Download Atenolol - University of Vermont

Atenolol: once-daily cardioselective beta blockade for angina pectoris
G Jackson, J Schwartz, RE Kates, M Winchester and DC Harrison
Circulation 1980;61;555-560
Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX
72514
Copyright © 1980 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online
ISSN: 1524-4539
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://circ.ahajournals.org
Subscriptions: Information about subscribing to Circulation is online at
http://circ.ahajournals.org/subsriptions/
Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, 351 West Camden
Street, Baltimore, MD 21202-2436. Phone 410-5280-4050. Fax: 410-528-8550. Email:
[email protected]
Reprints: Information about reprints can be found online at
http://www.lww.com/static/html/reprints.html
Downloaded from circ.ahajournals.org at Dana Medical Library, University of Vermont on October 12, 2006
Atenolol: Once-daily Cardioselective
Beta Blockade for Angina Pectoris
GRAHAM JACKSON, M.B., JANICE SCHWARTZ, M.D., ROBERT E. KATES, PH.D.,
MARK WINCHESTER, M.D., AND DONALD C. HARRISON, M.D.
SUMMARY The physiology, pharmacokinetics and efficacy of atenolol, a cardioselective,-adrenergic
blocking agent, were evaluated in 10 patients with stable angina pectoris in a single-blind, dose-ranging study.
After a 1-month control placebo period, atenolol was administered once daily at dosages of 25, 50, 100 and 200
mg for 2-week periods. All patients had fewer anginal attacks and consumed fewer nitroglycerin tablets than
during the placebo period. Twenty-four-hour ambulatory ECG recordings showed a decrease in mean hourly
heart rate throughout the dosing period, with preservation of diurnal variation. Maximal, symptom-limited,
treadmill exercise tests performed 3 hours after drug ingestion showed significantly increased exercise time
and decreased double products for all doses, but especially with 100-mg and 200-mg doses. Exercise time 24
hours after drug ingestion continued to show a decrease in maximum heart rate and double product, with 100mg and 200-mg doses again being most effective. Atenolol serum levels correlated with percent reduction in exercise heart rate and increased exercise time. Serum levels rose linearly, with an average elimination half-life
of about 10 hours after chronic oral dosing. Thus, atenolol was an effective antianginal agent and suppressed
resting and exercise-stressed heart rate for 24 hours after ingestion when given in a 100-mg or 200-mg dose
once daily.
Drug Dosage Administration
THE BENEFICIAL EFFECTS of ,B-adrenergic
blockade in the treatment of angina pectoris is well
established.1' 2 The most widely used agent is propranolol. Since propranolol was introduced, various
/3-adrenergic blocking agents with differing properties
have been developed in an attempt to avoid the side
effects of generalized A3 blockade. Atenolol, a cardioselective /3 blocker, is one of these newer agents.
Because of initial favorable clinical reports in
Europe,3-5 we undertook a dose-ranging and antianginal efficacy study of atenolol in patients with
A single-blind protocol was used because of the
risks reported with sudden withdrawal off/ blockade.6
All drug preparations (including placebo) were given
as two identical tablets once daily at 8 a.m. Nitroglycerin was used for pain, but not for prophylaxis,
throughout the trial. Placebo was given for the first 4
weeks of the 12-week protocol, which served as an initial control period. In subsequent 2-week periods,
patients received 25 mg, 50 mg, 100 mg and 200 mg of
atenolol daily. Drug compliance was checked by tablet
count and measurement of serum drug levels.
stable, exercise-induced angina.
Materials and Methods
Antianginal Assessment
The patients kept a daily record of anginal attacks
and nitroglycerin consumption. These records were
reviewed by the investigators every 2 weeks, and side
effects were noted. At each visit, supine and standing
heart rates were determined from ECG recordings and
blood pressures were measured using a standard
sphygmomanometer. Only the data of the last week of
each 2-week period were used for comparisons to
avoid carry-over effects.7
Patients
Ten patients, seven men and three women, with a
mean age of 55 years (range 35-67 years) participated
in the study. Each patient gave written consent after
being informed of the details and objectives of the
study, and the protocol was approved by the Stanford
Medical Committee on the Use of Human Subjects in
Research. All had had clinically stable exerciseinduced angina for 3 or more months. No patient had
valvular heart disease, cardiac failure, obstructive airways disease, hypertension (resting diastolic pressure
> 100 mm Hg), diabetes, or thyroid or renal disease.
Exercise Testing
During the second week of each treatment period,
exercise testing was performed 3 hours and 24 hours
after drug ingestion. No food, caffeine or nitroglycerin
was consumed within the 2 hours before testing. With
continuous ECG monitoring, patients exercised on a
motor-driven treadmill until chest pain occurred
(symptom-limited). The exercise test began at a constant grade of 10% at 1 mph, with 0.5-mph increments
introduced every 3 minutes; a 12-lead ECG was
recorded before testing and at 3-minute intervals, and
three-lead ECGs were recorded each minute between
the 3-minute recordings. The blood pressure was
From the Division of Cardiology, Stanford University School of
Medicine, Stanford, California.
Supported in part by NIH training grant HL-07265, NIH
research grant HL-21221, and by funds from I.C.I. Americas, Inc.
Dr. Jackson is a Peel Medical Research Trust Traveling Fellow.
Address for correspondence: Donald C. Harrison, M.D., Chief,
Cardiology Division, Stanford University School of Medicine, Palo
Alto, California 94305.
Received June 28, 1979; revision accepted September 4, 1979.
Circulation 61, No. 3, 1980.
555
VOL 61, No 3, MARCH 1980
CIRCULATION
556
recorded at rest and after 1 and 3 minutes of each
treadmill stage. Changes in ST segments were measured during and after peak exercise. A downwardsloping depression of at least 1 mm persisting for
0.08 second or longer in at least five consecutive
beats was considered indicative of ischemia. Monitoring was continued for a minimum of 6 minutes after
exercise or until values returned to control levels.
All anginal episodes stopped after cessation of exercise.
WEEKLY ANGINA
12
ATTACK RATE
L
1-
10
Ambulatory Monitoring
During the second week of each 2-week period, a
24-hour ambulatory recording was performed. This
monitoring period included both peak and trough
treadmill tests. Patients were encouraged to engage in
their normal daily activity and wore recorders on the
same day of the week for each test. Avionics recording
systems were used and the tapes were analyzed on the
Stanford computer system.8 Heart-rate trends were
examined throughout the 24-hour period.
Serum Drug Levels
Five ml of heparinized blood was drawn 3 hours
(peak) and 24 hours (trough) after atenolol ingestion
(concomitant with treadmill testing and ambulatory
ECG monitoring). Serum atenolol concentrations
were determined by a high-pressure liquid chromatographic method.9
8
z
6
\ \X
\\\
4
Anginal Attack Rate and Nitroglycerin Consumption
The mean weekly incidence of angina and nitroglycerin consumption are shown in table 1 and figure
1. Compared with placebo, atenolol reduced the
anginal attack rate during all periods of its administration (p < 0.001). A dose response was present with a decreasing number of attacks with increasing dosage. Atenolol at doses of 100 mg and 200
mg was significantly superior to the 25-mg dose (p <
0.001), but there was no significant difference between
the 50-mg and 100-mg doses or the 100-mg and 200mg doses. The 200-mg dose was more effective than
the 50-mg dose (p < 0.005). Nitroglycerin consumption declined in a parallel, dose-related fashion. Com-
50
100
\ ID4\
200
2
Statistical Analysis
Data were analyzed for statistical significance by
the repeated-measures analysis of variance. For
variables where statistically significant (at the 5%
level) dose-response relationships were detected, further comparison of mean responses at different dose
levels was done using a matched-pairs t test.
125
-
----WEEKLY
CONSUMPTION x
NITROGLYCERIN
200
0
ATENOLOL
PLACEBO
FIGURE 1. Subjective data: weekly angina attack rate and
nitroglycerin use among the 10 patients during placebo and
atenolol periods.
pared with placebo, all dosages decreased nitroglycerin consumption significantly (p < 0.001), with no
significant difference between the 50-mg dose vs 100mg and 200-mg doses or the 100-mg dose vs the 200mg dose (table 1 and fig. 1).
Exercise Data
During the initial placebo period, peak and trough
significantly different, verifying the
reproducibility of the responses with the protocol
(table 2). All atenolol doses significantly reduced
resting and exercise heart rate at 3 hours (p < 0.001)
and 24 hours (p < 0.001) after ingestion (table 3 and
fig. 2). Atenolol was statistically most effective at 100-
tests were not
TABLE 1. Subjective Data
Placebo
Weekly angina attacks
Weekly nitroglycerin consumption
Values are mean
-
SEM.
12.1
8.0
2.2
2.6
25
50/100
25 mg
2.1
9.0
2.7 d= 1.5
Atenolol
100 mg
2.2
4.7 l1.
50 mg
5.4
2.3
1.2
2.3
1.3
200 mg
2.4
0.9
0.9
0.6
ATENOLOL FOR ANGINA PECTORIS/Jackson
TABLE 2. Placebo Data
al.
et
557
!
AT REST
Peak
Trough
80
p
Resting heart rate
(beats/min)
72.2
2.3
78.7
118.7
4.7
114.6
4
3.4
NS
4.2
NS
Exercise heart rate
(beats/min)
Resting SBP
E
141.1
139.2
8.8
7.2
NS
25
7"50
cc
(mm Hg)
Resting DBP
(mm Hg)
70
5I
60
_
-
ON EXERCISE
120
1tOl25
* 50
.100
* 200
a
,100
100 _-
cr
86.7
5.9
86.4
3.8
NS
50
163.9
384.5
7.7
30.3
NS
NS
40
90 _
Exercise SBP
(mm Hg)
167.0 * 8.8
413.5 - 34.9
Exercise time (sec)
Exercise ST
depression (mm)
Double product
1.6
198.3
siEM.
1
-
0.3
16.4
1.7
187.8
0.3
14.5
NS
NS
Values are mean
Abbreviations: SBP = systolic blood pressure; DBP =
diastolic blood pressure; double product = exercise heart
rate times systolic blood pressure divided by 100.
mg and 200-mg doses, with no significant difference
between the two. The maximal exercise double
product (heart rate times systolic blood pressure) at
the occurrence of chest pain was significantly reduced
at peak and trough testing by all atenolol doses (p <
0.001), but the 100-mg and 200-mg doses were
significantly more effective than the 25-mg or 50-mg
doses (p < 0.001) (fig. 3). The amount of exercise
necessary to produce angina 3 hours after drug ingestion was increased by all atenolol doses. At 24-hours
after drug ingestion, however, only 50-mg (p < 0.01),
100-mg (p < 0.005) and 200-mg doses of atenolol (p <
0.001) showed significant improvement compared
with placebo (fig. 3). ST depression was significantly
reduced 3 hours after drug ingestion by 25-mg and 50-
-
PLACEBO
PEAK
80
TROUGH
L
PLACEBO
PEAK
TROUGH
FIGURE 2. The effect of atenolol dosage increments
heart rate at peak and trough points.
on
doses (p < 0.05), but more markedly reduced for
100-mg and 200-mg doses compared with placebo
(p < 0.01). The response to 25 mg of atenolol did not
differ from the response to placebo. Only the 100-mg
(p < 0.02) and 200-mg (p < 0.02) doses of atenolol
produced significant reduction of ST depression 24
hours after drug ingestion.
mg
Twenty-four-hour Ambulatory ECGs
The mean hourly heart rate was plotted against
time for the full 24-hour period (fig. 4). All doses suppressed heart rate compared with placebo. Atenolol
100 mg and 200 mg were the most effective 24 hours
after drug ingestion (p < 0.001). The minimum and
maximum heart rates are shown in table 4. The mean
maximum heart rate during the placebo period was
119 beats/min. During administration of atenolol at
25, 50, 100 and 200 mg, the maximum heart rate was
103, 94, 89 and 88 beats/min, respectively, and oc-
TABLE 3. Atenolol Exercise Data
Resting heart rate
(beats/min)
Exercise heart rate
(beats/min)
Resting SBP
(mm Hg)
Resting DBP
(mm Hg)
Exercise SBP
(mm Hg)
Exercise time
(sec)
Exercise ST depression
(mm)
Double product
25 mg
Peak
Trough
62.1
70.9
2.1
*2.7
104.4
100.1
*3.6
131.7
*6.0
77.9
*3.7
-4.1
139.1
149.5
161.0
*7.5
477.2
*44.9
1.2
*0.3
151.0
*11.9
*7.5
81.6
*5.5
*7.7
407.5
*34.2
1.4
*0.3
170.0
13.8
50 mg
Peak
Trough
58.5
67.1
-3.0
i1.5
96.7
101.7
-3.1
-4.1
132.4
127.1
*6.4
-7.0
76.5
77.9
*2.5
*3.5
154.0
150.1
*9.1
*7.2
552.0
447.9
39.3
*35.7
1.06
1.5
*0.2
*0.3
159.0
147.0
*10.2
14.9
100 mg
Peak
Trough
54.3
61.5
-1.5
*2.9
89.5
99.4
*2.1
-3.9
128.0
130.8
*7.3
*5.5
76.4
75.2
*3.3
*4.1
143.9
153.1
-6.1
*9.0
527.5
459.0
*39.7
37.4
0.8
0.9
*0.3
*0.2
129.0
153.0
*8.0
13.4
Values are mean * SEM.
Abbreviations: SBP = systolic blood pressure; DBP = diastolic blood pressure; double
systolic blood pressure divided by 100.
product
200 mg
Peak
Trough
60.7
60.8
*2.9
*2.9
88.1
96.9
*4.0
*2.5
127.1
127.4
-8.0
*7.5
74.4
70.3
*3.5
*3.9
145.1
155.0
*6.9
48.3
508.3
541.7
i 35.3
*38.5
0.7
1.2
0.4
*0.4
128.0
152.0
14.1
8.7
exercise heart rate times
EXERCISE TIME (sec)
ST DEPRESSION (mm)
DOUBLE PRODUCT
550 1-
2.5
220
200
500 _-
200 _-
FIGURE 3. Though exercise time was
significantly prolonged at all peak levels,
only 100-mg and 200-mg doses were significantly effective at trough levels. Similarly,
the double product was more effectively
reduced by 100-mg and 200-mg doses at
trough points, as was the ST-segment
depression.
2
100
450 H
50
180
_
1.5 _
25
400
_
160
_
1
350
_
140
_
0.5
PEAK
TROUGH
PLACEBO
ATENOLOL (mg)
_
o
120
300
PLACEBO
PEAK
TROUGH
ATENOLOL (mg)
PEAK
TROUGH
PLACEBO
ATENOLOL (mg)
curred at the time of treadmill exercise testing. The
mean minimum heart rate for the placebo period was
55 beats/min, and occurred during sleep. During administration of 25, 50, 100 and 200 mg of atenolol, the
mean minimum heart rates were 52, 52, 47 and 47
beats/min, respectively. Diurnal variation in heart
rate was observed. Even with the higher atenolol
doses, no heart rates less than 45 beats/min were
recorded during the 24-hour period. Figure 5 is a
typical R-R interval plot that shows the increase in
R-R interval with increasing drug dosage and the
narrowing of the range of intervals recorded during
atenolol therapy.
Drug Levels
The mean peak steady-state serum atenolol concentrations were 117.4, 257.2, 437.2 and 916.5 ng/ml
after 2-week administration of atenolol at doses of 25,
50, 100 and 200 mg, respectively (fig. 6). The peak
serum levels increased linearly with increased dosage,
T
T
1
-
l
T
-
o PLACEBO
90
-
n -be
E
-C
:
a
50 | ATENOLIOL
80
cc
cr
cc
I
VOL 61, No 3, MARCH 1980
CI RCULATION
558
70
_
60
_
suggesting linear bioavailability and pharmacokinetics. The peak concentration during the 200-mg
dosing protocol was as high as 2000 ng/ml in one
patient. There was significant intersubject variability
in peak serum concentrations, with an average coefficient of variation for all four doses of 55%.
The mean trough steady-state serum atenolol concentrations were 23.0, 51.9, 67.8 and 103.7 ng/ml
after the 2-week administration of atenolol at doses of
25, 50, 100 and 200 mg, respectively (fig. 6). The
trough concentrations were 20.7 ± 10.6% (mean ±
SD) of the peak level when all data pairs were considered. Though adequate blood samples were not obtained to permit calculation of disposition parameters, these data suggest an average elimination halflife for atenolol of about 10 hours.
Side Effects and Toxicity Studies
One patient developed mild congestive cardiac
failure on 200 mg atenolol (with a peak serum drug
concentration of 1000 ng/ml), but this resolved with
dosage reduction and diuretic therapy. There were no
changes in SGOT, Alk Phos, total bilirubin, FBS, uric
acid, BUN, total protein, cholesterol, calcium, inorganic phosphate, albumin, LDH, hemoglobin,
hematocrit or white blood count. Nine of the 10
patients have continued on long-term atenolol therapy
with no complaints of vivid dreams, hallucinations,
depression or insomnia.
TABLE 4. Heart Rates Derived From 24-hour Ambulatory
Recordings
EG-
0
zW13
50 _
,a,q
_
8
10 12
14
16 18 20 22 24
TIME OF DAY
2
4
6
8
FIGURE 4. Mean hourly heart rate for individual atenolol
doses and placebo. Time of tablet ingestion is indicated by
arrow. bpm = beats/min.
Placebo
Atenolol (25 mg)
Atenolol (50 mg)
Atenolol (100 mg)
Atenolol (200 mg)
Values are mean
SEM.
Minimum
(beats/min)
Maximum
(beats/min)
55.1
52.2
50.3
47.0
47.3
118.7
103.5
94.3
88.8
87.7
-
1.0
1.5
1.4
0.8
1.7
4.1
4.2
2.0
4.1
4.4
ATENOLOL FOR ANGINA PECTORIS/Jackson et al.
5_
1
1
1
1
ATENO L0L
(200 mg)
cJ
z
c
O _-
1
5_
1-
0
01
0L
5
0
ATENOLOL
z
(50 mg)
1
g
1
*
1
1
1
-
|
*l
h,-1X
|
X
1
_
_
a
z
LU
c-,
LUJ
0.
F
ATENOLOL
(100 mg)
01
ATENOLOL
(25 mg)
0
5
7
1
12
1
1
1500
(40)
1750
PLACEBO
250
500
(120)
1000
1-250
(60)
(48)
R-R INTERVAL (msec)
750
(80)
FIGURE 5. By plotting R-R interval against percent frequency of occurrence, the 24-hour heart rate control is illustrated. With increasing dosage, the plot moves to the right,
indicating improved 24-hour heart rate control.
Discussion
Beta-adrenergic antagonists are well established in
the treatment of angina pectoris. The major beneficial
effect is achieved through reduction of myocardial oxygen consumption, primarily by decreasing exercise
heart rate and blood pressure.'0 11 As the mechanism
of action of these drugs is competitive inhibition of fl
receptors, little difference in antianginal benefit of
equipotent doses of individual agents would be expected once the maximum reduction of peak exercise
heart rate is achieved.10
Propranolol, one of the most widely used of the /3
blockers, has several clinical disadvantages: first, a
relatively short pharmacokinetic half-life (4-6 hours),
which has prompted (perhaps unnecessarily) frequent
dosing intervals;12 second, nonspecific f/ blockade with
potential pulmonary and peripheral vascular effects;
and third, central nervous system side effects (which
now constitute a compelling reason for discontinuing
/-blocker
therapy).'3
Atenolol, like propranolol, has a pure f antagonist
action'4' 1' but lacks intrinsic sympathomimetic activity and membrane-stabilizing activity.'3 Potential
advantages of atenolol include its cardioselective /
blockade,'8' 17 a plasma half-life of 6-10 hours and a
pharmacodynamic half-life of 18 hours,15' 18 and the
lack of significant penetration into the central nervous system'5 (personal communication: Imperial
Chemical Corporation Laboratory). A single oral
dose of atenolol in normal volunteers has produced
blockade of exercise-induced tachycardia for at least
24 hours after ingestion.'8'20 At least one preliminary
antianginal study has shown that atenolol given twice
daily is as effective as propranolol7 and that for op-
559
timal dosages, atenolol was effective once daily.3
Another antianginal study reported that atenolol was
more effective than practolol.' Neither sedative
effects21 nor decreased reaction times22 after atenolol
administration have been reported. Although vivid
dreams have been sporadically reported during
atenolol therapy,23 they occur much less frequently
than with propranolol. In a report of patients who had
nightmares, hallucinations and insomnia on d
blockers, almost all noted a reversal of these side
effects after changing to atenolol.24
The protocol was designed to establish the presence
or absence of adequate A blockade throughout the 24hour period after the oral administration of atenolol
once daily. Reduction of peak exercise heart rate was
evaluated through treadmill stress testing 3 and 24
hours after atenolol ingestion at the time of peak and
trough serum atenolol levels. Twenty-four-hour ambulatory electrocardiographic recordings monitored
the heart rates under resting conditions and normal
daily activity to exclude major swings in heart rate
control. To assess the antianginal efficacy of atenolol,
we measured anginal attack rate, consumption of
nitroglycerin and changes in exercise tolerance in each
patient. By correlating serum atenolol levels with
anginal relief and exercise tolerance, we hoped to
define the optimum therapeutic dosing range, dosage
interval and the therapeutic antianginal serum concentration range.
Our results show that in stable angina, atenolol
significantly reduces the frequency of anginal attacks
X
1100
1000
900
E 800
zO
700
H
z 600
W
0
Z 500
0
-
-
-
-
ojC0 4002
W
H300
<~~~~
DOSE ADMINISTERED (mg)
FIGURE 6. Peak (filled circles) and trough (open circles)
steady-state serum atenolol concentration as a function of
dose. Each point represents the mean ± SEM of the subjects.
560
CIRCULATION
and nitroglycerin consumption, with 100-mg and 200mg doses being the most effective. The results from
24-hour ambulatory electrocardiographic monitoring
showed good control of heart rate throughout the 24hour dosing period with preservation of the normal
nighttime bradycardia. Atenolol significantly prolonged the duration of exercise at the time of peak
serum levels and significantly reduced the peak exercise heart rate, double product and ST depression.
Though all dose increments significantly reduced exercise heart rate at trough serum levels, only the 50-mg,
100-mg and 200-mg doses significantly increased exercise time when compared with placebo.
In these studies, the serum concentration of atenolol
related to the magnitude of the effect and can be used
as a dosing guideline. We found a mean trough serum
concentration of about 70 ng/ml was necessary to insure adequate therapeutic benefit throughout the 24hour dosing interval. This level was achieved with a
chronic oral dose of 100 mg once daily.
Our studies show that atenolol is a potent antianginal agent. We observed that adequate 24-hour
heart rate control is possible with 50-mg, 100-mg or
200-mg doses administered once daily. When only the
hemodynamic variables are considered, there is no
significant difference between the 50-mg, 100-mg and
200-mg dosages. Regarding anginal relief, the 200-mg
dosage was superior to the 50-mg dosage (p < 0.005),
but did not significantly differ from the 100-mg
dosage, although four patients subjectively benefited
most from the 200-mg dosage. This report supports
the initial choice of 100 mg of atenolol for antianginal
benefit and increase in exercise tolerance when given
once daily. If this dose is well tolerated, advancement
to 200-mg/day for optimal therapeutic effect may be
required, depending on the clinical response. Cardioselectivity is relative and does not imply complete cardiospecificity; therefore, caution is advised with the
administration of any 3 blocker to patients with
bronchospastic disorders. In addition, the atenolol
dosage or the dosage interval may need to be altered in
the presence of renal impairment because excretion is
almost entirely via the kidneys. Nonetheless, with its
reduced side effects, cardioselectivity and once-daily
dosing schedule, atenolol shows promise of significant
advantages over currently available 3 blockers.
Acknowledgments
The authors thank Gail Yee, Sally Mancini, Inez Rodriguez, Cay
Fotopolos and Gary Sanders for their technical assistance; -Helena
Kraemer for statistical consultation; Gale Pickering and Cathy
Cassady for the manuscript preparation; and Dr. Howard Burchell
for his editorial assistance.
References
1. Harrison DC: Circulatory Effects and Clinical Uses of Beta-
VOL 61, No 3, MARCH 1980
adrenergic Blocking Drugs. Amsterdam, Excerpta Medica,
1972
2. Alderman EL, Davies RO, Crowley JJ, Lopes MG, Brooker
JZ, Friedman JP, Graham AG, Matlof HM, Harrison DC:
Dose response effectiveness of propranolol for the treatment of
angina pectoris. Circulation 51: 964, 1975
3. Jackson G, Harry JD, Robinson C, Kitson D, Jewitt DE: Comparison of atenolol with propranolol in the treatment of angina
pectoris with special reference to once daily administration of
atenolol. Br Heart J 40: 998, 1978
4. Roy P, Day L, Sowton E: Effect of a new 0-adrenergic blocking
agent, atenolol (Tenormin), on pain frequency, trinitrin consumption, and exercise ability. Br Med J 3: 195, 1975
5. Erikssen J, Osvik K, Dedichen J: Atenolol in the treatment of
angina pectoris. Acta Med Scand 201: 579, 1977
6. Shand DG: Propranolol withdrawal. N Engl J Clin Prac 27:
331, 1973
7. Jackson G, Atkinson L, Oram S: Double-blind comparison of
tolamolol, propanolol, practolol and placebo in the treatment
of angina pectoris. Br Med J 1: 708, 1975
8. Spitz AL, Fitzgerald JW, Harrison DC: Ambulatory
arrhythmic quantification by a correlation technique. In Computers in Cardiology. IEEE Computer Society, Long Beach,
California, 1977, pp 225-233
9. Yee YG, Rubin P, Blaschke TF: Atenolol determination by
high-pressure liquid chromatography and fluorescence detection. J Chromatog 171: 357, 1979
10. Jackson G, Atkinson L, Oram S: Reassessment of failed betablocker treatment in angina pectoris by peak exercise heart rate
measurements. Br Med J 3: 616, 1975
11. Robinson BF: Relation of heart rate and systolic blood pressure
to the onset of pain in angina pectoris. Circulation 35: 1073,
1967
12. Thadani V, Parker JO: Propranolol in the treatment of angina
pectoris. Comparison of duration of action in acute and sustained oral therapy. Circulation 59: 571, 1979
13. Forrest NA: Oxprenolol and a thiazide diuretic together in the
treatment of essential hypertension - a large general practice
study. Br J Clin Prac 27: 331, 1973
14. Harry JD: The demonstration of atenolol as a betaadrenoceptor blocking drug in man. Postgrad Med J 53 (suppl
3): 65, 1977
15. Barrett AM: The pharmacology of atenolol. Postgrad Med J 53
(suppl 3): 158, 1977
16. Fitzgerald JD: Why another beta-antagonist. Postgrad Med J
53 (suppl 3): 52, 1977
17. Astrom H: Comparison of the effects on airway conductance of
a new selective beta-adrenergic blocking drug, atenolol, and
propranolol in asthmatic subjects. Scand J Resp Dis 56: 292,
1975
18. McAinsh J: Clinical pharmacokinetics of atenolol. Postgrad
Med J 53 (suppl 3): 74, 1977
19. Shanks RG, Kelly JG, Carruthers SG, McDevitt DG: Correlation of reduction of exercise heart rate with blood levels of
atenolol after oral and intravenous administration. Postgrad
Med J 53 (suppl 3): 70, 1977
20. McDevitt DG, Kelly JG, Johnston GD, Shanks RG: Investigation of chronic dosing regimens of atenolol. Postgrad Med J 53
(suppl 3): 79, 1977
21. Betts TA, Blake A: The psychotropic effects of atenolol in normal subjects: preliminary findings. Postgrad Med-J 53 (suppl 3):
151, 1977
22. Bayliss PFG, Duncan SM: The effects of atenolol and
methyldopa on simple tests of central nervous function. Br J
Clin Pharmacol 2: 527, 1975
23. Simpson WT: Nature and incidence of unwanted effects with
atenolol. Postgrad Med J 53 (suppl 3): 162, 1977
24. Henningsen NC, Mattiasson I: Long-term clinical experience
with atenolol - a new selective A3- 1 -blocker with few side effects
from the central nervous system. Acta Med Scand 205: 61, 1979