Clin. Cardiol.
19, 691-697 (1996)
Systemic Side Effects of Topical Beta-Adrenergic Blockers
WII.LIAMC.
STEWART,
M.D.,WILLIAM
P. CASTELLI,M.D.*
Glaucoma Service at the Department of Ophthalmology at the Medical University of South Carolina, Charleston,South Carolina,and
*the Framingham Heart Study, Harvard Medical School, Boston, Massachusetts. USA
Summary: Glaucoma, a disease that affects between 1 and
3% of the population above the age of 60, is most commonly
treated by topical beta-adrenergic blockers. Although eftec-
tive in lowering intraocular pressure and helping to preserve
sight, beta blockers also may have adverse influences on the
cardiac, pulmonary, and central nervous systems, and on en-
docrine functions. Clinicians' awareness that their patients
may be treated with topical beta blockers will help them to
elicit this information and the history, prescribe the medicine
correctly, and be cognizant of a possible role this medicine
may have in any deterioration of a patient's systemic clinical
status.
Key words: glaucoma, cardiac arrhythmias, heart failure, re-
active airway disease, exercise tolerance, central nervous sys-
tem, intrinsic sympathomimetic activity, beta]-selectivity
Introduction
Chronic open-angle glaucoma is a disease characterized by
elevated intraocular pressure, optic nerve degeneration, and
visual field deterioration that may lead to blindness. Although
unusual before the age of 60, the prevalence of glaucoma in-
creases in the older population, to approximately 1'% between
Supported in part by unrestricted grants from Research to Prevent
Blindness. Inc., New York, N.Y., and Otsuka America
Pharmaceuticals, Inc.. Rockville, Md.
Address for reprints:
William C. Stewart, M.D.
Storm Eye Institute
Medical University of South Carolina
171 Ashley Avenue
Charlehion. SC 29425-2236, USA
Received: August 7, 1995
Accepted with revision: October 16, 1995
60 and 70,3% between 70 and 80, and > 9% in those over 80
years of age. I An equal or greater number of patients also may
have elevated intraocular pressure without glaucomatous
damage, a condition called ocular hypertension. I
Chronic open-angle glaucoma is treated by reducing the
intraocular pressure. Although laser and conventional surgi-
cal techniques can be used to decrease the pressure, the initial
treatment generally is medical. The most common agent used
to treat chronic open-angle glaucoma is a topical beta-adren-
ergic blocker. I Current commercially available topical beta-
adrenergic blockers, along with their basic pharmacologic
properties, are listed in Table I.
Soon after topical beta blockers were introduced in the late
1970s, systemic side effects, many severe, were reported.2 In
the first 7 years of commercial production, 32 patients died
following topical timolol therapy, mostly from cardiac or pul-
monary complications.' In addition, several more common
evere side effects were described, including reduced
exercise tolerance, central nervous system symptoms, psy-
chological changes, and worsened serum lipid levels.
Topical beta-adrenergic blockers typically gain access to
the systemic circulation through the lacrimal system, from
where they may be absorbed through the nasal mucosa." Top-
ical beta-adrenergic blockers also may gain access into the
systemic circulation through the conjunctival vessel^.^ Blood
levels achieved from topical beta-adrenergic blocker therapy
are detectable by assay and usually are not as high as those
following appropriate oral dosing (Table In predisposed
individuals, however, only a small amount of a systemically
absorbed beta blocker may produce significant side effects.
Patients with glaucoma generally are older, have other
chronic conditions, use multiple medications, and may be un-
der the care of several physicians. Systemic adverse events as-
sociated with glaucoma medications, particularly beta block-
ers, may not be recognized in this population, and patients may
fail to mention their eye drops when providing a drug history.x
Consequently, the participation of a topical beta blocker in the
patient's illness may potentially be overlooked.
The purpose of this article is to review the systemic side ef-
fects of topical beta-adrenergic blockers and the mechanism
by which they occur. Treatment implications based on the
ophthalmic literature, where they exist, also are discussed.
 19328737, 1996, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960190904 by Cochrane France, Wiley Online Library on [25/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
692 Clin. Cardiol. Vol. 19, September 1996

I Commercially available topical beta-adrenergic blockers

TABLE
Generic name Brand name Company Receptor selectivity
Timolol maleate Timoptic Merck, Sharpe & Dohme 131. n?
Betaxolol suspension Betoptic-S Alcon [J I
Betaxolol solution Betoptic Alcon rj I
Levobunolol Betagan Allergan Rl,132
Metipranolol Optipranolol Bausch & Lomb 131, B?
Carteolol Ocupress Otsuka Iil,Bz
Timolol in gelrite Timoptic XE Merck, Sharpe & Dohme SI3i3Z
Timolol hemihydrate Betimol Ciba Vision Ophthalmics 11(1,8?

Blood level Concentration

Generic name ISA at up to 1 h (pg/ml) (%) Dose
Timolol maleate - 0.54k3.5 0.25,0.50 q.d.,b.i.d.
Betaxolol suspension - 0 0.25 bid.
Betaxolol solution - 0 0.50 b.i.d.
Levobunolol - 0.21-15 0.25,0.50 q.d.. b i d .
Metipranolol - 0.136 0.3 bid.
Carteolol + 0 1 .o bid.
Timolol in gelrite - 0.00028 0.25.0.50 q.d.
Timolol hemihydrate - 0.818 0.25,0.50 b.i.d.
Ahbreviutions:ISA = intrinsic sympathomimetic activity.

CardiovascularEffects trinsic sympathomimetic activity are probably of no greater

Congestive Heart Failure
Congestive heart failure most commonly results from coro-
nary heart disease9 which causes poor peripheral perfusion
and oxygen delivery to the heart.IoThis results in several com-
pensatory mechanisms to maintain cardiac function, including
elevated sympathetic tone,Icl2 increased heart rate? activa-
tion of the renin-angiotensin system?. 13 release of atrial natri-
uretic peptides? and initiation of the Frank-Starling mecha-
n i ~ m .These
~ compensatory mechanisms help maintain
cardiac function in the short term. However, these mecha-
nisms may worsen cardiac dysfunction long-term, which
again increases the drive for compensatory mechanisms and
results in a deleterious self-perpetuatingcycle?, lo,
Beta blockade may contribute to congestive heart failure by
its negative inotropic action. Patients with congestive heart
failure thought most at risk from beta blockade are those with
siglllfcant hypoperfusion, severe pulmonary or systemic ede-
ma, or a recent acute decompensation episode.14 Topical
adrenergic blockade rarely has been reported to contribute to
congestive heart failure, with most cases being associated
with timolol. Is Betaxolol, a betal-selective blocker, is report-
ed to have 20%less betal-binding activity at the cardiac re-
ceptors than timolol.16*l7 However, congestive heart failure
also has occurred with topical betaxolol use.18No deaths from
cardiac failure have been noted with topical beta blockers.'. l 9
The above clinical studies are based on case reports, and no
current guidelines are available specifically for treatment im-
plications using topical beta blockers. Beta blockers with in-
benefit than agents without this property with regard to safety
in this group of patients.2"
Some authors have speculated whether beta-blocker ther-
apy may be beneficial in selected patients with congestive
heart f a i 1 ~ r e .2c22
I ~ ~ The exact mechanism of this potential
beneficial effect is not known with certainty.21It may be relat-
ed to breaking the negative cycle, described above, caused by
the intensive sympathetic discharge as an initial compensa-
tion for congestive heartfailure.I4 More evidence is needed to
determine whether beta blockers benefit selected patients
with congestive heart failure.22
Arrhythmia
Beta blockers reduce sinus node automaticity, prolong
sinoatrial, intra-atrial, and atrioventricular (AV) conduction
times, as well as increase AV nodal refractoriness. His-
Purkinje system automaticity, refractoriness, and conduction
have been reported to be depressed to a variable extent.13In
patients with underlying conduction system disease, these ef-
fects may cause bradycardia and heart block.2JBeta blocker$
also suppress subsidiary pacemaker function, which may lim-
it the ability of the heart to compensate for loss of primary
pacemaker function.24
Many reports in the ophthalmology literature indicate the
potential for side effects related to conduction defects from
topical beta blockers and have included syncope, bradycar-
dia, systemic hypotension,Is*25 palpitation, arrhythmia,?'. 26
and heart block.2sCardiac arrest and death have been report-
ed from topical beta-blocker use.2s In addition, timolol

W. C. Stewart and W. P. Castelli: Side effects of beta-adrenergic blockers
maleate has been noted to cause bradycardia and dizziness in
a patient simultaneously treated with quinidine.?' Although
betaxolol is a beta]-selectiveblocker with less receptor bind-
ing in the heart,'('. this medicine has been associated with
cardiac arrhythmia and syncope.'x Details of the above cases
have not been published, nor have studies been undertaken
regarding specific indications for topical beta-blocker treat-
menK with regard to cardiac arrhythmia.
In selected patients, beta blockers may help prevent ar-
rhythmia and sudden death. Except for sotalol (Class 111),19
beta blockers generally are classified as a Class I1 antiarrhyth-
mic." The potential beneficial effect of beta blockers as an
antiarrhythmic result from the lessening of the arrhythmo-
genic effect of excessive sympathetic drive, the Class I action
of some beta blockers, prolongation of the action potential,
and chronic dosing resulting in reduced mean sympathetic
tone.23
Serum Lipid Levels
The risk of coronary heart disease increases as cholesterol
levels rise. This is true not only for total chole~terol,~~
but for
the serum lipid fractions and triglyceride levels as well.
Orally prescribed nonselective beta blockers may adversely
affect serum lipids including triglycerides, low-density lipo-
protein (LDL),and high-density lipoprotein (HDL) levels, as
well as the total cholesterol/HDL ratio. However, total
cholesterol levels appear minimally affected.'. Betat- se-
lective blockers mirror, but with less change, the influence of
nonselective beta-blocker^.^^ In contrast, agents with intrinsic
sympathomimeticactivity have little influence on serum lipid
levels.v
Studies evaluating the effect of topical formulations on
serum lipid levels generally reflect those of oral beta blockers.
Coleman et al. applied 0.5% topical timolol maleate to the
eyes of 28 healthy volunteers, aged 21 to 60 years (mean age
35.1, years), for an average of 76 days. No significant change
was observed in total cholesterol,LDL,35or triglyceride lev-
els. However, baseline HDL levels decreased by 0.14 ? 0.29
pmol/l. The largest decline in HDL levels was noted in those
individuals with the highest baseline values.
In another study, West and Longstaff monitored lipid levels
in 17 patients with elevated intraocular pressure who used
topical timolol, a nonselective beta blocker.36After 15weeks
of treatment, the investigators observed no significant
changes in total cholesterol levels or lipid fractions.
Freedman er al. compared the effects of topical carteolol
1.0% and timololO.5% on plasma lipid levels in 58 healthy
adult men.37Treatment with each drug resulted in a signifi-
cantly smallerdecrease in HDL with carteolol ( - 3.3%, -0.04
p o I / l ) than timolol maleate (- 8.0% -0.10 pnol/l). Neither
drug \ignificantlychanged the levels of total cholesterol,LDL,
or triglycerides.
A multicenter trial is currently being conducted to deter-
mine whether topical beta blockers affect serum lipid fractions
in ocular hypertensive or glaucoma patients. Further work is
required to determine the importance, treatment implications,
19328737, 1996, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960190904 by Cochrane France, Wiley Online Library on [25/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
693
and patient groups which are at particular risk of adverse lipid
level changes when treated with topical beta blockers.
Exercise Tolerance
Mechanism: Exercise produces a number of physiologic
changes, including reduced maximum tachycardia38and car-
diac 39 as well as limited peripheral vasodilation,
which may be modified by beta-adrenergic blockers. All of
the above influences may reduce effort tolerance and total
oxygen uptake in the peripheral t i s ~ u e . ~ ~ , ~ ~
Poor peripheral vasodilation also impairs skin blood flow
and may affect sweating and temperature regulation!I In ad-
dition, beta blockade appears to influence core temperature
regulation and may increase the risk for dehydration and hy-
perthermia?
Topical beta blockade has been noted to decrease exercise
tolerance in normal individuals.Doyle et al. showed that top-
ical timolol maleate reduced maximum heart rate and time to
exhau~tion.~' In addition, Leier et al. demonstrated that timo-
lo1 maleate significantlydecreased maximum heart rate both
chronically and acutely.43Atkins showed that after topical
timolol maleate, heart rate as well as the product of heart rate
and systolic blood pressure were reduced significantly.4
However, betaxolol, a beta]-selective blocker, produced no
change in these parameters.4
Although many glaucoma patients are older and do not at-
tempt exercise because of systemicdebilities, the influenceof
beta blockade may have therapeutic implications. Chronic
exercise,even walking, has been shown to reduce intraocular
pre~sure.4~ Consequently, beta-blocker preparations which
influence exercise less may be shown in the future to have an
advantage in some glaucoma patients.
Nocturnal Hypotension
The treatment of systemic hypertension is vital in reducing
long-term mortality associated with this disease.46However,
a drop in nocturnal blood pressure has been noted in some pa-
tients taking oral beta blockers for systemic hypertension.
Some beta blockers cause reduced nocturnal pressure (me-
teroprolol, metoprolol, cilazapril,sotolol),while others do not
(atenolol,pindolol, l a b e t a l ~ l ) .The
~ ~ systemic
.~~ significance
of nocturnal hypotension,if any, is not currently understood.'"
Several articles, however, have suggested that nocturnal
systemic hypotension may play a role in progressionof chron-
ic open-angle glaucoma. Claridge and Smith noted no mean
change in pulsible ocular blood flow overnight in normal or
glaucomatousindividuals before or after topical beta-blocker
therapy, although some individuals had large decreases in oc-
ular blood flow. They suggest that nocturnal hypotension may
be a risk factor for glaucomatousprogre~sion.~~ Hayreh eta/.
found no difference in nocturnal blood pressure in patients
who either remained stable or showed glaucomatous progres-
sion over time. However, a trend did exist indicating that pa-
tients who showed visual field progression and were being
treated for systemic hypertension had lower nocturnal blood

694 Clin. Cardiol. Vol. 19, September 1996
pressure than patients who remained stable.50 In contrast,
Grahdm et 01. demonstrated significantly lower mean noctur-
nal arterial blood pressure and larger dips in blood pressure in
their patients who had progressive field loss than in stable pa-
tients5'
These studies suggest that in selected individuals nocturnal
hypotension could be associated with progression of glauco-
tnatous defects. However, this association is yet to be con-
firmed and the best method of prevention yet to be explored.
Pulmonary
Reactive Airway Disease
Beta-adrenergic blockade may worsen reactive airway dis-
ease due to antagonism of the beta;! receptors known to exist
in the lung.s2The exact mechanism of this effect remains un-
known. The fact that beta;!-adrenergic receptors are blocked
by these agents may not be a complete explanation since nor-
mal individuals do not develop bronchoconstriction with
beta-blocker therapy.53An increase in bronchial tone due to
the unmasking of the parasympathetic nervous system or al-
pha adrenoreceptors, or the effect of endogenous mediators,
has been suggested as the cause of worsened disease in beta
blocker-treated asthma patients.", 5s
Topical beta-adrenergic blockers have been reported to in-
crease the symptoms related to reactive airway disease and
bronchitis.15s 57 In addition, signs of worsening reactive air-
way disease have been noted, including increased wheezing,
dyspnea, cough, and bronchial s p a ~ m . l ~ * ~ ~
With topical therapy, worsening of reactive airway disease
has been associated mostly with nonselective beta blockers.58
Timolol maleate, a nonselective beta blocker, has been noted
to increase the need for bronchial dilator therapy in 47% of
asthmatic individuakS9Respiratory arrest within 20 min of
receiving the first drop of timolol maleate has been observed
in a patient with underlying reactive airway disease.60In the
first 8 years of its commercial availability, 12 respiratory
deaths were associated with timolol maleate.61
Betaxolol, a commercially available beta\-selective antag-
onist, theoretically should avoid pulmonary-related side ef-
fects. Several reports showed no effect of betaxolol on mean
forced expiratory volume over the first second of expiration
(FEV I ) in asthmatics.62-64while timolol produced a decrease
of 25% from @ Schoene et al. noted that 12 pa-
tients who reported increased respiratory symptoms on betax-
0101 actually had no worsening in airway function.6s
However, worsening of asthmatic signs66and symptoms
possibly leading to hospitalization28still may occur with be-
taxolol therapy. Hugues noted that in 10 asthmatic patients
receiving betaxolol, 9 showed no mean reduction in vital
capacity or FEVI,but one had worsening of the FEVi by >
15%.5x In a 2-year follow-up of 101 patients with reactive
airway disease treated with betaxolol, studied by Weinreb et
al., 9 were withdrawn from therapy because of worsening of
their pulmonary status. During the follow-up period, the
mean ratio of FEVt to forced vital capacity (FVC) fell from
19328737, 1996, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960190904 by Cochrane France, Wiley Online Library on [25/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
66 to S4%.67Spiritus and Casciari have noted that in asthmat-
ic patients treated with betaxolol, one-third had increased
symptoms and one-half had a 15% decrease in FEVl .6x
The partial agonism associated with intrinsic sympath-
ornimetic activity theoretically might help prevent pulmonary
side effects resulting from beta blockade. Several studies
showed a trend to a lesser degree of worsening of FEVl in
patients treated with topical carteolol, which has intrinsic
sympathomimetic activity, versus agents without this proper-
ty (timolol, m e t i p r a n o l ~ l )However,
. ~ ~ ~ ~ ~in this study the det-
rimental effect of carteolol on lung function was still greater
than that ofbetaxol01.5~It is important to note that studies us-
ing oral preparations indicate that the recovery from an asth-
ma attack in patients treated with terbutaline is blocked by
pindolol, an agent with intrinsic sympathomimetic activity,
much as it is by propranolol, a nonselective beta b l ~ c k e r . ~ " . ~ '
Consequently, intrinsic sympathomimetic activity may have
little safety value in patients with reactive airway disease.s3
Central Nervous System
Beta-adrenergic blockers exert a neural depressant effect in
several different ways. First, these compounds can cross the
bloodhrain barrier, bind beta-adrenergic receptors, and re-
duce information flow that is associated with behavioral sys-
tems and under control of beta-adrenergic tone. Second, the
beta-adrenergic blocker can cross-bind with serotonin recep-
tors and act as an antagonist, and disturb the behavioral activ-
ities organized by these Finally, beta blockers
may exhibit a nonspecific effect which has been incomplete-
ly described.72Also, a peripheral mediated mechanism from
beta blockade has been reported, mostly due to antagonism of
the autonomic nervous system. Changes in the peripheral ~ L I -
tonomic tone are signaled through neural pathways to the
central nervous system. This may cause reflex changes in the
activity of central networks which can cause behavioral or
neural changes.72The peripheral effect is probably less, how-
ever, than the combined side effects on the central nervous
system.72
Topical beta-adrenergic blockers have been reported to
cause a variety of side effects on the central nervous system
(Table 11). The incidence of such reported side effects is ap-
proximately lo%, with about 5 % of patients having to dis-
continue the m e d i ~ i n e .This
' ~ is probably the most common
side effect related to topical beta-blocker use.57Younger pa-
tients, however, appear to tolerate this class of medicine with
fewer changes in psychological profile?3
Topical medicines which limit beta blockade may cause
fewer side effects on the central nervous system. Lynch et nl.
noted that patients who had such side effects on timolol
maleate had reduced symptoms on betaxolol, a betat-selec-
tive bl0cker.7~In addition, agents with intrinsic sympath-
omimetic activity may limit the central nervous system beta-
adrenergic and seratonin-receptor blockade and associated
side 75, 76 Currently, a multicenter trial is underway
examining the psychological profile and the side effects on
 19328737, 1996, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960190904 by Cochrane France, Wiley Online Library on [25/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
W. C. Stewart and W. P. Castelli: Side effects of beta-adrenergic blockers 695

II Central nervous system effects and other systemic reactions resulting from timolol
TABLE
~~~

Change in energy: Fatigue, somnolence,weakness

Change in mentation: Memory loss, confusion
Psychological changes: Hallucinations,depression
Somaticcomplaints: Headache,light-headedness,dizziness, paresthesias
Emotionalchanges: Emotional lability,tranquilization, anxiety
Dermatologicchanges: Rash, urticaria, hypopigmentation,alopecia, stomatitis
Gastrointestinalchanges: Nausea and vomiting, diarrhea, abdominal cramps,pain, dyspepsia
Othcr: Sexualimpotence,exacerbationof my asthenia gravis, reduced warning of diabetic hypoglycemic crises, arthropathy
Source:Ref. 1.

the central nervous system of patients treated with carteolol,
which has intrinsic sympathomimetic activity, versus a nons-
electivebeta blocker.
Endocrine
Concern about the use of beta-adrenergicblockers in dia-
betic patients arises from several potential side effects. One is
the lack of warning of hypoglycemic crisis and another is the
worsening of glucose tolerance. Several investigators have
noted that oral nonselective and beta ]-selectiveblockers may
reduce the awareness of patients who have a hypoglycemic
crisis by their effect on the autonomic nervous s y ~ t e m al-
? ~ ~ ~ ical
though this is a subject of controversy. In contrast, one study
noted that sweating, a prime symptom of hypoglycemia, ac-
tually was enhanced by both nonselective and selective beta
blockers.79.8o
Oral beta-blockers are known to cause a worsening of glu-
cose tolerance in patients who are borderline or overtly dia-
betic and have been associated with nonketotic hyperosmo-
lar hypoglycemic coma.81The mechanism for the increase in
glucose levels is not known completely, but it may involve
the limitation of insulin secretion from the pancreas, exacer-
bation of hepatic glycogenolysis,and reduced peripheral use
of glucose.81The above effects of beta antagonism on glu-
cose are believed to be mediated though the beta;! recep-
. ~ ~ that are either betal-selective or have intrinsic
t o r ~Agents
sympathomimetic activity are less likely to worsen glucose
Although an altered hypoglycemic response in diabetic pa-
tients has been reported with topical timolol maleate thera-
py?;! little information is available in the ophthalmic literature
regarding hypoglycemic response or altered glucose levels.
Conclusion
Careful attention to glaucoma medicines by the primary
care physician can help patients in several ways. First, knowl-
edge of these medicines will assure that they are remembered
and prescribed correctly on in-patient orders. Second, realiz-
ing the importance of these medicines will help assure that
they are not discontinuedindiscriminately,without communi-
cating with the ophthalmologist,and will facilitate the mainte-
nance of the patient’s vision in the presence of a potentially
blinding disease. Third, an awareness that topical beta-block-
er therapy may explain partially or wholly a change in a pa-
tient’s systemic condition will facilitate accurate patient care.
Primary care physicians also may help the ophthalmologist
by encouraging free communication regarding a patient’s
systemic care. Ophthalmologists generally have limited un-
derstanding of the effect of systemic beta-adrenergic block-
ade, and few indicationsexist in the ophthalmic literature re-
garding cases in which this class of medicine should not be
prescribed or the preparation modified.
In the future, the problem of systemic side effects from top-
~ beta-blocker use and systemiccomplicationsmay be alle-
viated in several ways. New classes of glaucoma medicines
will become available (e.g., topical prostaglandins) which
will reduce the need for topical beta blockers. Further re-
search regarding the systemic side effects of topical beta
blockers will help ophthalmologists and internists toward a
better understanding of the safest use of these medicines.
Acknowledgments
The authors acknowledgeBruce W. Usher, M.D., with grat-
itude for his review of this paper.
References
1. Stewart WC: Clinical Practice of Glaucoma. Thorofare, NJ:
SLACK, Inc., 1990.149-155,260-261
2. Zimmerman TJ, Kass MA, Yablonski ME, Becker B: Timolol
maleate.Efficacy and safety.Arch Ophrhalmoll979;97:65&658
3. Nelson WL, Fraunfelder FT,Sills JM, Arrowsmith JB, Kuritsky
JN: Adverse respiratory and cardiovascular events attributed to
timolol ophthalmic solution, 1978-1985.ArnJOphthalmolI986;
I02:606-6l1
4. Shields MB: TextbookofGlaucoma,ed. 2. Baltimore:Williams &
Wilkins, 1987:364
5. Kaila T, Karhuvaara S, Huupponen R, Iisalo E The analysis of
plasma kinetics and B-receptor binding and -blocking activity of
timolol following its small intravenous dose.Int J Clin Pham Ther
TOX1993;31 :351-357

696 Clin. Cardiol. Vol. 19, September 1996
6. Kaila T A sensitiveradioligand binding assay for timolol in plas-
ma. JPharmSci 1991;80296-299
7. Irvine NA. Lipworth BJ, McDevitt DG: A dose-ranging study to
evaluate the 8-adrenoceptor selectivity of single doses of betaxolol.
Br J Clin Pharmac 1990.30: 119-126
8. Stewart WC: Carteolol, an ophthalmic B-adrenergic blocker with
intrinsic sympathomimeticactivity. JGlaucom 1994; 3:339-345
9. Parmley WW. Pathophysiology of congestive heart failure. Clin
Cardiol 1995; 15(supplI):1-5-1-12
10. Eichhom El: The paradox of B-adrenergic blockade for the man-
agement of congestiveheart failure.Am J Med 1992; 92:527-538
11. Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlof G,
Mark AL: Direct evidence from intraneural recordings for in-
creased central sympatheticoutflow in patients with heart failure.
Circulation 1986;73:913-919
12. Packer M, Lee WH, Kessler PD, Gottlieb SS, Bernstein JL,Kukin
ML: Role of neurohormonal mechanisms in determining survival
in patients with severe chronic heart failure. Circulation 1987;
75(s~pplIV):IV-8CLIV-92
13. Cody RJ,Laragh JH: The role of the renin-angiotensin-aldosterone
system in the pathophysiology of chronic heart failure. In Drug
Trearment of Heart Failure (Ed Cohn JN). New York:Yorke
Medical Books, 1983
14. Eichhom El: Do beta-blockers have a role in patients with conges-
tive heart failure? Cardiol Clin 1994; 1 2 133-142
15. Zimmerman TJ, Baumann JD,Hetherington J: Side effects of tim-
0101. Sun, Ophthalmoll983; 28(suppl):243-249
16. Polansky JR: Comparison of plasma beta blocking activity of be-
taxolol and timolol. Int OphthalmolClin 1989; 29(suppl): 17-1 8
17. Vuori M-L, Ali-MelkkillT, Kaila T, Iisalo E, Saari KM: Bl- and &-
antagonist activity of topically applied betaxolol and timolol in the
systemic circulation.Acra Ophthalmol 1993; 71:682-685
18. Ball S: Congestive heart failure from betaxolol (letter). Arch
Ophthalmol1987; 105:320
19. Van Buskirk EM, FraunfelderFT.Ocular 8 blockers and systemic
effects. Am J Ophthalmol1984;9k623-624
20. Franciosa JA: 8-receptor-activeagents: Role of partial agonists in
patients with heart failure.J CardiovascPharmucoll989; 14(sup
pl5):S44447
21. Waagstein F: Beta blockers in heart failure. Cardiology 1993; 82
(SUPPI 3):13-18
22. Domanski MJ, Eichhom El: Beta blockade in congestiveheart fail-
ure-the need for a definitive study. Am J Cardiol1994;73:597-
599
23. Coumel P, Leclercq J-F, Escoubet B: Beta-blockers: Use for ar-
rhythmias. Eur Heart J 1987;8(suppl A):41-52
24. Kastor JA (Ed.):Arrhythmias. Philade1phia:W.B. Saunders, 1994
25. FraunfelderFT,Meyer SM: Systemicadverse reactions to glauco-
ma medications. Int Ophthalml Clin 1989; 29: 143-146
26. Champ AD, Shin DH, Petursson G, Cinotti D, Wortham E, Brown
RH, Silverstone DE, Atkins JM, Eto CY, Lue JC, Novack GD:
Effect of varying drop size on the efficacy and safety of a topical
beta blocker.Ann Ophrhalmoll989; 21:35 1-357
27. Betoptic S Product Monograph. Alcon Laboratories Inc., Fort
Worth, Texas, 1990
28. Nelson WL, Kuritsky JN:Early postmarketing surveillanceof b e
taxolol hydrochloride, September 1985-September 1986 (letter).
Am JOphthalmol1987; 103592
29. Hampton JR: Choosing the right 8-blocker. A guide to selection.
DWRS1994; 48:549-568
30. Wilson PWF, Catelli WO, Kannel WB:Coronaryrisk prediction in
adults (the Framingham Heart Study).Am J Curdiol1987;59(sup-
pl):91 G-94G
31. Roberts WC: Recent studies on the effects of beta blockers on
bloodlipid levels. Am Heart J 1989; 117:709-714
32. Ames Rp.Antihypertensivedrugs and lipid profiles.Am J Hyper-
tens 1988; 1:421-427
19328737, 1996, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960190904 by Cochrane France, Wiley Online Library on [25/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
33. LardinoisCK, Neuman S L The effects of antihypertensive agents
on serum lipids and lipoproteins. Arch Intern Med 1988; 148:
128CL.1288
34. van B m e l e n P The relevance of intrinsicsympathomimetic ac-
tivity for B-blocker-induced changesin plasma lipids. J Cardiovasc
Pharmacoll983; S(supp1):SS1 4 5 5
35. Coleman AL, Diehl DLC, Jampel HD, Bachorik PS, Quigley HA:
Topical timolol decreasesplasma high-density lipoprotein choles-
terol level.Arch Opththalmoll990;108: 1260-1 263
36. West J, Longstaff S: Topical timolol and serum lipoproteins.Br .I
Ophthulmol1990;741663-664
37. Freedman SF, Freedman NJ, Shields MB, Lobaugh B, Samba GP,
Keates EU, Ollie A: Effects of ocular carteolol and timolol on plas-
ma high-density lipoprotein cholesterol level. Am J Ophthalmol
1993; 116:600611
38. Tesch PA: Exercise performance and &blockade. Sports Med
1985; 2:389-412
39. L t r o m H Haemodynamic effectsof beta-adrenergic blockade. Br
Heart J 1968; 3044-49
40. Kaiser P, Hylander B, Eliasson K, Kaijser L: Effect of betal-selec-
tive and nonselectivebeta blockade on blood pressure relative to
physical performance in men with systemic hypertension.Am J
Cardioll985; 55:79&84D
41. Gordon NF,Duncan JJ: Effect of beta-blockers on exercise physi-
ology: Implications for exercise training. Med Sci Sports &err
1991; 23:668476
42. Doyle WJ, Weber PA, Meeks RH: Effect of topical timolol maleate
onexerciseperformance.ArchOphfhalmol1984,102:1517-1518
43. Leier CV, Baker ND, Weber PA: Cardiovascular effects of oph-
thalmic timolol.AnnIntern Med 1986; 104: 197-199
44. Atkins JM: Effects of topical beta blockers on cardiovascularfunc-
tion during exercise.Int Ophrhalmol Clin 1989; 29(suppl):S23
45. Passo MS, Hunt SC, Elliot DL, Goldberg L: Regular exercise low-
ers intraocular pressure in glaucoma patients. Invest Ophthalmol
VisSci 1994; 13(suppl):1254
46. Sleight P Cardiovascular risk factors and the effects of interven-
tion.Am HeartJ 1991; 121:990-995
47. Raftery EB, Carrageta MO: Hypertensionand beta-blockers.Are
they all the same?Int J Caniiol1985; 7:337-346
48. Mayer J, Weichler U, Hems-Mayer B, SchneiderH, Marx U.Peter
JH:Influenceof metoprolol and cilazapril on blood pressure and on
sleep apnea activity. J Cardiovasc Pharmacol1990; 16952-96 1
49. Claridge KG, Smith S E Diurnal variation in pulsatile ocular blood
flow in normal and glaucomatous eyes. Sun, Ophthalmol 1994;
38(suppl):S1984205
50. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WLM: Noc-
turnal arterial hypotension and its role in optic nerve head and ocu-
lar ischemic disorders.Am J Ophthalmoll994; 117:603-624
5 1. Graham SL, Drance SM, Wijsman K, Douglas GR, Mikelberg FS:
Ambulatory blood pressure monitoring in glaucoma. The nocturnal
dip. Ophthalmology 1995; 102:6 1-69
52. McNeill RS: Effect of a beta-adrenergic-blocking agent, propra-
nolol,onasthmatics.Lancer 1964;2:1101-1102
53. Lafdahl C-G: Antihypertensive drugs and airway function, with
special reference to calcium channel blockade. J Cardiovasc
Pharmacol1989; I4(suppl IO):S4O-S51
54. Lafdahl C-G: Selectivity of 13-adrenoceptoragonists and antago-
nists in asthmatics. Eur J Respir Dis 1982;63(suppI 120):1-53
55. Tattersfield AE: Beta adrenoceptorantagonistsand respiratory dis-
ease. J CardiovascPharmacol1986 8(suppl4):S35439
56. SchoeneRB,Martin TR, Charan NB,French C L Timolol-induced
bronchospasm in asthmatic bronchitis. J Am Med Assoc 1981;
245:146&1461
57. Van Buskirk EM: Adverse reactions from timolol administration.
Ophthalmology 1980;87:447450
58. Hugues FC: Clinical studies of systemic effects of topical beta
blockers.Int OphthalmolClin 1989; 29(suppl):S19-S20
59. Avom J, Glynn RJ,Gurwitz JH, Bohn RL. Monane M. Everitt DE,
GiIden D, Choodnovsky I: Adverse pulmonaryeffects of topical U
 W. C. Stewart and W. P. Castelli: Side effects of beta-adrenergic blockers
blockers used in the treatment of glaucoma. J Glaucoma 1993;
2: 158-165
60. Botet C, Grau J, Benito P, Coll J, Vivancos J: Timolol ophthalmic
solution and respiratory arrest. Arch Intern Med 1986; 105:
306-307
61. Wandel T, Charap AD, Lewis RA, Partamian L, Cobb S, Lue JC,
Novack GD, Gaster R, Smith J, Duzman E: Glaucoma treatment
with oncedaily levobunolol.Am JOphthalmoll986 101:298-304
62. Van Buskirk EM, Weinreb RN, Berry DP, Lustgarten JS, Podos
SM, Drake MM: Betaxolol in patients with glaucoma and asthma.
Am J Ophthalmol1986; 101531-534
63. Schoene RE3, Abuan T, Ward RL,Beasley CH: Effects of topical
betaxolol. timolol, and placebo on pulmonary function in asthmat-
ic bronchitis.Am J Ophthalmol1984;97:8&92
64. Martin T:Effects of topical beta blockers on pulmonary function.
In? Ophthalmol Clin 1989;29(suppl):S21
65. Schoene R, VerstappenA, McDonald M: Betaxolol use not relat-
ed to adversepulmonary reactions reported in patients with reactive
airway disease: A report on 12 double-masked rechallenges. Glau-
coma 1992; 14:3945
66. Harris LS, Greenstein SH, Bloom A F Respiratorydifficultieswith
betaxolol (letter).AmJ Ophthalmol1986; 102.274
67. Weinreb RN, Van Buskirk EM, Cherniack R, Drake MM: Long-
term betaxolol therapy in glaucoma patient with pulmonary dis-
ease.Am JOphthalmol1988;106:162-167
68. Spiritus EM, Casciari R Effects of topical betaxolol, timolol, and
phcebo on pulmonary function in asthmaticbronchitis (letter).Am
JOphthalmol1985;100:492-494
69. Ki tazawa Y,Hone T, Shirato S: Eficacy and safety of caneolol hy-
drochloride: A new beta-blocking agent for the treatment of glau-
coma. In Acta: XXN International Congress of Ophthalmology
(Ed.Henkind P). Phi1adelphia:J.B.LippincottCompany, 1983
70. Svedmyr N, Ronn 0:Undersokningav den kliniska relevansen av
beta- I -selektivitetoch egenstimuleringfor adrenergabeta-blocker-
are hos astmatiker.Sandoz IEdwkrift 198I ;8 I :18-2 1
697
7 I. Lammers JWJ, Folgering HTM, van Herwaarden CLA: Ventila-
tory effects of long-term treatment with pindolol and metoprolol in
hypertensive patients with chronic obstructive lung disease. Br J
Clin Phannacol1985;20:201-210
72. Koella WP: CNS-related (side-)effects of &blockers with special
reference to mechanisms of action. Eur J Clin P h a m c o l 1985;
28(suppl):55-63
73. Forte ELI, Weber PA: Psychologiceffects of topical timolol maleate.
ContempOphthalmolForum 1987; 5:11-18
74. Lynch MG, Whitson JT,Brown RH, Nguyen H, Drake MM: Topi-
cal 8-blocker therapy and central nervous system side effects. A
preliminary study comparing betaxolol and timolol. Arch Oph-
thalmol1988; 106:908-911
75. MiddlemissDN, Blakebomugh L, Leather SR: Direct evidence for
an interactionof beta-adrenergic blockers with the 5-HT receptor.
Nature 1977; 262289-290
76. Middlemiss DN, Buxton DA, Greenwood D T Beta-adrenoceptor
antagonists in psychiatry and neurology. Pharmacol Ther 198 1 ;
12419437
77. Tse WY. Kendall M: Is there a role for beta-blockers in hyperten-
sive diabetic patients? DiabericMedicine 1994; 1 I , 137-144
78. Ken D, Macdonald IA,Heller SR, Tattersall RB: Beta-adrenocep-
tor blockade and hypoglycaemia. Br J Clin Pharmucol 1990; 29:
685-693
79. Held PH, Yusuf S, Furberg CD: Calcium channel blockers in acute
myocardial infarction and unstable angina: An overview. Br Med J
1989;299: 1187-1 192
80. Abramson EA, Arky RA,Woeber KA: Effects of propranolol on
the hormonal and metabolic responses to insulin-induced hypogly-
caemia. Lancet 1966; ii:138&1390
8 I . Houston DC: Adverse effects of antihypertensivedmg therapy on
glucose intolerance. Cardiol Clin 1986; 4 1 17-1 35
82. Velde TM, Kaiser FE: Ophthalmic timolol treatment causing al-
tered hypoglycemic response in a diabeticpatient. Arrh Intern Med
1983; 143:1627