Method of Action

The tear layer represents a complex mixture of mucins for increased viscosity, antimicrobial proteins, growth factors, inflammatory suppressors, and electrolytes for proper osmolarity (Fig. 34.1). Artificial tears cannot completely substitute this complex composition of human tears. Their mechanism of action includes adding volume to the tear film while in contact with the ocular surface. In order to remain in contact with the ocular surface, hydrogels are an essential ingredient of artificial tears. Hydrogels are polymers that swell in water and retain moisture to increase viscosity. The mucous adhesive properties of hydrogels prolong the contact time of artificial tears on the eye. The following hydrogels have been used in artificial tears: hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), carbopol, polyvinyl pyrrolidone, polyethylene glycol (PEG), polyvinyl alcohol (PVA), dextran, hyaluronic acid, glycerin, and carbomer 940 (polyacrylic acid). There have been no large scale, masked, comparative clinical trials to evaluate the wide variety of hydrogels available. However, using wavefront sensing and ocular coherence tomography, PEG drops showed significant worsening of visual quality, compared with CMC, PVA, and glycerin-containing artificial tears.¹

There are many different types of preservatives in artificial tears. Benzalkonium chloride (BAK) and chlorobutanol, which can be toxic when used more than four times a day, are older preservatives. Preservatives, such as GenAqua (Sodium Perborate), Purite (sodium chlorite) and Polyquad (Polyquaternium-1) are less damaging to the ocular surface than BAK.2,3 Purite degrades to chloride ions and water after instillation. GenAqua is converted to water and oxygen on contact with the tear film.

The presence of ‘inactive ingredients’ provides unique surface protective properties to artificial tears. For example, compatible solutes may help surface healing by osmoprotection. HP-Guar forms a cross-linked viscoelastic gel when exposed to eye surface (pH 7.5). This gel increases viscosity and bioadhesive properties while promoting the retention of its two demulcents (polyethylene glycol 400 and polypropylene glycol). It has been suggested that HP-guar preferentially binds to the more dry or damaged areas of the surface epithelial cells, providing protection for these cells.4–6

Viscous tears have a longer retention time, as they are not easily drained out of the eye through the lacrimal outflow system. Oil-containing eye drops may be added if meibomian gland dysfunction is present. These eye drops will replenish the lipid layer of the tear film and prevent tear evaporation. Moderately hypotonic artificial tears containing PVA, as well as bicarbonate-containing tears have been shown to promote OSD healing in severe dry eyes.7–10

Delivery System

Artificial tears are available in multidose preserved formulations, as well as single-use non-preserved formulations.

Dosage

Artificial tears may be dosed on many different schedules, including an as-needed basis. BAK-preserved drops are usually well tolerated when used four times a day or less. If artificial tears are needed more than four times a day then GenAqua or Polyquad preserved tears are better choices, avoiding the toxicity of BAK. In moderate to severe OSD, preservative-free solutions should be used. It is apparent that there is no single artificial tear eye drop that provides the entire surface healing strategies required in OSD (bicarbonate ions, hypotonicity, viscosity, non-preserved). However, understanding of the mechanism of action of the different hydrogels, additives and preservatives in artificial tears will aid the clinician in directing the OSD patient to the optimal tear substitute.

Side Effects

Side effects of artificial tear substitutes may include redness, stinging and ocular irritation, as well as allergy to one of the ingredients. Viscous artificial tears may cause unacceptable blurry vision in some individuals. Higher-viscosity tears can cause eye irritation by crystallization on the lids and lashes.

Mechanism of Action

Topical corticosteroids are currently the most effective, potent treatment modalities for the medical management of ocular inflammation, an important hallmark of OSD. Although there is no generally accepted explanation for the mechanism of action of ocular corticosteroids, they are thought to act by inducing lipocortins, proteins that inhibit phospholipase A2. It is postulated that these proteins control the biosynthesis of potent inflammatory mediators, including prostaglandins and leukotrienes by inhibiting the release of arachidonic acid, their common precursor. Corticosteroids inhibit the inflammatory response to a variety of inciting agents that may delay wound healing. They inhibit fibrin and collage deposition, capillary dilation, capillary proliferation, leukocyte migration, fibroblast proliferation, and scar tissue formation associated with the process of inflammation. The two traditional groups of corticosteroids are the ketone steroids (prednisolone, dexamethasone, fluorometholone, medrysone, rimexolone, and difluprednate) and the ester steroids (loteprednol).

Delivery System

Corticosteroids are available in a diverse range of preparations, including solutions, suspensions, emulsions and ointments (Table 34.1). Topical steroids in a suspension, or viscous formulation have increased ocular contact time and can thereby double the corneal and aqueous steroid concentrations, compared with the same drug used as a solution.¹¹ There is no prospective clinical trial comparing the relative efficacy of generic with branded topical steroids, though studies point to the possible advantage of smaller particle size in branded drops conferring greater efficacy and bioavailability.¹² The relative potency of corticosteroids depends on the molecular structure, concentration, and release from the vehicle. For example, dexamethasone is a very potent steroid, but does not penetrate ocular tissues well. In contrast, prednisolone is less potent and has better ocular penetration. Steroids, such as loteprednol etabonate and fluorometholone are less potent, but have safer side effect profiles. Compared to dexamethasone and prednisolone, loteprednol etabonate and fluorometholone are reported to have lower rates of intraocular pressure (IOP) spikes. A retrospective review of 30 patients with IOP elevation to a mean of 31.1 millimeters of mercury after prednisolone acetate use for keratoplasty reported a 41% reduction in IOP after switching to loteprednol etabonate. Yet in one study, IOP elevations with loteprednol occurred more commonly in females after an average of 2 months of treatment.¹³

Dosage

To our knowledge, no studies have conclusively outlined the optimal steroid concentrations for treating various OSD conditions. Studies have evaluated topical corticosteroid penetration into human aqueous humor (Fig. 34.2).¹⁴ For conditions primarily affecting the ocular surface where intraocular antiinflammatory therapy is not needed, fluorometholone alcohol 0.1%, loteprednol etabonate 0.5% and prednisolone sodium phosphate 0.5% are viable options. When intraocular penetration is indicated, the more potent prednisolone acetate, dexamethasone or difluprednate emulsion should be considered. In randomized, controlled studies, loteprednol etabonate has demonstrated excellent results in treating external inflammation, such as seasonal allergic conjunctivitis and giant papillary conjunctivitis with a favorable side effect profile.^15,16 Topical corticosteroids with lower aqueous penetration are not as effective as those with higher intraocular penetration in the management of intraocular inflammation.¹⁴ Compared to prednisolone acetate 1%, loteprednol etabonate 0.5% has been found to be less effective in patients with acute anterior uveitis.¹⁷

Side Effects

Prolonged administration of corticosteroids may result in a rise in IOP with subsequent damage to the optic nerve. In glaucoma patients or patients with a previous steroid response, close monitoring of the IOP is extremely important. Use of corticosteroids may also result in formation or progression of posterior subcapsular cataracts. Additional side effects include delayed wound healing, corneal and scleral thinning or perforation. Prolonged treatment with corticosteroids may suppress the host response and thus increase the susceptibility of secondary ocular infections, including bacterial, viral, fungal, and parasitic infections. In patients whose symptoms worsen with attempted corticosteroid weaning, switching to less potent antiinflammatory therapy is a viable alternative. Due to the well-known complications associated with prolonged corticosteroid therapy, long-term treatment should be reserved for severe, disabling OSD, and such patients must be closely monitored. Compared to dexamethasone, difluprednate, and prednisolone, loteprednol and fluorometholone have lower rates of these complications. Patients with corneal disease that may affect the measurement of IOP need be closely followed for side effects of corticosteroid use, as these measurements may be inaccurate in cases of corneal thinning or edema.

Considered a corticosteroid primarily targeting ocular surface inflammation, fluorometholone alcohol 0.1% may adequately control signs and symptom of dry eyes in patients with keratoconjunctivitis sicca (KCS). In a randomized, controlled trial, fluorometholone alcohol 0.1% used q.i.d. for 30 days demonstrated a beneficial effect on both subjective and objective clinical parameters of moderate-to-severe KCS patients, reportedly without complications.¹⁸ A mild corticosteroid with low intraocular penetration, fluorometholone alcohol 0.1% may have a lower likelihood of increasing intraocular pressure, compared to prednisolone or dexamethasone.¹⁴ A short-term treatment option for patients with moderate keratoconjunctivitis sicca, topical loteprednol etabonate 0.5% used four times a day for 4 weeks may be beneficial in improving objective clinical parameters with an acceptable benefit–risk ratio. A randomized, masked clinical trial comparing loteprednol to vehicle reported greater improvement in objective variables, including corneal fluorescein staining and conjunctival injection, particularly in a subset of patients with more severe clinical findings of inflammation.¹⁹

Mechanism of Action

Cyclosporine A (CsA) is a fungal-derived peptide that prevents activation and nuclear translocation of transcription factors that are required for inflammatory cytokine production and T-cell activation. Its major clinical effect is disruption of expression of interleukin-2 by helper T cells, thereby preventing T-cell proliferation. Studies have demonstrated that cyclosporine 0.05% can be an effective treatment for management of herpetic stromal keratitis, graft-versus-host disease (GVHD), ocular rosacea, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and post-LASIK dry eye.²⁰

Delivery System

Available as an FDA-approved treatment for dry eye disease since 2003, cyclosporine 0.05% ophthalmic emulsion has been investigated for management of ocular surface diseases that have an underlying inflammatory etiology. Cyclosporine is not water soluble, and as a result must be mixed in a lipophillic vehicle. Different soluents have variable tolerance in patients. Compounding of cyclosporine drops is possible in cyclodextran, gum cellulose, maize oil and olive oil in concentrations ranging from 0.05% to 2.0%.

Dosage

In severe cases, higher concentration cyclosporine A 2% can provide symptomatic relief. A double-masked, placebo-controlled trial to evaluate the short-term efficacy and safety of topical 2% cyclosporine A in a preservative-free vehicle for patients with severe VKC demonstrated a statistically significant decrease in both signs and symptoms with no observed side effects over the course of the study.²¹ For the treatment of patients with steroid-dependent atopic keratoconjunctivitis (AKC), cyclosporine A 2% dissolved in maize oil and dosed four times daily to both eyes appears to be an effective means to improve signs and symptoms, allowing patients to be weaned off topical corticosteroids.²²

Cyclosporine 0.05% may lead to improved tear film regularity and ocular surface health. In a randomized clinical study of moderate to severe dry eye patients, baseline tear production, as determined by Schirmer testing (with anesthesia), increased to a significantly greater degree in the cyclosporine 0.05% group than in the vehicle group. Also, compared to vehicle, patients treated with cyclosporine 0.05% demonstrated greater improvements in blurred vision that could be explained by the improvement in corneal fluorescein staining.²³ Combination therapy with topical cyclosporine A and topical steroids has been successfully used in treating moderate to severe DES. While cyclosporine does not contribute to the rapid anti-inflammatory effect of corticosteroids, it has a better side effect profile and is safer for long-term use. It is possible to begin treatment of the ocular surface by prescribing both topical steroids and cyclosporine at the same time. The concurrent short-term use of a topical steroid tapered over 1–2 months provides the benefit of faster symptom relief and improvement of ocular signs without accompanying serious complications.²⁴

Side Effects

The drug-related side effects of blurred vision, ocular stinging, and conjunctival hyperemia with drop instillation make this medication difficult to tolerate, especially with prolonged use. Other common reactions include discharge, tearing, and foreign body sensation.

Mechanism of Action

Azithromycin is a broad-spectrum macrolide antibiotic that contains nitrogen on its macrolide ring. It inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit of susceptible microorganisms. It has high tissue penetration and a prolonged half-life. Macrolide antibiotics, such as azithromycin exhibit antiinflammatory properties. Studies have demonstrated that they can inhibit the production of proinflammatory cytokines and the production of matrix metalloproteinases (MMPs).²⁵

Although the specific antiinflammatory mechanism of action remains unknown, the suppression of the nuclear transcription factor nuclear factor kappa B (NF-κB) has been shown to play a role. Furthermore, the concentration of macrolide antibiotics, such as azithromycin within polymophonuclear leukocytes (PMNs) may also modulate their role in infection-mediated inflammation.26,27 With respect to ocular inflammatory diseases, an in vitro study found azithromycin in DuraSite as effective in suppressing MMPs in the corneal epithelium and endothelium as doxycycline (a tetracycline analog with known antiinflammatory properties, see below) in both human and bovine cells.²⁸

Delivery System

Azithromycin is extremely lipophillic, making a stable aqueous preparation difficult. When coupled with a vehicle containing polycarbophil it can be formulated into a stable aqueous preparation. It binds to the mucin-coated surfaces of the eye (including the palpebral conjunctiva), resulting in the formation of a sustained-release gel that prolongs the release and availability of the drug on the ocular surface and enhances the penetration of the drug into the eyelids, conjunctiva, and cornea.29,30

Dosage

The recommended dose of azithromycin is one drop twice a day for the first 2 days and then one drop a day for the next 5 days. A single topical dose in healthy individuals demonstrated azithromycin achieved significant tissue concentrations and maintained those levels for up to 24 hours.³¹ Peak concentrations of azithromycin of more than 200 µg/g of tissue were achieved in human eyelid tissue as the drug accumulated over the 7 days of therapy. Furthermore, 5 days after discontinuing the medication, tissue concentrations of azithromycin of more than 50 µg/g were still present in the eyelids. Similar results were found for corneal and conjunctival samples.³⁰

Side Effects

Eye irritation occurs in approximately 1–2% of patients. Other adverse reactions from topical azithromycin were reported in less than 1% of patients and included ocular reactions (blurred vision, burning, stinging and irritation upon instillation, contact dermatitis, corneal erosion, dry eye, eye pain, itching, ocular discharge, punctate keratitis and visual acuity reduction) and non-ocular reactions (facial swelling, hives, nasal congestion, periocular swelling, rash, sinusitis, urticaria).

Mechanism of Action

Vitamin A is essential for maintaining the health of epithelial cells throughout the body. Vitamin A deficiency adversely affects conjunctival and corneal epithelial cells, causing loss of goblet cells and leading to increased epidermal keratinization and squamous metaplasia of the mucous membranes.³² Vitamin A can exist in three forms: retinol, retinal, and retinoic acid. Many tissues requiring vitamin A store the vitamin as an ester of retinal. Vitamin A is stored as fatty acyl esters of retinol in the lacrimal gland. It is also present as retinol in the tears of rabbits and humans. Its presence in tears provides the rationale for treating OSD with vitamin A.³²

Delivery System

Topical vitamin A is available as aqueous ophthalmic retinyl palmitate solution 0.05% combined with polysorbate 80 1% (an emulsifier). Vitamin A (All trans retinoic acid) can be formulated as a suspension or an ointment ranging in strength from 0.005% to 0.05%.

Dosage

Topical vitamin A used four times daily has demonstrated improvement in blurred vision, Schirmer scores without anesthesia, and impression cytologic analysis in patients with dry eye.³² Topical therapy with retinoic acid ointment 0.05% can be an effective treatment of keratinization seen in cicatrizing diseases involving the cornea and conjunctiva. Vitamin A eye drops can be used as adjunct therapy with artificial lubricants for treatment of dry eyes.

Side Effects

Topical vitamin A is known to be an irritant of the ocular surface and its dose should be progressively reduced to the minimal effective dose to treat ocular surface keratinization.³³

Mechanism of Action

Natural human tears contain essential components for maintaining the ocular surface, such as vitamin A, epidermal growth factor, fibronectin, and other cytokines. Because these components are also present in serum, the application of autologous serum is thought to offer advantages over artificial tear substitutes that lack these essential components. Compared to pharmaceutical lubricants, autologous serum eye drops more closely mirror the biochemical components of natural tears, containing vitamins, immunoglobulins, and growth factors, some in higher concentrations than natural tears. The pH of natural tears and serum is 7.4 and the osmolarity of tears and serum is approximately equivalent. Certain components are present in higher concentration in serum, compared with natural tears: vitamin A, TGF-β, lysozyme, and fibronectin (Table 34.2).³⁴ It is possible that serum concentration of certain components may be harmful to the ocular surface, which explains the rationale for using dilute serum.

Delivery System

In previously reported studies, the serum concentration has ranged from 20% to 100%.³⁵ In order to formulate autologous serum eye drops, blood is drawn from the patient and allowed to coagulate. Autologous serum is separated from other blood components through centrifugation. The separated serum is then re-suspended in balanced salt solution or artificial tears in either a 20% or 50% concentration and frozen in small aliquots. Prior to freezing, the containers should be covered to prevent exposure of the contents to light, as some of the serum components may degrade. The lack of a preservative in the autologous serum requires the necessary aliquot or small amount be defrosted and refrigerated between applications.

Dosage

Protocols reported for preparation and use of autologous serum eye drops exhibit considerable variation. Currently, no data have definitively defined the optimal concentration of autologous serum most appropriate for the treatment OSD. Studies have described the use of serum eye drops for treatment of persistent epithelial defects, severe dry eyes, KCS associated with Sjögren’s syndrome and graft-versus-host disease, superior limbal keratoconjunctivitis, and recurrent erosion syndrome.35–38 In patients with neurotrophic keratopathy, topical autologous serum drops used six to eight times per day, results in improved visual acuity, decreased corneal fluorescein staining, and increased corneal sensitivity that correlated with improvement in corneal nerve morphology as measured with confocal microscopy.³⁹ Autologous serum has been shown to be superior to conventional treatment with artificial tears in a randomized, crossover study, including patients with severe KCS. After 3 months of 50% autologous serum, patients showed significant improvement in subjective symptoms and impression cytology analysis, corneal staining with rose bengal staining, Schirmer’s test without anesthesia, and fluorescein tear clearance test in comparison with those who instilled artificial tears.⁴⁰ The use of 50% autologous serum eye drops appears to be an efficacious medical treatment modality for persistent corneal epithelial defects that are recalcitrant to conventional medical therapy.⁴¹

Side Effects

A potential disadvantage of serum eye drops is the limited stability. The bottles of autologous serum must be kept in the freezer or the refrigerator. Currently, no studies delineate the minimum freezer temperature required for adequate storage. After approximately 30 days, the bottle kept in the refrigerator must be discarded and replaced with a new bottle. Another disadvantage is the risk of blood-borne infection arising for patients and others handling serum. A donor could potentially transmit hepatitis to a recipient or to staff handling the serum. With prolonged use, an initially sterile dropper could become contaminated. Bacterial contamination poses a potential risk either during the production of the serum tears or during prolonged use of the eye drops. The drops are also not typically covered by insurance and must be made by a compounding pharmacy, so continued use can become expensive. Caution should be exercised in prescribing autologous serum eye drops as scleral vasculitis and melting has been reported in a patient with rheumatoid arthritis. Immune complex deposition in the peripheral cornea and subsequent inflammation could be encountered given that antibodies are found in serum. Other possible side effects include discomfort, worsening corneal epitheliopathy, microbial keratitis and conjunctivitis, and eyelid eczema.³⁴

Method of Action

Tacrolimus is a macrolide immunosuppressive agent produced by the fermentation of Streptomyces tsukubaensis. The method of action of tacrolimus involves the blockage of transcription of cellular communications molecules, including interleukin 2, inhibiting the antigen presenting role of Langerhans cells, and reducing the activation of T cells.42,43)

Delivery System

Tacrolimus ointment is approved for the treatment of moderate to severe atopic dermatitis. It is available in 0.03% and 0.1% ointment for cutaneous use. Inactive ingredients include mineral oil, paraffin, propylene carbonate, white petrolatum and white wax.

Dosage

Tacrolimus can be compounded into a 0.02% ophthalmic suspension or ointment by a compounding pharmacy. Its use in the eye is considered off-label. There have been no prospective comparative trials of the efficacy of the different strengths. Tacrolimus dermatologic ointment has been reported to control ocular surface inflammation in all three strengths when applied 1–2 times a day in the inferior fornix, without any detectable blood levels. Tacrolimus has been demonstrated to treat intractable allergic conjunctivitis, atopic blepharoconjunctivitis, atopic keratitis, recalcitrant vernal keratoconjunctivitis, and giant papillary conjunctivitis.44–47 In a retrospective interventional case series, tacrolimus 0.02% placed twice daily in the inferior fornix was effective in severe ocular surface inflammatory diseases.⁴⁸ Application of tacrolimus dermatological ointment may present an alternative treatment in advanced ocular surface inflammation without the potential side effects of long-term steroid use.

Side Effects

Reported side effects include redness, stinging, and burning of the eyes. Allergic reaction to the dermatologic formulation has also been reported. Other side effects with doses used for dermatologic conditions may include acne, swollen or infected hair follicles, increased sensitivity of the skin to cold or hot temperatures, lymphadenopathy, skin tingling, flu-like symptoms, skin infections, chickenpox or shingles. Tacrolimus may have a potential to impair local immune surveillance.

Mechanism of Action

Derived from a South American shrub Pilocarpus jaborandi, pilocarpine is a muscarinic cholinergic parasympathomimetic agonist that binds to muscarinic M3 receptors. In humans, it can cause pharmacologic smooth muscle contraction and exocrine gland stimulation.⁴⁹ Cevimeline hydrochloride is an orally administered derivative of acetylcholine that also binds to muscarinic M3 receptors in exocrine glands and stimulates exocrine gland secretion.

Delivery System

Pilocarpine (Salagen tablets, Novartis Pharmaceuticals, Basel, Switzerland) is currently available in 5 and 7.5 mg tablets for oral use. Cevimeline (Evoxac, Daiichi Pharmaceutical Corp, Montvale, NJ) 30 mg tablets are typically taken three times daily; maximum dosage is 90 mg/day.⁵⁰

Dosage

Use of oral secretogogues is beneficial for addressing both the ocular and oral mucosal manifestations of Sjögren’s syndrome. Most patients require 20 mg/d of pilocarpine in divided doses for a therapeutic response. According to recommendations in a review article published in JAMA, in cases with residual salivary gland function, oral pilocarpine and cevimeline are the treatment of choice. Recommended doses balancing efficacy and adverse effects are the following: pilocarpine 5 mg q.i.d. and cevimeline 30 mg t.i.d.⁵¹ In a placebo-controlled clinical trial of Sjögren’s syndrome patients suffering from xerosis of the eyes and mouth, significant relief in reported ocular symptoms, including decreased use of artificial tears was noted at a dose of 30 mg/day after 12 weeks of therapy.⁴⁹ Response to pilocarpine may require 6–12 weeks of therapy.

Side Effects

With oral pilocarpine use, excessive sweating is the most commonly reported side effect, occurring in approximately 40% of patients. Other common reactions include side effects of cholinergic stimulation, such as the following: nausea and vomiting, rhinitis, diarrhea, excessive salivation, salivary gland enlargement, miosis, headache and GI irritation, tremor, and bradycardia. Patients should be closely monitored for severe reactions include arrhythmias, AV block, severe hypotension, and bronchospasm.

Mechanism of Action

Tetracyclines are oral antibiotics originally derived from Streptomyces aureofaciens. Their method of action is through inhibition of binding of aminoacyl-tRNA primarily to 70S ribosomes but also to 30S ribosomes. The inhibition leads to a bacteriostatic effect of the tetracyclines, including doxycycline. Additionally, this class of antibiotics also exhibits antiinflammatory properties. The tetracyclines inhibit metalloproteinases, reduce angiogenesis, and reduce apoptosis.

Delivery Systems

The tetracyclines are available in numerous oral compounds, including tetracycline, the semisynthetic doxycycline hyclate, doxycycline monohydrate and minocycline.⁵² Tetracycline must be taken on an empty stomach half an hour before, or 2 hours after meals. This is because food prevents absorption of tetracycline into the bloodstream. Minocycline and doxycycline absorption are not affected by food and can be taken at mealtime. All of these tetracyclines must be taken with a full glass of water to prevent esophageal ulceration.

Dosage

Tetracycline is available in 250 and 500 mg tablets; Doxycycline is available in 20, 50, and 100 mg tablets. Minocycline is available in 50 and 100 mg tablets.

Side Effects

In addition to gastrointestinal (GI) concerns, all of the tetracyclines may stain developing teeth in children, induce vaginal or oral candidiasis, and cause dose-related dizziness and photosensitivity. Tetracycline may make the skin more sensitive to sunlight (photosensitivity); this effect depends on the variety of tetracycline and the amount taken. Photosensitization is most likely with doxycycline and least likely with minocycline. Additionally, minocycline may be associated with the development of autoantibodies, including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA) and antiphospholipid antibodies with or without associated clinical symptoms. Minocycline may result in dose-related dizziness. It has been reported to cause pseudotumor cerebri and to precipitate arthritis and systemic lupus erythematosus, especially in young women.53,54

Tetracyclines as a group in general can be poorly tolerated, due to gastrointestinal upset and require a difficult dosing regimen. Patients can better tolerate doxycyclines, due to their easier dosing regimen. Due to its acidic pH of 2-3, doxycycline hyclate can result in GI upset. Enteric-coated doxycycline hydrate (Doryx) is better tolerated, while doxycycline monohydrate (pH 5-6) is best tolerated with the least amount of gastrointestinal adverse reaction. In the treatment of OSD, doxycycline and minocycline are used at lower doses than those required for the bacteriostatic effect, and are used for a longer treatment period. At the lower doses, these drugs appear to have a greater antiinflammatory effect.

Mechanism of Action

Vitamin A is essential for the differentiation of mucus-secreting epithelium of the eyes, skin, gastrointestinal tract, and genitourinary tract. Loss of mucin and goblet cells in the conjunctiva leads to squamous metaplasia with keratinization of the conjunctiva and cornea. Severe forms of hypovitaminosis A, such as xerosis, corneal ulceration, and keratomalacia, can be seen in countries with a high prevalence of malnutrition.⁵⁵ In the developed world, hypovitaminosis A can present in the wake of malnutrition from a variety of causes, such as psychiatric conditions, chronic gastrointestinal and liver disease and bariatric surgery through the disruption of fat-soluble vitamin absorption.⁵⁶ It is important to have a high clinical suspicion of hypovitaminosis A, as it can initially be misdiagnosed or overlooked, in part, due to clinical signs being easily represented as simple epithelial erosions seen in keratoconjunctivitis sicca or exposure keratopathy. Without appropriate vitamin A supplementation, ocular surface conditions can be refractory to medical or surgical intervention and lead to progressive blinding disease. With the increasing popularity of bariatric surgery, the risk of vitamin A deficiency is increasing in the developed world. As a result, the ophthalmologist must be mindful of this possible etiology in the differential diagnosis of ocular surface disease.

Delivery System

Prescription-strength vitamin A dosage forms are available from 8,00 up to 25 0000 units. Various over-the-counter preparations can be obtained in doses lower than prescription-strength. Vitamin A is fat soluble and is therefore only available in capsule form or as an oil liquid supplement.

Dosage

Recommended daily intake and various dosing regimens are highlighted in Table 34.3. The dose of vitamin A is variable, depending on the level of deficiency. Vitamin A levels can be determined by blood test.

Side Effects

With usual doses, no common reactions have been reported. Serious reactions reported with high-dose supplementation include the following: hepatotoxicity, severe nausea and vomiting, mood changes, such as irritability, drowsiness, vertigo, delirium, headache, increased intracranial pressure, papilledema, coma and anorexia.

Mechanism of Action

Dietary modifications and nutritional supplements can promote ocular surface health. An essential part of normal growth and development, essential fatty acids (EFA) cannot be synthesized and must therefore be acquired through dietary intake. Precursors of eicosanoids, omega-3 and omega-6 EFAs are hormones involved in the inflammatory cascade. Four groups of eicosanoids have been identified: leukotrienes, thromboxanes, prostacyclins, and prostaglandins. Omega-3 molecules act as antiinflammatory and anticoagulation mediators. On the converse, omega-6 molecules are proinflammatory and proplatelet aggregator mediators. The overall inflammatory state in the body is influenced by the ratio of omega-6 to omega-3 fatty acids. Omega-3 and omega-6 fatty acids compete for the same enzyme in two distinct pathways that result in antiinflammatory and proinflammatory derivatives, respectively (Fig. 34.3).⁵⁷

Delivery System

Essential fatty acids can be obtained via dietary supplementation. Omega-3 essential fatty acids include docosahexaenoic acid (DHA), alpha linoleic acid (ALA), and eicosapentaenoic acid (EPA). Omega-3 fatty acids can be acquired by consuming the following oily, cold-water fish: salmon, sardines, tuna, mackerel, and herring.⁵⁸ One serving of salmon or mackerel could provide 1.5–3.5 g of omega-3 fatty acids. Omega-3 fatty acids are also available in vegetarian dietary choices. A number of different seeds and their oils and some nuts contain varying amounts of ALA. Flaxseeds (linseeds) and their oil typically contain ≈45–55% of fatty acids as ALA.⁵⁸ Omega-6 EFAs include linoleic acid (LA), gamma linoleic acid (GLA), dihomogamma-linoleic acid (DGLA), and arachidonic acid. Sources of omega-6 fatty acids include soybean oil, palm oil, grapeseed oil, sunflower oil, poultry, nuts, and cereals.⁵⁹ The omega-6 fatty acid linoleic acid (distinct from alpha linoleic acid) is the main polyunsaturated fatty acid in most Western diets and is typically consumed in 5- to 20-fold greater amounts than the omega-3 fatty acid, alpha linoleic acid.⁶⁰ Omega-3 derived from fish oil has a distinct fishy odor. Removal of the ester will remove the fish odor from the oil. Re-esterification of the omega-3 molecule may increase both the efficacy, as well as the serum concentration of omega-3.

Dosage

In a prospective randomized controlled trial, daily doses of 6 g of flaxseed oil (equivalent to 3.3 g/day of omega-3 fatty acids) resulted in a decrease in the RBC and plasma ratios of omega-6 to omega-3 fatty acids, compared to controls. Additionally, improvements in overall ocular surface disease index (OSDI) score, tear break-up time (TBUT), and meibum score were noted. This prospective clinical study found that dietary supplementation with omega-3 fatty acids induced a change in the fatty acid saturation content in meibum.57,59

In a small study, patients receiving lower doses of omega-3 fatty acids (450 mg of eicosapentaenoic acid, 300 mg of docosahexaenoic acid and 1000 mg of flaxseed oil) had an increase in aqueous tear secretion. No significant effect in meibum lipid composition or aqueous tear evaporation rate was reported, perhaps, due to the choice of active ingredients in the omega-3 dose, the trial length, and the dosing schedule in a population with chronic dry eye syndrome.⁶⁰ Review of dietary diaries of > 32 000 patients enrolled in the Women’s Health Study revealed that a higher dietary intake of omega-3 fatty acids is associated with a decreased incidence of dry eye syndrome in women. Also, low dietary intake of omega-3, a high omega-6 to omega-3 ratio, or both increase the risk of clinically diagnosed dry eye.⁶¹ In clinical studies, supplementation with the combination of LA and GLA or with evening primrose oil (EPO), which contains both of these fatty acids, resulted in improvement of keratoconjunctivitis sicca syndrome.⁶²

Side Effects

A tolerable upper intake level for omega-3 fatty acids has not been established. However, some studies have shown a possible increased risk of bleeding and hemorrhagic stroke following supplementation with high-dose omega-3. Individuals who have disorders involving bleeding, who have a tendency to bruise very easily, or who are taking blood thinners should consult their doctor before taking high doses of omega-3 fatty acids. Gastrointestinal distress, flatulence and eructation have all been reported as short -term side effects.