A Comparison of the Side Effects of

Atenolol and Propranolol in the Treatment

of Patients with Hypertension
J. George Fodor, MD, PhD, Arun ChoCkalingam, MS, PhD, Aidan Drover, MD,

Frank Fifield, MD, and Cecil J. Pauls, MD

A single-blind study was conducted in 52 hypertensive patients, aged 25 to 68 years, to

compare the side effects of an equally effective antihypertensive regimen of pro pranolol
and atenolol. All patients had a history of side effects with beta-blocker therapy. Patients
were treated with propranolol 40 to 160 mg bid for 8 weeks, followed by atenolol 50 to 100
mg given once daily for 8 weeks, and then rechallenged with the required dosage of
pro pranolol for 8 weeks. Mean systolic and diastolic blood pressures were controlled
during all three treatment phases. Side effects showed a definite trend toward improve-
ment during the atenolol treatment phase. CNS side effects, in particular, showed signifi-
cantly (P < .05) reduced severity scares and overall incidence rates during the atenolol
treatment phase. In conclusion, this study showed that at equally effective antihyperten-
sive dosages the hydrophilic beta blocker atenolol produced significantly fewer CNS side
effects than the lipophilic beta blocker propranolol.

T he beneficial effect of treating hypertension is Fortunately,

increased
the selection
considerably in recent
of available
years,
drugs
thereby
has
in-
now fully established. The advantages of inten-
sive therapy have been shown in a number of trials, creasing the possibilities of “tailoring” antihyper-
beginning with the VA studies,12 and followed by tensive drugs for specific patients. Some of these
the findings of other major randomized clinical agents (calcium blockers, ACE inhibitors) are rela-
trials such as HDFP,3 IPPPSH,4 the Australian tively new and a more complete clinical evaluation
Study,5 MRC Trial on Mild Hypertension,6 and the may require several more years of careful observa-
European Working Party on Hypertension in the El- tion. However, as beta blocker therapy is concerned,
derly.7 Therefore, on the surface, the problem of sufficient clinical experience has accumulated to
treating or not treating hypertension is clearly in permit an objective assessment of the relative merits
favor of treatment. However, the issue is not as sim- of different types of beta blockers.
ple as that. Increasingly, the question is being asked Traditionally, beta blockers have been classified
whether lowering blood pressure and preventing according to two potentially clinically significant
complications of hypertension is not offset by the characteristics, namely, cardioselectivity and lipo-
decreased feeling of well-being in large numbers of philicity. The concept of lipophilicity is important
patients. To what extent is well-being adversely af- when considering central nervous system (CNS) side
fected by antihypertensive therapy? This depends effects of beta blocker therapy because penetration
on the nature of the individual and the choice of of the blood-brain barrier is thought to occur by
therapy. simple passive diffusion at a rate that is largely de-
termined by the lipophilicity of the compound.8
From the *Memorial University of Newfoundland (Drs. Fodor and After chronic oral administration in man, the
Chockalingam) St. John’s, Newfoundland, Canada, and the Regional
brain-plasma concentration ratio for propranolol
Medical Group (Drs. Drover, Fitield, and Pauls) Carbonear General
has been shown to be considerably higher than for
Hospital, Carbonear, Newfoundland, Canada. Address for reprints: Dr.
J.George Fodor, Faculty of Medicine, Memorial University, St. John’s, atenolol.9 Among such CNS side effects are fatigue,
Newfoundland, Canada A1B 3V6. sedation, sleep disturbances, depression, psychosis,
Received: November 25, 1986. and cognitive changes.
Revised: May 25, 1987. If lipid-soluble beta blockers show a tendency to
Accepted: June 18, 1987. cause CNS side effects because of a higher concen-

892 #{149}
J CIIn Pharmacol 1987;27:892-901
 SIDE EFFECTS OF ATENOLOL AND PROPRANOLOL

lent electrolytes), standard urinalysis (including mi-

TABLE I
croscopy), and 12-lead electrocardiogram (ECG) re-
Patient Characteristics (N = 52) vealed no other clinically significant disease states
or laboratory abnormalities. However, patients who
CharacterIstics No. % had known contraindications or hypersensitivity to
beta-blocker therapy were excluded as were those
Sex with known alcoholism or a history of drug abuse.
Male 24 46
Each patient who entered the study provided
Female 28 54
written consent after being informed about the ob-
Age (years) jectives of the study, the protocol, and the risks and
Mean (range) 46.5 25-68 benefits of treatment.
Origin
Caucasian 52 100 Study Design
Prior Antihypertensive Therapy
A 24-week, nonrandomized, single-blind study was
(at entry)
3.8 conducted that consisted of three consecutive
Thiazide diuretic 2
Beta blocker 28 53.8 phases of treatment beginning with propranolol for 8
Methyldopa 2 3.8 weeks, followed by atenolol for 8 weeks, and con-
Combination5 18 34.6 cluding with propranolol for another 8 weeks (re-
Nonet 2 3.8 challenge). Patients were treated with 40 mg, 80 mg,
or 160 mg of propranolol given twice daily at 8 AM
* All except three patients receiving Aldoril5, a combination of methyldopa
and hydrochiorothiazide, were treated with a combination of thiazide diuretic and 8 PM at the required dosage during the initial
and beta blocker in free combination. treatment phase. The required dosage was estab-
t Two patients experienced side effects with prior antihypertensive beta lished by titration to achieve a satisfactorily con-
blocker therapy but were not receiving treatment at the time of entry into the
study. trolled blood pressure for each patient, as judged by
the investigator. If a patient could not achieve a sat-
isfactorily controlled blood pressure or experienced
intolerable side effects during this 8-week phase,
treatment with atenolol could begin immediately at
tration in brain tissue, then a lower incidence of
50 mg or 100 mg given once daily at 8 AM for 8 weeks;
CNS side effects might be expected with a hydro-
the investigator then judged whether these patients
philic beta blocker such as atenolol. Therefore, this
should be rechallenged with propranolol at the end
study was conducted to compare the side effects of
of the atenolol treatment period. Patients were re-
the cardioselective, hydrophilic beta blocker ateno-
challenged with the required dosage of propranolol
lol and the nonselective, lipophilic beta blocker pro-
during the final 8-week phase of the study.
pranolol.
Placebo tablets were precisely matched in appear-
ance to the drugs and administered according to an
METHODS appropriate schedule to blind the patient from the
identity of the active drug. Compliance was deter-
Outpatients who had mild-to-moderate essential mined by counting the remainder of prepackaged
hypertension, who were previously treated with a tablets returned at each scheduled visit and by
beta-adrenergic blocker, given alone or in combina- comparing the number of tablets returned with the
tion with a diuretic, and who had experienced number prescribed.
mild-to-moderate side effects or had other com- Systolic and diastolic (phase V) blood pressure
plaints were selected for the study. Patients with a measurements were made in the supine and stand-
satisfactorily controlled blood pressure who had re- ing position. Three measurements, separated by 30-
ceived diuretic therapy were allowed to continue second intervals, were made at each visit with a
treatment at the same dosages. All other medica- standard mercury manometer and cuff. Whenever
tions that could affect blood pressure were discon- possible, these measurements were made by the
tinued before the study began. same individual at the same time of day taken from
Patients who satisfied the above criteria could the same arm. Pulse rates were determined coinci-
enter the study if a complete medical history and dent with blood pressure measurements.
physical examination, routine hematology (com- Specific symptoms common to all beta blockers,
plete blood count and differential, platelet estimate), and those common to propranolol and atenolol, as
and serum chemistry (SMA-12, creatinine, monova- well as diuretics were assessed. The primary inves-

CARDIOVASCULAR PHARMACOLOGY 893

 FODO1I ST AL

100

80
72%

U) 68%
z
5Q ‘N
U.

I-

‘Si 40-
‘SI
0.

20
0-
-
80mg
_____
_____
29%
______

60mg
WV 2% VI
320mg
2%
25mg
I’

80mg
26%
_____
______

160mg
l..
______ 2%
V
320mg
VI

PROPRANOLOL ATENOLOL PROPRANOLOL

(n=41) (n=50) (n=46)

DAILY DOSAGE

Figure 1. Distribution of dosages after 8 weeks of treatment with propranolol and otenolol.

tigators dispensed the study medication and were Statistical Methods

the only persons who knew the identity of the study
drug and the phase of treatment. Each patient was All hemodynamic and adverse experience variables
questioned at each scheduled visit by an interviewer were analyzed using analysis of variance (ANOVA)
who was blinded as to the identity of the study med- techniques and were adjusted for “unbalancedness”
ication and did not know the phase of treatment. among the three treatment periods and compared
These interviews were audiotaped, coded, and then using least-significance-difference procedures. The
reviewed independently by other investigators who adverse experiences were analyzed by ANOVA for
evaluated the incidence and severity of symptoms all patients who entered the study as well as for the
during the final phase of the study. At the time of subset of patients who showed a given side effect
scoring, the audiotape reviewers were blinded to the after at least 4 weeks of treatment with propranolol
identity of the drug and did not know the phase of during the first treatment period. The data obtained
treatment. after 2 weeks in all three treatment phases were
All clinical evaluations of safety and efficacy were tabulated but not included in any analysis because
performed at each scheduled visit after 2, 4, and 8 of possible confounding attributable to the carry
weeks of treatment in each phase of the 24-week over effect of previous therapy.
study except as follows: complete physical examina- Adverse experiences were evaluated on the basis
tion (entry and week 24); EGG and laboratory tests of the severity as well as incidence as follows: (1) an
(entry and weeks 8, 16, and 24). analog scale was used to rank adverse experiences

894 #{149}
J ClIn Pharmacol 1987;27:892-901
 SIDE EFFECTS OF ATENOLOL AND PROPRANOLOL

TABLE II

Mean Supine and Standing Blood Pressures After 4 and 8 Weeks of Treatment with
Propranolol and Atenolol (N = 52)

Treatment Phase
FIrst Period, Final PerIod,
Propranolol Atenolol Propranolol

Supine blood pressure (mmHg) systolic/diastolic 138/83 135/80 137/83

Standing blood pressure (mmHg) systolic/diastolic 138/85 134/82 136/85
Pulse rate (beats/mm)
Supine 66 66 67
Standing 68 68 69

Note: The overall mean values are the mean of all measurements recorded * Statistically signi ficant (P <.05) difference bet wee,, propranolol and ateno-
during a treatment phase. 101(ANOVA).

on a 0 (not present) to 10 (very severe) scale; and (2) a torily to 50 mg of atenolol as compared with a
binomial analysis (0 = no, I = yes) based solely upon slightly lower percentage (68-72%) of patients who
whether or not an adverse experience occurred. The received 80 mg of propranolol daily.
analog scale analysis compared the sum of the sever-
ity scores, which is the product of the adjusted Blood Pressure and Pulse
means times the number of patients included in the
analysis. The binomial analysis by ANOVA tech- Nearly three-fourths of patients had a controlled su-
niques is known to be robust for responses between pine diastolic blood pressure (DBP < 90 mmHg) upon
approximately 20 and 80%. Statistical significance entry into the study. All but three of the remaining
was declared at the P < .05 level for all analyses. patients had a DBP below 95 mmHg and no patient
had a DBP above 100 mmHg upon entry into the
study.
RESULTS As shown in Table II, mean supine and standing
systolic/diastolic blood pressures were below
Fifty-eight patients entered the study and six pa- 140/90 mmHg during all three treatment phases.
tients were excluded from the analysis because of Mean supine and standing diastolic blood pressures
concomitant therapy, very early withdrawal from were lower after 4 and 8 weeks of treatment with
the study, or noncompliance; of these, three patients atenolol compared with the corresponding diastolic
were excluded because a diuretic was added to their blood pressures in either propranolol treatment
antihypertensive regimen after the study began; a phase. Although blood pressure assessments were
fourth patient experienced mild shortness of breath made after 2 weeks of treatment in each phase, these
(SOB) and wheezing during the first week of treat- data were not analyzed because of a possible carry-
ment with propranolol, 40 mg bid, and voluntarily over effect from the preceding treatment phase.
withdrew; a fifth patient was withdrawn after expe- The statistical analysis (ANOVA) of overall stand-
riencing SOB with propranolol, 40 mg bid, and mild ing and supine systolic/diastolic blood pressures
SOB and moderate CNS adverse experiences (night- showed significant differences (P < .05) between the
mares and dizziness) during the first week of treat- first propranolol treatment phase and the atenolol
ment with 50 mg of atenolol; a sixth patient was treatment phase. Similarily, there were significant
noncompliant with therapy. Thus, 52 patients were differences (P < .05) in the standing and supine dia-
eligible for inclusion in the analysis. stolic blood pressures between the atenolol treat-
Table I summarizes characteristics of 52 hyper- ment phase and the propranolol rechallenge during
tensive patients who were eligible for inclusion in the final 8 weeks of the study. There were no signifi-
the analysis; all were white, between 25 and 68 cant differences in blood pressures between the first
years of age (mean = 46.5 years). and final propranolol phases.
In Figure 1, the daily regimen of propranolol and As indicated in Table II, there were no significant
atenolol needed to control blood pressure indicated differences among the three treatment phases for
that 76% of the study population responded satisfac- either supine or standing pulse rates.

CARDIOVASCULAR PHARMACOLOGY 895

 FODOR ET AL

D First Propramlol Period

50 - AtenoloI

Propranolol Renflallenge
lll<0.001-I l-p<0.l-l

40 i-p<O.O0l---l i-p<0.01-I
I-p<0.0l--
l-p< 0.0 1-I
U) I-p<0.OOH

C.,
“ 30
I-

‘SI

I-p<O.l--l

20

U)

0. 1-I
10

0 to
SHORTNESS TIREDNESS DEPRESSED EARLY NIGHTMARES DIZZINESS
OF MOOD AWAKENINGS
BREATH
n=52 n=51 n=52 n=52 n=52 n=52

Figure 2. Overall sum of severity ratings during 8 weeks of treatment with propranolol and atenolol. Statistically significant differences (P
< .05) among treatment phases (ANOVA).

Adverse Experiences the atenolol treatment phase followed by worsening

during the propranolol rechallenge. In a comparison
Ten patients did not complete the first propranolol of first-period treatment with propranolol and treat-
period due to intolerable side effects and were ment with atenolol, these differences were statisti-
switched to atenolol; of these, eight completed the cally significant (P < .05) for SOB, early awakenings,
atenolol treatment phase satisfactorily, while two and nightmares, although a marked difference (P
were unable to tolerate either lipophilic or hydro- <.1) between the two treatments also was shown for
philic beta blocker therapy and did not complete the tiredness, depressed mood, and dizziness. Tiredness
atenolol treatment phase. Three of the eight patients and early awakenings worsened significantly (P
who did complete the atenolol treatment phase went <.05) during the propranolol rechallenge as com-
on to complete the propranolol rechallenge period, pared with the atenolol treatment phase, and de-
while the five remaining patients were not rechal- pressed mood and dizziness showed severity scores
lenged with propranolol. that were identical to the first-period treatment with
Figures 2 to 4 illustrate adverse experiences for propranolol.
which statistically significant differences were As indicated in Figure 3, a similar trend toward
shown among any of the three treatment phases. improvement during the atenolol treatment phase,
As indicated in Figure 2, the severity scores followed by worsening during the propranolol re-
showed a definite trend toward improvement during challenge, occurred in a separate binomial analysis

896 #{149}
J Clin Pharmacol 1987;27:892-901
 SIDE EFFECTS OF ATENOLOL AND PIIOPRANOLOL

First PrOpr100lOl Period

Alenolol

Propranolol Redialleag.
40’

1-9(0.01-I 1-pOOl-I
I- p<O.Ol-I I- p’O.Ol-4

30’
U)
I-
z
151 l-p<ZO.O1-l

I- p<. 0.1-I
I-p-.0.05 -I
20

IfiUn iU
-p<O.O1-I
I-
z I-pKO.05---4
15I

151 I00

SHORTNESS OF
BREATH
#{252}. DEPRESSED
MOOD
EARLY
AWAKENINGS
NIGHTMARES INSOMNIA
I-p<O.O5-I

DIARRHEA

Figure 3. Overall incidence rates during 8 weeks of treatment with propranolol and atenolol (N 52) (ANOVA).

based solely upon whether or not an adverse experi- during the propranolol rechallenge. This trend was
ence occurred. particularly evident for the CNS adverse experi-
The percentage of patients who experienced ad- ences including insomnia which, as indicated in
verse experiences was lower with atenolol as com- Table III, was only evaluated in the separate bino-
pared with the first-period propranolol for all ad- mial analysis.
verse experiences except cold extremities (10.1%,
first-period propranolol vs 12.4%, atenolol) and gen- Laboratory Tests
eralized weakness (5.4%, first-period propranolol vs
8.6%, atenolol); both of which showed a slight sta- There were no clinically significant trends in the
tistically nonsignificant increase during the atenolol mean values for any laboratory tests; and EGG,
treatment phase. As shown under “percent re- serum chemistry, and urinalysis did not reveal clin-
sponse” in Table III, there were significant (P < .05) ically significant changes in the status of any patient
differences for shortness of breath, depressed mood, during the three treatment phases.
nightmares, insomnia, and diarrhea in a comparison
of the first propranolol period and the atenolol DISCUSSION
treatment phase. During the propranolol rechal-
lenge, depressed mood, early awakenings, and in- This study was conducted to compare the side ef-
somnia worsened significantly (P < .05) as compared fects of an equally effective antihypertensive regi-
with the atenolol treatment phase. men of the lipophilic beta blocker propranolol and
Figure 4 illustrates a subset analysis of the sum of the hydrophilic beta blocker atenolol in patients
the severity scores for only patients who experi- who had a history of complaints associated with II-
enced a given side effect at week 4, week 8, or both, pophilic beta-blocker therapy. Most of the patients
during the first propranolol treatment period. As be- were treated with either propranolol or metoprolol
fore, the subset analysis for these patients showed a before entering the study. We were particularly in-
definite trend toward improvement during the terested in CNS side effects since there is substantial
atenolol treatment phase followed by worsening published information that associates these particu-

CARDIOVASCULAR PHARMACOLOGY 897

 FODOII ET AL

D First Propranolol Period

Atenolol

40 p<O.OO1-l
0 Propranolol

I-p<O.OOl---I

I-p<O.OOH
Fp<O.05-I
Fp-.O.0l-4 I-p<O.05--I
30 l-p<O.OO1-I
no I-p< 0.00 1-I
C.,
U)
I.-
no 0. I-I
151 20
Fp<O.05-1
151 I-p<O.OOH
U)
U.
0
E
10 I-p<O.H
I-p<O.05---I

SHORTNESS
Io COLD
919Lu
TIREDNESS DEPRESSED EARLY
PUD__
NIGHTMARES DIZZINESS
OF EXTREMITIES MOOD AWAKENINGS
BREATH
n-19 n6 n=15 o=11 n=11 n 14 n5

Figure 4. Sum of severity ratings for subset of patients who experienced a side effect during first pro pranolol period (ANOVA).

lar unwanted effects with physicochemical proper- treatment phase. The audiotaped interviews were
ties that can significantly affect the pharmacoki- evaluated by an independent investigator and only
netics and extent of drug distribution into the cen- data obtained after 4 and 8 weeks of treatment were
tral nervous system (see below). Of course, many analyzed to minimize possible carry-over effect of
patients do not necessarily associate the occurrence previous therapy. Finally, the methodologic ap-
of CNS side effects, such as nightmares or other proach was intended to produce data that could be
sleep disturbances, with treatment; therefore, it was evaluated by parametric methods of analysis, and
necessary to use a structured interview designed to the analog scale used in this study allowed for inter-
elicit this information rather than rely on spontane- val quantification of side effects.
ous reporting. In addition, the trial was designed to Our results showed a distinct improvement in side
simulate the clinical practice setting because the effects during the once-daily atenolol treatment
clinical practitioner is most likely to switch antihy- phase as compared with either initial therapy with
pertensive therapy when there is evidence of side propranolol or subsequent rechallenge, particularly
effects or complaints sufficient to undermine com- for the subset of patients who experienced a given
pliance. All patients were switched to atenolol after side effect at week 4 and/or week 8 during the first
8 weeks of continuous therapy with propranolol, or propranolol period. As can be noted in Table III,
sooner if intolerable side effects occurred. Notably, there were statistically significant differences be-
ten patients did not complete the first propranolol tween treatment phases for most of the side effects
period because of intolerable side effects; all ten across all comparative analyses, and the differences
were switched to atenolol and eight of these patients among treatments are most noteworthy for CNS side
completed the atenolol phase satisfactorily. effects. It is also noteworthy that the dosages of pro-
Therefore, in essence, five times as many patients pranolol used in this study were comparatively low
did not complete the initial therapy with proprano- since all but 2% of patients received 160mg or less of
lol than those who did not complete the atenolol propranolol. Therefore, marked differences in side

898 #{149}
J ClIn Pharmacol 1987;27:892-901
 SIDE EFFECTS OF ATENOLOL AND PROPRANOLOL

TABLE Ill

P Values* for the Comparative Analyses of Adverse Experiences

f Subset AnalysIs (N = 4-20) Overall Analysis (N = 50-52)

Analog Scale Percent Response Analog Scale Percent Response

Adverse
Experience Pro Aten Pro Pro Aten Pro Pro Aten Pro Pro Aten Pro

Shortnessof breath Pc.O01 P<.OO1 P<.001 P<.0i

P<.001 p<.o1 p<.oo1 P<.01
Wheezing NS NS NS NS
Cold extremities P <.05 NS NS NS
Tiredness P<.O01 P<.001 P<.O1 NS
P<.05 P<.05
Weakness NS NS NS NS
Depressed mood P<.001 P<.001 NS P<.01
P<.05 P<.05
Earlyawakenings P.z.001 P<.O1 P<.O1 P<.0i
p<.o1 P<.oo1
Nightmares P<.001 P>.001 P.<.01 P<.05
P<.05 P<.05
Dizziness P<.05 P<.05 NS NS
P<.05 P<O.O1
Nausea or vomiting NS P <.05 NS
Diarrhea P<.01
P<.O1 P<.05
Constipation NS NS
Insomnia P <.001 P <.01
P<.01 P<.01
P<.05
Muscle cramps NS NS
Dry mouth or eyes NS NS

Pro = propranolol; Ate,, = atenolol. t Subset analysis included only those patients who experienced a given side
NS = not statistically significant (P >05), ANOVA. effect at week 4. week 8, or both during the first propranolol treatment period.
* P values indicating significant differences (P <.05) among the three treat- Adverse experiences not evaluated on an analog scale.
ment phases.

effects between the two therapeutic modalities are sociated with high water solubility, that is, hydro-
not attributable to disproportionately high dosages philicity. Hydrophilicity has important clinical im-
of the lipophilic beta blocker. Further, it is unlikely plications because it directly affects the pharmaco-
that cardioselectivity might explain the observed kinetics of a drug.
differences since recent clinical data also show a The cardioselective, hydrophilic beta blocker
markedly higher incidence of CNS side effects with atenolol and the nonselective, lipophilic beta
the cardioselective beta blocker metoprolol as com- blocker propranolol differ markedly in their oc-
pared to atenolol.1#{176} However, metoprolol and ateno- tanol-aqueous buffer distribution coefficients,
lol differ with respect to their physicochemical prop- which Woods and Robinson11 have shown to be 20.2
erties. and 0.015 (pH 7.4, 37#{176}C)for propranolol and ateno-
The physicochemical properties of a drug are im- lol, respectively. Consequently, the pharmacoki-
portant because they can affect biologic processes netics of propranolol and atenolol differ markedly.
that enable a drug to both reach and interact with its In particular, the hydrophilic atenolol does not un-
sites of action. One such property is hydrophilicity, dergo significant first-pass or systemic hepatic me-
which is readily predictable on the basis of the mo- tabolism, and peak blood concentrations are rela-
lecular structure of the drug and easily measured by tively predictable and constant, showing only about
the octanol-aqueous buffer distribution coefficient. a threefold or fourfold variability among pa-
A relatively high distribution coefficient is asso- tients.12-13 In contrast, the lipophilic propranolol
ciated with low water solubility, that is, lipophilicity shows approximately a twentyfold variability
and a relatively low distribution coefficient are as- among patients at therapeutic dosages.14

CARDIOVASCULAR PHARMACOLOGY 899

 FODOII ET AL

Physicochemical properties also determine the hallucinations during 3 weeks of treatment with ei-
rate and extent of distribution (Vd) into body tissues, ther propranolol 80 to 160 mg bid or metoprolol 50 to
which is generally proportional to lipophilicity but 200 mg bid as compared with only eight episodes of
limited by the extent of plasma protein binding. nightmares and hallucinations during the 3-week
Hence, the moderately lipophilic and poorly protein cross-over treatment with atenolol 100 mg given
bound beta blocker metoprolol has a high Vd (5.6 once daily. All patients reported nightmares or hal-
L/kg), whereas the highly lipophilic and highly pro- lucinations with the lipophilic beta blockers as
tein bound propranolol has a lower Vd (3.6 L/kg). In compared to three patients during atenolol treat-
contrast, the hydrophilic and poorly protein bound ment. In the study by Cove-Smith and Kirk,2#{176}19
beta blocker atenolol has a comparatively low Vd patients experienced no significant CNS side effects
(0.7 L/kg); this also has clinical implications since with atenolol 100 mg as compared to placebo but the
the tightly packed endothelial capillary cells of the introduction of metoprolol 200 mg caused a signifi-
brain, unlike other capillary cells, limits the diffu- cant increase (P < .05) in the incidence of sleep dis-
sion of drugs in general and particularly that of hy- turbances and restless nights in comparison to pla-
drophilic compounds. cebo and to atenolol. Hence, double-blind, placebo-
The clinical relevance of these findings has been controlled studies corroborate the clinical relevancy
studied by a number of investigators. Betts15 evalu- of lipophilicity.
ated the effects of four beta blockers on both subjec-
tive and electroencephalographic (EEG) measures of CONCLUSION
sleep. The number of reported dreams and the de-
gree of insomnia were both significantly (chi-square
In conclusion, this study showed that at equally ef-
test; P < .01) increased during the time in which the
fective antihypertensive dosages, the hydrophilic
lipophilic beta blockers propranolol and pindolol
beta blocker atenolol produced significantly fewer
were administered as compared with placebo and
CNS side effects than the lipophilic beta blocker
atenolol. The effect of atenolol was the same as that
propranolol.
of placebo. Subsequent analysis of the EEG data
showed a significant (P < .001) reduction in rapid
eye movement (REM) sleep percentages from base- REFERENCES
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were fewer total subjective side effects in the ateno- tension: 2. Results in patients with diastolic blood pressure aver-
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