The Pharmaceutical Journal Vol 263 No 7074 p900-905
December 4, 1999 Continuing Education

Eye disorders

Mydriatic-cycloplegic drugs and corticosteroids

By Lucy C. Titcomb, MCPP, MRPharmS

Atropine, a solanaceous alkaloid derived from Atropa belladonna (deadly nightshade) is an organic ester of tropic acid and tropine.¹ The first antimuscarinic to be used in medicine, it is the most potent of the mydriatic-cycloplegic drugs with a duration of action of up to two weeks.
Cyclopentolate, a synthetic ester first prepared in the early 1950s,² is an antimuscarinic drug which rapidly produces cycloplegia and mydriasis of short duration. It is the most widely used cycloplegic today.
Homatropine is a semisynthetic alkaloid formed by combining mandelic acid with tropine.³ Its duration of action is less than that of atropine but slightly longer than that of cyclopentolate. It has largely been replaced by cyclopentolate in clinical use.
Tropicamide, a synthetic derivative of tropic acid, became available for ocular use in the late 1950s. Its faster onset and shorter duration of action, compared with those of other antimuscarinic agents, is due to its greater diffusibility (a result of a lower pKa) and a higher proportion of unionised drug available for corneal penetration.

Other mydriatic-cycloplegic drugs Hyoscine (or scopolamine) is another naturally occurring alkaloid and is found chiefly in Hyoscyamus niger (henbane). It is not as powerful a cycloplegic as atropine, and produces an effect of shorter duration.
Oxyphenonium bromide and lachesine chloride are quaternary ammonium anti-muscarinic agents with cycloplegic and mydriatic properties similar to, but less prolonged than, those of atropine. Although these agents are not commercially available in eye-drop form, ophthalmic preparations are available from specialised centres. They are used in patients in whom the lengths of action of tropicamide and cyclopentolate are insufficient for the clinical indication but who are allergic to atropine.^4,5 Homatropine, being chemically closely related to atropine, would be contraindicated in such patients.

Side effects of mydriatic-cycloplegic drugs

The side effects of this group of drugs are caused by their pharmacological action at muscarinic receptors throughout the body.
A 10ml eye-drop bottle of atropine 1 per cent contains 100mg atropine, more than enough to kill an adult patient. One drop (0.05ml) contains 500μg of the drug, slightly less than the normal adult dose of the drug when given by the subcutaneous route. It is not surprising, therefore, that the systemic side effects of this group reflect the clinical use of drugs in practice.⁶ A popular textbook on drugs for optometrists,⁷ referring to the toxic effects of atropine, contains the aide-mιmoire "blind as a bat, dry as a bone, red as a beetroot and as mad as a hatter" to reflect the drug's effects on the eye, secretory organs, skin vasculature and central nervous system (CNS), respectively.
Systemic side effects are seen less often with the less potent antimuscarinics.⁸ However, loss of consciousness and pallor in a 10-year-old child after the administration of one drop of 0.5 per cent tropicamide to each eye has been reported⁹ and there are several papers reporting psychotic and central nervous system reactions to cyclopentolate. The literature on adverse effects from homatropine is scanty.⁸
Pharmacists should be aware of the potential for topically applied antimuscarinics to cause systemic side effects and be vigilant with regard for the potential for abuse with drugs which have CNS side effects.¹⁰
Altering the viscosity of the vehicle for tropicamide has been shown to result in adequate dilation with much lower concentrations of the drug. This has been recommended in order to reduce potential risks of side effects and systemic toxicity.¹¹
Ocular side effects include blurred vision due to mydriasis and cycloplegia, photophobia, stinging and burning, allergic reactions, including contact dermatitis of the facial skin with atropine, and the precipitation of acute closed angle glaucoma (ACAG) in patients with a shallow anterior chamber.¹² Mydriatic-cycloplegic drugs, through their paralysis of the ciliary muscle, reduce the pull on the scleral spur which opens the trabecular meshwork, the route through which aqueous humour leaves the eye. Thus they can increase the intraocular pressure, which should be evaluated periodically during therapy with these drugs.
The degree of pigmentation of the iris effects the response of the eye to mydriatic-cycloplegic drugs. Eyes with blue irides exhibit a deeper cycloplegia of faster onset.¹³ This may be attributable to mechanical blockade by chromatophores (pigment containing cells), which hinder the drug molecules from reaching their receptor sites or binding of the drug by pigment cells, which occur in greater density in dark irides.¹⁴

Clinical use

These drugs are used clinically for both their mydriatic and cycloplegic effects.
The clinical applications of the antimuscarinics used in ophthalmology vary according to the drug's potency as this affects its duration of action and the degree of cycloplegia achieved. For example, atropine is not used for routine ophthalmoscopy as the patient would experience blurred vision, due to mydriasis and cycloplegia, for up to two weeks after the test. Similarly, tropicamide is not normally used for cycloplegic refraction as the cycloplegia obtained with this drug is incomplete.

Mydriatic use

Ocular examination Without mydriasis, a clinician will see the optic disc only reasonably well, especially in the elderly, because pupil size decreases with age. Therefore, antimuscarinic drugs are instilled to dilate the pupil to facilitate a more thorough examination of the fundus (the inner surface of the eye, covered by the retina), lens, periphery and vitreous humour.¹⁵
Tropicamide is an ideal drug for mydriatic use because of its rapid onset, mydriatic efficacy,¹⁶ minimal cycloplegia and brief duration of action. Cyclopentolate and homatropine are less useful because of their cycloplegic effect and prolonged duration of action, and atropine is far too long-acting to be used as a mydriatic.
After the examination, the patient will have difficulty reading with the treated eye(s) for the rest of the day. They should not drive home because glare could lead to an accident.
Cholinergic agents, such as pilocarpine, are not normally used to reverse the effects of mydriatic drugs used for eye examination because of the discomfort the cholinergic agents cause through strong miosis and ciliary spasm. These effects can be more prolonged than the mydriasis produced by tropicamide. The exception is the patient with a shallow anterior chamber in whom the pupil should not be left dilated because of the risk of precipitating ACAG. In such cases, an a-adrenergic antagonist such as thymoxamine (unfortunately no longer commercially available but obtainable from specialist centres) is an effective and safe alternative to cholinergic miotics which reduce the depth of the anterior chamber.¹⁷

Fundus photography and photocoagulation Fundus photography, including fluorescein angiography (a technique using injected fluorescein dye to visualise the retinal vasculature), and retinal photocoagulation (laser treatment of the retina to prevent vasoproliferation) are procedures which must be performed with the pupil well-dilated to obtain satisfactory results. In these cases, tropicamide is usually used in conjunction with the sympathomimetic phenylephrine.

Uveitis Pupillary dilatation is required in uveitis (inflammation of the uvea - the pigmented, vascular layer of the eye, the iris, ciliary body and choroid) to prevent the formation of posterior synechiae which are adhesions between the pupil margin and the anterior surface of the lens (Figure 2). Antimuscarinic drugs are used, on occasions with phenylephrine, to produce a strong and wide mydriasis. This combination is also helpful in breaking posterior synechiae that have already developed. The adhesions are less likely to develop when the pupil is fully dilated because of reduced contact between the iris and lens. Atropine is the drug of choice. However, shorter-acting mydriatics, such as homatropine or cyclopentolate, because of their short duration of action, allow some recovery from mydriasis giving the pupil mobility and consequently also reduce the risk of developing posterior synechiae.

Figure 2: posterior synechiae

In severe cases, a subconjunctival injection of Mydricaine, a product which contains atropine, procaine and adrenaline, may be used.

Centrally located cataracts By increasing the pupillary diameter, patients with centrally located cataracts such as nuclear sclerotic or posterior cataract may experience significant improvement in visual acuity. Use of mydriatic may forestall the need for cataract extraction in patients at surgical risk.

Pre-operative use In order to undergo surgical procedures that require the visualisation of structures behind the iris, such as cataract extraction, vitrectomy and retinal detachment surgery, the pupil must be adequately dilated before surgery.
The drugs most frequently used in preoperative dilatation prior to cataract extraction are cyclopentolate combined with the sympathomimetic phenylephrine.¹⁸ In a study of 11 elderly patients undergoing cataract extraction and eight healthy volunteers, Haaga et al¹⁹ showed that two 35μl drops of cyclopentolate 1 per cent, instilled one minute apart, resulted in maximum pupillary dilatation 30 minutes after the drug application. This regimen resulted in aqueous humour levels of cyclopentolate 3,000 times higher than those in plasma. None of the subjects experienced, subjectively or objectively, adverse effects attributable to cyclopentolate.

Cycloplegic use

Cycloplegic refraction Optometrists use mydriatic-cycloplegic drugs when assessing refractive error in children. The ciliary muscle of the child is paralysed to give a true reading in an objective test to determine the prescription for the child's refractive error. Without use of the drug, accommodation by the child would give a false, low reading.
The drugs most frequently used in cycloplegic refraction are atropine and cyclopentolate, as there is significant residual accommodation with other drugs.
The choice of cycloplegic will depend upon the patient's age and iris pigmentation. The more potent atropine, which is usually administered as an eye ointment twice a day for three days prior to refraction, is preferred for infants and children up to five, and patients with dark irides.²⁰ Administration of a cyclopentolate-containing cycloplegic mixture as a spray is an effective, and less irritating, alternative to eye-drops.²⁰

Amblyopia Amblyopia is a dimness of vision that is commonly known as "lazy eye". Use of atropine can be an alternative to patching of the normal eye in the treatment of suppression amblyopia (a visual defect). The resultant cycloplegic blur in the eye with normal vision may force fixation with the amblyopic eye.

Uveitis The cycloplegic action of atropine relieves the pain associated with this inflammatory process by abolishing spasm of the ciliary muscle. The cycloplegia also reduces the thickness and convexity of the lens, lessening the opportunity for the formation of posterior synechiae.

Postoperative use Cycloplegic drugs are sometimes used postoperatively to reduce pain associated with secondary uveitis, to prevent redetachment of the retina following detatchment repair and to prevent choroidal detachment following trabeculectomy.

Corneal abrasion Cyclopentolate or homatropine are often used as an immediate treatment following corneal abrasion to reduce ciliary spasm in this extremely painful disorder. Two recent trials investigating new treatments for corneal abrasions included use of a cycloplegic drug in all treatment groups.^21,22

Corticosteroids

Corticosteroids are widely used in ophthalmology through local administration (using eye-drops, ointments and local injections) and systemically (using both the oral and parenteral routes). They are used to control ocular inflammation which can lead to reduced vision.
There is a large range of topical eye preparations containing corticosteroids on the market (Table 2). Some formulations contain viscolisers to increase contact time and enhance penetration. Several corticosteroids are combined with one or more antibiotics. Two preparations are available in the form of preservative-free eye-drops. Eye ointments, with the exception of Maxitrol eye ointment, are also free of preservatives.

Corticosteroids inhibit the formation of prostaglandins and leukotrienes, which are involved in the inflammatory response, by a reduction of phospholipase A2.²³
Ophthalmic steroids vary in their ability to cross the cornea. To penetrate the cornea, which contains both the hydrophobic epithelium and endothelium and hydrophilic stroma, the ideal topical ophthalmic steroid should be biphasic in its polarity. Acetate and alcohol derivatives of the base compound render the steroid molecule more lipophilic, while sodium phosphate and hydrochloride salts make the steroid more hydrophilic.¹⁷ Thus the ability of a corticosteroid to penetrate the eye following topical administration, and therefore its anti-inflammatory potency, is dependent not only upon the potency of the steroid, its concentration and the corneal contact time, but also on the solubility characteristics of the derivative. The presence or absence of preservative can also significantly alter the pharmacokinetics of topical steroids.²⁴
The absence of the epithelium (one of the barriers to penetration) is a scenario often encountered in practice in traumatised eyes. This will also substantially affect the passage of steroid into the eye. In such cases, the hydrophilic sodium phosphate derivative of prednisolone penetrates the cornea in much higher quantities than the lipohilic acetate.²⁵
In clinical practice, therefore, all these factors which affect the anti-inflammatory potency of a topical corticosteroid must be taken into account and an ophthalmologist must choose the most appropriate drug, salt, concentration and frequency of application to achieve a suitable response in each individual case.

Side effects of corticosteroids

The use of topical corticosteroids can be associated with cataract formation, a rise in intraocular pressure, increased susceptibility to microbial infections, retardation in corneal epithelial healing and corticosteroid uveitis.

Cataract formation Topical corticosteroids, like those administered by other routes, can lead to the formation of posterior subcapsular cataracts indistinguishable from age-related cataract.²⁶

Rise in intraocular pressure The clinical picture of open angle glaucoma can result from the topical administration of corticosteroids. The hypertensive response is reversible and can occur in both normal and glaucomatous eyes.²⁷ This side effect usually develops between two and eight weeks after starting therapy, and the intraocular pressure and outflow facility return to their original levels within one to three weeks of stopping the treatment. Armaly²⁸ found that the rise in intraocular pressure was greater in certain individuals with a genetic predisposition; these patients are often labelled as "steroid responders".
Topical corticosteroids do not all have the same propensity to cause an intraocular pressure rise. Fairbairn and Thorson²⁹ compared the intraocular pressures of non-glaucomatous steroid reactors given beta-methasone 0.1 per cent, fluoromethalone 0.1 per cent and fluoromethalone 0.25 per cent. While the mean intraocular pressure of patients receiving fluoromethalone 0.1 per cent did not change, that of patients receiving the 0.25 per cent strength increased by 1.7mmHg and in patients receiving betamethasone 0.1 per cent by 7.5mmHg.
The authors concluded that while fluoromethalone may not be entirely devoid of pressure elevating effects, it is less likely to raise intraocular pressure than prednisolone, dexamethasone or betamethasone. However, Morrison and Archer³⁰ suggested that some caution must still be exercised when using the drug on susceptible individuals as in their study comparing the effects of fluoromethalone and dexamethasone on intraocular pressure of corticosteroid responders, one patient showed a comparable response to both drugs.
Clobetasone butyrate 0.1 per cent has been shown to have little or no effect on intraocular pressure when compared with dexamethasone 0.1 per cent and with hydrocortisone 1.5 per cent.³¹ The same result was seen with prednisolone 0.5 per cent and with hydrocortisone 1.5 per cent.³²
The recently introduced steroid, rimexolone, while as effective as prednisolone acetate 1 per cent in the treatment of uveitis, is less likely to cause a rise in intraocular pressure.³³ Leibowitz et al found that its potential for elevating IOP is less than that of dexamethasone sodium phosphate and prednisolone acetate and comparable to that of fluoromethalone in steroid responsive patients.³⁴ The absence of rises in IOP with rimexolone has been confirmed in two studies using the steroid for control of inflammation following cataract surgery.^35,36

Increased susceptibility to microbial infections The therapeutic indications for topical corticosteroids in summaries of product characteristics include the treatment of non-infected inflammatory conditions. The exclusion of infective conditions is because steroids reduce the immunologic defence mechanisms lowering resistance to many types of infections.
Topical corticosteroids are used by ophthalmologists in the treatment of microbial infection following its diagnosis, in combination with appropriate anti-microbial agents. Lavin and Rose³⁷ and Claoué and Stevenson³⁸ described a high incidence of inappropriate use of these drugs by general practitioners. Both sets of authors advise general practitioners not to prescribe topical ophthalmic steroids without first seeking the opinion of an ophthalmologist.

Retardation in corneal healing The time required for epithelial regeneration is increased in eyes treated with ocular steroids. Effects on collagen synthesis and fibroblast activity have been proposed as a possible mechanism.

Corticosteroid uveitis Paradoxically, the topical use of dexamethasone or prednisolone can lead to acute inflammation of the anterior segment of the eye.³⁹ The incidence is higher in the black population (5.4 per cent) than in the white population (0.5 per cent). Changing the formulation of the preparation in the assumption that the uveitis is related to the vehicle does not help as this condition can occur with both the sodium phosphate and alcohol derivatives of dexamethasone.

Clinical use of corticosteroids

Allergy and hypersensitivity reactions Mild forms of allergic conjunctivitis respond well to antihistamines and mast cell stabilisers but severe forms of vernal (allergic) or atopic keratoconjunctivitis may require topical corticosteroids. Phlyctenular keratoconjunctivitis is an inflammation of the cornea and conjunctiva caused by an allergic reaction to the cell wall antigens of an infecting organism, usually staphylococci.
It is often treated with a combination of an antibiotic and a steroid, for example, Predsol-N.

Uveitis Topical corticosteroids are widely used in the treatment of uveitis, in combination with cycloplegic drugs. In severe cases, sub-conjunctival or orbital floor injections and oral treatment may be indicated.⁴⁰

Herpes simplex keratitis Aciclovir combined with betamethasone 0.1 per cent has been shown to produce a more rapid response with significantly fewer treatment failures than aciclovir and placebo in patients with disciform keratitis, a form of herpes simplex keratitis involving a cell-mediated response to antigens.⁴¹

Ophthalmic surgery Combinations of topical steroids and antibiotics are used to suppress inflammation following ophthalmic surgery. In general, the use of postoperative steroids rarely exceeds six weeks. However, in conditions in which long-term local immunosuppression is required, such as following penetrating keratoplasty (corneal grafting), a steroid may be used long term with an instillation frequency as low as one drop every third day.

Other uses Topical corticosteroids are used for many other conditions:⁴² in episcleritis (a localised inflammation of the white of the eye) which is not responsive to systemic non-steroidal anti-inflammatory agents; in the initial treatment of alkaline burns; in the early stages of thyroid ophthalmopathy; together with appropriate antibiotic therapy in microbial keratitis; and following anterior segment laser surgery.

Other anti-inflammatory agents

Problems associated with the side effects of topical corticosteroids have encouraged the development of alternative anti-inflammatory agents.
Topical non-steroidal anti-inflammatory drugs, such as diclofenac,⁴³ flurbiprofen⁴⁴ and ketorolac,⁴⁵ have been shown to be effective for some of the indications of topical corticosteroids (for which they are now used). In addition, they have been shown to be useful in the prevention of postoperative cystoid macular oedema^46,47 and may also possess inherent antimicrobial properties.⁴⁸
However, until more data are available about this relatively new class of drugs, topical ophthalmic corticosteroids, which have been used for over 40 years, will continue to be used in a wide range of ophthalmic disorders.

Mrs Titcomb is directorate pharmacist, ophthalmology, Birmingham and Midland eye centre, City hospital NHS Trust, Birmingham