administered furosemide as an antihypertensive agent* and in the management of congestive heart failure.3J Our experience in a large outpatient population and studies of other workers”v5 have documented the effectiveness of orally administered furosemide in the management of hypertensive patients. The dose-response curve of furosemide is unusually broad,s and the drug is effective in increased doses in the presence of renal insufficiency.7-10 Relatively few serious side effects have been reported after administration of large doses for short periods11-14; however, data are not available on the effectiveness or safety of large doses given for extended periods. Furosemide has been used as a diuretic agent and as an adjunct to antihypertensive therapy in our clinic since 1964. A retrospective analysis of results in patients receiving large dose, long-term furosemide therapy forms the basis of this report. Methods

From the Georgetown University Medical Division, District of Columbia General Hospital, Washington,D. C. Manuscript accepted July 25,

1973.

Address for reprints: William J. Mroczek, MD,

Box 355, District of Columbia General Hospital, Washington, D. C. 20003.

546

April 1974

A review of the records of patients attending the Hypertension Clinic at the District of Columbia General Hospital revealed that 22 patients had received at least 80 mg of furosemide daily for at least 24 consecutive months. All patients were considered to have essential hypertension on the basis of family history, serum electrolyte determinations and a rapid sequence intravenous pyelogram. All 22 patients were Negro, and 8 were male. The average age was 50 f 10 years (36 to 70 years). Before initiation of furosemide therapy two patients (Cases 4 and 19) had clinical evidence of congestive heart failure despite digitalization and full doses of antihypertensive and diuretic agents. All patients had electrocardiographic evidence of left ventricular hypertrophy. No patient was uremic; however, six had mild azotemia (blood urea nitrogen 20 to 40 mg/lOO ml). Twelve patients had accelerated hypertensive retinopathy (flame-shaped hemorrhages and cotton wool exudates); three of these had papilledema. The remainder of the patients had either grade I or II Keith-Wagener-Barker changes.

The American Journal of CARDIOLOGY

Volume 33

FlROBEMI)E

All patients had previously received other diuretic agents for at least 3 months: hydrochlorothiazide, 100 mg daily (13 patients); hydrochlorothiazide, 100 mg, plug triamterene, 200 mg daily (6 patients); hydrochlorothiazide, 100 mg, plus spironolactone, 100 to 250 mg daily (3 patients). They had also received standard antihypertensive agents administered in full doses (methyldopa, 2 g; hydralazine, 300 mg; reserpine, 0.50 mg daily). Furosemide was initially substituted for the previous diuretic agent at a dose of 40 mg twice daily, by mouth. This dose was increased if arterial pressure could not be adequately controlled with the maximal dose of the standard antihypertensive agent, or if the patient had evidence of sodium retention or congestive heart failure. Treatment was continued using the same dose of antihypertensive medication as that previously administered. All patients were receiving a “no added salt diet” which, in the population studied, represents a daily intake of 5 to 10 g of sodium chloride. Patients were examined in the Hypertension Clinic at weekly, biweekly or monthly intervals. At each clinic visit the patients were questioned as to possible side effects, and body weight was measured. Arterial pressure was determined with a mercury sphygmomanometer with the patient in the sitting position and after 2 minutes of quiet standing. The sitting and standing arterial pressure values from three consecutive clinic visits were averaged and rounded off to the nearest 5 mm Hg. Mean arterial pressure was calculated as the diastolic pressure plus one third of the pulse pressure. Blood pressure control was deemed adequate if there was at least a 10 percent reduction in mean arterial pressure and the diastolic pressure was maintained at 100 mm Hg or less. Blood for laboratory analysis, by methods described elsewhere,’ was obtained at biweekly or monthly intervals. Supplemental potassium was administered as a 25 percent potassium chloride solution if the serum potassium level was below 3.5 mEq/liter or if electrocardiographic or clinical signs of hypokalemia were present.

Results Table I shows the effect of large doses of furosemide and commonly used antihypertensive agents on arterial pressure and weight. The patients were followed up for an average of 32 f 7 months. Table II shows the various doses of furosemide administered. The average reduction in mean arterial pressure at the end of almost 3 years of this combination therapy was 16 percent (from an average of 193/124 to an average of 163/104 mm Hg). Fifteen patients had decreases in mean arterial pressure ranging from 13 to 46 percent (average 22 percent). The reduction in mean arterial pressure was less than 10 percent in five patients, and two patients (Cases 5 and 12) had net increases in arterial pressure. In four patients (Cases 2, 10, 15 and 19) the substitution of furosemide for the previously used diuretic agent allowed a reduction in the dose of antihypertensive medication. The hypertensive retinopathy markedly decreased in all 12 of the patients with grade III or IV retinopathy

THERAPY FOR HYPERTENSION-MROCZEK

ET AL.

TABLE I Changes in Weight and Arterial Pressure After Long-Term Large Dose Furosemide and Antihypertensive Drug Therapy

Weight(lb)

Case no.

Age (yr)

1 2 3 4 5 6 7 a 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Ave. SD

59 46 54 70 46 42 45 45 36 38 42 49 41 65 67 55 39 45 65 61 44 39 50 *lo

Before

After

140 210 209 206 265 172 204 260 170 140 188 218 188 163 154 208 239 210 206 233

127 192 220

171 243 153 134 196 229 208 182 147 190 237 204 193 220

168 298 202 k40

157 281 194 &38

175 216 166

Arterial Pressure(mm Hg) Before 170/110 170/120 180/110 180/110 220/130 180/130 230/140 280/165 180/120 160/100 150/120 130/80 160/120 210/120 180/100 laoji30 200/130 200/130 240/140 240/140 220/160 180/130 193/124 x+35/19

After 160/90 130/80 200/100 140/100 240/160 115/90 220/120 300/150 170/120 130/90 150/100 140/100 140/100 180/100 150/100 160/90 140/100 140/100 120/80 160/100 170/100 160/100 163/104 zt42/19

Ave. = dverage; SD = standard deviation.

TABLE II Duration

and bosage of Furosemide

Therapy

Duration (mo) ofDailyOralDose of Furosemide Caseno.

a 9 10 11 12 13 14 15 16 17 19 20 21 22

(Keith-Wagener-Barker classification), and papilledema disappeared within 2 months (Table III). The average weight decreased from 202 f 40 lb to 194 f 38 lb after 32 months of therapy. Seventeen patients lost an average of 15 f 11 lb. The initial responses to furosemide therapy were increased diure-

April 1974

80-60mg

200-320mg

13 9 22 40 a 7 4 10 3

28 5 15

2 29 16 13 3 3

... a 3 12 23

360-640mg

... 6 27 17 12 31 6 3 26 16 33 15 9

The American Journal of CARDIOLOGY

Total Duration of Furosemide Therapy(mo)

... 14

*. . ... 16 19 21 14 18 12 12

... 1 ... 22 20 ... ... ...

...

Volume 33

41 28 37 47 26 31 26 25 21 25 41 46 29 44 31 26 26 24 36 27 32

547

FUROBEMDE

THERAPY FOR HYPERTENSlON-MROCZEK

ET AL.

tients had diabetes mellitus before institution of furosemide therapy; one of, them required an increased dose of orally administered hypoglycemic agents. In addition, three patients who had no history of diabetes manifested clinical diabetes while receiving furosemide therapy. The condition of these patients was controlled with diet and orally administered hypoglycemic agents. Five patients (Cases 3,5,11,18 and 21) required supplemental potassium administration because of a serum potassium level below 3.5 mEq/liter. No patient had symptoms of hypokalemia.

TABLE III Clinical Characteristics of Patients Before and After Large Dose Furosemide and Antihypertensive Therapy Patients (no.)

Congestive

After

2 22

0 22

6

3

3 9 8 2

0 2 18 2

heart failure

Left ventricular hypertrophy by electrocardiogram Azotemia Retinopathy* Grade IV Grade III Grade II Grade I *Keith-Wagener-Barker

-

Before

classification.

TABLE IV Laboratory Studies After Long-Term Large Dose Furosemide and Antihypertensive Therapy (mean values in 22 patients treated for 32 months) Before Hematocrit Blood urea nitrogen (mg/lOO ml) Fasting blood glucose (mg/lOO ml) Sodium (mEq/liter) Potassium (mEq/liter)* Uric acid (mg/lOO ml) SGOT (units/ml) Alkaline phosphatase (Bessy-Lowry units)

38 f 21 f

5 7

94 f

34

143 4.0 7.8 14 1.5

*Five patients received supplemental semide therapy. SGOT = serum glutamic oxaloacetic

i f f f f

4 0.4 2.4 6 0.6

After 41 f 21 f

5 12

101 & 25 142 3.9 10.3 16 1.9

potassium

It f f f f

during

3 0.4 2.2 8 0.8

furo-

transaminase.

sis, weight loss and, in 2 patients, clearing of congestive heart failure. Although no patient had clinical evidence of sodium retention, it was necessary to increase the dose of furosemide to more than 80 mg/ day to maintain adequate control of arterial pressure in all patients. With subsequent increases in dose, the potentiation of the antihypertensive effect was repeatedly noted; however, weight loss and diuresis were not consistent and did not appear to be related to the antihypertensive response. No differences in antihypertensive response were noted between men and women. Table IV shows the effect of furosemide on blood chemistry values. There were no significant changes except for an increase in uric acid observed in all 22 patients. Three patients (Cases 6, 8 and 11) had an average increase of 18.5 mg/lOO ml in blood urea nitrogen; however, three others (Cases 4, 19 and 21) had an average decrease of 14.2 mg/lOO ml. Two pa-

548

April 1974

The American Journal of CARDIOLOGY

Discussion Despite maximal doses of antihypertensive agents and diuretic agents, the arterial pressure of the patients studied was inadequately controlled before treatment with furosemide. The substitution of furosemide for the previous diuretic agent permitted adequate control of arterial pressure in 15 patients; in 4 of these patients control of arterial pressure was accomplished with reduced doses of antihypertensive agents. Seven patients had no significant improvement in arterial pressure or clinical status although there was no obvious clinical difference between these patients and the 15 who responded to therapy. Mechanism of beneficial effects of furosemide therapy: Data from previous studies in our laboratory may help to explain the beneficial effects of furosemide in these patients. Most antihypertensive drugs have sodium-retaining properties that can be associated with expansion of the plasma and extracellular fluid volumes, and these volume changes may account for either decreased responsiveness to antihypertensive agents or the development of apparent drug resistance.i5 It is possible that the large doses of antihypertensive agents administered to the patients in this study necessitated the increased doses of furosemide to overcome this effect. It seems logical to hypothesize that the previously administered diuretic agents were not potent enough to prevent the sodium retention caused by the maximal doses of the antihypertensive agents. The potency of furosemide and its increased potency in larger doses blocked the sodium-retaining properties of the antihypertensive agents, thus allowing the latter to exert their full antihypertensive effect. Recent studies by Dustan et al.‘c emphasize the importance of precise volume control in maintaining blood pressure reductions during antihypertensive treatment. During the initial stages of furosemide therapy, all patients lost weight (average 4.5 * 2.1 lb during the first week of therapy). This initial weight loss was thought to represent diuresis and loss of body fluids. The weight change over the remaining 32 months could not be entirely accounted for by a net fluid loss and probably represented changes in caloric balance. When furosemide is given intravenously, its antihypertensive effects are unrelated to weight loss and diuresis.’ In this study we repeatedly noted that subsequent increases in the dose of furosemide resulted in an additional antihypertensive effect that was apparently unrelated to either diuresis or weight loss. This

Volume 33

F-

antihypertensive action usually occurred with oral doses of 200 to 600 mg daily. Our findings are in agreement with those of Hutcheon and Leonard,4 who observed that the antihypertensive action of orally administered furosemide in doses of 100 to 200 mg daily was independent of diuresis. The mechanism of this antihypertensive action of large doses of furosemide could have been related to changes in fluid volume or to a decrease in cardiac output, as originally postulated by Wolfer et a1.,17 since these variables were not measured in our study. The possibility exists that the large doses of furosemide had an antihypertensive action independent of diuresis, as found by Hutcheon and Leonard,4 since there was no change in body weight on a week to week basis when the dose of furosemide was increased to more than 100 mg daily. Side effects: Although the average value for blood urea nitrogen did not change in the 22 patients,, an increase was noted in 3. Investigation of this azotemia revealed no pre- or postrenal origin, and this deterioration of renal function was thought to represent progression of the underlying hypertensive disease process. A rise in serum uric acid levels was noted in all patients. Four patients were receiving probenecid before furosemide therapy and in two additional patients, clinical gout developed during the study. In one of the two patients with known diabetes it was

‘?HERAPY FOR HYPERTENSWN-MROCZEK

ET AL.

necessary to increase the dose of tolbutamide from 1 g daily to 2 g daily. Clinical diabetes, which became apparent in three other patients receiving furosemide therapy, was effectivelytreated with diet and 500 mg of tolbutamide administered twice daily. It is not known if the previous administration of thiazide diuretic agents or the large doses of furosemide alone accounted for the high rate of diabetes mellitus in these patients. Therefore, in addition to monitoring of serum electrolytes and blood urea nitrogen, it seems advisable to monitor blood glucose levels at frequent intervals in patients receiving large doses of furosemide. Clinical implications: Our study demonstrated that large doses of furosemide (80 to 640 mg daily) administered over 2 l/2 years produced no toxic effects and had side effects similar to those of thiazide diuretic agents (hypokalemia, hyperglycemia and hyperuricemia). When combined with standard antihypertensive agents, furosemide not only prevents their sodium-retaining properties, thus allowing them to exert their full effect, but also may exert an additional antihypertensive effect. The combination of standard antihypertensive agents with large doses of furosemide appears to permit better control of arterial pressure than that obtained with other diureticantihypertensive combinations in patients with moderately severe or severe hypertension.

References 1. Davldov M, Kakaviatos N, Finnerty FA Jr: Antihypertensive properties of furosemide. Circulation 3.5125-135, 1967 2. Davkfov M, Kakaviatoa N, Flnnerty FA Jr: Intravenous administration of furosemfde in heart failure. JAMA 200:824-829, 1967 3. Davidov M, Kakavlatos N, Flnnerty FA Jr: The use of furosemide in refractory heart failure. Am Heart J 76:143-144, 1968 4. Hutcheon DE, Leonard G: Diuretic and antihypertensive actions of furosemide. J Clin Pharmacol7:26-33, 1967 5. Atkins LL: Furosemide in the treatment of geriatric patients. Geriatrics 21:143-149, 1966 6. Tknmerman RJ, Springman FR, Thorns RK: Evaluation of furosemide, a new diuretic agent. Curr Ther Res 6:88-94. 1964 7. Mroczek WJ, Davidov M, Gavrllovich L, et al: The value of aggressive therapy in the hypertensive patient with azotemia. Circulation 40:893-904, 1969 8. Muth RG: Diuretic properties of furosemide in renal disease. Ann Intern Med 69:249-261, 1968 9. Rerman LB, Ebrahimi A: Experiences with furosemide in renal disease. Proc Sot Exp Biol Med 118:333-336, 1965

10. Big doses of furosemide in renal failure. Lancet 2:803-804, 1971 11. Schwartz OH, David DS, Rfggio RR, et al: Ctotoxicity induced by furosemfde. N Engl J Med 282:1413-1414, 1970 12. Humphrey8 DM: Acute gout apparently precipitated by furosemide. Br Med J 1:1024-1025. 1966 13. Wffeon AE, Mehra SK, Gomersaff CR, et al: Acute pancreatiiis associated with furosemide therapy. Lancet 1:105, 1967 14. Tolvonen S, Mustala 0: Diibetogenic action of furosemide. Br Med J 1:920-921, 1966 15. Mroczek WJ, Davkfov M, Gavrilovich L, et al: Influence of the extracellular fluid volume on antihypertensive drug response (abstr). Clin Res 18:93, 1970 16. Dustan HP, Tarazi RC, Bravo EL: Dependence of arterial pressure on intravascular volume in treated hypertensive patients. N Engl J Med 286:861-866, 1972 17. WoHer HJ, Schenider KW, Gattenlohner W, et al: Behandlung der arteriellen Hypertonie mit Fursemid. Munchen med Wochenschr 106:1767-1773, 1964

April 1974

The American Journal of CARDIOLOGY

Vdume 33

549