Once-a-day treatment of hypertension with pindolol

Administration of a once-daily dosage of pindolol seems to be a simple and effective way to treat mild to moderate hypertension and one that produces relatively few side effects. In most cases, gradual titration of the drug seems unnecessary and the optimum dose can be given initially without increasing the risk of side effects. Thus, a simpler regimen can be instituted which may encourage patient compliance- a factor of great importance in view of the long duration of the therapy. (AM HEART J 104:413, 1982.)

Giiran Frithz, M.D., Uppsala, Sweden

Every physician knows that one of the main prob- lems of long-term drug therapy, in general, and of treating hypertension, in particular, is to have the patient continue taking the drug. Various methods can be used to overcome this problem and one of these is to make administration of the drug as simple as possible, that is, twice daily or, perhaps even better, once daily.

As pointed out earlier in this symposium, pindolol (Visken) is characterized by a high potency, and the beta-blocking effect of a single dose may persist up to 24 hours. Of course, there is no direct correlation between the beta-blocking effect of a drug, as mea- sured by the inhibition of isoprenoline-induced tachycardia, and the antihypertensive effect, which is a much more complex mechanism. However, it suggests the possibility of less frequent administra- tion of pindolol in the treatment of hypertension. Hitherto, pindolol has usually been given twice or three times daily to hypertensive patients. Against this background, the following studies were carried out to investigate the possibility of treating patients with milder forms of hypertension with only a single daily dose of pindolol.

FIRST STUDY

The first study involved 16 outpatients with pre- viously untreated hypertension of mild to moderate severity. All received a routine examination that included ECG, funduscopy, chest x-ray examina- tion, determination of electrolytes and creatinine in serum, and analysis of urine for protein, glucose, and

From the Department of Medicine, Central Hospital, University of Upp- sala.

Reprint requests: G. Frithz, M.D., Professor of Medicine, Department of Medicine, Central Hospital, S-631 88 Eskilstuna, Uppsala, Sweden.

0002-8703/82/080413 + 04$00.40/O 0 1982 The C. V. Mosby Co.

Table I. Age and sex distribution of patients in first study

Age WI Total

30-39 40-49 50-59 No.

Men 2 5 3 10 Women 3 3 6

Table II. Patient groups in first study according to WHO severity grades and to Keith-Wagener-Barker classifica- tion of eye fundus

WHO I WHOZZ FHO FHZ FHZZ

Men 7 3 5 2 3 Women 5 1 3 2 1

blood cells; if necessary, further investigation such as intravenous pyelography, angiography, and hor- mone analysis were carried out.

The age and sex distribution of the patients are shown in Table I. In Table II the patients have been grouped according to the World Health Organiza- tion (WHO) criteria of hypertension as well as to the funduscopy changes according to Keith, Wagener, and Barker. The patients had to have a supine diastolic blood pressure (DBP) of L 105 mm Hg registered on at least two different occasions to be enrolled in the study.

The first phase of the study lasted 3 weeks, during which the patients received a placebo. Patients whose DBP fell below 105 mm Hg during this period were to be excluded from the study. The blood pressure at the end of the placebo period was recorded as the initial value in the calculations. Active treatment was initiated with 5 mg of pindolol given orally at 8 A.M. Supine blood pressure was

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mmHg Table MA. Supine blood pressure before and after 4 200-

,189 Baseline Under Previous T.I.D. or months of treatment (mean -+ SEM) in first study _

180- ‘\, Before After

up to 20 mg/d. 18 cates treatment treatment P \ \ 14 cases \ 180 \ up to 320 mgld. 14 cases Systolic BP 181 * 7 150 + 8 <O.OOl

\ (210-170) (165-120) \ 147 Diastolic BP 110 L 3 91 f 3 <O.OOl

_ . (120-105) (100 80) - 140- -

120- Table 1118. Number of patients on each pindolol dose level

118 - ‘,

in the fourth month \ \ \ IO mg 15 mg 20 mg

loo- \ ‘\ 89 89 91 80

. WHO I patients 3 7 2 WHO II patients 1 3

80- : I

No 0 3 8 9 months Treat- I 4

ment Plndolol Once a Day patients were receiving 15 mg, and the third patient 10 mg, 15 mg or 20 mg 20 None reported sleep mg. disturbances.

Fig. 1. Effects of pindolol once a day in 44 outpatients with hypertension (WHO grades I and II).

measured at intervals of 4 weeks. The criterion of adequate control was considered to be a pressure of under 165/95. The dose of pindolol was increased, if necessary, in steps of 5 mg up to a single daily dose of 20 mg. Doses higher than 20 mg were not consid- ered suitable for this study. The period of active treatment was 4 months. Thus, patients requiring 20 mg daily were observed for one month on that dose.

The blood pressure was measured by the same person with the same mercury sphygmomanometer after 10 minutes of rest. Diastolic pressure was recorded at the end of phase 5, that is, disappear- ance of the sounds. The pressure was always mea- sured before the tablet intake that day.

Of the 16 patients, 14 achieved the criteria set for satisfactory pressure control, that is, a pressure of < 165/95 mm Hg. The two patients who failed to reach that level were in the WHO II group and had a diastolic pressure of 100 mm Hg after 4 months, that is, after 1 month on 20 mg pindolol.

The results after 4 months of treatment as well as the dosages of pindolol at that time are shown in Table III. It may be observed that the mean dosage of pindolol is somewhat lower for patients in the WHO I group than for those in the WHO II group.

Three patients reported side effects, for which pindolol may have been responsible. One com- plained of palpitations, one of dizziness, and one of slight nausea after taking the tablets. The first two

SECOND STUDY

A subsequent multicenter study was conducted to determine if satisfactory blood pressure control could be maintained with a single dose of pindolol in patients previously treated with multiple doses of a beta blocker.

A total of 57 hypertensive patients were included who had previously achieved a supine diastolic pressure of 100 mm Hg or less for at least 6 weeks on multiple doses of either pindolol, alprenolol, or propranolol.

Patient distribution according to age, sex, and degree of hypertension (based on WHO criteria) as well as the duration of hypertension is shown in Table IV.

The patients were switched to pindolol once daily, beginning with 10 mg given in the morning. Blood pressure was determined at intervals of 4 weeks, and if a satisfactory level (diastolic pressure at or below 100 mm Hg) was not maintained, the dose was increased by 5 mg at each visit up to a single dose of 20 mg. Pindolol was given at 8 A.M. and blood pressure was measured under standardized conditions as described before, The duration of the study was 36 weeks.

A total of 44 patients completed the trial and constitute the basis for the statistics. In four patients, a diastolic pressure of 100 mm Hg could not be maintained even on 20 mg and these patients were excluded from the study. One patient died of a myocardial infarction after 8 weeks. Four patients experienced side effects of sufficient severity to necessitate discontinuation of treatment. These side effects included vertigo after tablet intake (three

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Number 2, Part II Once-daily pindolol antihypertensive therapy 415

Table IV. Patient groups in second study according to age, sex, WHO grade, and duration of hypertension

n

Total No. in study

Age <40

40-59 >60

Sex Men Women

WHO severity grade I II

Duration of hypertension <1 yr

l-2 yr 3-5 yr 6-10 yr

>lO yr

57

9 Blood PULW Blood Pulse 40 pressure rate pressure rate

8 fmm H&9 @Pm) fmm f-k) @Pm)

37 20

32 25

5 31 10

7 4

patients) and gastrointestinal distress, that is, diar- rhea (one patient). Four patients moved from their districts or failed to turn up for control tests.

The results are shown in Fig. 1, which depicts the mean values for the initial blood pressure, the pressures after treatment with multiple doses of beta blockers (i.e., at the start of the trial), and the pressure after 36 weeks on a single daily dose of pindolol. The average daily dose after 9 months was 13 mg. It is apparent from this figure that no statistical difference exists between the pressures before and after the trial; that is, the pressures obtained on a once-daily dosage of pindolol com- pared with the initial pressures obtained on multiple doses of beta blockers.

The duration of the study, 36 weeks, was certainly long enough to rule out any possibility of a carryover effect from the previous treatment.

In these studies the optimum dose of pindolol was reached by gradual titration. However, for practical reasons, it is more advantageous to initiate therapy with the optimum dose. The previous studies indi- cated that the optimum once-daily dose of pindolol was about 15 mg. Therefore, a study was performed to compare the tolerability of 15 mg pindolol given once daily versus 5 mg administered three times daily.

THIRD STUDY

Twenty ambulatory patients, 15 men and five women, with moderate hypertension, previously untreated, entered the study. The criterion for acceptance was a diastolic blood pressure of 2 105 mm Hg on at least two occasions maintained during

Table V. Effects of pindolol treatment, 15 mg once daily (group A) and 5 mg three times daily (group B), on mean blood pressure and pulse rate in third study

Group A Group B (n = 10) (n = 10)

After 4 wk of placebo

After 4 wk of active treatment

After 12 wk of

active treatment

164/107 74

147193 69

141185 71

174/108 76

149/94 70

147/88 69

an initial placebo period of 4 weeks. The blood pressure was measured under standardized conditions in the morning, always before the first tablet intake that day. The patients were randomly divided into two groups, that is, group A, which received 15 mg once daily, and group B, which received 5 mg three times daily. Double-blind conditions were obtained by using identical blister packages.

The mean supine blood pressure and heart rate at the end of the placebo period and after 4 and 12 weeks of active treatment are shown in Table V. After 4 weeks of active treatment, blood pressure was significantly reduced in both groups. No differ- ence in pressure reduction was found between the two groups after either 4 or 12 weeks of therapy. Side effects were. recorded in three patients. One patient taking 5 mg twice daily discontinued treat- ment after 1 week because of fatigue and vertigo and another complained of sleep disturbances but con- tinued therapy. The third patient, who was on the 15 mg once-daily regimen, noticed vertigo 2 hours after tablet intake. Thus, pressure control appears to be the same whether pindolol is given once daily or the same dose is divided into three doses daily. The side effects also appear to be of the same degree with both forms of administration.

DISCUSSION

In all three studies blood pressure was measured in the morning to obtain an interval of 24 hours from the last tablet intake. Of course, it could be argued that it is better to measure the pressure during the day while the patient is pursuing his or her normal activities. However, it is well established that the effect of an oral dose of pindolol reaches its peak after about 3 to 4 hours, so there is little reason to believe that the pressure control would be less

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satisfactory during the day. Furthermore, recent studies by Gordon in Australia showed, in patients who cooperated in measuring their own blood pres- sure during the day, little difference in overall pressure control whether pindolol was administered once, twice, or three times daily.

It is worth noting that, in all studies, few patients reported sleep disturbances or nightmares on the once-daily dose regimen. This is difficult to explain, as pindolol penetrates the central nervous system

and its effect is long lasting. However, it may be that this well-known side effect of beta blockade is reduced when the dose is given only in the morn- ing.

No undesired beta blocker-induced bradycardia was observed. Since pindolol has a strong intrinsic sympathomimetic effect this complication is most unlikely to appear, even with high doses of the drug.