DIURETICS AS INITIAL TREATMENT FOR ESSENTIAL HYPERTENSION FRANK A. FINNERTY, JR Director, The Hypertension Center, Washington, DC, and Clinical Professor of Medicine, George Washington University School of Medicine, Washington, DC
1 In the United States, the thiazide diuretics are considered the cornerstone of all antihypertensive regimens for four reasons: by themselves, they are capable of controlling the blood pressure in 60-70% of the hypertensive population; they prevent the sodium retention produced by all other antihypertensive agents; they can be given once a day; and they are inexpensive. 2 Despite these advantages, the thiazides do cause hypokalaemia, hyperuricaemia and hyperglycaemia. The incidence of hypokalaemia (K < 3.0 mEq/l) is only 24Oo; the incidence of hyperuricaemia (uric acid > 10mg per cent is 3-4%; and the incidence of hyperglycaemia is 1-2%. 3 The possibility that a P-blocking agent combined with a thiazide diuretic might produce better BP control, prevent thiazide-induced abnormalities and exert a coronary prevention action with once daily administration would suggest that such a combination should be the ideal initial therapy for most patients with hypertension.
Introduction IN the United States, the thiazide diuretics are considered the cornerstone of all antihypertensive regimens for four reasons. By themselves they are capable of controlling BP in 60-70% of all patients with mild and moderately severe disease and it is estimated that 75% of the entire hypertensive population has mild disease (Finnerty, 1977). All other antihypertensive agents except for the diuretics - for instance, guanethidine (Smith, 1965), methyldopa (Bayliss & Harvey-Smith, 1962; Dollery & Harington, 1962), hydrallazine (H. Dargie, personal communication), minoxidil (Mehta et al., 1975), and even some of the P-blockers cause sodium retention when given by themselves (Epstein & Braunwald, 1966; Singh et al., 1971). If the sodium retention is left untreated, volume expansion develops which leads to a decreased sensitivity to the drug. Figure 1 shows the effect of daily injections of diazoxide on BP, plasma volume and extracellular fluid volume. Diazoxide seemed to control BP until day 9 when, despite increasing the dose of the drug, BP increased. This lack of response to the drug was associated with an increase in extracellular fluid volume. When the expanded extracellular fluid volume was treated with frusemide, there was return of sensitivity to diazoxide with a fall in arterial BP. Had the frusemide been administered first or at least concomitantly with diazoxide the sodium retention would have been blocked, thus preventing
0306-5251/79/140185-03 $01.00
subsequent volume expansion and the development
of-drug resistance. Figure 2 shows the same pharmacodynamic experiments in a patient receiving methyldopa as an outpatient. The methyldopa seemed to be controlling arterial BP for three and a half months. Despite increasing the dose of methyldopa, BP began to increase at this point. Here again the lack of response to methyldopa was associated with an increase in extracellular fluid volume; and again when the expanded volume was contracted with chlorthiazide, there was a return of response to methyldopa. Had the thiazide been administered first, this sequence of events would have been prevented. With the exception of guanethidine, reserpine and nadolol most antihypertensive agents must be administered at least twice daily and frequently three to four times daily. Surely all would agree that the more complicated the therapy, particularly the more frequent the administration, the less the patient compliance. The epitome of simplicity is obviously one tablet daily. To ensure compliance, it is important to keep treatment simple, at least in the beginning. Finally, the cost of treatment is of utmost importance. The average daily cost of hydrochlorothiazide 50 mg in the USA is 04 cents; and propranolol 40 mg (the only available P-blocker) twice daily is 24 cents. %.V Macmillan Journals Ltd.
186S
FRANK A. FINNERTY, JR
4'7. Except in patients taking digitalis, potassium levels of 3.5-3.0 mEq/l are not clinically significant and do not need treatment if the patient is asymptogt matic. (mmHg) About four of five patients on thiazide therapy incur a slight increase in serum uric acid (Finnerty, * * * * * 160 E 1978). Failure of the serum uric acid to increase Weight slightly, suggests that the patient is not taking the (lbs) 140 medication regularly. A slight increase in serum uric t5 f acid is not important in a patient with normal renal i L ECF and 10 i ' PV (I) function unless the value exceeds 10 mg per cent. In ,* I, my experience, the incidence of thiazides causing an Furomid daily_ increase in uric acid above 10 mg per cent is 3-4% tI t t t1 t1 t 1 t Diazoxide 300mg iv. and the incidence of thiazides causing acute gouty I. 10 15 20 arthritis is 2-3Wo. Thiazides should not be given to 0 5 patients with decreased renal function. Time (d) Hyperglycaemia occurs less often than either Figure 1 Serial determinationc of arterial BP, weight, hypokalaemia or hyperuricaemia in the range of 1-2% ECF (open) and PV (hatched columis) in a patient (Finnerty, 1978). Nevertheless, the thiazides can have receiving daily injections of dia a significant effect and one should monitor blood glucose three or four times a year. However, neither a positive family history or clinical evidence of One might well question hIow we can advocate diabetes contraindicates the use of thiazides, thiazide diuretics as our drug c f first choice, as they although diabetic control may need adjustment. cause such a high incidenc e of metabolic and Several recent studies have suggested that thiazides electrolyte abnormalities, thaat is, hypokalaemia, may elevate serum lipids especially in association hyperuricaemia and hyperglyca emia. with their hyperglycaemic effect (Hollander, 1973; The incidence of hypok.alaemia in patients Ames & Hill, 1976). Preliminary data gathered by M. receiving thiazides depends (on the definition of Moser, M. Maxwell and F.A. Finnerty, Jr hypokalaemia. If one defines iit as a potassium level (unpublished) in a multi-center trial in 300 thiazidebelow 3.5 mEq/l, the incidence ranges from 15-48%. treated patients have also demonstrated an increase Using this definition, the inci dence reported in the in triglycerides above the level that could be VA Cooperative Study (1970) was 235o. If, on the accounted for by a decrease in plasma volume. other hand, one defines hypokaalaemia as a potassium Studies of coronary risk factors suggest that blood level below 3.0 mEq/l, the inc idence varies from 2-
Arterial pressure
-
L
175
-
75-
120 0~
LL
>
Chlorothiazide 1.0gcc
xE 2000 E
Eg
a~
0
10
20
E
------r- MZhth-[-DPPA
- sn
30
I
40
50
I
a
60
70
80
90
100
Time (d)
Flgure 2 Serial determinations of arterial BP, weight, ECF (open) and PV (hatched columns) in a patient receiving daily methyidopa orally.
DIURETICS AND ESSENTIAL HYPERTENSION
changes such as those produced by the thiazides may increase susceptibility to coronary disease. In addition to an increase in triglycerides, thiazideinduced hypokalaemia might also play a role in the precipitation and aggravation of ischaemic heart disease. Hypokalaemia is reported to cause myofibrillar degeneration and other morphological changes in the heart that appear very similar to those produced by myocardial ischaemia. These myocardial lesions, as well as the electrophysiological disturbances caused by hypokalaemia, could play an important role in triggering a serious ventricular arrhythmia in ischaemic heart disease. Particularly intriguing are the data which suggest that P-blocking agents lower triglycerides (W. Hollander, personal communication) and that (Iblocking agents may be potassium-sparing (C.T. Dollery, personal communication). If these properties of P-blockers can be documented in
187S
patients taking diuretics, then it would seem that a f3blocker should indeed be the second-step drug of choice or just as logically that it might be given routinely with the thiazides as a first-step combination. Such a suggestion would be even more practical if the P-blocker were long-acting, permitting once daily administration. This would certainly be in keeping with data showing that a greater degree of BP reduction is accomplished by the combination of a thiazide with a P-blocker than with either drug alone (Chalmers et al., 1976). The possibility of better BP control blocking the thiazide-induced abnormalities and exerting a coronary prevention action, all with once daily administration, would suggest that the combination of a thiazide diuretic and a P-blocking agent would be the ideal initial therapy for most patients with hypertension.
References
AMES, R.P. & HILL, P. (1976). Increase in serum lipids during treatment of hypertension with chlorthalidone. Lancet, 1, 721-723. BAYLISS, R.I.S. & HARVEY-SMITH, E.A. (1962). Methyldopa in the treatment of hypertension. Lancet, 1, 763-768. CHALMERS, J., HORVATH, J., TILLER, D. & BURE, A.
(1976). Effects of timolol and hydrochlorothiazide on blood pressure and plasma renin. Lancet, ii, 328-331. DOLLERY, C.T. & HARINGTON, M. (1962). Methyldopa in hypertension. Clinical and pharmacological studies. Lancet, i, 759-763. EPSTEIN, S.E. & BRAUNWALD, E. (1966). The effect of fadrenergic blockade on patterns of urinary sodium excretion. Annls intern. Med., 65, 20. FINNERTY, F.A. (1977). The use of beta-blockers in hypertension. Clin. Therap., 1, 135-139. FINNERTY, F.A. (1978). Hypertension: Therapy - The stepped-care approach. Consultant, 126-139. HOLLANDER, W. (1973). Hypertension, antihypertensive drugs and atherosclerosis. Circulation, 48, 1112-1127.
MEHTA, P.K., MAMDANI, B., SHANSKY, R.M., MAHURKAR,
S.D. & DUREA, G. (1975). Severe hypertension: treatment with minoxodil. JAMA, 233, 249-252. NIES, A.S. (1977). Clinical pharmacology of antihypertensive drugs. Medical Clinics of North America, 61, 675-698. SEALEY, J.E. (1972). Aldosterone excretion. Physiologic variations in man, measured by radio immunoassay or double isotope dilution. Circulat. Res., 3, 367-378. SINGH, B.N., TILL, M. & KELLY, D.T. (1971). Effect of oxprenolol on patterns of urinary sodium excretion in man. Am. J. Cardiol., 27, 372-375. SMITH, A.J. (1965). Fluid retention produced by guanethidine. Circulation, 31, 490-496. VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP ON ANTIHYPERTENSIVE AGENTS (1970). Effects
of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mmHg. JAMA, 213, 1143-1152.
1 In the United States, the thiazide diuretics are considered the cornerstone of all antihypertensive regimens for four reasons: by themselves, they are capable of controlling the blood pressure in 60-70% of the hypertensive population; they prevent the sodium retention produced by all other antihypertensive agents; they can be given once a day; and they are inexpensive. 2 Despite these advantages, the thiazides do cause hypokalaemia, hyperuricaemia and hyperglycaemia. The incidence of hypokalaemia (K < 3.0 mEq/l) is only 24Oo; the incidence of hyperuricaemia (uric acid > 10mg per cent is 3-4%; and the incidence of hyperglycaemia is 1-2%. 3 The possibility that a P-blocking agent combined with a thiazide diuretic might produce better BP control, prevent thiazide-induced abnormalities and exert a coronary prevention action with once daily administration would suggest that such a combination should be the ideal initial therapy for most patients with hypertension.
Introduction IN the United States, the thiazide diuretics are considered the cornerstone of all antihypertensive regimens for four reasons. By themselves they are capable of controlling BP in 60-70% of all patients with mild and moderately severe disease and it is estimated that 75% of the entire hypertensive population has mild disease (Finnerty, 1977). All other antihypertensive agents except for the diuretics - for instance, guanethidine (Smith, 1965), methyldopa (Bayliss & Harvey-Smith, 1962; Dollery & Harington, 1962), hydrallazine (H. Dargie, personal communication), minoxidil (Mehta et al., 1975), and even some of the P-blockers cause sodium retention when given by themselves (Epstein & Braunwald, 1966; Singh et al., 1971). If the sodium retention is left untreated, volume expansion develops which leads to a decreased sensitivity to the drug. Figure 1 shows the effect of daily injections of diazoxide on BP, plasma volume and extracellular fluid volume. Diazoxide seemed to control BP until day 9 when, despite increasing the dose of the drug, BP increased. This lack of response to the drug was associated with an increase in extracellular fluid volume. When the expanded extracellular fluid volume was treated with frusemide, there was return of sensitivity to diazoxide with a fall in arterial BP. Had the frusemide been administered first or at least concomitantly with diazoxide the sodium retention would have been blocked, thus preventing
0306-5251/79/140185-03 $01.00
subsequent volume expansion and the development
of-drug resistance. Figure 2 shows the same pharmacodynamic experiments in a patient receiving methyldopa as an outpatient. The methyldopa seemed to be controlling arterial BP for three and a half months. Despite increasing the dose of methyldopa, BP began to increase at this point. Here again the lack of response to methyldopa was associated with an increase in extracellular fluid volume; and again when the expanded volume was contracted with chlorthiazide, there was a return of response to methyldopa. Had the thiazide been administered first, this sequence of events would have been prevented. With the exception of guanethidine, reserpine and nadolol most antihypertensive agents must be administered at least twice daily and frequently three to four times daily. Surely all would agree that the more complicated the therapy, particularly the more frequent the administration, the less the patient compliance. The epitome of simplicity is obviously one tablet daily. To ensure compliance, it is important to keep treatment simple, at least in the beginning. Finally, the cost of treatment is of utmost importance. The average daily cost of hydrochlorothiazide 50 mg in the USA is 04 cents; and propranolol 40 mg (the only available P-blocker) twice daily is 24 cents. %.V Macmillan Journals Ltd.
186S
FRANK A. FINNERTY, JR
4'7. Except in patients taking digitalis, potassium levels of 3.5-3.0 mEq/l are not clinically significant and do not need treatment if the patient is asymptogt matic. (mmHg) About four of five patients on thiazide therapy incur a slight increase in serum uric acid (Finnerty, * * * * * 160 E 1978). Failure of the serum uric acid to increase Weight slightly, suggests that the patient is not taking the (lbs) 140 medication regularly. A slight increase in serum uric t5 f acid is not important in a patient with normal renal i L ECF and 10 i ' PV (I) function unless the value exceeds 10 mg per cent. In ,* I, my experience, the incidence of thiazides causing an Furomid daily_ increase in uric acid above 10 mg per cent is 3-4% tI t t t1 t1 t 1 t Diazoxide 300mg iv. and the incidence of thiazides causing acute gouty I. 10 15 20 arthritis is 2-3Wo. Thiazides should not be given to 0 5 patients with decreased renal function. Time (d) Hyperglycaemia occurs less often than either Figure 1 Serial determinationc of arterial BP, weight, hypokalaemia or hyperuricaemia in the range of 1-2% ECF (open) and PV (hatched columis) in a patient (Finnerty, 1978). Nevertheless, the thiazides can have receiving daily injections of dia a significant effect and one should monitor blood glucose three or four times a year. However, neither a positive family history or clinical evidence of One might well question hIow we can advocate diabetes contraindicates the use of thiazides, thiazide diuretics as our drug c f first choice, as they although diabetic control may need adjustment. cause such a high incidenc e of metabolic and Several recent studies have suggested that thiazides electrolyte abnormalities, thaat is, hypokalaemia, may elevate serum lipids especially in association hyperuricaemia and hyperglyca emia. with their hyperglycaemic effect (Hollander, 1973; The incidence of hypok.alaemia in patients Ames & Hill, 1976). Preliminary data gathered by M. receiving thiazides depends (on the definition of Moser, M. Maxwell and F.A. Finnerty, Jr hypokalaemia. If one defines iit as a potassium level (unpublished) in a multi-center trial in 300 thiazidebelow 3.5 mEq/l, the incidence ranges from 15-48%. treated patients have also demonstrated an increase Using this definition, the inci dence reported in the in triglycerides above the level that could be VA Cooperative Study (1970) was 235o. If, on the accounted for by a decrease in plasma volume. other hand, one defines hypokaalaemia as a potassium Studies of coronary risk factors suggest that blood level below 3.0 mEq/l, the inc idence varies from 2-
Arterial pressure
-
L
175
-
75-
120 0~
LL
>
Chlorothiazide 1.0gcc
xE 2000 E
Eg
a~
0
10
20
E
------r- MZhth-[-DPPA
- sn
30
I
40
50
I
a
60
70
80
90
100
Time (d)
Flgure 2 Serial determinations of arterial BP, weight, ECF (open) and PV (hatched columns) in a patient receiving daily methyidopa orally.
DIURETICS AND ESSENTIAL HYPERTENSION
changes such as those produced by the thiazides may increase susceptibility to coronary disease. In addition to an increase in triglycerides, thiazideinduced hypokalaemia might also play a role in the precipitation and aggravation of ischaemic heart disease. Hypokalaemia is reported to cause myofibrillar degeneration and other morphological changes in the heart that appear very similar to those produced by myocardial ischaemia. These myocardial lesions, as well as the electrophysiological disturbances caused by hypokalaemia, could play an important role in triggering a serious ventricular arrhythmia in ischaemic heart disease. Particularly intriguing are the data which suggest that P-blocking agents lower triglycerides (W. Hollander, personal communication) and that (Iblocking agents may be potassium-sparing (C.T. Dollery, personal communication). If these properties of P-blockers can be documented in
187S
patients taking diuretics, then it would seem that a f3blocker should indeed be the second-step drug of choice or just as logically that it might be given routinely with the thiazides as a first-step combination. Such a suggestion would be even more practical if the P-blocker were long-acting, permitting once daily administration. This would certainly be in keeping with data showing that a greater degree of BP reduction is accomplished by the combination of a thiazide with a P-blocker than with either drug alone (Chalmers et al., 1976). The possibility of better BP control blocking the thiazide-induced abnormalities and exerting a coronary prevention action, all with once daily administration, would suggest that the combination of a thiazide diuretic and a P-blocking agent would be the ideal initial therapy for most patients with hypertension.
References
AMES, R.P. & HILL, P. (1976). Increase in serum lipids during treatment of hypertension with chlorthalidone. Lancet, 1, 721-723. BAYLISS, R.I.S. & HARVEY-SMITH, E.A. (1962). Methyldopa in the treatment of hypertension. Lancet, 1, 763-768. CHALMERS, J., HORVATH, J., TILLER, D. & BURE, A.
(1976). Effects of timolol and hydrochlorothiazide on blood pressure and plasma renin. Lancet, ii, 328-331. DOLLERY, C.T. & HARINGTON, M. (1962). Methyldopa in hypertension. Clinical and pharmacological studies. Lancet, i, 759-763. EPSTEIN, S.E. & BRAUNWALD, E. (1966). The effect of fadrenergic blockade on patterns of urinary sodium excretion. Annls intern. Med., 65, 20. FINNERTY, F.A. (1977). The use of beta-blockers in hypertension. Clin. Therap., 1, 135-139. FINNERTY, F.A. (1978). Hypertension: Therapy - The stepped-care approach. Consultant, 126-139. HOLLANDER, W. (1973). Hypertension, antihypertensive drugs and atherosclerosis. Circulation, 48, 1112-1127.
MEHTA, P.K., MAMDANI, B., SHANSKY, R.M., MAHURKAR,
S.D. & DUREA, G. (1975). Severe hypertension: treatment with minoxodil. JAMA, 233, 249-252. NIES, A.S. (1977). Clinical pharmacology of antihypertensive drugs. Medical Clinics of North America, 61, 675-698. SEALEY, J.E. (1972). Aldosterone excretion. Physiologic variations in man, measured by radio immunoassay or double isotope dilution. Circulat. Res., 3, 367-378. SINGH, B.N., TILL, M. & KELLY, D.T. (1971). Effect of oxprenolol on patterns of urinary sodium excretion in man. Am. J. Cardiol., 27, 372-375. SMITH, A.J. (1965). Fluid retention produced by guanethidine. Circulation, 31, 490-496. VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP ON ANTIHYPERTENSIVE AGENTS (1970). Effects
of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mmHg. JAMA, 213, 1143-1152.
