W H Frishman

Beta-adrenergic receptor blockers. Adverse effects and drug interactions.

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3-Adrenergic Receptor Blockers
Adverse Effects and Drug Interactions
WILLIAM H. FRISHMAN
SUMMARY Adverse effects of /3-adrenergic receptor blocking drugs can be divided into two cate-
gories: 1) those that result from known pharmacological consequences of /3-adrenergic receptor
blockade; and 2) other reactions that do not appear to result from /3-adrenergic receptor blockade.
Adverse effects of the first type include bronchospasm, heart failure, prolonged hypoglycemia,
bradycardia, heart block, intermittent claudication, and Raynaud's phenomenon. Neurological reac-
tions include depression, fatigue, and nightmares. It is not yet proven whether the /3,-selective
adrenergic blockers or those with partial agonist activity reduce the overall frequency of adverse
reactions seen with propranolol. Patient age does not appear, in itself, to be associated with more /3-
blocker side effects. Side effects of the second category are rare. They include an unusual oculomuco-
cutaneous reaction and the possibility of oncogenesis. There are also many drugs that interact with /3-
blockers, which may increase toxicity. Finally, there are specific patient characteristics where one
/3-blocker may be more effective and safer than another.
(Hypertension 11 [Suppl II]: II-21-II-29, 1988)
KEY WORDS /3-adrenergic receptor blockers
drug interactions
adverse effects /3-blocker toxicity
Adverse Effects of /3-Blockers
C
OMPARING and tabulating adverse effects
from different studies of /3-adrenergic
blockers is particularly difficult because of a
number of factors. These include the use of different
definitions of side effects, the kinds of patients stud-
ied, and study design features. Methods of ascertain-
ment and reporting adverse side effects also differ from
study to study.
1
Given these problems, the types and
frequencies of adverse effects attributed to various /9-
blocker compounds appear similar.
2
The side effect
profiles of /3-blockers are also remarkably close to
those seen with concurrent placebo treatments, attest-
ing to the remarkable safety margin of the /3-blockers
as a group.
13
The adverse effects of /3-adrenergic receptor
blockers can be divided into two categories: 1) those
from known pharmacological consequences of /3-
adrenergic receptor blockade; and 2) other reactions
that do not appear to result from /3-adrenergic receptor
blockade.
Side effects of the first type are widespread because
of the ubiquitous nature of the sympathetic nervous
system in the control of physiological and metabolic
From the Department of Medicine, The Albert Einstein College
of Medicine, Bronx, New York.
Address for reprints: William Frishman, M. D. , 1825 Eastchester
Road, Bronx, New York 10461.
function. They include asthma, heart failure, hypogly-
cemia, bradycardia, heart block, intermittent claudica-
tion, and Raynaud's phenomenon. The incidence of
these adverse effects varies with the /3-blocker used.
Side effects of the second category are rare. They
include an unusual oculomucocutaneous reaction and
the possibility of carcinogenesis.
Major Clinical Experiences
There have been extensive clinical studies designed
to identify the nature and frequency of side effects with
/3-blocking agents. The Boston Collaborative Drug
Surveillance Program
4
studied the effects of proprano-
lol (nonselective, no partial agonism) in 800 hospital-
ized patients and of practolol (/3,-selective with partial
agonism) in 199 patients. Forrest
3
reported on the ad-
verse reaction seen with oxprenolol (nonselective with
partial agonism) in 4400 patients receiving the drug for
angina pectoris. Zacharias et al.
6
reported on the side
effects seen with long-term atenolol 03,-selective,
long-acting) treatment in patients with hypertension.
The side effect profiles for pindolol (nonselective with
partial agonism)
7
"
9
and labetalol (nonselective, a-
blocker)
10
have also been assessed in extensive clinical
trials in hypertensive patients. The long-term /3-
blocker trials in thousands of myocardial infarct survi-
vors have reported on the adverse reactions with differ-
ent /3-blocking compounds used in this clinical
situation.'
3>
"-
| S
In the Boston Collaborative Surveillance Program,
4
11-21
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n-22 ANTIHYPERTENSIVE DRUG EFFECTS SUPPL II HYPERTENSION, VOL 11, No 3, MARCH 1988
TABLE 1. Adverse Reactions to Propranolol Among 800
Hospitalized Medical Patients*
Nature of reaction
Life threatening
Shock
Bradycardia and angina
Pulmonary edema
Complete heart block
Subtotal
Non-life threatening
Bradycardia
Hypotension
Congestive heart failure or fluid retention
Gastrointestinal disturbances
CNS disturbances (headache, dizziness,
fatigue, tinnitus, blurring of vision,
paraesthesias, depression)
Bronchospasm
Sensitivity reactions (rash, fever)
2:1 heart block
Elevation in serum phenytoin level
Subtotal
Total with adverse reactions
Patients
()
5
1
3
1
10
17
16
9
9
9
4
3
1
1
69
79
Adverse
reactions
(%)
0.6
0.1
0.4
0.1
1.3
2.1
2.0
1.1
1.1
1.1
0.5
0.4
0.1
0.1
8.6
9.9
With bradycardia in 3 cases and congestive heart failure in 1;
with syncope in 5 cases.
Modified from Greenblatt and Koch-Weser
4
with permission.
propranolol was used for mixed clinical indications,
and adverse reactions were reported in 79 patients
(9.9%). These are summarized in Table 1. Ten adverse
reactions were considered life threatening, and all ap-
peared to result from impaired cardiac function. Of the
69 other reactions, 43 also involved interference with
cardiac performance but were not deemed life threat-
ening. The frequency of side effects was independent
of the dose used. Adverse reactions were seen more
commonly among older patients.
4
In patients with hypertension, the frequency of ad-
verse reactions with atenolol were reported to be ap-
proximately 15% in a 4-year follow-up study.
6
In an
extensive literature survey in 15,753 patients receiving
pindolol, a similar incidence of side effects was seen.
16
The frequency of side effects reported in labetalol-
treated patients was similar to those described with
atenolol and pindolol.
10
Forrest
3
reported a 13.7% incidence of side effects
with oxprenolol in patients with angina pectoris. In 12
placebo-controlled long-term studies of patients sur-
viving acute myocardial infarction, the incidence of
side effects ranged from 7 to 20%.
3
' "-
13
The overall
incidence of severe side effects was not much different
from that seen with placebo treatment (Table 2).
3
The
reason for discontinuing treatment because of side ef-
fects in the largest of these trials (/3-Blocker Heart
Attack Trial [BHAT]: /3-Blocker Post-Infarction Trial)
are shown in Table 3.
In the long-term postinfarction studies using pro-
pranolol (BHAT) and timolol, analyses were per-
formed to assess the side effect profiles of /3-blockers
and placebo therapy in patients with regard to age.
1 7
"
In these trials, all patients that were entered were be-
lieved to be good candidates for /3-blocker therapy
without contraindications to their use. In the BHAT,
the percentages of patients with complaints were not
significantly different in patients under 60 years of age
from patients over 60 years of age.
17
When assessing
reasons for treatment discontinuation, the incidence of
congestive heart failure was greater in the older age
group; however, other adverse reactions were similar
in older and younger patients.
17
In the Norwegian ti-
molol study,
18
similar observations were made in pa-
tients under 65 years of age and in patients 65 or older.
Overall, it would appear that the nature and frequency
of side effects seen with /3-blocker use in the elderly
are similar to those seen with /3-blocker use in younger
patients.
Adverse Cardiac Effects Related to /3-Adrenergic
Receptor Blockade
Myocardial Infarction
There are several circumstances in which blockade
of/3-receptors may cause congestive heart failure: 1) in
an enlarged heart with impaired myocardial function,
where excessive sympathetic drive is essential to main-
tain the myocardium on a compensated Starling curve;
and 2) when the left ventricular stroke volume is re-
stricted and tachycardia is needed to maintain cardiac
output.
Considering the factors noted above, any /3-block-
ing drug may be associated with the development of
heart failure. Furthermore, it is possible that an impor-
tant component of heart failure may be accounted for
by increases in peripheral vascular resistance produced
by nonselective agents (e.g., propranolol, timolol, and
sotalol).
20
It has been claimed that /3-blockers with
intrinsic sympathomimetic activity are better in pre-
serving left ventricular function and less likely to pre-
TABLE 2. Percentage of Patients Who Stopped Taking Study fl-Blockers in Various Long-Term Placebo-Controlled,
Postinfarction Trials
Side effects
Heart failure
Hypotension
Bradycardia
Depression
Fatigue
Pulmonary problems
Practolol"
4.1/3.6*
0.6/0.1
0.5/0.1
0.2/0.3
0.3/0.1
NA
Timolol
12
2.9/2.1
2.8/1.2
3.9/0.2
NA
0.4/0.1
1.1/0.4
Metoprolol
13
0.6/1.0
4.2/1.9
2.6/0.7
0/0
0/0
0/0
Propranolol
3
4.0/3.5
1.2/0.3
0.7/0.3
0.4/0.4
1.5/1.0
0.9/0.7
Sotalol
14
2.6/3.8
2.1/0.7
4.4/0
0/0
0.9/0.7
0.5/0.2
Oxprenolol
15
1.8/1.2
0.3/0.2
NA
1.8/0.4
0.5/0.7
NA
Treatment group/placebo group. NA = not available.
Modified from Friedman
1
with permission.
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SIDE EFFECTS OF P-BLOCKERS/Frishman 11-23
TABLE 3. Percentage of Patients Withdrawn for Medical
Reasons in fi-Blocker Heart Attack Trial
Adverse effect
Cardiopulmonary
Congestive heart failure
Hypotension
Pulmonary problems
Sinus bradycardia
New or extended
myocardial infarction
Serious ventricular
arrhythmia
Heart block
Syncope
Neuropsychiatric
Tiredness
Disorientation
Depression
Faintness
Nightmares
Insomnia
Reduced sexual activity
Other
Gastrointestinal problems
Dermatologic problems
Cancer
Propranolol
4.0
1.2
0.9
0.7
0.4
0.3
0.1
0.1
1.5
0.6
0.4
0.5
0.1
0.2
0.2
1.0
0.3
0.2
Placebo
3.5
0.3
0.7
0.3
0.4
1.0
0.1
0.1
1.0
0.6
0.4
0.2
0.2
0.0
0.0
0.3
0.1
0.1
Significant
difference
No
Yes
No
No
No
Yes
No
No
No
No
No
No
No
No
Yes
Yes
No
No
Modified from /3-Blocker Heart Attack Trial Research Group
3
with permission.
cipitate heart failure,
21
but there have been limited in
vivo studies in humans to support this contention. In
dog-transplanted, denervated heart preparations, /3-
blockers with intrinsic sympathomimetic activity have
a positive rather than negative inotropic effect.
22
The
clinical significance of this effect in the intact organ-
ism is uncertain.
In patients with impaired myocardial function who
require /3-blocking agents, digitalis and diuretics can
be used, preferably with drugs having intrinsic sym-
pathomimetic activity or a-adrenergic blocking prop-
erties.
Sinus Node Dysfunction and
Atrioventricular Conduction Delay
Slowing of the resting heart rate is a normal re-
sponse to treatment with ^-blocking drugs with and
without intrinsic sympathomimetic activity. Healthy
individuals can sustain a heart rate of 40 to 50 without
disability, unless there is clinical evidence of heart
failure.
23
Drugs with intrinsic sympathomimetic activ-
ity do not lower the resting heart rate to the same
degree as propranolol
24
; however, all /3-blocking drugs
are contraindicated (unless an artificial pacemaker is
present) in patients with the "sick sinus syndrome."
25
If there is a partial or complete atrioventricular con-
duction defect, use of a /3-blocking drug may lead to a
serious bradyarrhythmia.
23
The risk of atrioventricular
impairment is not the same with all )3-blockers. Giudi-
celli and Lhoste
26
showed that in dogs, /3-blockade and
not membrane stabilizing activity is responsible for
atrioventricular conduction impairment. Compounds
like pindolol or oxprenolol, which have intrinsic sym-
pathomimetic activity in dosages producing /3-block-
ade, do not impair atrioventricular conduction to the
same extent as propranolol. The clinical significance
of this electrophysiological difference among /3-
blockers in patients with atrioventricular conduction
disease has not been determined.
fi-Adrenergic Receptor Blocker Withdrawal
Following abrupt cessation of chronic /3-blocker
therapy, exacerbation of angina pectoris and, in some
cases, acute myocardial infarction and death have been
reported.
27
"
29
Multiple double-blind randomized trials have con-
firmed the reality of a propranolol withdrawal reac-
tion.
27
"
30
The exact mechanism for the propranolol
withdrawal reaction is unclear. There is some evidence
that the withdrawal phenomenon may be due to the
generation of additional /3-adrenergic receptors during
the period of /3-adrenergic receptor blockade.
31
'
32
When the /3-adrenergic receptor blocker is then with-
drawn, the increased /3-receptor population readily re-
sults in excessive /3-receptor stimulation that will be
clinically important when the delivery and use of oxy-
gen is finely balanced, as occurs in ischemic heart
disease. Other suggested mechanisms for the with-
drawal reaction include heightened platelet aggregabil-
ity,
29
an elevation in thyroid hormone activity,
33
and an
increase in circulating catecholamines.
34
As it seems possible that postadrenergic receptor
blockade sensitivity may be due to the generation of
additional /3-adrenergic receptors, a /3-adrenergic re-
ceptor blocking drug with some partial agonist activity
might provide enough receptor stimulation to prevent
the generation of additional /3-adrenergic receptors.
33
Studies with atenolol, metoprolol, pindolol, and pro-
pranolol in normal subjects and patients indicate that
administration of pindolol is not associated with in-
creased sensitivity to isoproterenol after pindolol is
stopped, in contrast to the other /3-adrenergic receptor
blocking drugs that do not possess partial agonist activ-
ity.
Mi 37
Despite this difference with pindolol, it is still
prudent to discontinue all /3-blockers with caution in
patients with ischemic heart disease.
38
Adverse Noncardiac Side Effects Related to
-Adrenergic Receptor Blockade
Effect on Ventilatory Function
The bronchodilator effects of catecholamines on the
bronchial /3
2
-adrenergic receptors (JiJ are inhibited by
nonselective /3-blockers (e.g., propranolol and nado-
lol).
39
Comparative studies have shown, though, that
/3-blocking compounds with partial agonist activity,
40
0,-selectivity,
41
-
42
and a-adrenergic blocking actions
43
are less likely to increase airways resistance in asthma-
tics than propranolol. /3,-Selectivity, however, is not
absolute and may be lost with high therapeutic doses as
shown with atenolol and metoprolol. It is possible in
asthma to use a /3
2
-selective agonist (such as albuterol)
in certain patients with concomitant low-dose /3,-selec-
tive blocker treatment.
44
In general, all /3-blockers
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11-24 ANTIHYPERTENSIVE DRUG EFFECTS SUPPL n HYPERTENSION, VOL 11, No 3, MARCH 1988
should be avoided in patients with bronchospastic
disease.
Peripheral Vascular Effects (Raymud's Phenomenon)
Cold extremities and absent pulses have been report-
ed to occur more frequently in patients receiving /3-
blockers for hypertension compared with treatment
with methyldopa.
45
Among the /3-blockers, the inci-
dence was highest with propranolol and lower with
drugs having /3,-selectivity or intrinsic sympathomi-
metic activity. In some instances, vascular compro-
mise has been severe enough to cause cyanosis and
impending gangrene.
4
* This is probably due to the re-
duction in cardiac output and blockade of /3
2
-adrener-
gic receptor-mediated skeletal muscle vasodilation,
resulting in unopposed a-adrenergic receptor vasocon-
striction.
47
/3-blocking drugs with /3
r
selectivity or par-
tial agonist activity will not affect peripheral vessels to
the same degree as will propranolol.
Raynaud's phenomenon is one of the more common
side effects of propranolol treatment.
4849
It is more
troublesome with propranolol than practolol probably
because of the /3
2
-blocking properties of propranolol.
Patients with peripheral vascular disease who suffer
from intermittent claudication often report worsening
of the claudication when treated with /3-blocking
drugs.
50
'
31
Whether drugs with /3,-selectivity or partial
agonist activity can protect against this adverse reac-
tion has yet to be determined.
Hypogfycemia and Hypergtycemia
Several authors have described severe hypoglyce-
mic reactions during therapy with /3-adrenergic block-
ing dr ugs.
3 2
" Some of the patients affected were
insulin-dependent diabetics, while others were nondia-
betic. Studies of resting normal volunteers have dem-
onstrated that propranolol produces no alteration in
blood glucose values,
54
although the hyperglycemic
response to exercise is blunted.
In humans, mobilization of muscle glycogen is a /3-
receptor-mediated function (/3
2
-mediated), while
mobilization of liver glycogen depends on a-receptor
stimulation.
55
' ** As a result, /3-receptor blocking drugs
(especially nonselective /3-blockers) may retard recov-
ery from insulin-induced hypoglycemia. In humans,
Abramson et al.
32
showed that propranolol delayed the
return of blood glucose values to normal after insulin-
induced hypoglycemia. If liver glycogen is reduced by
fasting or illness, the concomitant use of nonselective
/3-blocking drugs may further prolong recovery from
hypoglycemia, since alternative stores cannot be mo-
1
bilized.
37
'
58
With propranolol, the normal hemody-
namic response to hypoglycemia may be altered with
an elevation of diastolic blood pressure due to an a-
constrictive response to reflex increases in plasma
catecholamines.
38
This enhancement of insulin-induced hypoglycemia
and its hemodynamic consequences may be less with
cardioselective agents (where there is no blocking
effect on /3
2
-receptors) and agents with intrinsic
sympathomimetic activity (which may stimulate /32-
receptors).
59
There is also marked diminution in the clinical
manifestations of sympathetic discharge associated
with hypoglycemia (tachycardia and tremor).
60
These
findings suggest that /3-blockers interfere with com-
pensatory responses to hypoglycemia and can mask
certain warning signs of this conditions. Other hypo-
glycemic reactions, such as diaphoresis, are not affect-
ed by /3-adrenergic blockade.
Central Nervous System Effects
Dreams, hallucinations, insomnia, and depression
can occur during therapy with /3-blockers.
48
'
61
These
symptoms are evidence of drug entry into the central
nervous system (CNS) and are especially common
with the highly lipid-soluble /3-blockers (propranolol
and metoprolol) that presumably penetrate the CNS
better. It has been claimed that /3-blockers with less
lipid-solubility (atenolol and nadolol) will cause fewer
CNS side effects.
42
'
a
~
6
* This claim is intriguing, but its
validity must be corroborated with more extensive
clinical experiences.
A recent retrospective study suggested that patients
receiving /3-adrenergic blockers had a higher incidence
of depression requiring antidepressant medication than
did patients not receiving the drug.
63
There were many
methodological problems in this study, and no firm
conclusions about depression incidence can be made.
63
Our group was unable to demonstrate the above obser-
vation in a large prospective study in patients over 80
years of age in which the prevalence and incidence of
depression on propranolol was identical to that of pa-
tients not receiving /3-blocker therapy.
66
In this same
study, patients on minor tranquilizers were much more
prone to depression than patients on /3-blockers.
66
Clinical pharmacological studies have generally
supported the view that /3-blockers do not have any
marked sedative effects. No such action could be
detected for propranolol, sotalol, oxprenolol, or
atenolol.
6
'
Skeletal Muscle Effects
In vitro studies demonstrate that propranolol can
produce neuromuscular blockade.
67
The direct actions
of epinephrine on skeletal muscle are mediated prob-
ably through /3
2
-receptors, and tremor is the most com-
mon side effect of /3
2
-stimulating drugs. Propranolol
has been shown to attenuate the ankle jerk, and a
prolonged curare-like effect has been described in one
patient.
68
Whether the cardioselective /3-blockers have
similar effects remains to be determined.
Muscle cramps can also occur with pindolol
48
and
have been described with practolol and propranolol.
69
The etiology of this side effect is unknown.
Miscellaneous Side Effects
Diarrhea, nausea, gastric pain, constipation, and
flatulence have been seen occasionally with all /3-
blockers ( 2- 11% of patients).
70
Patients on /3-blockers who develop anaphylac-
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SIDE EFFECTS OF P-BLOCKERS/Frishman 11-25
tic shock may not respond to the usual doses of /3-
agonists.
Hematologic reactions are rare. Rare cases of purpu-
ra
71
and agranulocytosis
72
have been described with
propranolol.
A devastating blood pressure rebound effect has
been described in patients who discontinued clonidine
while being treated with nonselective /3-blocking
agents. The mechanism for this may be related to an
increase in circulating catecholamines and an increase
in peripheral vascular resistance.
7374
Whether /3,-
selective or partial agonist /3-blockers have similar ef-
fects after clonidine withdrawal remains to be deter-
mined. It has not been a problem with labetalol.
75
Increases in patient weight may occur. Bengtsson
76
noted an average 1-kg weight increment in patients
taking alprenolol. A similar weight gain in patients has
also been noted with propranolol,
77
pindolol,
38
-
78
and
oxprenolol. The mechanism of this weight gain has not
been elucidated. However, treatment with diuretic
agents will commonly relieve it.
Adverse Effects Unrelated to /3-Adrenergic
Receptor Blockade
/8-Blockers have been associated with the develop-
ment of antinuclear antibodies.
79
In prospective clini-
cal trials, patients receiving acebutolol had a dose-
dependent increase in the development of positive
TABLE 4. Drug Interactions That May Occur with fi-Adrenoceptor Blocking Drugs
Drug Possible effects Precautions
Aluminum hydroxide gel
Aminophylline
Antidiabetic agents
Calcium channel inhibitors
(e.g., verapamil, diltiazem)
Cimetidine
Clonidine
Digitalis glycosides
Epinephnne
Ergot alkaloids
Glucagon
Halofenate
Indomethacin
Isoproterenol
Levodopa
Lidocaine
Methyldopa
Decreases /3-blocker absorption and therapeutic
effect
Mutual inhibition
Enhanced hypoglycemia; hypertension
Potentiation of bradycardia, myocardial
depression, and hypotension
Prolongs half-life of propranolol
Hypertension during clonidine withdrawal
Potentiation of bradycardia
Hypertension; bradycardia
Excessive vasoconstriction
Inhibition of hyperglycemic effect
Reduced /3-blocking activity; production of
propranolol withdrawal rebound syndrome
Inhibition of antihypertensive response to
/3-blockade
Mutual inhibition
Antagonism of levodopa's hypotensive and
positive inotropic effects
Propranolol pretreatment increases lidocaine blood
levels and potential toxicity
Hypertension during stress
Manoamine oxidase inhibitors Uncertain, theoretical
Phenothiazines
Phenylpropranolamine
Phenytoin
Quinidinc
Reserpine
Tricyclic antidepressants
Tubocurarine
Additive hypotensive effects
Severe hypertensive reaction
Additive cardiac depressant effects
Additive cardiac depressant effects
Excessive sympathetic blockade
Inhibits negative inotropic and chronotropic effects
of /3-blockers
Enhanced neuromuscular blockade
Avoid /3-blocker and aluminum hydroxide
combination
Observe patient's response
Monitor for altered diabetic response
Avoid use, although few patients show ill effects
Combination should be used with caution
Monitor for hypertensive response; withdraw
/3-blocker before withdrawing clonidine
Observe patient's response; interactions may
benefit angina patients with abnormal ventricular
function
Administer epinephnne cautiously;
cardio-selective /3-blocker may be safer
Observe patient's response; few patients show ill
effects
Monitor for reduced response
Observe for impaired resonse to /3-blockade
Observe patient's response
Avoid concurrent use of cardio-selective /3-blocker
Monitor for altered response; interaction may have
favorable results
Combination should be used with caution; use
lower doses of lidocaine
Monitor for hypertensive episodes
Manufacturer of propranolol considers concurrent
use contraindicated
Monitor for altered response, especially with high
doses of phenothiazine
Avoid use, especially in hypertension controlled by
both methyldopa and /3-blockers
Administer i.v. phenytoin with great caution
Observe patient's response; few patients show ill
effects
Observe patient's response
Observe patient's response
Observe response in surgical patients, especially
after high doses of propranolol
Modified from Hansten
93
with permission.
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11-26 AN+IHYPERTENSlVE DRUG EFFECTS SUPPL n HYPERTENSION, VOL 11, No 3, MARCH 1988
antinuclear antibody titers, and the overall incidence
was higher than that observed with propranolol.
79
Symptoms (generally persistent arthralgias and myal-
gias) related to this abnormality were infrequent (less
thari 1% with both drugs). Symptoms and antinuclear
antibody.titers were reversible upon discontinuation of
treatment.
79
Oculomucocutaneous Syndrome
A characteristic, immune reaction, the oculomuco-
cutaneous syndrome, affecting singly or in combina-
tion eyes, mucous and Serous membranes, and the
skin, often in association with a positive antinuclear
factor, has-been reported in patients treated with prac-
tolol ahd has led to the curtailment of its clinical
use.
80
'" Close attention,has been focused on this syn-
drome because of fears that other /3-adrenergic recep-
tor blocking drugs may be associated with it. In 19
patients with such a reaction with practolol, the lesions
healed after switching to atenolol treatment.
The main features in this syndrome in 439 patients
reviewed by Nichols (see ConOlly
23
) were as follows:
1) Eye: A gritty feeling in the eye may occur that can
progress to a panconjunctivitis; keratitis, and panniis
formation. In Nichols' series, 18 patients manifested
severe eye changes> 112 had corneal damage without
loss of sight, and 146 had eye changes without corneal
involvement. The average time to develop this syn-
drome was 23 months after initiating treatment.
2) Skin: The skin changes usually begin With a pruri-
tic rash involving the palms and.the soles of the feet.
Thickened .plaques that resemble psoriasis may ap-
pear. Immunofluorescent studies have revealed granu-
lar deposits at the dermalectodermal junction in some
cases.
82
. , .
3) Ear: Deafness with serious otitis media has been
reported in some patients receiving practolol.
Sclerosing Peritonitis
Thirty-three patients with this syndrome were in-
cluded in Nichols' report. Patients may present with
colicky abdominal pain or with an abdominal mass.
This condition may progress in spite of withdrawal of
the drug and may first develop up to a year after the
discontinuation of practolol. The peritoneum becomes
covered with a film of white fibrous tissue with thicker
plaques.
83
The natural history of this condition is Uh
T
known, and the diagnosis has usually been made at
laparotomy or autopsy. Most patients appear.to im-
prove with time after cessation of treatment. The mean
time to diagnosis of sclerosing peritonitis after starting
practolol was 37 months.
As with sclerosing peritonitis; many Of the other
practolol reactions are reversible by withdrawal of the
drug, together with treatment with topical corticoster-
oids, artificial tear solutions, antibiotic eye drops, and
oral corticosteroids.
84
An important consideration is whether the practolol
TABLE 5. .Clinical Situations That Would Influence the Choice of a fi-Blocking Drug
Condition Choice of /3-blbcker
Asthma, chronic bronchitis with
bronchospasm
Congestive heart failure
Angina
Atrioventricular conduction defects
Bradycardia
Rayriaud's phenomenon,
intermittent claudicatiori, cold
extremities
Depression
Diabetes mellitus
Thyrotoxicosis
Pneochrombcytoma
Renal failure
Insulin ahd sulphonylurea use
Clonidine
Oculomucocutaneous syndrome
Hyperlipidemia
Avoid all /3-blockers if possible; however, small,doses of /3i-selective blockers (e.g., acebutolol,
atenolol, metoprolol) can be used. ,-Selectivity islost with higher doses. Drugs with partial agonist
activity (e.g., pindolol, oxprdnolol) and labetalol with a-adrenergic blocking properties can also be
used
Drugs with partial agonist activity and labetalol might have an advantage, although /3-blockers are
usually contraindicated
In patients with angina at low heart rates, drugs with partial agonist activity probably contraindicated.
Patients with angina at high heart rates,but who have resting bradycardia, might benefit from a drug
with partial agonist activity. In vasospastic angina, labetalol may be useful; other jS-blockers should
be used with caution
/3-Blockers generally contraindicated, but drugs with partial agonist activity and labetalol can be tried
with caution
/3-Blockers with partial agonist activity and labetalol have less pulse slowing effect and are preferable
/3i-Selective blocking agents, labetalol, and those with partial agonist activity might have an advantage
Avoid propranolol. Substitute a /S-blocker With partial agonist activity or low lipid solubility
j9
r
Selective agents and partial agonist drugs are preferable
All agents will control symptoms, but agents without partial agonist activity are preferred
Avoid all /3-blockers unless an a-blocker is given. Labetalol may be used as a treatment of choice
Use reduced doses of compounds largely eliminated by renal mechanisms (nadolol, sotalbl, atenolol)
and those drugs whose bioavailability is increased in uremia (propranolol, alprtnolol). Also consider
possible accumulation of active metabolites (alprenolol, propranolol)
Danger of hypoglycemia but is possibly reduced using drugs with /3,-selectivity
Avoid sotalol (and other nonselective /3-blockers). Severe rebound effect with clonidine withdrawal
Stop drug. Substitute any other /3-blocker
Avoid nonselective /3-blockers; Use agents with partial agonism, /3,-selectivity or labetalol
Modified from Frishman
94
with permission.
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SIDE EFFECTS OF /3-BLOCKERS/FWj/iman H-27
reaction is specific for practolol or is the direct and
specific result of pharmacologically induced changes
by /3-blockade.
83
There have been few convincing pub-
lished reports of the oculomucocutaneous reaction
with oxprenolol
86
'" and propranolol.
88
'
w
In view of
the extensive clinical use of both oxprenolol and pro-
pranolol, these reactions, even if drug induced, are
exceedingly rare. There is need, however, for vigi-
lance during therapy with the newer /3-blockers.
Carcinogenicity
Pronethanol, the first /3-adrenergic receptor block-
ing drug to achieve widespread use, was withdrawn
by its manufacturer because it caused thymic tumors
and lymphosarcomata in mice, although it did not
do so in rats or dogs.
90
The doses used to produce these
tumors were 10 times the maximum therapeutic
concentration.
Tolamolol and pamatolol, two cardioselective (3-
adrenergic receptor blocking drugs, were withdrawn
from clinical trials because they caused mammary tu-
mors in mice and rats at high doses.
91
Other /3-
blockers, alprenolol, practolol, and timolol, have giv-
en some indication of tumorigenicity in rodents.
42
"
The relevance of these findings to causation of tu-
mors in humans is difficult to evaluate.
42
The doses
were high, and the relationship between malignant tu-
mors in animals and humans is not defined.
42
A dis-
turbing aspect has been the suggestion that this might
be a pharmacological property of /3-adrenergic recep-
tor antagonism rather than carcinogenicity by another
mechanism. Against the /3-blocker theory of carcino-
genesis is the fact that many /3-blocking drugs have
successfully undergone stringent carcinogenicity test-
ing in animals and have been used safely in humans.
Drug Interactions
The wide diversity of diseases for which /3-blockers
are employed raised the likelihood of their concurrent
administration with other drugs.
92
It is imperative,
therefore, that familiarity be obtained regarding the
interactions of /3-blockers with other pharmacological
agents. The list of commonly used drugs with which /3-
blockers interact is extensive (Table 4).
93
The majority
of the reported interactions have been reported for pro-
pranolol, the best studied of the /3-blockers, and may
not apply to other drugs in this case.
How to Choose a /3-Blocker
The various /3-blocking compounds given in ade-
quate dosage appear to have comparable, antihyper-
tensive, antiarrhythmic, and antianginal effects.
Therefore, the /3-blocking drug of choice in an individ-
ual patient is determined by the pharmacodynamic and
pharmacokinetic differences between the drugs in con-
junction with the other medical conditions the patient
might have (Table 5)."
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