Ординатура / Офтальмология / Английские материалы / Ophthalmic Drugs Diagnostic and Therapeutic Uses 5th edition_Hopkins, Pearson_2007

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OSMOLARITY

The osmolarity of freshly produced tears is about 300 mOsm/L and about 305–310 mOsm/L in the tear film (Murube et al 1998). An osmolarity value of 305 mOsm/L is equivalent to 0.95% sodium chloride. In 1908, the French ophthalmologist, Cantonnet, described the formulation of artificial tears from a 1.4% sodium chloride or 2.5% boric acid solution, which were intended to maintain the normal osmolarity of the tear film. Most artificial tear preparations are iso-osmolar. Some patients with an aqueous deficiency have a tear osmolarity higher than normal (about 329 mOsm/L), which can lead to a decrease in goblet cell density and in corneal glycogen levels and this, in turn, can cause epithelial defects and poor wetting of the ocular surface. In such cases, artificial tears with an osmolarity of 210–239 mOsm/L are intended to dilute the hyperosmolar tear film, lowering its osmolarity to that of normal tears. Although a hypo-osmolarity value of 150 mOsm/L is well tolerated, ocular irritation occurs at 75 mOsm/L. Distilled water, which represents the limit of hypo-osmolarity at 0 mOsm/L, can cause itching and epithelial oedema. However, it has been shown that in KCS, hypo-osmolarity alone does not guarantee relief from symptoms and that factors including viscosity and osmotic pressure might be significant.

pH

A pH of just the alkaline side of neutral, i.e. pH 7.4, is normally selected for the pH of artificial tears, but some products are more alkaline. Fassihi & Naidoo (1989) found a range of pH 4–9 in commercial preparations. Ubels et al (1995) found that bicarbonate vastly improved the recovery of damaged corneas when included in preservative-free artificial tears.

PRESERVATIVES

There is an increasing trend towards the use of preservative-free preparations either in the form of single-use containers such as Minims or in extemporaneously prepared eyedrops that are kept in the refrigerator after opening to reduce bacterial growth and discarded after 1 week.

However, normal multidose containers require the addition of an antibacterial preservative to prevent microbial contamination during use. Unfortunately, the one most frequently chosen is 0.01% benzalkonium chloride, which will at this concentration destabilize the tear film and shorten the tear break-up time (Holly 1978, Holly & Lemp 1977). In some formulations the concentration is reduced to 0.005%, or less, which does not interfere with tear film stability.

The toxic effects of preservatives have been studied (Bernal & Ubels 1991). They found that 0.01% benzalkonium chloride markedly reduces the corneal epithelial barrier to the uptake a fluorescein derivative,

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TEAR SUBSTITUTES

Tear substitutes are available commercially as eyedrops, gels and ointments. The water-soluble polymer that acts as a viscolizer in tear substitutes increases the wettability of the corneal surface, extends adhesion of the tear film and extends its retention time in the conjunctival sac.

Although dry eye represents the principal indication for the use of artificial tears, they are used adjunctively in the treatment of a large number of diseases of the anterior segment. In these conditions they can fulfil the following functions:

EYEDROPS

Hypromellose Hypromellose (hydroxpropyl methylcellulose) (HPMC) is the most common formulation of methylcellulose and has been in ophthalmic use since the 1940s. Compared to PVA, HPMC is more viscous and gives better surface wetting. It is not one single compound, but a mixture, and several grades are available whose properties are determined by the exact proportion of the component compounds. Different grades are designated by a numeric suffix which indicates the viscosity of a 2% solution.

Preparations

* With phenylephrine hydrochloride 0.12% (avoid in patients with narrow-angle glaucoma)

** With dextran 70 0.1% BAK, benzalkonium chloride

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Povidone Povidone (polyvinyl pyrrolidine) is a mixture of essentially linear synthetic polymers of 1-vinylpyrolidin-2-one of different chain lengths and molecular weights that functions as a non-ionic surfactant and in a concentration of 3–5% increases the viscosity of solutions. Povidone iodine has been widely used as a disinfectant including the care of contact lenses. It is sometimes combined with other viscolizers.

Preparations

GELS

Gels used as tear substitutes are synthetic polymers and in contrast to traditional polymers, such as methylcellulose and polyvinyl alcohol, they shear thinly on blinking. On instillation, vision is initially blurred but clears relatively quickly.

Carbomers Carbomers are synthetic high molecular weight polymers of acrylic acid cross-linked with either allyl ethers of sucrose or allyl ethers of pentaerythritol.

Carbomer 980 (polyacrylic acid) is the viscolizer used in Viscotears and Gel Tears. The gel has good water-binding properties, which help to form a stable tear film. It shows thixotropic properties (i.e. the gel is reversible). During blinking, liquefaction of the gel occurs followed by a reformation of the gel to reduce elimination from the tear film. These more viscous presentations have two principal advantages. First, they provide relief for longer and thus require fewer doses. Marquardt (1986) found that liquid gels had a retention time seven times greater than PVA and that patients could reduce dosing from 20 times a day to four times a day. This has the advantage of reducing corneal exposure to preservatives such as benzalkonium chloride. Second, they can provide protection during sleep when few natural tears are produced. This is particularly true for patients undergoing operations and in intensive care units, who are in a dry atmosphere and might be exposed to gases that cause drying.

Preparations

Continued

ARTIFICIAL TEARS AND OCULAR LUBRICANTS 253

Preparations (continued)

* Uses Carbomer 974P

BAK, benzalkonium chloride

OINTMENTS

These are normally mixtures of various paraffins (relatively inert hydrocarbon chemicals) with varying amounts of wool fat, the starting point for the manufacture of lanolin. Liquid paraffin and paraffin yellow soft (simple eye ointment) melt at ocular temperature and their greasy nature allows them to be retained for a longer period than eyedrops. Because they blur vision, they are usually used, often as an adjunct, at bedtime.

Preparations

* Yellow soft paraffin is the basis of simple eye ointment

MUCOMIMETIC AGENTS

A mucomimetic agent, hydroxypropylguarpolysaccharide (HP-guar) is employed in a novel product together with two demulcents – polyethylene glycol 400 (PEG) and propylene glycol – and is preserved with polidronium chloride (polyquad). A preclinical study of this formulation demonstrated long-term desiccation protection of the intact cornea and also epithelial cells in culture and has no apparent deleterious affects on cells. It also provided conditions in which a damaged corneal epithelium can recover normal barrier function (Ubels et al 2004). This agent has been shown to be more effective than carboxymethylcellulose in reducing the signs and symptoms of dry eye (Christensen et al 2004).

MUCOLYTIC AGENTS

A complication of keratitis sicca is the development of filamentary keratitis in which fine strands of degenerated epithelial cells and mucous become attached to the cornea. Although these filaments can be removed

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with forceps or a cotton bud, instillation of the mucolytic agent, acetylcysteine, can help to resolve them, together with any plaques of mucous. Unfortunately, this agent causes stinging in many patients. It is thought that acetylcysteine exerts its action by opening up disulphide linkages in mucus, which reduces its viscosity.

ALTERNATIVES TO ARTIFICIAL TEARS AND OCULAR LUBRICANTS

Sodium hyaluronate is a viscoelastic polymer normally present in the aqueous and vitreous humour and has been used to maintain a deep anterior chamber during anterior chamber surgery in order to avoid trauma to the corneal epithelium and surrounding tissues. Topical sodium hyaluronate (0.18%) is non-cytotoxic and has been used in the treatment of dry eyes when other artificial tear products have failed to achieve satisfactory results. It has been found to improve goblet cell density and to reduce inflammation of the ocular surface (Aragona et al 2002).

Sjögren’s syndrome suggests that inflammation is implicated in the pathogenesis of some cases of dry eye. Decreased tear production can result in inflammatory cell infiltration of the ocular surface, activation of the epithelium with increased expression of adhesion molecules and inflammatory cytokines and increased activity of matrix degrading enzymes such as MMP-9 in the tears (Pflugfelder et al 1999). A significant positive correlation has been found between the levels of inflammatory cytokines in the conjunctival epithelium and both the severity of symptoms of ocular irritation and fluorescein staining of the cornea.

NON-STEROIDAL ANTI-INFLAMMATORIES (NSAIDS)

The NSAID, diclofenac, has been administered topically in patients with filamentary keratitis secondary to dry eye and the filaments were resolved after 2 weeks of treatment and there was no recurrence during the follow-up period of 8 months (Grinbaum et al 2001). This NSAID appears to have had an inhibitory effect on fibroblastic activity at the base of the filaments. The increased comfort may have reduced blink rate with the result that fewer filaments were produced.

CORTICOSTEROIDS AND IMMUNOMODULATORS

Topical unpreserved methylprednisolone has been shown to be effective in reducing the symptoms of severe KCS in Sjögren’s syndrome and to decrease the levels of inflammatory cytokines. However, due to the chronic nature of this disease and the likelihood of patients developing steroid-related complications with their long-term use, topical nonpreserved methylprednisolone therapy appears to be most appropriate for short-term ‘pulse’ treatment of exacerbations of KCS (Marsh & Pflugfelder 1999).

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In 1993, a pilot study on ciclosporin ophthalmic ointment was undertaken, which demonstrated a beneficial effect (Laibovitz et al 1993). Ciclosporin is an immunosupressant drug that has been used to prevent the rejection of transplants.

A topical ciclosporin product is now available in the USA for the treatment of moderate to severe KCS. It is regarded as an immunoregulatory agent because of its ability to inhibit T cell activation and to downregulate the production of a number of pro-inflammatory cytokines. Significant improvement in rose Bengal staining of the conjunctiva and reduced superficial punctate keratitis have been reported (Stevenson et al 2000). In addition to decreasing the levels of inflammatory cells and markers, this agent augments the number of conjunctival goblet cells (Kunert et al 2002). After 1 month of treatment, patients noticed a reduction in dryness, itching and photophobia and after two further months an improvement was evident objectively. The response appeared to reach a peak after 6 months of treatment.

Accepting that dry eye disease appears to be caused by inflammation mediated by T-cell lymphocytes, Perry & Donnenfeld (2004) claimed that ‘ciclosporin A offers the first therapeutic treatment for patients with moderate-to-severe dry eye disease due to aqueous deficiency’. A 0.05% topical solution of this drug (Restasis) has been approved in the USA by the Food and Drug Administration (FDA).

When the efficacy of a topical corticosteroid, fluorometholone, was compared with a topical NSAID, flurbiprofen sodium, in the treatment of dry eye, the latter was found to be more effective in reducing symptoms and rose Bengal staining (Avunduk et al 2003).

References

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Chapter 16

Indications and contraindications for ophthalmic drugs

Although a somewhat imprecise method of drug delivery, for a long time use of topically applied eyedrops has been an accepted method of treating conditions of the conjunctiva, eyelids, adnexa and the anterior segment of the eye. An important characteristic that determines the usefulness of an agent is the ability to cross a selectively permeable membrane (e.g. the corneal epithelium). Having crossed this barrier, the drug will access to several structures in the anterior uvea and the aqueous chamber. The limit of activity of an agent in the aqueous humour would appear to be the lens and zonule, which act as a barrier to agents crossing into the vitreous. It is notable that adrenaline only causes macular problems in aphakic patients.

INDICATIONS

Generally, the indications for using medicinal products can be summarized under the following headings:

•Prevention of pathological change: in the treatment of glaucoma, drops and (rarely) systemic treatments are employed to prevent visual field loss arising from what is, to all intents, a symptomless condition. Early treatment of infections and inflammations can prevent scarring and other damage to the cornea and other structures while relieving symptoms.

•Relief of symptoms: complaints of irritation, pain, photophobia and visual problems are often the initial cause for the patient presenting and they will seek an early (if not immediate) resolution of the problems irrespective of the long-term prognosis. Patients are much more likely to show good concordance with treatments that make their eyes symptom-free.

•Cosmetic reasons: many ocular conditions are accompanied by outward signs, such as redness, swelling and discharge, few if any of which enhance the patient’s appearance. The patient, as well as wanting to feel better, will also wish to look better.

•Placebo: such is the fear of loss of vision that patients are very concerned about their eyes and any problem, however small, might