MODULE 10:12 COURSE CODE: C-5848

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1 30 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. 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 layer 1. 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 damage 2,3,4,5. 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 conditions 1,3. Cause of dry eye disease 1-6 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? IMPORTANT INFORMATION Under the new Vantage rules, all OT CET points awarded will be uploaded to its website by us. All participants must confirm these results on so that they can move their points from the Pending Points record into their Final CET points record. Full instructions on how to do this are available on their website.

2 CET This issue CET: Free Worth 2 standard CET points 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 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 instability 4. 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 irritation 4. 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 Size Cost NHS ( ) Hypromellose 0.3% 10mls 1.81 Hypromellose 0.5% Isopoto Plain 10mls 0.85 Hypromellose 1% Isopto Alkaline 10mls 0.99 Hypromellose and Dextran 70 < Table 1 Net cost of lubricant eye drops licensed as medicines available in the UK. BNF 53rd edition 8 need for the addition of preservatives 4,7. 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 Tears Naturale 15mls 1.68 Polyvinyl alcohol 1.4% Liquifilm 15mls 1.93 Polyvinyl alcohol 1.4% Sno tears 10mls 1.06 Carbomer % Gel tears 10g 2.80 Carbomer % Viscotears 10g 3.12 Carbomer % Liposic 10g 2.96 Preservative free 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, Carmellose 0.5% Celluvisc 30,90 units 5.75, 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 comfort 4. 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 product 4. 31

3 32 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 tears 9. 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 movements 10. 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 tolerated 11. One concern has been raised concerning sodium hyaluronate products containing high phosphate concentrations. In the British Journal of Name of % sodium Name of manufacturer Preservative system product hyaluronidate Aquify comfort drops 5% CIBA Vision Multidose use. Preservative system turns into oxygen and water on contact with the eye 12. Blink 0.15% AMO Multidose use. Contains OcuPure which breaks down on contact with the eye to sodium chloride and water 13. 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 with the eye 15. Vismed 0.18% TRB CHEMEDICA AC. Distributed by Cantor & Nissel in UK. Vismed 0.8% 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 developed 18. The phosphate concentration in this formulation was measured and found Unit dose product. Preservative free 16 Unit dose product. Preservative free 17 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

4 CET This issue CET: Free Worth 2 standard CET points 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 optometrists 19. 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 syndrome 20. 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 only 21. 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 morning 22. 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 cells 2. 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 day 23. 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 tears 24. 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 eyes 6,8. 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

5 Drug Brand name Presentation Licensed indications Diclofenac 0.1% Voltarol Ophtha multidose 5ml 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. 34 Diclofenac 0.1% Voltarol Ophtha 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 syndrome 6, 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 trials 3. 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 receiving both treatments 26. 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 antiinflammatory products. 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 practice 27 (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

6 CET This issue CET: Free Worth 2 standard CET points 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 flurbiprofen 27. 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 monitoring 27. 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 infections 28. An additional supply optometrist can prescribe diclofenac eye drops. Name of steroid Hydrocortisone 1% 1 Fluorometholone 0.1% 3 Dexamethasone 0.1% 4 Rimexolone 1% 4.5 Lotoprednol 0.5% 4.5 Prednisolone acetate 1% 5 < 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 Relative potency from clinical experience 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 posthydrocortisone. Absence of the epithelium in traumatic injuries will influence penetration of steroids 29,30. 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 phosphate 30. 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 cornea

7 36 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 grafts Preparation Average pressure rise mm (Hg) 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 UK 31,32,34. Rimexolone 1% This is regarded as a potent steroid but has a lower effect on intra-ocular pressure 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 inflammation Hydrocortisone Used for mild to moderate inflammation 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 < Table 5 IOP elevation for different steroid preparations 35 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. 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

8 CET This issue CET: Free Worth 2 standard CET points the multiple action group which have an antihistamine, mast stabilising and pro-inflammatory mediator inhibitory action role 36. 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 Otrivine- Antistin 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 use 8,6. Levocabastine 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 reaction 36. Currently it is not available in the UK. Emedastine (Emadine) 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 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. Epinastine (Relestat) 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) 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. Olopatadine (Opatanol) 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 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 fail 37. 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 day 37,38. 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

9 38 Allergy, Optrex Allergy and Vividrin. Lodoxamide (Alomide) 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). Nedocromil (Rapitil) 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 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 trial 39. Optometrists can supply sodium cromoglycate and lodoxamide in their OTC presentations and additional supply optometrists can supply all three in their POM presentations. Other agents 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

10 CET This issue CET: Free Worth 2 standard CET points 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 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 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 39 Please complete on-line by midnight on December You will be unable to submit exams after this date answers to the module will be published in our Jan 11 issue

11 CET answers Course code: c-5847 These are the correct answers to Module 10 Part 11, which appeared in our November 2 issue 40 1.The answer is d. Ofloxacin. This antibacterial inhibits DNA gyrase. All the others inhibit protein synthesis. 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 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 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 Want to further increase your knowledge? Join us for the Binocular Vision course - January or Vision in the Aged - February 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 Contact Dr Michelle L Hennelly by ing (m.hennelly@city.ac.uk) or call