CITY3011.qxd:CET 22/11/07 14:43 Page 30
`
`CET
`
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`TRAINING
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`
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`
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`
`MODULE 10:12
`
`COURSE CODE: C-5848
`
`Drugs used in the treatment of dry eye
`syndrome, anti-inflammatory drugs and
`topical anti-allergy drugs
`
`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.
`
`30/11/07 CET3
`
`0
`
`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 T-
`lymphocytes
`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.
`to
`Tear secretions are subject
`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
`anti-
`Parkinsonism 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
`
`CONFUSED ABOUT CET REQUIREMENTS? www.cetoptics.com/cetusers/faqs/
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`
`APOTEX 1047, pg. 1
`
`

`

`CITY3011.qxd:CET 22/11/07 14:43 Page 31
`
`Sponsored by:
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`
`CET
`
`30/11/07 CET3
`
`1
`
`Cost NHS (£)
`
`1.81
`
`0.85
`
`0.99
`
`1.68
`
`1.93
`
`1.06
`
`2.80
`
`3.12
`
`2.96
`
`5.75
`
`8.71
`
`5.75
`
`5.35
`
`3.40
`
`Name
`
`Brand name
`
`Hypromellose 0.3%
`
`Hypromellose 0.5%
`
`Isopoto Plain
`
`Hypromellose 1%
`
`Isopto Alkaline
`
`Hypromellose and
`Dextran 70
`
`Tears Naturale
`
`Polyvinyl alcohol 1.4%
`
`Liquifilm
`
`Polyvinyl alcohol 1.4%
`
`Sno tears
`
`Carbomer 980 0.2%
`
`Gel tears
`
`Carbomer 980 0.2%
`
`Viscotears
`
`Carbomer 980 0.2%
`
`Liposic
`
`Preservative free
`
`Hydroxyethylcellulose PF
`
`Minims
`
`Hypromellose 0.32%
`
`Artelac SDU
`
`Carbomer 980
`
`Viscotears
`
`Polyvinyl alcohol 1.4%
`
`Liquifilm
`
`Povidone 5%
`
`Oculotect
`
`Size
`
`10mls
`
`10mls
`
`10mls
`
`15mls
`
`15mls
`
`10mls
`
`10g
`
`10g
`
`10g
`
`30 units
`
`30 units
`
`30 units
`
`30 units
`
`20 units
`
`Carmellose 0.5%
`
`Celluvisc
`
`30,60 units
`
`5.75, 10.99
`
`Carmellose 0.5%
`
`Celluvisc
`
`30,90 units
`
`5.75, 15.53
`
`< Table 1
`Net cost of lubricant eye drops licensed as medicines available in the UK. BNF 53rd edition8
`
`of
`addition
`the
`for
`need
`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 night-
`time 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.
`
`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.
`
`Artificial tears
`is
`treatment
`The mainstay of
`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
`
`APOTEX 1047, pg. 2
`
`

`

`CITY3011.qxd:CET 22/11/07 14:43 Page 32
`
`CET
`This issue CET: Free ✔
`
`CONTINUING
`EDUCATION &
`TRAINING
`
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`
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`
`Name of
`product
`
`Aquify comfort
`drops
`
`% sodium
`hyaluronidate
`
`Name of manufacturer
`
`Preservative system
`
`5%
`
`CIBA Vision
`
`Multidose use.
`Preservative system turns
`into oxygen and water on
`contact with the eye12.
`Multidose use. Contains
`OcuPure which breaks
`down on contact with the
`eye to sodium chloride
`and water13.
`Unit dose product.
`Preservative free.
`
`Multidose-preservative
`free. One way delivery
`system that prevents
`contamination of the
`drops. Manufacturers give
`product 12-week shelf life
`once opened.
`
`Multidose use. Contains
`Oxyd, which turns into
`oxygen, sodium chloride
`and water when in contact
`with the eye15.
`
`Unit dose product.
`Preservative free16
`
`Unit dose product.
`Preservative free17
`
`Blink
`
`0.15%
`
`AMO
`
`Hyal-drop
`
`0.2%
`
`Bausch & Lomb
`
`Hycosan
`
`0.1%
`
`Bausch & Lomb
`
`Oxyal
`
`0.15%
`
`Kestrel
`
`Vismed
`
`0.18%
`
`Vismed
`
`0.8%
`
`TRB CHEMEDICA AC.
`Distributed by Cantor &
`Nissel in UK.
`
`TRB CHEMEDICA AC.
`Distributed by Cantor &
`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 Hylo-
`Comod 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
`
`Sodium Hyaluronate (Hyaluronic acid)
`Sodium hyaluronate
`is a
`linear
`polymer composed of long chains of
`repeating disaccharide units of N-
`acetylglucosamine 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.
`long-term
`In one
`trial using
`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.
`sodium
`trial,
`In
`one
`small
`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.
`raised
`One concern has been
`concerning
`sodium
`hyaluronate
`products containing high phosphate
`concentrations. In the British Journal of
`
`30/11/07 CET3
`
`2
`
`APOTEX 1047, pg. 3
`
`

`

`CITY3011.qxd:CET 22/11/07 14:44 Page 33
`
`30/11/07 CET3
`
`3
`
`Sponsored by:
`
`CONTINUING
`EDUCATION &
`TRAINING
`This issue CET: Free ✔ Worth 2 standard
`CET points
`To gain more standard CET points for this year’s PAYL series, enter online at: www.otcet.co.uk or  0207 878 2412
`
`CET
`
`the manufacturer, the manufacturers
`now state that Hycosan has been
`reformulated and is now phosphate
`free.
`
`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)
`
`APOTEX 1047, pg. 4
`
`

`

`CITY3011.qxd:CET 22/11/07 14:44 Page 34
`
`CET
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`
`Drug
`
`Brand name
`
`Presentation
`
`Licensed indications
`
`Inhibition of preoperative miosis during cataract surgery.
`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.
`
`Control of inflammation after Argon Laser Trabeculoplasty (ALT).
`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.
`
`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.
`
`Prophylaxis and reduction of inflammation and associated symptoms
`following ocular surgery.
`Contra-indicated in children.
`
`Diclofenac 0.1%
`
`Voltarol Ophtha
`multidose
`
`5ml
`
`Diclofenac 0.1%
`
`Voltarol Ophtha
`
`Packs of 5 and
`40 unit doses
`
`Flurbiprofen
`
`Ocufen
`
`40 x 0.4mls
`
`30/11/07 CET3
`
`4
`
`Ketorolac
`
`Acular
`
`5ml
`
`< Table 3
`Licensed indications of topical anti-inflammatory drugs used in ophthalmology
`
`the
`the values on
`that
`reported
`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
`that
`There are anecdotal reports
`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
`
`group
`the
`in
`treatments26.
`
`receiving
`
`both
`
`and non-steroidal
`steroids
`inflammatory products.
`
`anti-
`
`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 anti-
`inflammatory products used in the eye,
`
`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 pre-
`operatively they have no intrinsic
`mydriatic properties and do not replace
`the use of mydriatic agents for cataract
`
`APOTEX 1047, pg. 5
`
`

`

`CITY3011.qxd:CET 22/11/07 14:44 Page 35
`
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`surgery.
`the use of posterior
`Although
`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.
`that
`There
`is
`some evidence
`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.
`
`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
`
`Hydrocortisone 1%
`
`Fluorometholone 0.1%
`
`Dexamethasone 0.1%
`
`Rimexolone 1%
`
`Lotoprednol 0.5%
`
`Prednisolone acetate 1%
`
`Relative potency from clinical experience
`
`1
`
`3
`
`4
`
`4.5
`
`4.5
`
`5
`
`< Table 4
`Relative potency from Review of optometry Corticosteroids (5 - most potent)
`
`and
`inflammation
`operative
`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
`
`the
`hydrocortisone. Absence of
`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.
`are
`Corticosteroid
`compounds
`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.
`
`APOTEX 1047, pg. 6
`
`

`

`CITY3011.qxd:CET 22/11/07 14:45 Page 36
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`Dexamethasone 0.1%
`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.
`
`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 intra-
`ocular 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.
`
`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.
`
`to moderate
`
`Hydrocortisone
`Used
`for mild
`inflammation29-33.
`
`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
`
`Preparation
`
`Dexamethasone 0.1%
`
`Prednsiolone acetate 1%
`
`Fluorometholone 0.1%
`
`Hydrocortisone 0.5%
`
`Average pressure rise mm (Hg)
`
`22 +/- 2.9
`
`10 +/- 1.9
`
`6.1 +/- 1.4
`
`3.2 +/- 1.0
`
`< 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
`the
`Corticosteroids can suppress
`is
`immune system,
`therefore,
`it
`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.
`
`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-the-
`counter
`(OTC)
`preparation
`a
`In
`vasoconstrictor.
`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
`anti-
`histamines. 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
`desquamatio