- Email: [email protected]
EVALUATION OF BETA BLOCKADE, BENDROFLUAZIDE, AND PRAZOSIN IN SEVERE HYPERTENSION
271 The biochemical analysis of fetal blood has proved to be extremely reliable. In sickle-cell anaemia, &bgr; ’-globinchain synthesis in the absence of&bgr; chain was readily demonstrated in the two homozygous cases. In this series, homozygous -thalassaemia has been clearly distinguishable from the non-homozygous states. Our data also indicate that &bgr;-thalassaemia trait can be identified with a high degree of certainty. Even with the limited number of cases in our series, some of the benefits of prenatal diagnosis of the haemoglobinopathies can already be seen. 6 couples were spared the burden of having a child with a severe and chronic illness. Couples who had previously decided not to have any children changed their minds because of the availability of this procedure. Also, several parents who
would have had their pregnancies aborted, had prenatal diagnosis not been available, have allowed them to conOn the other hand, 3 couples lost their because of complications. Hence, the ultipregnancies mate acceptability of this procedure depends on the overall risk of fetal blood-sampling. If the risk is small, this procedure would be acceptable. However, if further experience shows that the risk is high, then alternative methods of prenatal diagnosis will have to be devised. These could include the development of safer methods for fetal blood sampling, or the use of methods which do not require fetal blood, such as stimulation of globinchain production in fibroblasts. With homozygous ot-thalassxmia, for example, prenatal diagnosis has been accomplished by quantitating oc-globin structural genes in amniotic-fluid fibroblasts. ISHowever, this approach is not useful in &bgr;-thalssaemia and sickle-cell ansemia where the -globin structural genes are intact. Further experience is required to ascertain whether the current approach will be adequate or whether other methods will be necessary. tinue
to term.
We thank Linda McKay, Cheryl Wilson, Antonella Anguis, and Jennifer Gampell for their help. This study was supported by grants from the N.I.H., National Foundation-March of Dimes, John A. Hartford Foundation, and a contract from the Department of Health, State of California. Y. W. K. is an Investigator of the Howard Hughes Medical Institute. R. A. F. is a Picker scholar of the James Picker Foundation.
Requests for reprints should be addressed to Y. W. K., San Francisco General Hospital, San Francisco, California 94110, U.S.A. REFERENCES
Kan, Y. W., Dozy, A. M., Alter, B. P., Frigoletto, F. D., Nathan, D. G. New Engl. J Med. 1972, 287, 1. 2. Kan, Y. W., Golbus, M. S., Klein, P., Dozy, A. M. ibid. 1975, 292, 1096. 3 Kan, Y. W., Golbus, M. S., Trecartin, R., Furbetta, M., Cao, A. Lancet, 1975, ii, 790. 4. Kan, Y. W, Golbus, M. S., Trecartin, R. New Engl. J. Med. 1976, 294, 1.
1039.
Alter, B. P., Friedman, S., Hobbins, J. C., Mahoney, M. J., Sherman, A. S., McSweeney, J. F., Schwartz, E., Nathan, D. G. ibid. p. 1040. 6. Kan, Y. W., Valenti, C., Carnazza, V., Guidotti, R., Rieder, R. F. Lancet, 1974, i, 79. 7. Golbus, M. S., Kan, Y. W., Naglich-Craig, M. Am. J. Obstet. Gynec. 1976, 5
124, 653. Kleihauer, E., Braun, H., Betke, F. Klin. Wschr. 1957, 35, 637. Kan, Y. W., Nathan, D. G., Cividalli, G., Crookston, M. C. Blood, 1974, 43, 411. 10 Schneider, R. G., Hosty, T. S., Tomlin, G., Atkins, R. Clin. Chem. 1974, 20, 74. 11 Kan, Y. W.,Nathan, D. G. Science, 1968, 161, 589. 12. Kan, Y. W., Forget, B G., Nathan, D. G. New Engl. J. Med. 1972, 286, 8
9
129. 13. Hobbins, J. C., Mahoney, M. J. Lancet, 1975, ii, 107. 14. Alter, B. P., Modell, C. B., Fairweather, D., Hobbins, J. C., Mahoney, M. J., Frigoletto, F. D., Sherman, A. S., Nathan, D. G. New Engl. J. Med. 1976,
295, 1437. 15 Kan, Y
W, Golbus, M. S., Dozy,
A. M. ibid. p. 1165
EVALUATION OF BETA BLOCKADE, BENDROFLUAZIDE, AND PRAZOSIN IN SEVERE HYPERTENSION A.
J. MARSHALL JESSICA POCOCK
D. W. BARRITT SUSAN T. HEATON
Bristol Royal Infirmary
20 patients with severe essential hypertension (average blood-pressure 211/123 mm Hg) had an inadequate fall in blood-pressure with beta blockade alone. They were given in random order either 5 and then 10 mg of bendrofluazide a day or prazosin 2 mg three times daily rising to 5 mg if required. The trial was a within-patient comparison of the two drug regimens. 10 patients who did not achieve a satisfactory fall in pressure with either agent were then given all three drugs together. When bendrofluazide 5 or 10 mg was added to beta blockade there was an average fall in mean blood-pressure, standing, of 13%. When prazosin was added to beta blockade the average fall in mean blood-pressure, standing, was 16%. 18 patients who completed the trial had an average final blood-pressure, standing, of 139/93 mm Hg. In the prazosin period 8 patients continued to complain of dizziness after the first 24 h. With bendrofluazide serum-potassium levels fell below 3·6 mmol/l in half the patients within the first two weeks of treatment. It is concluded that patients with essential hypertension already treated with beta blockade who need an additional agent will get a further fall in blood-pressure with 5 mg of bendrofluazide. Prazosin appears to be a potent and appropriate third agent.
Summary
Introduction BETA-BLOCKING agents are widely recommended for the treatment of hypertension. The virtual absence of a postural effect and the low incidence of interference with sexual activities account for their popularity. Any hypotensive agent, including the beta blockers, usually causes a fall to near normal levels of pressure in less severe hypertensives so that no second agent is necessary. However, one drug hardly ever suffices in the treatment of patients with a blood-pressure sustained at 200/115 mm Hg or more.’ The thiazide diuretics have been shown to be useful in combination with beta blockade.23 Prazosin is a new hypotensive agent which is thought to act as a vasodilator.4 We compared the effect of this drug with bendrofluazide when added to a beta-blocking agent and assessed the three drugs in combination. Our aim was to establish a simple and effective treatment regimen for severe
hypertension. Patients and Methods
20 severely hypertensive patients, 7 men and 13 women, whose response to beta blockade was inadequate, were entered into the study. Supine systolic blood-pressures immediately before starting beta blockade ranged from 180 to 246 (average 211 mm Hg) and diastolic pressures from 115 to 140 (average 123 mm Hg). The age range was 24 to 72 years (average 58 years). At entry to the trial each patient had taken for at least two months either 480 mg or more of propranolol (6) or oxprenolol (5) or 100 mg daily or more of atenolol (9). On these dosages supine systolic pressures ranged from 170 to 240 (average 192 mm Hg) and diastolic pressure from 105 to 147
272
(average 117 mm Hg). Important renal disease was excluded by examining the abdomen and the urine and measuring blood-urea. No patient had retinal haemorrhage, airways obstruction, or any evidence of heart-failure. All were outpatients and attended a clinic set aside specifically for the study. Only 2 observers were involved and they always read pressures blindly using the London School of Hygiene and Tropical Medicine sphygmomanometer (Rose Box). Diastolic pressures were read at phase 5. Patients attended at two-week intervals and blood-pressure was measured supine after lying for five minutes, after being erect for two minutes, and after one minute of two-step exercise. The heart-rate was counted in each position. Symptomatic side-effects were assessed during each period of treatment as follows. At each visit the patient was asked "How have you been feeling since your last visit?". Each was then asked fifteen direct questions and the replies recorded. Blood-urea and electrolytes were monitored throughout the study. During the period of diuretic therapy, each patient produced a two-day diary of everything taken by mouth and the results were analysed by a dietitian who estimated daily potassium intake. Statistical analyses were done by means of the paired Student’s t test.
Treatment
higher dose range of 5 mg three times daily. After the period of treatment with the first of the two drugs a placebo tablet was added to the beta blocker to allow a washout period of two weeks. The second drug was then added to beta blockade for either one or two months. Next the beta blocker was withdrawn and treatment continued with bendrofluazide or prazosin alone using whichever drug had produced the greater fall in pressure. Finally, patients whose control was inadequate on either combination of beta blockade and bendrofluazide or prazosin were given all three drugs together for a further period of observation. Results withdrawn because of inconsistent attendThe other 19 completed the trial and the analysis was made on their results. 10 patients were given bendrofluazide as the first additional agent and 9 had prazosin first. 10 patients had an unsatisfactory fall in pressure with each of the two regimens, and were therefore treated with all three drugs together. 1
man was
ance.
Blood-pressure Fall in blood-pressure achieved by
beta blockade reduction in the group was systolic blood-pressure 19.7 mm Hg (s.D.t28-2) (P<0-01), diastolic blood-pressure 6-0 mm Hg (s.D.±16-6) (P=not significant [N.S.]).
alone.-The
During the first three two-week periods beta blockade was continued alone at previous dosage. Bendrofluazide or prazosin was then added on a previously determined random basis. The two doses of bendrofluazide were 5 and 10 mg daily given without potassium supplements. Prazosin was given at a starting dose of 2 mg three times daily beginning in the evening. If control was achieved or if side-effects were troublesome the patient did not proceed to a second month of treatment at the
mean
Effect of adding bendrofluazide.-The average fall in pressure for the group and percentage fall in systolic, diastolic, and mean arterial pressures, supine, standing,
TABLE I-AVERAGE FALL IN BLOOD-PRESSURE WITH ADDITION OF BENDROFLUAZIDE OR PRAZOSIN
s.B.P.=Systolic blood-pressure. D.B.p.=Diastolic blood-pressure. M.A.p.=Mean arterial pressure. TABLE II AVERAGE FALL IN BLOOD-PRESSURE IN PATIENTS TAKING BETA BLOCKER PLUS BENDROFLUAZIDE
S.B.P.=Systolic blood-pressure. D.B.p.=Diastolic blood-pressure. M.A.p.=Mean arterial pressure.
273 TABLE III-FALLIN MEAN BLOOD-PRESSURE COMBINATION TREATMENT
(mmHg) WITH
86-112); 139/93 (mean arterial pressure 108) (range systolic pressure 118-156, diastolic pressure 78-109); and 140/91 (mean arterial pressure 107) after exercise (range systolic pressure 124-153, diastolic pressure 77-103). Table iv shows the mean change in heart-rate for this group of patients, supine, standing, sure
erect
and after exercise with the addition of both doses of each
agent.
Side-effects shown in table I. There was no statistically significant difference between the effect of 5 mg of bendrofluazide daily and 10 mg a day (table n). The fall in blood-pressure after two weeks’ treatment with the diuretic was not different from that measured after eight weeks (table n). Effect of adding prazosin.-7 of the 19 patients were given 2 mg three times a day, and 12 took first 2 and then 5 mg of prazosin three times daily. The fall in blood-pressure produced by the final dose of prazosin is shown in table i. A comparison of the effect of 2 and 5 mg of prazosin three times a day was made in those patients who received both doses. Increasing the dose resulted in a further fall of supine mean pressure of 7.9 mm Hg (s.D.ill-7), (P<0.05). The additional effect was also statistically significant in the erect and postexercise readings (p < 0 - 0 5). Placebo period.-In the group the mean arterial pressure was 5.9 mm Hg lower during the period when placebo tablets were given in addition to beta blockade as compared to treatment with the beta-blocking agent alone in the run-in period. (s.D.16-8) (P=N.S.). This difference was not statistically significant whether bendrofluazide or prazosin was the first additional agent
and after exercise,
(0.89118.75 vely).
are
mm
Hg, 10-3±14.99
mm
Of the 19 patients, 13 felt in normal health in the placebo period when they were taking beta blockade and ascorbic acid. Only 4 felt equally well in the first period of treatment with both prazosin and bendrofluazide but the number increased to 8 with both drugs in the second period when the dose was higher and to 11 in the period when beta blockade was withdrawn. Three of the fifteen questions revealed frequent symptoms, the most important was dizziness in the prazosin period. 3 patients complained of dizziness after the first dose only. 8 others were dizzy at times as the dose of 2 mg three times a day was continued. Fatigue was present in 6 patients in the first prazosin period and 2 with bendrofluazide. Headache occurred in 4 patients with each drug. 2 patients refused to continue with prazosin and 1 with bendrofluazide.
Bendrofluazide and Potassium Status Bendrofluazide was added to beta blockade in 18 patients. In 13 it was continued beyond the eight-week period of the trial. Observations were, therefore, available for these 18 for a mean period of twenty weeks (s.D. ±11). Supplementary potassium tablets were not
Hg, respecti-
Withdrawal continued on
of beta-blocking agent.-Patients who prazosin and bendrofluazide alone were analysed separately. On withdrawal of the beta-blocking agent the blood-pressures in both groups rose. The increase in systolic pressure was statistically significant in the supine and post-exercise positions in patients on prazosin and in the erect position in those on bendrofluazide (P<005). The rise in diastolic pressure was not significant. Combination
beta blockade, bendrofluazide, and prazosin.-The results of the 10 patients who received all three drugs together are shown in table in. Final blood-pressure results.-l patient who was unable to tolerate prazosin was excluded from the analysis of final blood-pressures. Of the remaining 18 patients, 8 were treated with two drugs and 10 with three. For the group the average blood-pressure (two outpatient attendances) was 155/94 mm Hg (mean arterial pressure 114) supine (range systolic pressure 132-173, diastolic pres-
of
-
given. Serum-potassium levels at the final estimation (mean twenty weeks’ treatment) had fallen from a pretreatment level of 4.1 (S.D. 0.16) to 3-66 mmol;1 (S.D. 0.36) (P<0’001). After only two weeks mean serum-potassium was 3.70 (s.0.:!::0.38). The lowest serum-potassium was 3-11 mmol/l. There was no significant difference between two and twenty week means. Mean daily potassium intake was 51mmol (S.D. + 19). Daily urine potassium excretion was measured from a twenty-four hour collection. Mean potassium excretion was 55 mmol (s.D.±20). The correlation coefficient of urinary potassium excretion with estimated dietary intake was 0-17.
Discussion The patients entering the trial were a consecutive group of severe hypertensives who had received adequate doses of beta-blocking drugs given for at least two months and whose blood-pressure levels required the addition of further agents. The severity of the hyperten-
TABLE IV—CHANGE IN HEART-RATE WITH ADDITIONAL AGENT
274 sion prevented frequent observations before treatment with beta blockade was begun but by the time of entry to the trial the patients were familiar with the clinic procedure. Because the variability of blood-pressure levels in individual patients interferes with assessments of the potency of hypotensive agents, we made measurements in three positions at two fortnightly clinic visists and the consistent pattern of response increases our confidence in the conclusions we draw about each treatment
regimen. The addition of 5 mg of bendrofluazide to beta blockade produced significant falls in systolic and diastolic pressure-supine, erect, and post-exercise. Percentage falls in mean pressure were about 12%. Unlike Wilkinson et all we did not find that the full hypotensive effect was delayed, there being no difference between two and four weeks. 5 mg daily was as effective as 10 mg. The addition of prazosin to beta blockade produced slightly greater falls in blood-pressure of about 15%. The postural effect of continued treatment with prazosin was quite small, the fall in average systolic pressure on standing being 12 mm Hg, exactly the same as occurred with bendrofluazide. Post-exercise pressures were similar to erect blood-pressures. In the group of 12 patients whose dose was increased from 2 to 5 mg three times daily, there were further significant falls. The prompt rise in pressure in the placebo period confirmed that the incremental effect was indeed due to the added agents. It is logical to add prazosin to bendrofluazide and beta blockade when the latter two fail to lower pressure adequately. In most patients further considerable falls can be expected. The effectiveness of this combination of two or three drugs in such a group of severe hypertensives is well shown by the final blood-pressure in the erect position: average systolic pressure 139, range 118-156, and diastolic pressure 93, range 78-109. The fall in blood-pressure achieved by giving both bendrofluazide and prazosin together was not significantly different from that expected if the falls produced by the two drugs individually were added (P=N.S.). It can therefore be concluded that the effects of the two drugs is purely additive. Because of the background of beta blockade in all but one treatment period, heart-rates were slow. In the period when beta blockade was withdrawn, supine heart-rates rose from an average of 64 to 85 and postexercise from 75 to 114 per minute. It is interesting, however, that the addition of bendrofluazide caused a small rise in the heart-rate which achieved significance post-exercise. On the other hand when prazosin was added to beta blockade there was a further slowing of the heart-rate in all positions. This reached significance in the supine position. If prazosin acts simply by vasodilatation we would have expected an increase in the heart-rate with its addition to beta blockade. This suggests to us that prazosin’s action may not be entirely ’
peripheral. We find the usual difficulty in assessing side-effects. There is for instance the inconsistency that half the patients who complained of some side-effect in the first period of treatment with both bendrofluazide and prazosin lost their complaints in the second period when the dose was increased. The most troublesome side-effect was dizziness from prazosin. The phenomenon is clearly
not confined to the first few hours. It seemed especially prominent in a period of unusually hot weather. It is important to start treatment with a dose not exceeding 2 mg given just before going to bed. If the dizziness and occasional collapse in the erect position is due to a precipitous fall of blood-pressure it is surprising that with continued treatment the hypotensive effect is so little to posture. The administration of 5 mg of bendrofluazide daily may cause potentially serious falls in serum-potassium levels. In 50% of our patients serum-potassium fell below 3.6 mmol/1 within a month. They continued on
related
bendrofluazide without additional potassium and came to no apparent harm. We have not observed any tendency for those with normal serum-potassium levels at four weeks to have lower levels after longer treatment. Dietary intake did not correlate with levels of serumpotassium, correlation coefficient=0.156. The average British diet is said to contain more than 50mmol of potassium daily.6 10 of our 20 patients appeared to take less than this. It seems to us easier to increase potassium intake by recommending certain potassium-rich articles of diet than by the use of potassium in tablet form. For instance the daily addition to the diet of a bowl of ’All Bran’ breakfast cereal with milk, a helping of spinach, and one cup of instant coffee with milk gives 80 mmol of potassium equalling ten ’Slow-K’ tablets. Recommendations The following principles should determine the physician’s choice of hypotensive agents: (1) there is still no way to predict which combination of drugs is most likely to be most effective for any given patient, although a logical approach is appropriate; (2) drugs used should be potent, as free as possible of side-effects, and few in number; (3) the effect of each agent and incremental dosage should be measured with care, usually with repeated observations, and those agents shown not to be making an effective contribution should be withdrawn. Starting with beta blockade, only one or two tablets daily are required. Patients with high initial pressures are likely to need an additional agent. The addition of one tablet daily of a thiazide diuretic will usually cause a further useful fall in blood-pressure, with a few in side-effects. Even severe hypertension the combination of these two agents, which could be given as a single daily tablet, may suffice. Their effectiveness can be judged in two weeks. For those who need a third agent, the addition of prazosin three tablets daily, may sometimes produce side-effects, but there will be few patients who are not satisfactorily controlled. Requests for reprints should be addressed Infirmary, Bristol BS2 8HW.
to D. W.
B., Bristol Royal
REFERENCES 1. Barritt, D. W., Marshall, A. J. Unpublished. 2. Prichard, B. V. S., Gillam, P. M. S. Br. med. J. 1969, i, 7. 3 Petrie, J. C., Galloway, D. B , Webster, J., Simpson, W. T., Lewis, J. A. ibid. 1975, iv, 133. 4. Constantine, J. W., McShane, W. K., Scriabine, A., Hess, H. J. Hypertension: Mechanisms and Management; New York, 1973. 5. Wilkinson, P. R , Issler, H., Hesp, R., Raftery, E. B. Lancet, 1975, i, 759. 6. Davidson, S., Passmore, R., Brock, J. F., Trunwell, A. S. Human Nutrition and Dietetics; London, 1975.
would have had their pregnancies aborted, had prenatal diagnosis not been available, have allowed them to conOn the other hand, 3 couples lost their because of complications. Hence, the ultipregnancies mate acceptability of this procedure depends on the overall risk of fetal blood-sampling. If the risk is small, this procedure would be acceptable. However, if further experience shows that the risk is high, then alternative methods of prenatal diagnosis will have to be devised. These could include the development of safer methods for fetal blood sampling, or the use of methods which do not require fetal blood, such as stimulation of globinchain production in fibroblasts. With homozygous ot-thalassxmia, for example, prenatal diagnosis has been accomplished by quantitating oc-globin structural genes in amniotic-fluid fibroblasts. ISHowever, this approach is not useful in &bgr;-thalssaemia and sickle-cell ansemia where the -globin structural genes are intact. Further experience is required to ascertain whether the current approach will be adequate or whether other methods will be necessary. tinue
to term.
We thank Linda McKay, Cheryl Wilson, Antonella Anguis, and Jennifer Gampell for their help. This study was supported by grants from the N.I.H., National Foundation-March of Dimes, John A. Hartford Foundation, and a contract from the Department of Health, State of California. Y. W. K. is an Investigator of the Howard Hughes Medical Institute. R. A. F. is a Picker scholar of the James Picker Foundation.
Requests for reprints should be addressed to Y. W. K., San Francisco General Hospital, San Francisco, California 94110, U.S.A. REFERENCES
Kan, Y. W., Dozy, A. M., Alter, B. P., Frigoletto, F. D., Nathan, D. G. New Engl. J Med. 1972, 287, 1. 2. Kan, Y. W., Golbus, M. S., Klein, P., Dozy, A. M. ibid. 1975, 292, 1096. 3 Kan, Y. W., Golbus, M. S., Trecartin, R., Furbetta, M., Cao, A. Lancet, 1975, ii, 790. 4. Kan, Y. W, Golbus, M. S., Trecartin, R. New Engl. J. Med. 1976, 294, 1.
1039.
Alter, B. P., Friedman, S., Hobbins, J. C., Mahoney, M. J., Sherman, A. S., McSweeney, J. F., Schwartz, E., Nathan, D. G. ibid. p. 1040. 6. Kan, Y. W., Valenti, C., Carnazza, V., Guidotti, R., Rieder, R. F. Lancet, 1974, i, 79. 7. Golbus, M. S., Kan, Y. W., Naglich-Craig, M. Am. J. Obstet. Gynec. 1976, 5
124, 653. Kleihauer, E., Braun, H., Betke, F. Klin. Wschr. 1957, 35, 637. Kan, Y. W., Nathan, D. G., Cividalli, G., Crookston, M. C. Blood, 1974, 43, 411. 10 Schneider, R. G., Hosty, T. S., Tomlin, G., Atkins, R. Clin. Chem. 1974, 20, 74. 11 Kan, Y. W.,Nathan, D. G. Science, 1968, 161, 589. 12. Kan, Y. W., Forget, B G., Nathan, D. G. New Engl. J. Med. 1972, 286, 8
9
129. 13. Hobbins, J. C., Mahoney, M. J. Lancet, 1975, ii, 107. 14. Alter, B. P., Modell, C. B., Fairweather, D., Hobbins, J. C., Mahoney, M. J., Frigoletto, F. D., Sherman, A. S., Nathan, D. G. New Engl. J. Med. 1976,
295, 1437. 15 Kan, Y
W, Golbus, M. S., Dozy,
A. M. ibid. p. 1165
EVALUATION OF BETA BLOCKADE, BENDROFLUAZIDE, AND PRAZOSIN IN SEVERE HYPERTENSION A.
J. MARSHALL JESSICA POCOCK
D. W. BARRITT SUSAN T. HEATON
Bristol Royal Infirmary
20 patients with severe essential hypertension (average blood-pressure 211/123 mm Hg) had an inadequate fall in blood-pressure with beta blockade alone. They were given in random order either 5 and then 10 mg of bendrofluazide a day or prazosin 2 mg three times daily rising to 5 mg if required. The trial was a within-patient comparison of the two drug regimens. 10 patients who did not achieve a satisfactory fall in pressure with either agent were then given all three drugs together. When bendrofluazide 5 or 10 mg was added to beta blockade there was an average fall in mean blood-pressure, standing, of 13%. When prazosin was added to beta blockade the average fall in mean blood-pressure, standing, was 16%. 18 patients who completed the trial had an average final blood-pressure, standing, of 139/93 mm Hg. In the prazosin period 8 patients continued to complain of dizziness after the first 24 h. With bendrofluazide serum-potassium levels fell below 3·6 mmol/l in half the patients within the first two weeks of treatment. It is concluded that patients with essential hypertension already treated with beta blockade who need an additional agent will get a further fall in blood-pressure with 5 mg of bendrofluazide. Prazosin appears to be a potent and appropriate third agent.
Summary
Introduction BETA-BLOCKING agents are widely recommended for the treatment of hypertension. The virtual absence of a postural effect and the low incidence of interference with sexual activities account for their popularity. Any hypotensive agent, including the beta blockers, usually causes a fall to near normal levels of pressure in less severe hypertensives so that no second agent is necessary. However, one drug hardly ever suffices in the treatment of patients with a blood-pressure sustained at 200/115 mm Hg or more.’ The thiazide diuretics have been shown to be useful in combination with beta blockade.23 Prazosin is a new hypotensive agent which is thought to act as a vasodilator.4 We compared the effect of this drug with bendrofluazide when added to a beta-blocking agent and assessed the three drugs in combination. Our aim was to establish a simple and effective treatment regimen for severe
hypertension. Patients and Methods
20 severely hypertensive patients, 7 men and 13 women, whose response to beta blockade was inadequate, were entered into the study. Supine systolic blood-pressures immediately before starting beta blockade ranged from 180 to 246 (average 211 mm Hg) and diastolic pressures from 115 to 140 (average 123 mm Hg). The age range was 24 to 72 years (average 58 years). At entry to the trial each patient had taken for at least two months either 480 mg or more of propranolol (6) or oxprenolol (5) or 100 mg daily or more of atenolol (9). On these dosages supine systolic pressures ranged from 170 to 240 (average 192 mm Hg) and diastolic pressure from 105 to 147
272
(average 117 mm Hg). Important renal disease was excluded by examining the abdomen and the urine and measuring blood-urea. No patient had retinal haemorrhage, airways obstruction, or any evidence of heart-failure. All were outpatients and attended a clinic set aside specifically for the study. Only 2 observers were involved and they always read pressures blindly using the London School of Hygiene and Tropical Medicine sphygmomanometer (Rose Box). Diastolic pressures were read at phase 5. Patients attended at two-week intervals and blood-pressure was measured supine after lying for five minutes, after being erect for two minutes, and after one minute of two-step exercise. The heart-rate was counted in each position. Symptomatic side-effects were assessed during each period of treatment as follows. At each visit the patient was asked "How have you been feeling since your last visit?". Each was then asked fifteen direct questions and the replies recorded. Blood-urea and electrolytes were monitored throughout the study. During the period of diuretic therapy, each patient produced a two-day diary of everything taken by mouth and the results were analysed by a dietitian who estimated daily potassium intake. Statistical analyses were done by means of the paired Student’s t test.
Treatment
higher dose range of 5 mg three times daily. After the period of treatment with the first of the two drugs a placebo tablet was added to the beta blocker to allow a washout period of two weeks. The second drug was then added to beta blockade for either one or two months. Next the beta blocker was withdrawn and treatment continued with bendrofluazide or prazosin alone using whichever drug had produced the greater fall in pressure. Finally, patients whose control was inadequate on either combination of beta blockade and bendrofluazide or prazosin were given all three drugs together for a further period of observation. Results withdrawn because of inconsistent attendThe other 19 completed the trial and the analysis was made on their results. 10 patients were given bendrofluazide as the first additional agent and 9 had prazosin first. 10 patients had an unsatisfactory fall in pressure with each of the two regimens, and were therefore treated with all three drugs together. 1
man was
ance.
Blood-pressure Fall in blood-pressure achieved by
beta blockade reduction in the group was systolic blood-pressure 19.7 mm Hg (s.D.t28-2) (P<0-01), diastolic blood-pressure 6-0 mm Hg (s.D.±16-6) (P=not significant [N.S.]).
alone.-The
During the first three two-week periods beta blockade was continued alone at previous dosage. Bendrofluazide or prazosin was then added on a previously determined random basis. The two doses of bendrofluazide were 5 and 10 mg daily given without potassium supplements. Prazosin was given at a starting dose of 2 mg three times daily beginning in the evening. If control was achieved or if side-effects were troublesome the patient did not proceed to a second month of treatment at the
mean
Effect of adding bendrofluazide.-The average fall in pressure for the group and percentage fall in systolic, diastolic, and mean arterial pressures, supine, standing,
TABLE I-AVERAGE FALL IN BLOOD-PRESSURE WITH ADDITION OF BENDROFLUAZIDE OR PRAZOSIN
s.B.P.=Systolic blood-pressure. D.B.p.=Diastolic blood-pressure. M.A.p.=Mean arterial pressure. TABLE II AVERAGE FALL IN BLOOD-PRESSURE IN PATIENTS TAKING BETA BLOCKER PLUS BENDROFLUAZIDE
S.B.P.=Systolic blood-pressure. D.B.p.=Diastolic blood-pressure. M.A.p.=Mean arterial pressure.
273 TABLE III-FALLIN MEAN BLOOD-PRESSURE COMBINATION TREATMENT
(mmHg) WITH
86-112); 139/93 (mean arterial pressure 108) (range systolic pressure 118-156, diastolic pressure 78-109); and 140/91 (mean arterial pressure 107) after exercise (range systolic pressure 124-153, diastolic pressure 77-103). Table iv shows the mean change in heart-rate for this group of patients, supine, standing, sure
erect
and after exercise with the addition of both doses of each
agent.
Side-effects shown in table I. There was no statistically significant difference between the effect of 5 mg of bendrofluazide daily and 10 mg a day (table n). The fall in blood-pressure after two weeks’ treatment with the diuretic was not different from that measured after eight weeks (table n). Effect of adding prazosin.-7 of the 19 patients were given 2 mg three times a day, and 12 took first 2 and then 5 mg of prazosin three times daily. The fall in blood-pressure produced by the final dose of prazosin is shown in table i. A comparison of the effect of 2 and 5 mg of prazosin three times a day was made in those patients who received both doses. Increasing the dose resulted in a further fall of supine mean pressure of 7.9 mm Hg (s.D.ill-7), (P<0.05). The additional effect was also statistically significant in the erect and postexercise readings (p < 0 - 0 5). Placebo period.-In the group the mean arterial pressure was 5.9 mm Hg lower during the period when placebo tablets were given in addition to beta blockade as compared to treatment with the beta-blocking agent alone in the run-in period. (s.D.16-8) (P=N.S.). This difference was not statistically significant whether bendrofluazide or prazosin was the first additional agent
and after exercise,
(0.89118.75 vely).
are
mm
Hg, 10-3±14.99
mm
Of the 19 patients, 13 felt in normal health in the placebo period when they were taking beta blockade and ascorbic acid. Only 4 felt equally well in the first period of treatment with both prazosin and bendrofluazide but the number increased to 8 with both drugs in the second period when the dose was higher and to 11 in the period when beta blockade was withdrawn. Three of the fifteen questions revealed frequent symptoms, the most important was dizziness in the prazosin period. 3 patients complained of dizziness after the first dose only. 8 others were dizzy at times as the dose of 2 mg three times a day was continued. Fatigue was present in 6 patients in the first prazosin period and 2 with bendrofluazide. Headache occurred in 4 patients with each drug. 2 patients refused to continue with prazosin and 1 with bendrofluazide.
Bendrofluazide and Potassium Status Bendrofluazide was added to beta blockade in 18 patients. In 13 it was continued beyond the eight-week period of the trial. Observations were, therefore, available for these 18 for a mean period of twenty weeks (s.D. ±11). Supplementary potassium tablets were not
Hg, respecti-
Withdrawal continued on
of beta-blocking agent.-Patients who prazosin and bendrofluazide alone were analysed separately. On withdrawal of the beta-blocking agent the blood-pressures in both groups rose. The increase in systolic pressure was statistically significant in the supine and post-exercise positions in patients on prazosin and in the erect position in those on bendrofluazide (P<005). The rise in diastolic pressure was not significant. Combination
beta blockade, bendrofluazide, and prazosin.-The results of the 10 patients who received all three drugs together are shown in table in. Final blood-pressure results.-l patient who was unable to tolerate prazosin was excluded from the analysis of final blood-pressures. Of the remaining 18 patients, 8 were treated with two drugs and 10 with three. For the group the average blood-pressure (two outpatient attendances) was 155/94 mm Hg (mean arterial pressure 114) supine (range systolic pressure 132-173, diastolic pres-
of
-
given. Serum-potassium levels at the final estimation (mean twenty weeks’ treatment) had fallen from a pretreatment level of 4.1 (S.D. 0.16) to 3-66 mmol;1 (S.D. 0.36) (P<0’001). After only two weeks mean serum-potassium was 3.70 (s.0.:!::0.38). The lowest serum-potassium was 3-11 mmol/l. There was no significant difference between two and twenty week means. Mean daily potassium intake was 51mmol (S.D. + 19). Daily urine potassium excretion was measured from a twenty-four hour collection. Mean potassium excretion was 55 mmol (s.D.±20). The correlation coefficient of urinary potassium excretion with estimated dietary intake was 0-17.
Discussion The patients entering the trial were a consecutive group of severe hypertensives who had received adequate doses of beta-blocking drugs given for at least two months and whose blood-pressure levels required the addition of further agents. The severity of the hyperten-
TABLE IV—CHANGE IN HEART-RATE WITH ADDITIONAL AGENT
274 sion prevented frequent observations before treatment with beta blockade was begun but by the time of entry to the trial the patients were familiar with the clinic procedure. Because the variability of blood-pressure levels in individual patients interferes with assessments of the potency of hypotensive agents, we made measurements in three positions at two fortnightly clinic visists and the consistent pattern of response increases our confidence in the conclusions we draw about each treatment
regimen. The addition of 5 mg of bendrofluazide to beta blockade produced significant falls in systolic and diastolic pressure-supine, erect, and post-exercise. Percentage falls in mean pressure were about 12%. Unlike Wilkinson et all we did not find that the full hypotensive effect was delayed, there being no difference between two and four weeks. 5 mg daily was as effective as 10 mg. The addition of prazosin to beta blockade produced slightly greater falls in blood-pressure of about 15%. The postural effect of continued treatment with prazosin was quite small, the fall in average systolic pressure on standing being 12 mm Hg, exactly the same as occurred with bendrofluazide. Post-exercise pressures were similar to erect blood-pressures. In the group of 12 patients whose dose was increased from 2 to 5 mg three times daily, there were further significant falls. The prompt rise in pressure in the placebo period confirmed that the incremental effect was indeed due to the added agents. It is logical to add prazosin to bendrofluazide and beta blockade when the latter two fail to lower pressure adequately. In most patients further considerable falls can be expected. The effectiveness of this combination of two or three drugs in such a group of severe hypertensives is well shown by the final blood-pressure in the erect position: average systolic pressure 139, range 118-156, and diastolic pressure 93, range 78-109. The fall in blood-pressure achieved by giving both bendrofluazide and prazosin together was not significantly different from that expected if the falls produced by the two drugs individually were added (P=N.S.). It can therefore be concluded that the effects of the two drugs is purely additive. Because of the background of beta blockade in all but one treatment period, heart-rates were slow. In the period when beta blockade was withdrawn, supine heart-rates rose from an average of 64 to 85 and postexercise from 75 to 114 per minute. It is interesting, however, that the addition of bendrofluazide caused a small rise in the heart-rate which achieved significance post-exercise. On the other hand when prazosin was added to beta blockade there was a further slowing of the heart-rate in all positions. This reached significance in the supine position. If prazosin acts simply by vasodilatation we would have expected an increase in the heart-rate with its addition to beta blockade. This suggests to us that prazosin’s action may not be entirely ’
peripheral. We find the usual difficulty in assessing side-effects. There is for instance the inconsistency that half the patients who complained of some side-effect in the first period of treatment with both bendrofluazide and prazosin lost their complaints in the second period when the dose was increased. The most troublesome side-effect was dizziness from prazosin. The phenomenon is clearly
not confined to the first few hours. It seemed especially prominent in a period of unusually hot weather. It is important to start treatment with a dose not exceeding 2 mg given just before going to bed. If the dizziness and occasional collapse in the erect position is due to a precipitous fall of blood-pressure it is surprising that with continued treatment the hypotensive effect is so little to posture. The administration of 5 mg of bendrofluazide daily may cause potentially serious falls in serum-potassium levels. In 50% of our patients serum-potassium fell below 3.6 mmol/1 within a month. They continued on
related
bendrofluazide without additional potassium and came to no apparent harm. We have not observed any tendency for those with normal serum-potassium levels at four weeks to have lower levels after longer treatment. Dietary intake did not correlate with levels of serumpotassium, correlation coefficient=0.156. The average British diet is said to contain more than 50mmol of potassium daily.6 10 of our 20 patients appeared to take less than this. It seems to us easier to increase potassium intake by recommending certain potassium-rich articles of diet than by the use of potassium in tablet form. For instance the daily addition to the diet of a bowl of ’All Bran’ breakfast cereal with milk, a helping of spinach, and one cup of instant coffee with milk gives 80 mmol of potassium equalling ten ’Slow-K’ tablets. Recommendations The following principles should determine the physician’s choice of hypotensive agents: (1) there is still no way to predict which combination of drugs is most likely to be most effective for any given patient, although a logical approach is appropriate; (2) drugs used should be potent, as free as possible of side-effects, and few in number; (3) the effect of each agent and incremental dosage should be measured with care, usually with repeated observations, and those agents shown not to be making an effective contribution should be withdrawn. Starting with beta blockade, only one or two tablets daily are required. Patients with high initial pressures are likely to need an additional agent. The addition of one tablet daily of a thiazide diuretic will usually cause a further useful fall in blood-pressure, with a few in side-effects. Even severe hypertension the combination of these two agents, which could be given as a single daily tablet, may suffice. Their effectiveness can be judged in two weeks. For those who need a third agent, the addition of prazosin three tablets daily, may sometimes produce side-effects, but there will be few patients who are not satisfactorily controlled. Requests for reprints should be addressed Infirmary, Bristol BS2 8HW.
to D. W.
B., Bristol Royal
REFERENCES 1. Barritt, D. W., Marshall, A. J. Unpublished. 2. Prichard, B. V. S., Gillam, P. M. S. Br. med. J. 1969, i, 7. 3 Petrie, J. C., Galloway, D. B , Webster, J., Simpson, W. T., Lewis, J. A. ibid. 1975, iv, 133. 4. Constantine, J. W., McShane, W. K., Scriabine, A., Hess, H. J. Hypertension: Mechanisms and Management; New York, 1973. 5. Wilkinson, P. R , Issler, H., Hesp, R., Raftery, E. B. Lancet, 1975, i, 759. 6. Davidson, S., Passmore, R., Brock, J. F., Trunwell, A. S. Human Nutrition and Dietetics; London, 1975.