1. health and fitness
2. disease

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MODULE 10:12
Drugs used in the treatment of dry eye
syndrome, anti-inflammatory drugs and
topical anti-allergy drugs
30/11/07 CET
30
COURSE CODE: C-5848
Elaine Mann
This article will cover the factors causing dry eye syndrome and the drugs, both
topical and systemic, used in its treatment. Also the effectiveness and
limitations of topical corticosteroids, non-steroidal anti-inflammatory drugs,
mast cell stabilisers and antihistamines.
Drugs used in the diagnosis
and treatment of dry eye
syndrome
Tear production
The tear film normally consists of three
layers:
1. A thin outer lipid layer
2. A thick middle aqueous layer
3. An innermost mucin layer1.
Although at one time, tears were
conceived as a discreet three layered
structure, recent research suggest that
these layers interact forming complex
structures. Some experts believe that in
dry eye there is a hyperosmolarity of
tears,
which
activates
the
Tlymphocytes and production of
inflammatory
cytokines.
Current
understanding of the pathogenesis of
dry eye disease has proceeded from
recognition of a lack of, or altered
quality of tears, to recognition of
inflammation as the key pathogenic
mechanism whether from a systemic
autoimmune disease or a local
autoimmune event. Often a negative
feedback loop is set up where
inflammation produces epithelial
damage, producing further secretion of
inflammatory
mediators,
which
produces more damage2,3,4,5.
Tear secretions are subject to
parasympathetic,
sympathetic,
hormonal (androgen) and emotional
regulation. Hormonal factors are
important in Non-Sjögren’s associated
keratoconjunctivitis sicca (KCS) as it is
often associated with post-menopausal
women. One explanation is that the
lack of androgens disrupts the function
of the meibomian glands leading to a
loss of (or a reduction in) the outer
lipid layer in tears causing an increased
evaporation of tears. The decrease in
androgens is also thought to allow the
accumulation of lymphocytes in the
lachrymal tissue and increased
secretion
of
pro-inflammatory
cytokines, which contributes to dry eye
conditions1,3.
Cause of dry eye disease1-6
This can be caused by lack of tear
production (eg vitamin A deficiency,
drugs,
Sjögren’s
syndrome),
evaporation loss (eg blepharitis) and
abnormalities in the mucin or lipid
components of the tear film which
impairs the spreading of the tears (eg
alkaline
burns,
Stevens-Johnson
syndrome and cicatricial pemphigoid).
Blepharitis affects the meibomian
gland and reduces the outer lipid layer
allowing increased evaporation.
Drugs aggravating dry eye conditions
These include drugs possessing an
anticholinergic
action
eg
antiParkinsonism drugs, (benzhexol,
orphenadrine),
antihistamines,
tricyclic
anti-depressants,
phenothiazines,
anti-arrhythmics,
diuretics, retinoids, beta-blockers, oral
contraceptives and benzalkonium
chloride.
Treatment
The aims of treatment are to relieve the
symptoms of dry eyes and to restore,
prevent, or minimise structural damage
to the ocular surface. Obviously any
treatment should be accompanied by
life style changes eg avoid dry smoky
atmospheres etc. to maximise the
effectiveness of the treatment.
Treat underlying conditions – Blepharitis
Anterior/posterior blepharitis should
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Artificial tears
The mainstay of treatment is
replacement by artificial tears (table 1).
They produce comfort but are also
thought to reduce ocular inflammation
by lessening tear osmolarity and
flushing out inflammatory and other
noxious
agents.
Patients
are
encouraged to use when necessary,
and, if possible, reduce the number of
drops to one drop four times a day.
Most multi-dose products have
preservatives to prevent microbial
contamination and the most commonly
one used is benzalkonium chloride
(BAK). Long-term use of BAK causes
damage to the epithelial surface and
decreases tolerability due to irritation.
It can exacerbate ocular inflammation
and induce tear film instability4.
As an alternative to BAK oxidate
transient preservatives were developed
which dissipate upon contact with the
eye reducing the risk of ocular surface
damage. Examples of these are
GenAqua (Novartis) and Purite
(Allergan) which are found in products
classed as devices rather than licensed
as medicines. However, even these
preservatives
can
cause
mild
irritation4.
To reduce the problems caused by
BAK, the consensus is that any
artificial tears used more than six times
a day should be preservative-free.
Preservative-free products are usually
expensive as they are in unit dose
packaging and may be difficult to
manipulate. A dispensing system has
been produced (used in Hycosan) that
allows a multi-dose preservative-free
product. The mechanism for the
dispensing system protects the
preservative free artificial tear formula
from contamination eliminating the
Name
Brand name
Hypromellose 0.3%
Size
Cost NHS (£)
10mls
1.81
Hypromellose 0.5%
Isopoto Plain
10mls
0.85
Hypromellose 1%
Isopto Alkaline
10mls
0.99
Hypromellose and
Tears Naturale
15mls
1.68
Polyvinyl alcohol 1.4%
Liquifilm
15mls
1.93
Polyvinyl alcohol 1.4%
Sno tears
10mls
1.06
Carbomer 980 0.2%
Gel tears
10g
2.80
Carbomer 980 0.2%
Viscotears
10g
3.12
Carbomer 980 0.2%
Liposic
10g
2.96
Hydroxyethylcellulose PF
Minims
30 units
5.75
Hypromellose 0.32%
Artelac SDU
30 units
8.71
Carbomer 980
Viscotears
30 units
5.75
Polyvinyl alcohol 1.4%
Liquifilm
30 units
5.35
Povidone 5%
Oculotect
20 units
3.40
Carmellose 0.5%
Celluvisc
30,60 units
5.75, 10.99
Carmellose 0.5%
Celluvisc
30,90 units
5.75, 15.53
Dextran 70
Preservative free
< Table 1
Net cost of lubricant eye drops licensed as medicines available in the UK. BNF 53rd edition8
need
for
the
addition
of
preservatives4,7. Vismed multi is also a
preservative-free multi-dose system.
There does not appear to be much
difference between the various types of
artificial tears with the main
differences being the presence or
absence of preservatives and the
viscosity. Products with low viscosity
are less likely to impair vision eg
blurring, but are retained for a much
shorter period of time in the eye.
Hypromellose and polyvinyl alcohol
have low retention time with the latter
a longer retention time than
hypromellose. More viscous products
eg carbomers remain in the eye longer
but can cause blurring of vision.
Sufferers with more severe symptoms
are willing to trade the increased
blurred vision of the more viscous
products for the increased comfort4.
Gels and ointments, which are more
viscous, tend to be reserved for nighttime use or for the more serious dry eye
conditions. In preserved products, an
increase in viscosity increases the
contact time between the preservative
and the ocular surface and this possible
adverse effect must be balanced against
the increased duration of action of
product4.
31
30/11/07 CET
be treated by applying a warm flannel
or pads to warm the eyelid gland
secretions and to promote evacuation
of the oil. Good lid hygiene will also
remove crusting and clean the gland
orifices. This can be done with warm
water
alone,
although
most
practitioners recommend adding a few
drops of baby shampoo. Topical fusidic
acid is commonly used if required but
in refractory cases oral tetracyclines (if
no
contra-indications)
may
be
necessary for one to two months.
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32
Sodium Hyaluronate (Hyaluronic acid)
Name of
% sodium
Sodium hyaluronate is a linear
polymer composed of long chains of
repeating disaccharide units of Nacetylglucosamine and glucuronic
acid. It is a naturally occurring
substance found in connective tissue
and in synovial fluid. In the eye, it is
found in the vitreous and in the
aqueous
humour
at
a
lower
concentration. It is also a natural
component of tears9.
Although there are several products
on the market they are all classified as
devices with a CE mark and are not
prescribable by GPs (table 2).
Therefore, patients must obtain their
supplies from hospitals which are
under pressure to cut their drug
expenditure
or
purchase
these
products themselves.
In one trial using long-term
hyaluronidate treatment, an improved
cytology score was seen after three
months. How hyaluronidate improves
the ocular surface is currently
unknown but several mechanisms have
been advocated. Hyaluronidate is a
natural polymer and its concentration
increases in response to ocular damage.
It can stabilise the ocular surface
epithelial barrier and the suggestion is
that it may be directly involved in the
process
of
epithelial
repair.
Hyaluronate may play a part in
controlling the localised inflammation
often present in patients with
keratoconjuctivitis sicca. Hyaluronate
also increases the stability of the
precorneal tear film, due to its water
retentive properties, which improve
ocular surface wettability. Finally,
hyaluronate has viscoelastic properties
that can lubricate the ocular surface
reducing friction during blinking and
ocular movements10.
In
one
small
trial,
sodium
hyaluronate 0.1% has been found to be
more effective than 1.4% polyvinyl
alcohol. There was a significant
decrease in symptoms of burning and
stinging and a significant lower Rose
bengal staining. It was also found to be
safe and well tolerated11.
One concern has been raised
concerning
sodium
hyaluronate
products containing high phosphate
concentrations. In the British Journal of
product
hyaluronidate
Aquify comfort
5%
Name of manufacturer
Preservative system
CIBA Vision
Multidose use.
drops
Preservative system turns
into oxygen and water on
12
contact with the eye .
Blink
0.15%
AMO
Multidose use. Contains
OcuPure which breaks
down on contact with the
eye to sodium chloride
13
and water .
Hyal-drop
0.2%
Bausch & Lomb
Unit dose product.
Preservative free.
Hycosan
0.1%
Bausch & Lomb
Multidose-preservative
free. One way delivery
system that prevents
contamination of the
drops. Manufacturers give
product 12-week shelf life
once opened.
Oxyal
0.15%
Kestrel
Multidose use. Contains
Oxyd, which turns into
oxygen, sodium chloride
and water when in contact
15
with the eye .
Vismed
0.18%
TRB CHEMEDICA AC.
Unit dose product.
Distributed by Cantor &
Preservative free
16
Nissel in UK.
Vismed
0.8%
TRB CHEMEDICA AC.
Unit dose product.
Distributed by Cantor &
Preservative free
17
Nissel in UK.
< Table 2
A selection of sodium hyaluronidate “devices” available
Ophthalmology, there has been a report
of five cases of deep calcium
deposition in the cornea associated
with ocular surface disease and
frequent use of hyaluronic acid
artificial tears. All patients used one
formulation of phosphate buffered
hyaluronate eye drops (found in HyloComod and Hycosan) when rapid
calcification developed18.
The phosphate concentration in this
formulation was measured and found
to be much higher than other products.
(50.9 mmol/l. compared to <0.1 mmol/l
to 10.9 mmol/l.) The authors
concluded that the hyaluronate
artificial tear formulation favours the
formation of insoluble crystalline
calcium phosphate deposits in
presence of epithelial keratopathy due
to the high phosphate concentration in
the product. Although, the patients
used the product significantly much
more frequently than recommended by
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Acetylcysteine
Acetylcysteine is a derivative of the
amino acid L- cysteine. It is
commercially available as a 5%
solution in 0.35% hypromellose
(Ilube). It decreases the viscosity and
tenacity of mucus and this liquefying
action is due to the presence of a free
sulphydryl group, which opens up
disulphide bonds present in mucus. It
is useful in patients who have sticky
viscous mucus on the eye (filamentary
keratitis). Other strengths 10% and
20% are available from specialist
manufacturers. However, strengths
greater than 5% do sting on
application. Ilube can be sold, supplied
or administered by additional supply
optometrists19.
Topical Ciclosporin
Ciclosporin is a fungal derived peptide.
It prevents activation and nuclear
translocation
of
cytoplasmic
transcription factors, which are
required for cell activation and
inflammatory cytokine production. In
clinical trials, topical application has
been reported to increase aqueous tear
production and decrease ocular
symptoms. It has also been reported as
healing corneal ulcers associated with
Sjögren’s syndrome20. Ciclosporin
should not be used if the patient has an
active infection or a history of herpes. It
can cause some burning when applied
to the eye.
In the UK, topical ciclosporin 0.2%
ointment (Optimmune) is a veterinary
product licensed for the treatment of
canine keratoconjunctivitis. As it is an
unlicensed product in humans, doctors
prescribing it must take full
responsibility, obtained informed
consent and counsel patients well
explaining why it is labelled for animal
use only21. Ciclosporin eye drops 1%
are available from Moorfields Eye
Hospital as a ‘special’. A ciclosporin
0.05% eye drop emulsion (Restasis),
has been approved by the Food and
Drug Administration (FDA) but it is not
commercially available in the UK.
Restasis comes in unit dose packages
and is instilled night and morning22.
In a multicentre randomised trial,
topically applied ciclosporin A 0.05%
was reported to produce significant
improvement in the signs and
symptoms of dry eye disease in
patients with aqueous deficiency and
keratoconjunctivitis
sicca.
Other
studies show a significant decrease in
the levels of both inflammatory cells
and markers in the conjunctival
epithelium and an increase in the
number of goblet cells2.
Autologous serum eye drops
These are prepared by the National
Blood Service from the patient’s own
serum. Unfortunately, a positive
serology for hepatitis B and C, syphilis
and HIV excludes patients from this
treatment. The patient donates
approximately one pint of blood and
the serum is extracted and diluted with
saline, decanted into eye drop bottles
and is frozen. Approximately 150
bottles are produced from each pint of
blood
and
the
process
takes
approximately six weeks. The patient
needs to keep the stock frozen but one
bottle should be allowed to thaw daily
at room temperature. Once defrosted
this bottle should be kept in the fridge
and discarded at the end of the day23.
There is no standard concentration
agreed with some centres using 20%,
some 50% and other neat autologous
serum. More research on the optimum
strength and dose is required (usually
four to six times a day) plus data on
long-term use.
The exact components in autologous
serum eye drops that produce the
beneficial effect have not been
identified. Several tear factors have
been identified to be of importance in
the maintenance of normal corneal and
conjunctival epithelium. These include
epidermal growth factor (EGF), which
accelerates
corneal
epithelial
proliferation, Vitamin A, which if
deficient in tears may lead to epithelial
metaplasia and transforming growth
factor ß
(TGF-ß), which controls
epithelial proliferation. All these
factors are found in serum, although at
a different concentration to tears24.
The obvious disadvantage is that
patients need to donate blood 3-4 times
a year and if they are medically unfit to
do so are excluded from this treatment.
There appears to be few side effects or
complications reported with the main
problems being anaemia, risk of
infection as the eye drops are
unpreserved, and protein deposits on
the eye (reversible on stopping the
product)23.
Topical steroids
Topical steroids improve both the signs
and symptoms of dry eye in patients
with moderate to severe dry eye who
continue to have symptoms despite
treatment or have evidence of corneal
disease. Short two-week courses have
been used to treat exacerbation of
inflammatory symptoms. However,
their use is limited by the side effect
profile (see later).
Other drug treatments
Parasympathetic agents
Pilocarpine (Salagen) oral tablets can
increase secretions via stimulation of
the parasympathetic nervous system. It
is licensed for the treatment of
xerostomia and dry eyes in Sjgören’s
syndrome.
The recommended dose is 5mg four
times a day with meals and bedtime. If
tolerated but the response is
insufficient, the dose can be increased
to 30mg a day in divided doses. It is
contra-indicated
in
uncontrolled
asthmatics and obstructive pulmonary
disease.
Also iritis and any eye disease where
miosis is undesirable. Care should be
taken in patients with cardiac disease
as it can cause palpitations.
Side effects include those associated
with
excessive
parasympathetic
stimulation, such as increased
sweating, increased urinary frequency,
gastrointestinal disturbances including
diarrhoea, flu-like symptoms and
headaches.
In
clinical
trials,
pilocarpine has been found to be more
effective in resolving dry mouth rather
than dry eyes6,8.
Bromhexine
Bromhexine is a secretolytic that
increases the production of serous
mucus. One trial on patients with
Sjögren’s syndrome (dose 48 mg/day)
33
30/11/07 CET
the manufacturer, the manufacturers
now state that Hycosan has been
reformulated and is now phosphate
free.
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Drug
Brand name
Presentation
Licensed indications
Diclofenac 0.1%
Voltarol Ophtha
5ml
Inhibition of preoperative miosis during cataract surgery.
multidose
Treatment of post-operative inflammation in cataract surgery.
Control of ocular pain and discomfort associated with corneal epithelial
defects after excimer PRK surgery or accidental non-penetrating
trauma.
Diclofenac 0.1%
Voltarol Ophtha
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34
Packs of 5 and
Control of inflammation after Argon Laser Trabeculoplasty (ALT).
40 unit doses
The relief of the ocular signs and symptoms of seasonal allergic
conjunctivitis (SAC).
Treatment of inflammation and discomfort after strabismus surgery.
Treatment of ocular pain and discomfort after radial keratotomy.
Flurbiprofen
Ocufen
40 x 0.4mls
The inhibition of intraoperative miosis.
The management of post-operative and post-laser trabeculoplasty
inflammation in the anterior segment of the eye in patients in whom
steroid therapy is not recommended.
Ketorolac
Acular
5ml
Prophylaxis and reduction of inflammation and associated symptoms
following ocular surgery.
Contra-indicated in children.
< Table 3
Licensed indications of topical anti-inflammatory drugs used in ophthalmology
reported that the values on the
Schirmer test were significantly higher
after bromhexine than after placebo.
Also the break-up time was increased
after bromhexine, which suggests that
the drug has a dose-dependent effect on
lachrymal gland secretion in Sjögren’s
syndrome6, 25.
Androgens
There are anecdotal reports that
systemic androgen therapy in women
can help dry eye syndrome but there
have not been any clinical trials. A
topical testosterone cream/gel is in
phase 1 clinical trials3.
Flaxseed oil
Flaxseed oil contains linoleic acid and
has been reported to help dry eye. In a
trial, one group of patients with
meibomian gland dysfunction were
given tablets containing linoleic acid
(28.5mg) and gama-linolenic acid
15mg.
One group had only lid hygiene and
one group had both tablets and lid
hygiene. Most improvement was seen
in
the
group
treatments26.
receiving
both
Surgical and other treatments
Patients whose condition is aggravated
by lid abnormalities may benefit from
corrective surgery.
For patients in whom artificial tears
are not sufficient, punctal occlusion
may be effective for both preserving the
patient’s own natural tears and
prolonging the effect of instilled tears.
Plugs are initially used and they can be
temporary (collagen – a few days to
gauge benefit) or semi-permanent
(silicone).
They have the advantage of being
reversible if epiphora develops.
Permanent occlusion with laser or
thermal cautery can be performed but
this should always follow a trial with
plugs as this is not readily reversible.
Anti-inflammatory drugs
There are two main types of antiinflammatory products used in the eye,
steroids and non-steroidal
inflammatory products.
anti-
Non-steroidal anti-inflammatory drugs
(NSAID)
Endogenous prostaglandins play a
significant role in the initiation and
maintenance of ocular inflammation.
They increase the permeability of the
blood ocular barrier, affect intraocular
pressure and produce miosis and
conjunctival hyperaemia. NSAIDs
primarily act as cyclooxygenase
inhibitors and reduce the formation of
endogenous
prostaglandins
from
arachidonic acid, thereby preventing
the formation of prostaglandins. There
are many valid clinical uses for
NSAIDs in ophthalmology but as the
commercial products have very few
licensed indications, they may be used
outside their licensed indications in
clinical practice27 (table 3).
Although these drugs do inhibit
intra-operative miosis if instilled preoperatively they have no intrinsic
mydriatic properties and do not replace
the use of mydriatic agents for cataract
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Topical corticosteroids
Topical corticosteroids are widely used
in ophthalmology for anterior segment
inflammation. They have poor
posterior penetration and therefore oral
therapy or systemic or local injections
should be used in conditions affecting
the posterior segment. The main uses
are in uveitis, suppression of post-
Name of steroid
Relative potency from clinical experience
Hydrocortisone 1%
1
Fluorometholone 0.1%
3
Dexamethasone 0.1%
4
Rimexolone 1%
4.5
Lotoprednol 0.5%
4.5
Prednisolone acetate 1%
5
35
< Table 4
Relative potency from Review of optometry Corticosteroids (5 - most potent)
operative
inflammation
and
keratoconjuncitivitis. They have been
used under specialist supervision with
aciclovir for herpes simplex keratitis.
Corticosteroids act at the first step of
the arachidonic acid pathway by
inhibiting phospholipase, which is
responsible for converting membrane
phospholipid into arachidonic acid. By
preventing
the
formation
of
arachidonic acid, corticosteroids
effectively block both cyclooxygenase
and lipoxygenase pathways, which
normally
lead
to
pain
and
inflammation. This is in contrast to
NSAIDs, which act only on the
cyclooxygenase
pathway.
Corticosteroids also stabilise mast cells
preventing degranulation and the
release of histamine and other
inflammatory mediators, which give
rise to vasodilation and oedema.
Corticosteroids, although effective,
do have limitations, with serious
ocular side effects.
In articles on topical corticosteroids
for ophthalmic use, there is variation of
opinion on their relative potencies
(table 4). Although relative potencies
have been measured for oral
administration and in skin tests, this
can
not
be
extrapolated
to
ophthalmology as potency is also
dependent on penetration into the
anterior chamber. Also the salts have a
significant effect with prednisolone
acetate
having
much
greater
penetration than prednisolone sodium
phosphate while the reverse is true of
hydrocortisone. Absence of the
epithelium in traumatic injuries will
influence penetration of steroids29,30.
In one paper, prednisolone acetate
1% was found to have a much higher
concentration in the anterior chamber
than
dexamethasone.
However,
dexamethasone is seven times more
potent weight per weight than
prednisolone and therefore this would
compensate for the low concentration.
Despite this, prednisolone acetate 1%
was found to be more potent than
dexamethasone 0.1%30.
Corticosteroid
compounds
are
generally lipophilic and have poor
solubility so have to be formulated as a
suspension
(dexamethasone,
prednisolone acetate) or as a salt, eg
sodium phosphate30.
To reduce side effects it is important
to use as short a course as possible and
to taper the dose down slowly as the
condition improves to prevent rebound
inflammation.
Prednisolone acetate 1%
This is one of the most commonly
prescribed topical steroids and is one
of the most clinically potent. It
penetrates the cornea and anterior
segment well and is one of the drugs of
choice
for
anterior
uveitis.
Prednisolone acetate 1% is effective for
moderate to severe forms of ocular
inflammation such as episcleritis,
scleritis, iritis, inflammatory keratitis,
uveitic glaucoma, and chemical or
thermal burns of the cornea29-33.
30/11/07 CET
surgery.
Although the use of posterior
chamber intraocular lenses has
reduced the incidence and severity of
complications
following
cataract
surgery, some still occur especially in
eyes with pre-existing anterior disease.
Many well-designed randomised,
prospective double masked clinical
studies provide evidence that topical
NSAIDs are useful in the prophylaxis
and management of postoperative
inflammation
following
cataract
surgery. Evidence seems to suggest that
diclofenac and ketorolac are slightly
more effective than flurbiprofen27.
NSAIDs can be used in place of
steroids when steroid use would not be
appropriate or to reduce steroid side
effects. One example could be in low
risk surgery to reduce inflammation but
to avoid such steroid side effects as
increased
intraocular
pressure.
However, more clinical evidence to
support a wider role is required.
There is some evidence that
prophylactic NSAID is beneficial in
preventing cystoid macular oedema
(CMO) and there is evidence of synergy
between NSAIDs and steroids. Due to
the increased risk of side effects with
this combination, it should only been
undertaken by specialists with careful
patient monitoring27.
The main side effects of NSAIDs are
local irritation (transient burning,
stinging and conjunctival hyperaemia).
None of them have proved to be safe or
effective in children and the
manufacturers of Acular state that the
drops are contra-indicated in children.
All are contra-indicated in patients
allergic to, or showing severe adverse
drug reactions to acetylsalicylic acid
and they should be used with caution
in patients with bleeding disorders and
underlying ophthalmic infections28.
An additional supply optometrist can
prescribe diclofenac eye drops.
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30/11/07 CET
36
Dexamethasone 0.1%
Preparation
Average pressure rise mm (Hg)
This is used for moderate to severe
inflammation. It has the greatest effect
on intra-ocular pressure and ideally
should be used for short courses only.
As it is available as a preservative-free
product, it is used in conditions where
preservatives would be a problem but a
moderate/strong steroid is required eg
following corneal grafts29-33.
Dexamethasone 0.1%
22 +/- 2.9
Prednsiolone acetate 1%
10 +/- 1.9
Fluorometholone 0.1%
6.1 +/- 1.4
Hydrocortisone 0.5%
3.2 +/- 1.0
Loteprednol
Loteprednol 0.5% is a steroid that is
available in the USA and is expected to
be launched in the UK. It has been
designed to be a “site active”
corticosteroid. It is licensed for the
treatment of steroid responsive
inflammatory conditions associated
with the palpebral and bulbar
conjunctiva, cornea, and anterior
segment of the globe. It appears to be
slightly less potent than prednisolone
acetate but is less likely to cause a
clinically significant increase in intraocular pressure.
Another formulation of loteprodnol
(Alrex) is available in the US. It is a
lower strength 0.2% and is licensed for
the treatment of seasonal allergic
conjunctivitis. There are currently no
plans to launch it in the UK31,32,34.
< Table 5
IOP elevation for different steroid preparations35
responders. Many cases of ocular
inflammation resolves within this time
and steroids can start to be tailed off.
Suppression of the immune system
Corticosteroids can suppress the
immune system, therefore, it is
important to make a competent
diagnosis of “red eye”. If caused by an
infection, particularly herpes, then the
steroid treatment can encourage the
infection to progress leading to corneal
ulceration and damage to vision.
Formation of cataracts
Prolonged use can lead to the formation
of posterior subcapsular cataracts.
Rimexolone 1%
This is regarded as a potent steroid but
has a lower effect on intra-ocular
pressure29-33.
Fluorometholone 0.1%
This is a weaker steroid and is useful
for treating mild to moderate
inflammation. It is less likely to cause
an increase in intra-ocular pressure and
therefore is used to treat chronic
inflammation29-33.
Hydrocortisone
Used
for
mild
inflammation29-33.
to
moderate
Side effects
Raised intraocular pressure
Although steroids can increase the
intra ocular pressure (table 5), it is
unlikely to occur much before 3-5
weeks of continual use, even in steroid
Anti-allergic drugs
A variety of drugs are used in the
treatment of allergic conjunctivitis.
These include anti-histamines, mast
cell stabilisers and in one over-thecounter
(OTC)
preparation
a
vasoconstrictor. In severe cases,
corticosteroids are used but only short
term due to the adverse effects
associated with long-term use.
Topical treatment generally appears
to be more effective in the treatment of
allergic conjunctivitis than systemic.
This is because higher concentrations
of drugs can be achieved in the
conjunctiva with topical application
and the onset of action is faster. Lower
systemic blood levels leads to fewer
side effects with topical antihistamines. Oral antihistamines can
produce dry eye as a side effect, which
allows allergens better access to the
conjunctiva and lack of tears prevents
effective removal of allergens that do
enter the eye.In some patients, a
combination of both topical and oral
antihistamines are required to control
symptoms and if widespread systemic
allergic symptoms occur patients
should be on systemic therapy.
Immune response
The ocular conjunctiva is a mucosal
surface that is highly exposed to
environmental allergens. In sensitive
individuals, prior exposure to the
antigen causes the production of
Immunoglobulin E which binds to the
mast cell. After further antigen
exposure mast cell degranulation
occurs with release of histamine,
leukotrienes
and
prostaglandins.
Histamine causes itching, redness and
swelling and is associated with the
early phase reaction. Leukotrienes and
prostaglandins act synergistically to
enhance vascular permeability and
prostaglandins are also associated with
mucus discharge and redness.
Mast cells also release cytokines,
which are involved in the late phase
inflammatory response, which is
responsible
for
epithelial
desquamation and injury. Expression of
intercellular
adhesion
molecule
(ICAM)-1 occurs, which leads to the
recruitment of eosinophils and
neutrophils.
Antihistamines
There are two groups of topical
antihistamines. The antihistamines and
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Antazoline
This is only available in a combination
product
with
xylometazoline
(Otrivine-Antistin) which can be sold
over-the-counter. Both antazoline and
xylometazoline are contra-indicated in
narrow angle glaucoma as they can
precipitate an acute attack in
susceptible patients due to their
mydriatic activity. Xylometazoline is a
vasoconstricting agent that decreases
vascular congestion and eyelid oedema
via alpha receptor stimulation. It has
no effect on diminishing the allergic or
inflammatory response and has no
effect
on
pruritis.
Although
sympathetic vasoconstrictors are
effective in reducing hyperaemia they
should only be used short-term as they
can cause rebound hyperaemia with
long term use.
The main side effects of OtrivineAntistin are stinging on instillation,
blurred
vision,
and
headache.
Occasionally some patients have
reported systemic side effects due to
the xylometazoline eg palpitations,
paleness and sweating. Its use in
allergic
conjunctivitis
is
not
recommended in the PRODIGY
guidelines due to the possibility of
systemic side effects and that it is only
recommended for short-term use8,6.
levocabastine in reducing and
preventing ocular itching but similar
efficacy in controlling hyperaemia. It
also is more effective than nedocromil.
Its main side effect is headache
(11%)36.
Mast cell stabilisers and
antihistamines
Azelastine (Opilast)
An antihistamine and mast cell
stabiliser, azelastine is licensed for the
treatment of seasonal and perennial
allergic conjunctivitis in adults and
children over 12. Its main side effects
are ocular burning (30%), headache
(15%) and bitter taste (10%)36.
This antihistamine acts on both H1 and
H2 receptors, stabilises mast cells and
has an anti-inflammatory effect. It
tends to have a rapid onset and a long
duration of action of eight hours.
It appears to be superior to
olopatadine in reducing itching in a
small conjunctival antigen study. In
trials it was found to have similar
tolerability to the other agents used in
the treatment of allergic conjunctivitis
but has been reported to cause upper
respiratory tract infection symptoms
(10%)36.
Due to it being very new it is not
available to additional supply
optometrists.
Ketotifen (Zaditen)
Levocabastine is a selective H1
antagonist and has also been shown to
down regulate ICAM-1 expression. In
trials it has shown to be more effective
than topical sodium cromoglycate for
the treatment of seasonal allergic
conjunctivorhinitis and as efficacious
and well tolerated as lodoxamide. It is
effective in the suppression of the early
phase reaction but does not suppress
the development of a late phase
reaction36. Currently it is not available
in the UK.
Ketotifen is an antihistamine, a mast
stabiliser, acts as an eosinophil
inhibitor and inhibits plateletactivating factor.
It is effective against ocular itching
and hyperaemia and its effects are seen
within 15 minutes of application. Its
duration of action is eight hours.
In a three-week parallel group study
of ketotifen and olopatadine in 66
patients with seasonal allergic
conjunctivitis, ketotifen was found to
reduce the itching and hyperaemia
more than olopatadine. However in
another two-week trial ketotifen was
found to be less effective than
olopatadine. Its main side effects are
conjunctival injection (7%) and
headache (1.5%)36.
Emedastine is a selective H1 blocker
and has a potent and selective effect in
inhibiting eosinophil chemostaxis. It
has found to be more effective than
Olopatadine is a long acting
antihistamine with an additional mast
cell stabilising action and has been
found to reduce ICAM-1 expression. It
is effective in pruritis for up to eight
hours and in an antigen challenge
study it was found that a single drop
was more efficacious than two weeks
of nedocromil treatment. Its main side
effect is headache (7%)36.
Optometrists are able to supply
antazoline, and azelastine, providing
there is an OTC pack available.
Azelastine, emedastine, ketotifen,
and olopatadine are available to
additional supply optometrists as is
levocarbastine but currently no
product is available in the UK
Epinastine (Relestat)
Levocabastine
Emedastine (Emadine)
Olopatadine (Opatanol)
Mast cell stabilisers
These are effective in both the
treatment and prophylaxis of allergic
conjunctivitis but their onset of action
is
slower
than
the
topical
antihistamines.
For
effective
prophylaxis they should be started
before the patient is exposed to the
allergen. A number of trials show good
efficiency against placebo but there are
very few trials directly comparing
different mast cell stabilisers.
Many authors now recommend
using a joint antihistamine mast cell
stabilising
product.
However
PRODIGY recommends reserving these
agents as second line when other
agents fail37.
Sodium Cromoglycate
Both PRODIGY and the National
Prescribing Centre in the MeReC
guidelines recommend the use of
sodium cromoglycate as the first line
mast cell stabiliser. It is effective,
cheap, has a good safety record and
was the first mast cell introduced.
There is no lower age limit for its use
in children and its main side effect is
transient burning and stinging. One
disadvantage is that it should be used
four times a day37,38.
It is licensed for the treatment of
both allergic conjunctivitis and vernal
keratoconjunctivitis and is available
for OTC sale for both perennial and
SAC. OTC brands include Boots hay
fever relief, Clariteyes, Opticrom
37
30/11/07 CET
the “multiple action” group which
have an antihistamine, mast stabilising
and
pro-inflammatory
mediator
inhibitory action role36.
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Allergy, Optrex Allergy and Vividrin.
Lodoxamide (Alomide)
30/11/07 CET
38
Lodoxamide is only licensed for the
treatment of allergic conjunctivitis in
adults and children over four years of
age. The dose is one drop four times a
day.
It is also available as an OTC product
Alomide allergy (same indication and
ages).
altogether more effective than sodium
cromoglycate. However, the trial
contained only 34 patients lasted five
months and was a parallel group study,
not a randomised control trial39.
Optometrists can supply sodium
cromoglycate and lodoxamide in their
OTC presentations and additional
supply optometrists can supply all
three in their POM presentations.
Nedocromil (Rapitil)
Other agents
Nedocromil is licensed for the
treatment of both allergic conjunctivitis
and vernal keratoconjunctivitis (VKC)
in adults and children over six years
old. For allergic conjunctivitis, the dose
is one drop twice a day but can be
increased to four times a day and for a
maximum of 12 weeks. For VKC, the
dose is one drop four times a day. The
main side effects are a transient burning
and stinging and a distinctive taste has
been reported.
In one small trial of children between
4-17 years with VKC, it was found that
nedcromil had a faster efficacy and was
NSAIDs have generally found to be
inferior to multiple action topical
antihistamines in the treatment of
allergic conjunctivitis although only
diclofenac is licensed for (SAC). Its
only advantage is that it is available as
a preservative free product for patients
allergic to preservatives. For severe
cases, topical corticosteroids have been
used but long-term use should be
avoided due to the adverse effects.
In some small trials topical
ciclosporin A has been found to be
effective in the treatment of allergic
conjunctivitis and VKC. However, more
research is required on the role of
ciclosporin A before it can be
recommended for routine use. It is also
not licensed for these conditions.
Conclusion
Current
understanding
of
the
pathogenesis of dry eye disease has
changed from a lack of, or altered
quality of tears to recognition of
inflammation as the key pathogenic
mechanism.
Interesting new developments are the
use of NSAIDs in conditions outside
their licensed indication and a new
“site-activated” topical steroid.
About the author
Elaine Mann is currently a hospital
pharmacist and is the lead clinical
pharmacist for ophthalmology at Leeds
Teaching Hospital Trust.
References
See www.optometry.co.uk/references
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Module questions
Course code: c-5848
Please note, there is only one correct answer. Enter online or by form provided
An answer return form is included in this issue. It should be completed and returned to CET initiatives (c-5848) OT,
Ten Alps plc, 9 Savoy Street, London WC2E 7HR by December 26 2007.
2. Which one of the following is incorrect regarding benzalkonium chloride?
a) It is the most commonly used preservative
b) It aids tear film stability
c) It exacerbates ocular inflammation
d) Long term use can cause damage to the epithelial surface
3. Which one of the following lubricant drops is a carbomer 980?
a) Oculotect
b) Liquifilm
c) Celluvisc
d) Liposic
4. Hyaluronic acid is:
a) a derivative of the amino acid L- cysteine
b) polymer composed of units of N-acetylglucosamine and glucuronic acid
c) a fungal derived peptide
d) a serum deprived product
5. Which one of the following statements is correct?
a) Systemic androgens have been reported to be useful in treating dry eyes in
women in anecdotal reports
b) The recommended dose of Cevimeline is 5mg four times a day with meals and
bedtime
c) In clinical trials pilocarpine tablets are equally effective in resolving
symptoms of dry eyes and dry mouth
d) Bromhexine is also a parasympathetic agent
6. Which one of the following steroids produces the least rise in intra-ocular
pressure?
a) Dexamethasone 0.1%
b) Fluorometholone 0.1%
c) Hydrocortisone 0.5%
d) Prednisolone acetate 1%
7. Which one of the following statements is incorrect?
a) Ketorolac is contra-indicated in children
b) Topical flurbiprofen has shown to be more effective than topical diclofenac
c) Prophylactic NSAID is beneficial in preventing cystoid macular oedema
d) Topical NSAIDs are contra-indicated in patients allergic to acetyl salicyclic
acid
8. Which one of the following is the most potent steroid?
a) Dexamethasone 0.1%
b) Prednisolone acetate 1%
c) Rimexolone 1%
d) Fluorometholone 0.1%
9. Which one of the following statements is incorrect?
a) Loteprednol 0.5% is a “site active” steroid
b) A significant rise in intra ocular pressure is unlikely to occur much before 3-5
weeks of continual use even in steroid responders
c) Corticostroids only act on the cyclooxygenase pathway
d) One advantage of dexamethasone is that it is available in a preservative free
product
10. Which one of the following does not have a mast cell stabilising action?
a) Azelastine
b) Ketotifen
c) Antazoline
d) Epinastine
11. Which one of the following is licensed for the treatment of vernal
keratoconjunctivitis?
a) Nedocromil
b) Lodoxamide
c) Emedastine
d) Levocabastine
12. Which one of the following cannot be supplied by an additional supply
optometrist?
a) Azelastine
b) Epinastine
c) Emedastine
d) Ketotifen
Please complete on-line by midnight on December 26 2007 - You will be unable to submit exams after this date – answers to the module will be published in our Jan 11 issue
39
30/11/07 CET
1. Vitamin A deficiency causes dry eye syndrome by:
a) Decreasing the production of the outer lipid layer of tears
b) Impaired spreading of tears
c) Lack of tear production
d) Malfunction of the meibomian gland
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CET answers
Course code: c-5847
These are the correct answers to Module 10 Part 11, which appeared in our November 2 issue
1.The answer is d.
Ofloxacin. This antibacterial inhibits DNA gyrase. All the others inhibit protein
synthesis.
30/11/07 CET
40
2.The answer is c.
Fusidic acid eye drops. The diamidines have been available as P medicines for
many years and chloramphenicol eye drops since June 2005.
3.The answer is d.
Polyfax eye ointment. All the antibiotics are prescription only medicines but
Polyfax was made available to additional supply optometrists in June 2005.
4.The answer is b.
chloramphenicol. Bacitracin is primarily active against Gram-positive bacteria,
levofloxacin is a relatively recently-introduced fluoroquinolone and tobramycin is
not available as a single component ophthalmic preparation in the UK.
5.The answer is d.
Thymidine kinase. Carbonic anhydrase is an enzyme involved in the secretion of
aqueous humour, DNA gyrase is an enzyme needed by the bacterium for the
synthesis of DNA and is inhibited by fluoroquinolones. DNA polymerase is inhibited
by aciclovir triphosphate.
6.The answer is d.
Tobradex which contains tobramycin and dexamethasone. All the other
preparations contain/contained polymyxin B.
7.The answer is b.
blockade of NMDA receptors. This is the mode of action of the neuronal protective
agent memantine. All of the other mechanisms of action lower intraocular
pressure.
8.The answer is a.
betaxolol 0.5% solution. Betaxolol 0.25% is less effective than the other agents in
lowering intraocular pressure.
9.The answer is d.
Stimulates cholinergic receptors. Pilocarpine is a cholinergic or
parasympathomimetic agent.
10.The answer is c.
Brimonidine. Adrenaline and dipivefrin, which is converted to adrenaline, are nonselective -stimulants, apraclonidine is a selective 2 –stimulant, but its
selectivity is not as great as that of brimonidine.
11.The answer is c.
Carbonic anhydrase inhibitors. This is an adverse effect of brinzolamide and
dorzolamide.
12.The answer is a.
Brimonidine. The combination products of dorzolamide, latanoprost and travoprost
are called Cosopt, Xalacom and Duotrav respectively.
CET to a Masters - OT and City join forces to provide CET points
CITY UNIVERSITY and OT have
joined forces allowing readers to
achieve CET points through to a
full Masters in Clinical Optometry.
This year's series is in two parts:
Paediatric Optometry (January June) and Optometric Managment
of Anterior Segment Eye Disease
(June - December). Successfully
complete the MCQs accompanying
the current article and receive 2
CET points. Readers wishing to
work towards a postgraduate
qualification may obtain 10
postgraduate credits by sitting a
three hour examination relating to
the OT CET articles. This
examination is held in May of each
year and is based on all the City
CET articles published in 2007.
Want to further increase your
knowledge? Join us for the
Binocular Vision course - January
13 - 15 or Vision in the Aged February 10 - 12 2008.
Alternatively, start your
'Additional Supply/Supplementary
Prescribing' training with the
Principles of Therapeutics
distance learning module. CET
days are running on the first day
of each course. Those attending
the three day modules at City may
also take an examination to obtain
a further 15 postgraduate credits.
For further information see
www.city.ac.uk/optometry/msc.
Contact Dr Michelle L Hennelly by
emailing (m.hennelly@city.ac.uk)
or call 0207 040 8352.