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A LONG-TERM STUDY OF THE ANTIHYPERTENSIVE EFFECT OF ALPRENOLOL
M. Brian Comerford and Alex Pringle
From the Hypertension Clinic, The North Middlesex Hospial, London, England
Abstract. Twenty patients, known to have essential hypertension, were treated for an average period of 30 months with alprenolol (Aptin@). Initially, the dose reponse to 200 mg u p to 800 mg daily was observed. Nine patients were well controlled on alprenolol alone (mean 555 mg daily). The mean decrease at 36 months was 31 121 supine and 28/25 standing in comparison with the initial placebo readings. Ten other patients, who were only partially controlled on alpre- nolol alone, were eventually well controlled by a combination of alprenolol with either hydra- lazine or chlorthalidonr.
No difference was observed in the antihypertensive effects of propranolol and alprenolol in a comparative exercise study on six of the patients.
One patient was withdrawn from the study. Side-effects of transient lassitude occurred in four patients. No signs of bronchial obstruction, postural hypotension or cardiac decompensa- tion were observed.
,9-adrenergic blocking drugs, such as proprano- lo1 and alprenolol, have now been accepted as established compounds with proven antihyper- tensive effect. Their clinical use has gradually increased during the last 2 to 3 years. There have been few reports on their effect on the blood pressure levels during and after exercise (7, 13, 14, 15) and even fewer reports on long- term treatment exceeding 2 years in duration, of hypertensive patients (10, 17).
At the beginning of 1970, the decision was taken to initiate a long-term controlled study of a group of outpatients known to have benign essential hypertension, and who would be treat- ed with alprenolol (Aptin@) a p-receptor anta- gonist whose effectiveness in angina pectoris and cardiac arrhythmias at that time had been well documented, and whose results in the early studies in hypertension were encouraging (7, 16).
The principle objectives of the study were to determine the effect on the blood pressure of alprenolol 400 mg daily (the standard dose recommended in angina pectoris), the response
to increasing doses of 600 mg and 800 mg daily, and to measure the effect when combined with other antihypertensive agents such as hydrala- zine or chlorthalidone.
During 1972, the effect of alprenolol on exercise blood pressure levels was compared with propranolol, as it had been observed that normalisation time (i. e. time taken from cessa- tion of exercise to the restoration of the pre- exercise level of blood pressure) was more rapid under the effect of alprenolol than pro- pranolol in a group of angina patients (8). Although alprenolol and propranolol after intravenous administration have both been shown to reduce the mean brachial artery pres- sure to the same extent, at rest and during exercise, the effects are thought to be due to different haemodynamic patterns (9).
MATERIAL This report covers the response of 20 patients (6 male, 14 female, mean age 50 years) treated for an average period of 30 months. Patients selected for the study from the Hypertension
15
Clinic of the hospital were those ”new cases” 2-week run-in period awaiting the results of referred for investigation and previously un- treated with accepted antihypertensive therapy, and also those known cases of essential hyper- tension who were suffering from unacceptable side-effects while on methyldopa, bethanidine or guanethidine. Five patients were in stage 1 of the disease according to the WHO classifi- cation (3) and 15 in stage 2.
A summary of clinical information is pre- sented in Table I. All 20 patients had pre-treat- ment supine systolic pressures of between 247 and 170 mm Hg and diastolic pressures be- tween 104 and 141 mm Hg (mean 207 and 124 mm Hg). Patients with frank heart failure, retinopathy grade I11 to IV or renal hyperten- sion were excluded from the study.
METHOD On first attending the Clinic, special atten- tion was paid to the full clinical evaluation including retinal examination, electrocardio- gram, urinary analysis, VMA estimation, full blood examination (including blood urea and electrolytes), X-ray of the chest, and intrave- nous pyelogram. Initially, every patient had a
- investigations, followed by a 2-week course of placebo tablets (half a tablet q. i. d.) identical in shape, colour, size and taste to the alpreno- lo1 100 mg tablet. Alprenolol was then prescri- bed at a dose of 50 mg q. i. d. for 2 weeks, increasing to 100 mg q. i. d. for 4 weeks, 150 mg q. i. d. for 4 weeks and finally 200 mg q. i. d. depending on the individual response, and aiming for a maximum diastolic pressure of 100 mm Hg lying or standing. Patients re- turned to the hospital for blood pressure exa- minations every 2 to 4 weeks until the hyper- tension was stable and controlled for 3 months, when subsequent follow-up visits were arranged every 4 weeks.
All blood pressure recordings were taken in the supine position (after 5 minutes) and stand- ing position (after 3 minutes) using the London School of Hygiene and Tropical Medicine sphygmomanometer to reduce observer bias and digit preference (12). The blood pressure cuff was applied to the patient’s right arm, and the diastolic pressure recorded at the muff- ling of the Korotkoff sounds (i. e. phase 4).
In those patients whose blood pressure was
Table I. Clinical information concerning investigated patients.
Patient Age Sex WHO Retinal Family Duration of classifi- changes history hypertension cation (Keith- of hyper- in months
Wagener) tension ~~
2 I1 Yes 15 2 I1 Yes 3 1 I Yes 4 1 I Yes 6 2 I Yes 108 2 I No 7 2 I Yes 288 2 I No 10
No 3 2 I 2 I1 No 24 1 11 No 10 2 1 No 70 1 I Yes 48 2 I Yes 84 2 I No 12 2 1 No 6 2 I No 84
No 12 2 I1 1 I1 Yes 12
Yes 36
1 66 ? 2 58 ? 3 42 d 4 48 ? 5 41 ? 6 25 ? I 53 ? 8 60 2 9 35 9
10 61 ? 11 52 Y 12 66 Q 13 32 ? 14 38 d 15 55 ? 16 54 ? 17 51 c? 18 60 c? 19 59 d 20 54 ? 2 I
16
not adequately controlled (i. e. a diastolic pres- sure exceeding 100 mm Hg when both lying and standing on two consecutive visits) after 3 months on alprenolol 800 mg daily, combina- tion therapy was initiated, using either hydra- lazine (Apresoline@) 25 to 50 mg q. i. d., or chlorthalidone (Hygroton@) 50 mg 0. m. for 5 days each week. The decision whether to pre- scribe hydralazine or chlorthalidone was based on an alternating method, and not randomally allocated to the patients concerned.
Such combination therapy continued until the blood pressure levels were controlled for three months when the dose of alprenolol was reduced stepwise to 400 mg daily, and the dose of chlorthalidone or hydralazine also decreased. No potassium supplements were prescribed.
Laboratory investigations (haematology, electrolytes, blood urea and liver function tests) were repeated every 6 months, and the initial electrocardiogram repeated after a 2 to 3-year period.
During the third year of treatment, an addi- tional investigation was carried out in a group of 6 patients to compare the effects of alpre- nolol and propranolol on post-exercise blood
pressure levels and heart rates. Patients were seen in the morning and carried out a set exer- cise test on an electrically braked ergometer bicycle (in most cases 300 kpm/min = 50 W, for 3 minutes, followed by 600 kpm/min for 3 minutes, i. e. total of 2,700 kpm, or 450 Wmin) at a standard time of between 1 and 2 hours following tablet administration. Blood pressure recordings were made at 2-minute in- tervals with the patients sitting on the bicycle, commencing 6 minutes before onset of exer- cise, with the first post-exercise reading being taken immediately following cessation of exer- cise, and the final reading taken 10 minutes later. No recordings were made during the exercise period because of their unreliability. Heart rates were recorded at the same intervals from a standard electrocardiogram using a left praecordial V lead. There was an initial run-in period of 2 weeks during which the patient continued with his usual dose of alprenolol in standard tablet form, giving the opportunity for two practice runs on the bicycle. Then fol- lowed a random double-blind crossover study in which patients received equipotent doses (based on inhibition of exercise-induced tachy-
Table 11, Resting blood pressure in mm Hg during placebo and initial alprenolol treatment periods.
Patient Placebo 200 mg daily 400 mg daily 600 mg daily 800 mg daily
Supine Standing Supine Standing Supine Standing Supine Standing Supine Standing
1 2351118 207/104 242/110 227/119 220/121 255/123 227/110 192/113 212/112 191/108 2 1821115 169/116 167/111 140/105 147/97 132/97 continues on 200 mg daily 3 1701112 173/115 170/104 160/114 147/101 142/102 continues on 400 mg daily 4 1951117 1661130 184/128 178/128 164/109 144/105 160/102 1451108 cont. on 600 mg daily 5 220/151 2201139 1661109 1571118 174/115 1671117 1631103 1461105 1641101 1581105 6 176/114 167/120 145/109 142/106 151/111 140/107 170/114 166/114 160/92 149/93 7 2621150 2361148 238/115 243/147 245/155 2411143 215/121 2011135 200/116 183/130 8 2001120 195/122 219/119 164/98 203/140 187/117 190/129 1571118 18811 18 1581103 9 2011118 180/118 192/118 174/115 1831105 172/109 158/99 155/104 cont. on 600 mg daily
10 2201123 215/125 230/117 1931105 2531127 2521121 2541123 224/98 1791128 16711 15 11 194/114 194/126 190/113 156/100 174/102 162/105 180/100 175/111 157/110 1541109 12 2351129 206/110 227/108 188/109 207/136 185/116 220/131 198/127 2051130 1901124 13 1851118 173/120 175/110 172/105 1551104 146/106 142/100 123/95 cont. on 600 mg daily 14 171/104 166/107 162/104 147/106 154190 140188 continues on 400 mg daily 15 2381144 215/125 2371139 224/129 240i136 2161123 205/125 176/107 2141116 181/107 16 2261116 2101111 214/112 209/111 1971124 195/118 184/102 184/92 1981106 194/107 17 1901140 180/130 220/128 149/109 186/122 176/126 183/120 177/123 1771121 165/103 18 214/140 206/125 243/133 212/114 231/155 189/114 210/120 193/119 2141126 176/102 19 1801111 177/114 187/121 150/112 206/123 178/107 1861122 157/115 1551108 119/94 20 247/115 2451120 2351109 2041104 196197 195/89 190197 177197 177199 166/104
Means 2071123 1951121 202/116 1791113 192/119 1811112
17
cardia (1)) of either alprenolol 100 mg tablets or propranolol 40 mg tablets, identical in co- lour, shape, size and taste. The daily dose of /?-blocker was that on which the patient had already been stabilized, or the equivalent dose of propranolol. All patients received one week’s course of both compounds with the exercise test being repeated at the end of each treatment week. When the results at this stage were assessed and found to be equivocal, it was decided to extend the study to two 4-week treatment periods on each compound, in a randomized order, with the exercise test repea- ted at the end of each 4-week period.
RESULTS Long-term effects of alprenolol in hypertension Twenty patients were under treatment with alprenolol in the dose range of from 200 mg to 800 mg daily (mean 577 mg daily), and the resting blood pressure recordings during the placebo and initial alprenolol periods are re- corded in Table 11. At the end of this dose- response period, there evolved two distinct groups of patients depending on whether or not alprenolol alone controlled the hyperten- sion.
Nine patients were well controlled and con- tinued on alprenolol alone and the six monthly readings are classified in Table 111. The mean decrease at the end of 12 months in compari- son with placebo reading was 26/15 supine and 33/22 standing. All patients continued on their original maximum dose of alprenolol with the exception of 2 patients. One patient (No. 2) had to reduce the dose of 400 mg after 4 weeks due to the onset of lassitude which subsequent- ly settled within 2 to 3 weeks. The other pa- tient was able to reduce the daily dose from 800 mg to 600 mg when the standing blood pressure settled to 123183. However, the dose had to be increased again to 800 mg daily 9 months later in view of the slowly increasing level in both the supine and standing blood pressure readings.
Eleven patients were not adequately control- led by alprenolol alone. One patient was with-
18
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W F m
12
00 e 2: I 3
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0
, W 00
W s m I 4
s N
drawn when she developed a chest infection in November 1970 during the eighth month of alprenolol treatment which her family physi- cian discontinued. She subsequently died two months later of left ventricular failure. At post mortem examination, an enlarged heart was observed with a severe degree of atheroma in all coronary arteries.
Subsequently 10 patients responded to a com- bination with alprenolol, of either hydralazine or chlorthalidone (Tables IV and V). Although the effect on the diastolic pressure levels appears to be more marked with hydralazine than chlorthalidone, the sample numbers are too small to be significant. At 12 months' combination therapy with hydralazine in four patients, the mean decrease in comparison with placebo was 39/10 supine and 34/16 standing, and in comparison with the recordings at the end of alprenolol alone treatment, 1418 and 6/11 respectively. The equivalent figures for combination chlorthalidone treatment in 6 pa- tients were 56/35 and 55/26, and 23/15 and 17/8.
There were no significant changes in the means of the weights of these three groups of patients throughout the period of treatment.
COMPARATIVE EXERCISE STUDY BETWEEN ALPRENOLOL AND
PROPRANOLOL Taking the means of the reading at the end of the treatment periods for each of the 6 pa- tients, it was seen that the heart rates and blood pressures at rest, on cessation of exer- cise, and 10 minutes after exercise, were not significantly different for the two drugs (Tab- le VI).
EFFECTS ON LABORATORY DATA Five patients had a temporary increase of either the alpha or gamma fractions of the serum protein, which reverted to normal after one month and were considered insignificant. A fall in the serum potassium level in 2 pa- tients, to 2.9 and 3 mEq/l was also noticed - the one patient on alprenolol alone subsequent-
M
z 9 z
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M C z 9 z
B 4 ._ v)
M C V .+
9 z
8 4 .- v)
I
I
I
I
I
I
W s 2
s: z m
r- i
s 3 . t- t- 3
2
2 3 . N
m 3 3
;j
2
0 N
3
5 N
v1
9 2
19
8 T
able
V.
Supi
ne a
nd s
tand
ing
bloo
d pr
essu
re r
ecor
ding
s in
gro
up o
f pa
tien
ts t
reat
ed w
ith
com
bina
tion
of a
lpre
nolo
l 80
0 rn
g da
ily a
nd c
hlor
thal
idon
e 50
mg,
15
0 m
g, t
o 25
0 m
g w
eekl
y.
Patie
nt
Plac
ebo
End
of
alpr
enol
ol
6 m
onth
s’ c
ombi
na-
12 m
onth
s’ c
ornb
ina-
18
mon
ths’
com
bina
- 24
mon
ths’
cor
nbin
a-
No.
tr
eatm
ent
tion
trea
tmen
t tio
n tr
eatm
ent
tion
trea
tmen
t tio
n tr
eatm
ent
Supi
ne
Stan
ding
Su
pine
St
andi
ng
Supi
ne
Stan
ding
Su
pine
St
andi
ng
Supi
ne
Stan
ding
Su
pine
St
andi
ng
7 26
2115
0 23
6/14
8 20
0111
6 18
3/13
0 17
3/10
0 15
3110
5 17
7110
1 15
9110
3**)
-
-
-
-
15
238/
141
2151
125
2141
116
1811
107
199/
125
1691
114
2261
111
1971
122*
*’)
2201
124
2021
120
2021
107
1901
107
17
190/
140
1801
130
1771
121
165/
103
1611
109
1571
100
153/
108
145/
95
1611
101
1551
103
1631
102
1551
101
18
2141
140
2061
125
2141
126
176/
102
187/
115
157/
99
160/
99
145/
97*)
15
9193
13
4/78
16
5199
14
9187
16
2261
116
210/
111
1981
106
1941
107
168/
101
165/
105
1831
97
174/
106*
*) -
-
-
-
-
-
-
20
2471
1 15
250/
120
1771
101
1661
104
163/
88
166/
86
142/
79
1441
85*)
-
Mea
ns
2301
134
2161
127
1971
114
1781
109
1751
106
161/
102
174/
99
161/
101
-
-
*)
Patie
nts
18 a
nd 2
0 w
ere
able
to
redu
ce d
ose
of a
lpre
nolo
l fr
om 8
00 m
g to
600
mg
daily
. **
) R
ecei
ving
chl
orth
alid
one
50 m
g da
ily e
xcep
t Sa
turd
ays
and
Sund
ays.
Tab
le V
I. B
lood
pre
ssur
e re
adin
gs a
nd h
eart
rat
es (
mea
n va
lue t S
EM
) of
the
6 p
atie
nts
taki
ng p
art
in e
xerc
ise
tole
ranc
e te
st (
sitti
ng p
ositi
on).
(M
eans
of
two
read
ings
for
eac
h co
mpo
und.
)
Com
poun
d R
estin
g C
essa
tion
of
2 m
in
4 m
in
6 m
in
10 m
in
exer
cise
po
st-e
xerc
ise
BP
HR
B
P H
R
BP
HR
B
P H
R
BP
HR
B
P H
R
Alp
reno
lo1
151*
3110
0~2
68*2
19
6*5/
98*2
99
*3
1791
-21l
OO
k3 8
2+2
164k
4/10
114
76*2
15
3i31
1002
3 75
1-2
147-
t3/1
00*2
7
31
2
Prop
rano
lol
153*
4/10
0*2
62*2
. 20
2%7/
96”2
97
*3
179&
5/96
*3
75*3
16
3k41
97t3
71
*2
156*
3/99
*3
68*2
15
1 *4/
100*
3 6
7a
2
ly reverted to 4.0 mEq/l, but the other patient receiving chlorthalidone was prescribed potas- sium chloride supplements (600 mg b. i. d.). All other laboratory investigations remained un- changed throughout the study.
SIDE-EFFECTS No side-effects were reported during this 3- year period with the exception of transient slight lassitude occurring in four patients who with one exception (patient No. 2) were able to continue treatment with alprenolol at an unchanged dose. No signs of bronchial obstruc- tion, postural hypotension or cardiac decom- pensation were observed.
DISCUSSION The first objective in this study was to deter- mine the effect on the blood pressure of in- creasing doses of alprenolol from 400 mg up to 800 mg daily. In approximately 50 O/O of the patients under study, there was a definite response to a mean daily dose of 577 mg daily (range of 200 mg to 800 mg daily) in that after six months’ treatment, there was a reduction of 34/14 supine and 39/26 standing. These fi- gures correlated well with previously reported short-term studies with alprenolol (4, 7, 16) given for 8 to 12-week periods. In those pa- tients treated for 30 to 36 months, there was a further reduction in blood pressure levels suggesting that the clinical response to alpre- nolol is similar to that found with propranolol (11). It is suggested that long-term treatment is essential for the complete control of those patients showing an early positive response. I t is interesting that throughout this period of time, there was no clinical nor radiological evidence of incipient heart failure, and that the only side-effects reported were those of lassitude which was transient and did not neces- sitate discontinuation of treatment.
In those patients who were not adequately controlled after 5 to 6 months’ treatment with increasing doses of alprenolol up to 800 mg daily for 3 months, it would appear that con- sideration should be given towards combina-
tion therapy with either hydralazine or chlor- thalidone. Such a course was found necessary in the remaining 50 O/O of the patients who, with one exception, were all subsequently well controlled. It has been suggested that sustained treatment of arterial hypertension with a com- bination of a peripherally acting drug like hydralazine, and a ,!?-adrenergic blocking agent may have therapeutic advantages, especially in terms of avoiding unwanted side-effects (13). Our results in this limited number appear to support this opinion.
In the small series where alprenolol was combined with chlorthalidone, a satisfactory result was observed in 5 out of the 6 patients, starting within 6 months of combined treat- ment, and continuing for up to 24 months. One study (2) indicates that alprenolol was valuable as an antihypertensive agent in com- bination with saluretics. It has also been sug- gested (6) that a lower dose of each compound, when used in combination, can be effective in the treatment of hypertension.
The findings in relation to the antihyperten- sive effects, before and after exercise, of alpre- nolol and propranolol showed no differences between the two compounds. It has been repor- ted that arterial blood pressure changes were also of the same order with both compounds during exercise (9).
That the antihypertensive effect of alpreno- lo1 and propranolol, both at rest and during physical exercise, is related to a reduction in cardiac output has already been well docu- mented (9, 14). The actual mechanism of this effect is still under investigation. It has recent- ly been reported that alprenolol induced a sig- nificant decrease in systolic and diastolic blood pressures, and plasma renin activity, and that these decreases were significantly correla- ted (11). It may well be that future long-term studies with ,+blockers in hypertension should involve patients grouped into low, normal and high plasma renin activity, as has already been started by Buhler et al. (5).
The results of this long-term study confirm the conclusions of shorter term studies with
21
alprenolol in the treatment of mild to mode- 7. Furberg C & Michaelson G: Effect of Aptin, a p-adrenergic blocking agent, in arterial hyperten- rate hypertension, used alone or in combina- sion. Acts Med Stand 186: 447, 1969.
tion with hydralazine or chlorthalidone. I t 8. Hetherington D J, Comerford M B, Nyberg G & Besterman E M M: Comparison of two adrener- was found to be a safe and effective gic beta-receptor blocking agents, alprenolol and
with good control of raised blood pressure propranolol, in treatment of angina pectoris. Br Heart J 35: 320, 1973.
It was also shown to have a hypotensive effect nerstedt R: The haemodynamic effects of alpreno- in association with exercise. Throughout the lo1 and propranolol at rest and during exercise in
hypertensive patients. Pharmacol Clin 2: 34, 1969. study, side-effects were minimal and transient. 10. Prichard B N C & Gillam P M S: Treatment of
levels in both the upright and supine position. 9. Johnsson G, de Guzman M, &
1.
2.
3.
4.
5.
6.
REFERENCES Ablad B, Johnsson G, Norrby A & Solve11 L: Pontency and time-effect relationship in man of propranolol and H 56/28 - comparative studies after oral administration. Acta Pharmacol suppl 2: 85, 1967. Angervall G & Bystedt U: The effect of alpreno- lo1 and alprenolol in combination with saluretics in hypertension. Acta Med Scand suppl 554: 39, 1974. Arterial Hypertension and Ischaemic Heart Di- sease. Preventive aspects. Report of an Expert Committee. WHO Techn Rep Ser No. 231, 1962. Bengtsson C: Comparison between alprenolol and propranolol as antihypertensive agents. Acta Med Scand 192: 415, 1972. Buhler F R, Laragh J H, Baer L, Darracott Vaughan Jr E & Brunner H R: Propranolol inhi- bition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hyper- tensive diseases. N Engl J Med 287: 1209, 1972. Castenfors J, Johnsson H & Or6 L: Effect of alprenolol on blood pressure and plasma renin activity in hypertensive patients. Acta Med Scand 193: 189. 1973.
hypertension with propranolol. Br Med J 1: 7, 1969.
11. Prichard B N C: Propranolol as an antihyperten- sive agent. Am Heart J 79: 128, 1970.
12. Rose G A, Holland W W & Crowley E A: A sphygmomanometer for epidemiologists. Lancet 1: 296, 1964.
13. Sannerstedt R, Stenberg J, Vedin A, Wilhelmsson C & Werko L: Chronic beta adrenergic blockade in arterial hypertension. Hemodynamic influences of dihydralazine and dynamic exercise and clinical effects of combined treatment. Am J Cardiol 29: 718, 1972.
14. Shinebourne E, Fleming J & Hamer J: Effects of beta-adrenergic blockade during exercise in hyper- tensive and ischaemic heart disease. Lancet 2: 1217, 1967.
15. Shinebourne E: Evidence that the effect of beta- adrenergic blockade on the haemodynamic respon- se of hypertensive patients to exercise is not solely rate-dependent. Cardiovasc Res 3: 52, 1969.
16. Tibblin G & Ablad B: Antihypertensive therapy with alprenolol, a @-adrenergic receptor antago- nist. Acta Med Scand 186: 451, 1969.
17. Zacharias F J, Cowen K J, Prestt J, Vickers J & Wall B G: Propranolol in hypertension: A study of long-term therapy, 1964-1970. Am Heart J 83: 755, 1972.
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