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OPHTHALMOLOGY
9
Ophthalmic
manifestations
of urological drugs
SONIA SZAMOCKI AND JAMES S.A. GREEN
The potential ophthalmic side-effects of commonly
prescribed urological drugs have been discussed in the
literature and emphasised in surgical and ophthalmological
training for some time, although no clear guidelines have
been established. In this article the authors provide some
practical advice to assist prescribers.
T
hree classes of medication have been
implicated in causing or worsening
existing ophthalmological conditions,
including alpha-blockers such as
tamsulosin, PDE5-inhibitors such as
sildenafil, and anticholinergics, including
oxybutynin. Some associations have
been purely theoretical, others based
on case reports with no suggestion of a
mechanism. The maxim ‘prescribe with
caution’ may be sound advice from a
medico-legal point of view, but it is not
a practical guide for clinicians keen to
minimise harm to their patients. This article
discusses each class in turn, presenting
the evidence in the literature to date, and
summarises the recommendations for their
use with regards to their ophthalmological
side-effects.
TRENDS IN UROLOGY & MEN’S HEALTH
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ALPHA-BLOCKERS AND FLOPPY
IRIS SYNDROME
Alpha-blockers are widely prescribed in
the UK. It is estimated that in the age
group 70–79 around 46% of men describe
having classical lower urinary tract
symptoms (LUTS),1 and with drug treatment
being first line for these symptoms a
significant proportion of these patients
will be prescribed an alpha-blocker. Highly
selective alpha-blockers such as tamsulosin
have been found to have a relatively low
side-effect profile, with only around 5%
of patients experiencing symptoms of
dizziness, although there are varying reports
on the incidence of retrograde ejaculation.
Another common complaint associated
with advancing age is the development
© Paul Whitten/Science Photo Library
Sonia Szamocki, foundation year doctor,
Barts Health NHS Hospital Trust, London;
James S.A. Green, Consultant Urological
Surgeon, Barts Health NHS Hospital Trust,
London and Visiting Professor, London
South Bank University www.trendsinmenshealth.com
OPHTHALMOLOGY
10
Figure 1. Intraoperative floppy iris: the iris
becomes flaccid and unpredictable during
cataract surgery
of cataracts. This clouding of the lens is
a significant cause of visual impairment
in older age, and over 300 000 eyes are
operated on in the UK per year.2 During
cataract surgery the pupil must be dilated
with antimuscarinic eye drops, such
as tropicamide, to allow access to the
crystalline lens in the anterior chamber
of the eye. During surgery intraoperative
floppy iris syndrome (IFIS) can occur
(Figure 1) and this has been linked to
concurrent alpha-blocker use. IFIS is a triad
of progressive intraoperative pupillary
constriction, iris prolapse and a flaccid,
unpredictable iris.
The first suggestion of an association
between alpha-blockers and IFIS came
from Chang and Campbell who reported
that 96% of their cohort who developed
IFIS were, or had been, on tamsulosin.3
Other alpha-blockers were not implicated
in this study.
The association seems to be particularly
strong with tamsulosin. A retrospective
study from Canada found the incidence
of IFIS to be 86% in tamsulosin-treated
patients compared to 15% in patients on
alfuzosin.4 However, while the incidence
of IFIS in the general population has
been reported to be between 0.6 and
3.7%, reports on the incidence of IFIS
in patients exposed to tamsulosin vary
widely from 37.9% to 100%.3,5–9 IFIS has
been found to be associated with other
alpha-blockers including doxazocin,
although much less strongly.10,11
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The proposed mechanism for IFIS with
alpha-blockers is through the blockade
of the alpha-1 receptors, specifically
alpha-1a receptors, which are found
both in the prostate and in the iris. In
the eye the dilator muscles of the iris
are under sympathetic control, mediated
by these alpha-1 receptors, while the
radial constrictor muscles are under
parasympathetic control. It is thought
that drugs like tamsulosin block the
alpha-receptors responsible for pupil
dilatation, thereby resulting in unopposed
parasympathetic action with a constricted
pupil and an unstable and ‘floppy’ iris.
Other alpha-blockers have varying
selectivity for this receptor subtype, which
may explain the variation in the incidence
of IFIS with different alpha-blockers.
One problem in establishing causality is that
the effect is not dose dependent;12 nor does
it seem to be correlated with how long the
drug is taken or the time since last use. IFIS
has been reported occurring several years
after stopping tamsulosin,3 suggesting
a permanent effect on the iris. However,
numerous studies have looked at whether
patients on tamsulosin experiencing IFIS
in one eye also experience this in the
contralateral eye during a subsequent
operation. This does not seem to be the case,
suggesting that the effect of tamsulosin is
unlikely to be a permanent one.12,13
The time taken for tamsulosin to affect the
iris is also disputed. Chang et al suggested
that it would only occur after a minimum
of 2 weeks of taking the drug.3 Others have
found detectable effects on iris dilatation
intraoperatively after only 2 days of taking
tamsulosin.14 Chang et al also carried out
a study where they stopped tamsulosin
1–8 weeks prior to surgery and found no
significant difference in the severity of IFIS.15
It appears then that while there is clear
evidence for a role for tamsulosin in the
development of IFIS the mechanism is
not clear-cut, nor can the outcomes be
predicted based on the duration of therapy
Box 1. Recommendations on the
use of alpha-blockers in relation to
cataract surgery
● Anyone not currently on
alpha-blockers should not
commence these until after
cataract surgery
● If an alpha-blocker has already
been started and the risk of
urinary retention is low, patients
can stop taking tamsulosin at
least 2 weeks in advance of
surgery with the involvement of
the ophthalmologist
● If the patient is at significant risk
of retention it is advisable to
continue the tamsulosin and
inform the ophthalmologist
or the dose. The question is whether alphablockers should be stopped prior to surgery
if there is no reliable preoperative method
to predict whether IFIS will occur?
Some have raised the possibility that
the concurrent use of anticholinergic
eye drops such as atropine to dilate
the iris while withholding alpha-blockers
will push some patients into urinary
retention. There is very little evidence
to support this; indeed, anticholinergics
have been used increasingly with and
without alpha-blockers to treat LUTS with
low rates of retention.16
The recommendations for alpha-blockers
in relation to cataract surgery are listed in
Box 1.
PDE5-INHIBITORS AND
NON-ARTERITIC ANTERIOR ISCHAEMIC
OPTIC NEUROPATHY
Non-arteritic anterior ischaemic optic
neuropathy (NAION) is a neuropathy that
is associated with compromised blood
supply to the optic nerve (Figure 2). It
is associated with cardiovascular risk
factors and can be thought of as an optic
nerve ‘stroke’, although the cause of this
condition is far from clear. It presents as
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OPHTHALMOLOGY
11
overlap between patients using PDE5inhibitors and those experiencing NAION.
Figure 2. Retina of patient with non-arteritic
anterior ischaemic optic neuropathy (NAION)
sudden, unilateral, complete or partial loss
of vision, usually on waking. Few patients
become permanently blind and 42% of
patients improve markedly within 6 months,
although 12% of patients develop worsening
visual impairment and 15% of patients find
their other eye becomes involved within
5 years.17,18 There are no clinically effective
treatments for this condition.
It is thought that NAION develops in
patients with already ‘crowded’ optic disks,
where a large number of nerve fibres are
packed into a small space. This, combined
with existing cardiovascular risk factors,
reduces flow to the optic nerve, particularly
at night when arterial hypoperfusion is
most likely to occur.
PDE5-inhibitors have been developed
specifically to increase arterial flow to endorgans due to their vasodilatory action.
Despite this apparently contradictory
mechanism there have been suggestions
from a number of small studies that
PDE5-inhibitors increase the risk of
NAION. McGwin et al reported that in a
case-control series of 76 patients there
was a statistically significant difference
only if the patient had suffered a previous
myocardial infarction.19 Other reports have
been from case studies alone.
PDE5-inhibitors, such as sildenafil, are
very commonly used drugs for erectile
dysfunction, and they are used particularly
in patients with existing cardiovascular
disease. This means that there is significant
TRENDS IN UROLOGY & MEN’S HEALTH
MARCH/APRIL 2016
Despite this, there is no clear evidence
that PDE5-inhibitors can in any way be
implicated in the development of NAION.
A post-marketing safety database of
sildenafil reported no NAION in almost
40 000 patients.20 Gorkin et al reported
that the incidence of NAION in sildenafil
users was not significantly different to
the incidence in the general population of
American men over 50.21
Sildenafil is associated with mild and
transient visual changes, particularly
with blue–green colour discrimination.
This is thought to be due to the crossinhibition of PDE6, which is found in
the photoreceptor cells in the retina.
The recommendations on prescribing of
PDE5-inhibitors in relation to NAION are
given in Box 2.
ANTICHOLINERGIC THERAPY AND
GLAUCOMA
Anticholinergics are first-line treatments
for the management of overactive bladder
(OAB) and urinary urge incontinence (UUI)
and work by inhibiting M3 receptors in the
detrusor smooth muscle of the bladder.
Anticholinergic side-effects, such as dry
mouth and constipation, arise due to the
Box 2. Recommendations on use of
PDE5-inhibitors and non-arteritic
anterior ischaemic optic neuropathy
(NAION)
● Patients starting sildenafil should
be counselled on possible transient
changes in colour discrimination
● Patients with a significant
cardiovascular history should
also be counselled on NAION as
a precaution
● Patients with pre-existing
NAION in one eye should not be
prescribed PDE5-inhibitors
interaction of these drugs with muscarinic
receptors in other tissues such as the
mouth and bowel.
Acute-angle closure glaucoma (AACG) is
a sight-threatening condition whereby
the outflow of aqueous humour from the
anterior chamber of the eye is blocked,
leading to a catastrophic rise in intraocular
pressure and eventually infarction of
the optic nerve (Figure 3). Angle closure
manifests usually in patients already
suffering from chronic glaucoma with
narrow drainage channels, also known
as ‘narrow angles’, which are at risk of
suddenly being closed. Patients already
being treated for glaucoma will be
Closed angle
Cornea
Cornea
Trabecular
meshwork
Iris
Open angle
Iris
Trabecular
meshwork
Lens
Ciliary body
Ciliary body
Lens
Figure 3. Pathophysiology of acute-angle closure. Pupillary dilatation can close the angle and
block the outflow of aqueous humour leading to a rapid rise in intraocular pressure
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OPHTHALMOLOGY
12
regularly followed up to assess the size of
these ‘angles’, to establish whether they
are at risk of angle closure.
Box 3. Recommendations on the use
of anticholinergic drugs in patients
with glaucoma
One well-documented precipitating
factor pushing patients from chronic
glaucoma into angle closure is exposure
to dark. Pupillary dilatation in these
conditions leads to a further narrowing of
the angle, occasionally completely blocking
the outflow channels and causing a rapid
rise in intraocular pressure. Treatment
includes various topical eye drops to
increase the outflow of aqueous humour
and reduce its production, intravenous
acetazolamide, and eventually surgical
management with peripheral iridotomy
to create a new tract for the drainage of
aqueous humour.
● All patients being started on
anticholinergic medication for
OAB or UUI should be asked about
their glaucoma history. If patients
have open-angle glaucoma or
treated, closed-angle glaucoma
and are under the supervision
of an ophthalmologist, it is safe
to prescribe
● Patients who cannot characterise
their glaucoma should be
re-referred to clarify this before
commencing anticholinergic drugs
Ophthalmologists are therefore always
careful to assess the depth of the angle
before administering topical dilating
drops with anticholinergic activity, such
as atropine, when examining the eye. It
follows then that other anticholinergics
could potentially also cause pupillary
dilatation and therefore put patients at risk
of developing AACG.
Although this mechanism sounds entirely
plausible, in clinical practice this effect
is extremely rare when using urological
drugs. Only one case report exists of
an 80-year-old lady taking oxybutynin
2.5mg twice daily who developed unilateral
AACG that was successfully treated
with iridotomy.22
However, because of these concerns, all
major trials involving anticholinergics
have excluded patients with narrow
angles, including the Overactive Bladder:
Judging Effective Control and Treatment
(OBJECT) study and the Antimuscarinic
Clinical Effectiveness Trial (ACET). Not one
patient in these large trials has reported
AACG as an adverse event.23,24
It is therefore extremely difficult to assess
the incidence of AACG in patients taking
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anticholinergic drugs, as high-risk patients
have generally been excluded from trials.
It is worth noting that the actual reported
incidence of AACG with anticholinergics still
remains incredibly low. In Japan a review of
367 patients started on oxybutynin asked
each patient about their glaucoma history
and, where unclear, patients were sent to an
ophthalmologist for clarification. Patients
with open-angle glaucoma and treated,
closed-angle glaucoma were started on
oxybutynin with no adverse effects.25
Recommendations on the use of
anticholinergic drugs in glaucoma are
given in Box 3.
CONCLUSION
In summary, a whole range of potential
ophthalmic complications have been
associated with the use of urological
drugs, although causality is far from
proven in each case. Perhaps the most
compelling case is for tamsulosin’s effect
on intraoperative behaviour of the iris,
and ophthalmologists are well aware of
the increased surgical complexity of these
cases. In most centres, these cases will
be performed by a senior surgeon. The
evidence for the role of PDE5-inhibitors
in NAION and anticholinergic drugs in
glaucoma is far less convincing, and while
a good history will help to identify the
patients at risk, the actual incidence of
ophthalmic side-effects is extremely low.
Declaration of interests: none declared.
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