Pharmacology and Refraction

12 Pharmacology and Refraction

Charles G. Connor, Freddy W. Chang

ROUTES OF DRUG ADMINISTRATION A drug produces its effect when an appropriate concentration reaches the site of action. Because the eye has a variety of anatomical barriers, the chemical properties of a drug must be taken into consideration when one is choosing a drug delivery route for the treatment of an ophthalmic disorder. There are three routes of administration for ocular drug delivery: direct injection, systemic administration, and topical administration. Direct injection is the local administration of a particular pharmacological agent into a selected ocular tissue. Examples include subconjunctival, anterior and posterior, sub-Tenon's, and retrobulbar injections. Direct injection offers the advantage of rapid achievement of therapeutic levels, but it is associated with a higher risk of toxicity. Direct injection is useful for administration of anesthesia, steroids, and antibiotics. Drug levels comparable to those achieved with direct injection may be achieved with the use of fortified topical solutions.' In general, it is difficult for a systemically administered drug or metabolite of a drug to penetrate the eye. Like the central nervous system (eNS), the eye has a physiological barrier called the blood-retinal barrier, that allows the passage of agents that are very lipid soluble or have a small molecular size. In most cases, the ocular drug concentration is lower in the eye than in plasma and other tissues. Some drugs can become concentrated in tears, providing the cornea with a constant source of the medication. This can be therapeutic, or it can be responsible for adverse ocular effects. For example, isotretinoin, a synthetic retinoid used in the treatment of dermatological disorders, is secreted into tears by the lacrimal gland.v' With therapeutic doses of isotretinoin, the tear concentration of the drug can be relatively high and is thought to be responsible, in part, for the characteristic ocular irritation associated with isotretinoin therapy. Some drugs can enter the eye through the retinal or uveal circulation. For systemically administered drugs to penetrate ocular tissues, they 432

must be lipid soluble or have sufficiently small molecular size. By far the most common route of administration used to treat ophthalmic disorders is topical delivery. Topical ophthalmic drugs come in a variety of forms: eyedrops, ointments, paper strips, conjunctival inserts, iontophoresis, and contact lenses. Solutions are the most common way to deliver topical ocular medications and often have some type of bottIe-top color coding for easy recognition (Figure 12-1, A and B). For example, agents used for dilation often have red tops, even though they differ in mechanism of actions and drug classes. Eyedrops and suspensions are noninvasive methods of drug administration and offer several advantages, such as quick absorption and easy administration. The effect of topical drops depends on the following: • Size of the drop (the average volume is 20 IJ.I, with a range of 10 to 70 IJ.I) • Volume of the conjunctival sac (7-10 IJ.I, with 30 IJ.I the maximum) • Health of the corneal epithelium • Patient compliance The average size of an ophthalmic drop is 20 IJ.\. The conjunctival sac contains approximately 10 IJ.I of tears and has a maximum capacity of 30 IJ.\. The excess fluid is lost. Generally, it spills over the edge of the lid or is drained via the punctum into the nasolacrimal system. Absorption of the drug through the nasal mucosa may result in adverse systemic effects. Drugs can produce local irritation that may result in excess tearing. Excess tearing dilutes and facilitates the elimination of a topically administered drug, decreasing the therapeutic effect. Zaki et al.' showed that instillation of a 30-1J.1 drop causes reflex blinking that can deposit up to 30% of the dose of the drug onto the eyelashes. Each blink can remove about 2 IJ.I of excess tear fluid.' Reflex tearing subsides after about 5 min. If two drops of an agent are required, the drops should be separated by a minimum of 5 min if maximum absorption of both is desired.

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B

A Figure 12-1 A, Representative examples of agents used to induce mydriasis and cycloplegia. Note that despite their differing drug classes and mechanisms of action, these agents can be readily recognized by the red medication cap. B, Various ophthalmic medications. Note that agents used for dilation can be easily recognized by the red cap (arrow).

The ocular penetration of any drug is enhanced when the corneal epithelium is unhealthy, irregular, or ulcerated. Most drugs that solubilize in the tear film enter the eye primarily through the cornea." On average, only 1% to 10% of a drug dose topically applied to the eye is absorbed. A drug's contact time with ocular tissues can be measured by its residence time in the tear fluid. The residence time is the time required for the loss of 95% of the initial amount of drug from the tear fluid. Residence times for ocularly administered agents range from 4 to 23 min.' Lipophilic drugs tend to be absorbed more quickly and completely across the membrane barriers of the eye-that is, they tend to have longer residence times-than do hydrophilic drugs. The corneal epithelium contributes to more than 90% of the cornea's resistance to drug penetration for hydrophilic beta blockers." Not surprisingly, changes in corneal permeability occur during ocular inflammation, when the structural integrity of the cornea is altered. Pavan-Langston and Nelson? reported that the antiviral trifluridine was well absorbed across the corneas of patients with herpetic iritis but not by the corneas of healthy subjects. Corneal integrity can be compromised not only by disease and trauma, but also by preservatives and anesthetics. One way to increase corneal permeability is to apply a local anesthetic topically before administering a medication. The corneal epithelium tolerates large variations in pH and tonicity. Maurice" showed that the sodium permeability of the corneal epithelium is pH dependent and that exposure to 10% sodium chloride solution for 10 min did not alter epithelial permeability. Epithelial permeability has been shown to decrease under hypoxic conditions." Thus, use of daily or extended wear contact lenses might alter the bioavailability of the selected therapeutic agent.

Once the practitioner has decided that ophthalmic drops are the appropriate form of treatment, instillation technique becomes critical, because the rate of solution drainage from the conjunctival sac is directly proportional to the instilled volume. If 50 III is instilled, 90% of the dose is cleared in 2 min. If only 5 III of the same agent is instilled, it takes 7.5 min for 90% of the dose to clear," This finding and others from related studies suggest that a combination drug product is preferable to two separate agents when multiple-drug therapy is indicated." Topical administration can result in systemic effects through absorption from the nasolacrimal systems the nasopharynx; or, rarely, conjunctival vessels. Bytaking a careful patient history and selecting the most appropriate agent, the practitioner can often prevent untoward effects and avoid drug interactions.

INSTILLATION OF TOPICAL AGENTS The following technique for instillation of eyedrops (solutions and suspensions) maximizes ocular contact time, minimizes drug loss, increases ocular absorption, and decreases systemic absorption.":" Figure 12-2 illustrates the procedure. 1. Tilt the patient's head back so that it is almost horizontal. Gently grasp the lower eyelid between your thumb and index finger and pull it away from the globe. Instruct the patient to look up (Figure 12-2, A). 2. Shake the container and remove the cap. Instill one drop inside the lower eyelid. Hold the tip of the dropper clear of the sweep of the lashes about an inch above the pocket. Avoid contamination of the eyedropper tip (Figure 12-2, B).

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A

c

B Figure 12-2 A, When administering ophthalmic solutions, first gently grasp the lower eyelid between your thumb and index finger and pull it away from the globe. Instruct the patient to look up. B, Instill one drop of the solution inside the lower eyelid. Hold the tip of the dropper clear of the sweep of the lashes about 1 inch above the pocket. C, After administration of the ophthalmic solution, the patient should close his or her eyes for about 3 min. At the same time, he or she should apply gentle pressure to the puncta to prevent drainage and minimize systemic absorption. The patient should avoid closing the eyes tightly so the drug will not be expelled.

3. Place the drop on the conjunctiva, not on the cornea. The cornea has more nerve endings and is more sensitive than the conjunctiva to changes in pH or osmotic pressure. 4. If the solution is stable at 4 C, it is preferable to instill cold eyedrops. A cold drop has a mild anesthetic effect and slightly delays irritation. 14 5. It may be useful to hold the eyelid for a few seconds after placing the drop in the cul-de-sac to allow the drop to settle. 6. When releasing the lower lid, bring it upward until it touches the globe to minimize overflow. IS 7. Instruct the patient to close his or her eyes gently for about 3 min and apply gentle pressure to the

puncta to prevent drainage and minimize systemic absorption. Closing the eyes tightly will expel the drug (Figure 12-2, C).

0

ALTERNATIVE FORMS OF DRUG DELIVERY Sometimes, administering a topical agent in solution is not the most appropriate method of drug delivery. For example, delivery of topical medication to children can be difficult because of their lack of understanding and cooperation. A number of alternatives to the instillation of eyedrops are available.

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Sprays

Gels

Topically applied sprays are an alternative to ophthalmic solutions, especially for the delivery of mydriatics and cycloplegics. Wesson et al. 16 were able to achieve clinically effective mydriasis using a cycloplegic-mydriatic spray. Patients were more compliant and experienced less burning when the spray was used than when ophthalmic drops were used. The authors concluded that this method is as efficacious as ophthalmic drops and more tolerable. Another advantage of the spray is that it may be applied to closed eyes. Bartlett et al." recommended that the spray be applied to the closed eyelids and the patient be instructed to blink. When the drug reaches the tear film after several blinks, the patient experiences a mild stinging sensation. Excess solution should be wiped off. A second spray might be necessary, especially if the eyes were closed too tightly. A study confirms Bartlett's suggestion that use of mydriatic sprays on closed eyelids is as efficacious as use of mydriatic drops in open eyes for children." The disadvantages of the spray method include the inability to deliver precise dosing, the lack of an established dose-response relationship for this type of administration, the potential for drug contamination, and the fact that most ophthalmic medications are not currently formulated for this type of application. More studies are needed to determine dosing, frequency, and potential adverse effects associated with this method.

Polymer-based aqueous gels are an alternative to ointments if prolonged drug contact time is desired." Like ointments, gels prolong the contact of the drug with ocular tissues, increasing the medication's bioavailability. Release of the drug occurs by diffusion and by erosion of the gel surface. Release is rapid for hydrophilic drugs and slower for hydrophobic agents. Tears enter the gel and dissolve its hydrophilic polymer, allowing the drug to be released from the gel into the tears. Because gels can act as a drug reservoir, dosing frequency may be decreased. For example, the gel form of pilocarpine is administered once a day, compared with four times/day for pilocarpine drops. The polymers used in the gels are usually cellulose derivatives." Gel preparations are usually more expensive than ophthalmic drops, but improved compliance and treatment outcome may justify the added expense. Elson et al. 23 showed that patient compliance improved by 35% when the dosing frequency was decreased from four times/day to once a day. There are two artificial tear formulations that use gels: Tears Again (Ocusoft) and GenTeal lubricant eye gel (elBA). These products give added ocular surface contact time while decreasing the blur that accompanies use of an ointment.

Ointments Ointments are the second most commonly used method of ophthalmic drug delivery, the advantages being that they require less frequent administration, provide longer contact time, and lubricate an unhealthy epithelium. Eye ointments appear to be useful as protective agents after trauma." but they are a potential mechanical barrier to the instillation and penetration of concomitantly applied ophthalmic drops. I Therefore, patients should be instructed to instill drops before applying the ointment when the two methods are used together. Some patients will not tolerate ointments because of the blurring of vision and poor cosmetic appearance. In addition, the ointment's prolonged contact with the eyelids can result in an allergic response to either the active agent or the preservatives. Bartlett and Iaanus" recommended reducing the volume of the ointment instilled if blurred vision is a problem. Generally, ophthalmic ointments drain via the lacrimal sac at a much slower rate than do eyedrops." Figure 12-3 illustrates the instillation of a topical ointment. The procedure is similar to that described for ophthalmic solutions, except that a strip of ointment, instead of a solution, is placed in the cul-de-sac.

Iontophoresis In iontophoresis, a direct current repels ions into cells or tissues. When iontophoresis is used for ocular drug delivery, the current drives the drug into ocular tissues. The technique is used to deliver agents such as 5fluorouracil to control cell proliferation after glaucoma drainage surgery. The technique has potential as a replacement for subconjunctival injection. Other agents that have been delivered through iontophoresis include anesthetics, antibiotics, and antifungal agents."

Paper Strips Impregnated paper strips are an efficient delivery system for dyes.19 Two of the most common diagnostic dyes are rose bengal and fluorescein (Figure 12-4). Because both agents are prone to contamination when formulated in solution, they are available in impregnated paper strips. The use of the fluorescein strip rather than the liquid dye form prevents contamination." Fluorescein strips are useful for contact lens fitting (rigid gas-permeable lenses), applanation tonometry, and determination of the patency of the nasolacrimal duct and tear breakup time. Rose bengal crosses the membrane of dead cells but not vital ones and therefore is useful for diagnosis of dry eye, dendritic keratitis, neuroparalytic keratitis, and exophthalmos. The concentration of rose bengal dye delivered to the ocular surface by means of a wetted strip is relatively low and is soak

Figure 12-4 A, Two examples of agents used on impregnated strips are fluorescein and rose bengal dyes. B, Impregnated strips are individually packaged for single use on a patient.

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time/technique-dependent. This suggests that the results of clinical studies using rose bengal strips may be different than if precise volumes of commercially available 1% liquid rose bengal dye were applied." The surface area of the fluorescein-impregnated portion of a strip can be designed to control the amount of fluorescein delivered to the eye." The Dry Eye Test (DET) modified fluorescein strip provides a significant reduction in sensation upon application, improved reliability, and better precision than a conventional fluorescein strip."

Ocular Inserts Ocular inserts are now also called conjunctival inserts. Two general types of ocular inserts exist: erodible and nonerodible (Figure 12-5). The erodible insert has the advantage of not requiring removal. However, differences in tear production among patients can result in erratic drug-release kinetics." Ocular inserts avoid pulse delivery of drugs and may provide a controlled rate of drug delivery. The potential advantages of ocular inserts over solutions or ointments include more effective therapy with reduced side effects and increased efficiency of drug delivery. Controlled-release ocular inserts have been found to increase the amount of drug that is absorbed into the aqueous humor when compared to eyedrops. One group of investigators observed with ocular inserts 42 times the conjunctival absorption, 24 times as much drug reaching the ciliary body, and 9 times the concentration in the aqueous humor" compared to that with topical drops. In addition, a successful therapeutic outcome is less dependent on patient compliance than it is with other methods. 3D Ocular inserts require fewer doses, but they can be displaced from the eye, especially during sleep. This problem may be reduced by using an insert with shape and size that closely resemble the space between the lower lid and the eye. Benjamin and Cygan." Land and Benjamin." and Cygan and Benjamin" measured the dimensions of the cul-de-sac and suggested that inserts based on these dimensions might improve comfort and could have other advantages as well (see Figure 12-5, C). Bloomfield et al." were the first to suggest that collagen might be a suitable carrier for sustained ocular drug delivery. They found that collagen inserts produced higher levels of gentamicin in the tear film than did drops, an ointment, and a subconjunctival injection. The collagen shield is designed to be a disposable, shortterm, therapeutic bandage contact lens for the cornea. It conforms to the shape of the eye, protects the corneal surface, and provides lubrication as it dissolves. The collagen shield has been used to treat wounds and deliver a variety of medications to the cornea and other ocular tissues." Since the idea of using a bandage soft contact lens to deliver drugs to the cornea was first proposed by

c Figure 12-5 A and B, Examples of ocular inserts. C, A mold of the inferior conjunctival sac. (Courtesy of Dr. William /. Benjamin.)

Waltman and Kaufman in 1970,35 bandage hydrogel contact lenses have been used to protect eyes with a wide variety of ocular surface conditions, including epithelial defects, erosions, corneal transplants, the effects of refractive surgery, and dry eye." Most of the previous attempts at using contact lenses for ophthalmic drug delivery have focused on soaking the contact lens in a drug solution to load the drug. One of the recent studies focused on soaking the lens in eye drop solutions for one hour followed by insertion of the lens into the eye. Nine researchers studied five different drugs comparing the amount of drug released from eye drops to contact lenses soaked in eye drops. They concluded that the amounts of drug released by the lenses are lower or of the same order of magnitude as the

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amount of drug released by eye drops. However, contact lenses made with particle-laden hydrogels released therapeutic levels of drug for a few days. Particle-laden hydrogels show promise as candidates for ophthalmic drug delivery." Another promising insert is a flexible metallic coil with a hydrophilic, drug-containing polymeric coating."

Transdermal Drug Delivery Topical products applied to the skin have been used for centuries for the treatment of local skin disorders. The use of the skin as a route for systemic drug delivery is of relatively recent origin. Transdermal delivery is diffusion of the drug through the skin. Drug delivery is a slow but constant release, taking 30 to 60 minutes before onset of drug action. It does eliminate the first-pass effect on the drug, which allows higher concentrations to reach the affected tissue and maintain an effect over hours. Transdermal delivery is ideal for drugs that need to be administered in continuous low dosage over long periods of time such as hormones. Patients continue to be attracted to the user friendly attributes of transdermal systems, leading to better compliance with their treatment regimens. One of the greatest disadvantages to transdermal drug delivery is the possibility that a local irritation will develop at the site of application. Erythema, itching, and local edema can be caused by the drug, or other excipients in the formulation. Both topical and transdermal drug products are intended for external use. However, topical dermatologic products are intended for localized action on one or more layers of the skin (e.g., sunscreens). Some medication from these topical products may unintentionally reach systemic circulation, but it is usually in subtherapeutic concentrations and does not produce effects of any major concern except possibly in special situations, such as the pregnant or nursing patient. On the other hand, transdermal drug delivery systems use the percutaneous route for systemic drug delivery, but the skin is not the primary target organ. Generally, drug absorption into the skin occurs by passive diffusion. The rate of drug transport depends not only on its aqueous solubility but is also directly proportional to its oil/water partition coefficient, its concentration in the formulation vehicle, and the surface area of the skin to which it is exposed. When drug penetration into deeper skin layers is desired, oleaginous bases have proven superior to creams and water-soluble bases, which are attributable to their skin-hydrating properties. Steroids have been more effective topically when applied in a petrolatum base than when applied in a cream vehicle." The mainstay of treatment for dry-eye syndrome has been the use of topical tear substitutes. Management of the condition is aimed at replenishing the eyes' moisture and/or delaying evaporation of the patient's natural

tears. A paradigm shift suggests dry eye is not caused by lack of tear volume alone, but by a deficiency of various tear components (growth factors), resulting in epithelial pathology and inflammation of the ocular surface. Sullivan" has shown androgens playa key role in regulating the function of both the lacrimal and meibomian glands Patients who report severe dry eye are more likely to have low testosterone levels. Previous research from our laboratory has shown that androgenic supplemented artificial tears were somewhat effective in relieving the symptoms of dry eye. But poor solubility of the androgens resulted in considerable ocular irritation and poor patient compliance." Transdermal delivery of testosterone could be used to treat dry eye. Steroidal hormones, such as testosterone, are small, fatsoluble molecules that are easily absorbed across the skin where they can be stored in the fat tissues. These hormones can reach a saturation level that is sufficiently high so that the fatty tissue diffuses them into the capillaries for uptake by the general blood circulation and transport them to the target tissues such as the meibomian and lacrimal glands. During the transdermal delivery process, the skin does not inactivate these steroid hormones, nor does it produce harmful metabolites from them. By comparison, transdermally delivered steroidal precursors and hormones are more bioavailable than equivalent dosages of orally administered steroid hormones. The application of a transdermal cream to the eyelids so as to deliver medication to the eye is shown in Figure 12-6. In a masked placebo controlled study, we showed that 3% testosterone cream with transdermal delivery increased tear production by 35% in dry eye patients." The use of the testosterone cream reduced the severity of the treated dry eye patients from moderate to mild based on OSDI scores. The OSDI (Ocular Surface Disease Index) is a valid and reliable questionnaire for measuring the severity of dry-eye disease. Patients report a 50% decrease in symptoms with cream use. The cream works best for women 40 to 60 years of age and is least effective in males."

THE PHARMACOLOGY OF DILATION AND REVERSAL

Mydriatics Mydriatics have been used since the development of the direct ophthalmoscope to aid in the examination of the periphery of the crystalline lens, the vitreous, and the retina. Their use increased with the advent of the binocular indirect ophthalmoscope (see Chapter 14). There are the two opposing muscles in the iris-the sphincter and the dilator-both of which are under the control of the autonomic nervous system. On the dilator

Pharmacology and Refraction

Figure 12-6 Topical application of testosterone cream to the skin of the upper and lowers eyelids for transdermal delivery in the investigational treatment of dry eye.

muscle, which is controlled mainly by the sympathetic nervous system, alpha receptors are stimulated to produce contraction and mydriasis. The sphincter of the iris is innervated mainly by the parasympathetic nervous system. Stimulation of cholinergic muscarinic receptors produces pupillary constriction. When sphincter muscarinic receptors are blocked by anticholinergic drugs, muscle paralysis occurs with resultant mydriasis as well as cycloplegia.

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Most mydriatics, such as phenylephrine (e.g., AKDilate and Neo-Synephrine) and hydroxyamphetamine (Paradrine), are sympathomimetics. These drugs are alpha receptor agonists that bind to and activate alpha receptors located on the dilator muscle, Muller's muscle, and conjunctival vascular smooth muscle. This results in dilation, increased palpebral aperture, and conjunctival blanching, respectively. Eyes with light irides dilate faster and more completely than do more darkly pigmented eyes, because there is less pigment in the iris to sequester the drug." The mydriatic effect of these agents occurs within minutes and can last up to 4 to 6 hr, depending on eye color and the drug and concentration used. Using a local anesthetic before instillation of a mydriatic can facilitate the drug's effect, because the anesthetic decreases blinking and tearing and changes the permeability of the epithelium to the mydriatic agent. It also attenuates any burning or stinging produced by instillation of the mydriatic. Increased lacrimation and keratitis have been reported with the administration of mydriatics. With phenylephrine, dilation increases in a dose-dependent manner up to a maximal concentration of 5%. Concentrations greater than this do not facilitate mydriasis and are associated with a greater incidence of adverse effects." Although alpha agonists produce mydriasis, the pupil still reacts to bright light, requiring the use of cycloplegic for procedures such as indirect ophthalmoscopy." Variations in responses to mydriatics are due not only to differences in eye color, but also to age. In older patients, a common side effect of phenylephrine is the release of pigment granules from the iris neuroepithelium. In many cases it mimics the appearance of iritis, but without the characteristic signs of inflammation." In general, the pigment granules appear 30 min after instillation of phenylephrine and increase in number for 1 to 2 hr. They generally subside 12 to 24 hr after initial administration of phenylephrine. Gonioscopy shows that affected eyes have greater trabecular pigmentation than do normal eyes but do not demonstrate a measurable increase in intraocular pressure (IOP).45 The elderly patient also has a different response to the mydriatic actions of hydroxyamphetamine, an indirectly acting sympathomimetic. Hydroxyamphetamine is less efficacious than a direct-acting mydriatic in older patients. Results from a study by Semes and Bartlett" suggest that there is a loss of sympathetic tone in older patients. Finally, in the elderly, phenylephrine produces less mydriasis than cycloplegic agents." Preterm infants are more likely to have episodes of abdominal distention, emesis 24 hours after their first screening examination for retinopathy of prematurity (ROP) than on the day preceding the examination. Current doses of mydriatics inhibit duodenal motor activity and delay

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gastric emptying, and these gastrointestinal effects of mydriatics may underlie the feeding difficulties seen in preterm infants on the day of screening examinations for ROp. 4 7 Alpha agonists are common ingredients in over-thecounter (OTe) ocular "decongestants," such as Visine and Clear Eyes, usually found in concentrations of 0.125% and higher. These drugs are used for conjunctival blanching and are advertised to "soothe tired eyes" or "to get the red out." Many alpha agonists are also incorporated into OTC allergy preparations. These agents produce conjunctival blanching, as a result of alpha-receptor-mediated vascular constriction, as well as mydriasis." Chronic use of decongestants such as these causes rebound hyperemia or an increase in conjunctival injection. This phenomenon is due to several physiological and pharmacological changes at the tissue level. When alpha receptors are stimulated, they produce vascular constriction. This results in conjunctival blanching but also reduces tissue blood supply. With chronic administration of the alpha agonist, the tissue compensates by decreasing the number of alpha receptors present and altering the second-messenger coupling (desensitization), with the result that more drug is required for the same effect. In addition, because blood supply is decreased by vasoconstriction, metabolic waste products accumulate, which causes rebound vasodilation. The net effect of desensitization and accumulation of these vasoactive substances is greater dilation of the conjunctival vessels, or, to the patient, a redder eye (the rebound effect). Systemic absorption of topically administered alpha agonists, although rare, can result in tachycardia, elevated blood pressure, headache, and arrhythmia. Cardiovascular side effects are less common with lower concentrations, but they can be significant with a concentration of 10%. Three cases of acute hypertension and 15 cases of myocardial infarction, 11 of which were fatal, have been reported." Thus these drugs are relatively contraindicated in patients with heart disease, hypertension, diabetes, narrow angles, and hyperthyroidism. Additional contraindications for the use of alpha agonists for mydriasis are a fixed intraocular lens and shallow anterior chamber angles. However, the risk of missing serious ocular disease by not dilating the patient with narrow angles is significantly greater than the danger of precipitating an angle closure." The topical application of alpha agonists for mydriasis should be used with caution in patients taking inhibitors (MAOls), tricyclic antidepressants, and antihypertensive medications. Mydriatics are indicated for routine examination of the eye,and there are also absolute indications for the use of these agents." It should be apparent from the extensive but not exhaustive list of indications for pupil dilation presented in Box 12-1 that routine dilation should

Box 12-1

Indications for Pharmacological Mydriasis Before Fundus Examination

• Recent onset of floating opacities in the vitreous humor or flashes of light • Sudden decrease in visual acuity • Unexplained loss of visual field • Ocular pain or redness of unknown etiology • Postoculofacial or head trauma • History of diabetes • Presence of media opacities • History of peripheral retinal degeneration or detachment • Pupil defect or miosis

be the standard of care in an ophthalmic practice. For adequate examination of the ocular fundus, pupil dilation is required. Patients often ask, "Is it safe to drive after dilation?" A study by Watts et al" showed that dilating the pupils did not reduce the patient's Snellen distance visual acuity. However, pupil dilatation significantly decreased the ability of participants to recognize lowcontrast hazards and avoid them, and increased glare sensitivity. The decreases in vision performance were not, however, significantly related to the decrement in driving performance. Pupil dilatation appears to impair selected aspects of driving and vision performance and patients should be advised accordingly. 50 Consistent with the changes in visual performance after dilation, Potamitis et al." observed a decrease in simulated daylight driving performance in young people.

Cycloplegia Anticholinergic agents block muscanruc receptors located on the ciliary muscle and prevent acetylcholine or other muscarinic agonists from binding to them. This produces ciliary muscle paralysis, cycloplegia, and mydriasis. Examples of cycloplegics and their dosages are given in Table 12-1. The standard dilation/cycloplegic regimen is 2.5% phenylephrine with 1% tropicamide, preceded by the administration of proparacaine. Combination agents are available, but their effects are no different from those of individual agents." They include 0.2% cyclopentolate and 1% phenylephrine (Cyclomydril), 0.3% scopolamine and 10% phenylephrine (Murocoll-2), and 0.25% tropicam ide and 1% hydroxyamphetamine (Paramyd). The anticholinergic effects of topical anticholinergic agents are directly related to their onset and duration of action. Most have a rapid onset of action (within 30 min) and variable duration of action. For mydriasis and cycloplegia, atropine has a longer onset of action (60 min) and a long duration of action (12 days).

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Agents Available for Cycloplegia MYDRIASIS

Drug

Atropine (e.g., Atropisol and Isopto Atropine) Tropicamide (e.g., Mydriacyl and Tropicacyl) Homatropine (e.g., Isopto Homatropine and AK-Homatropine) Scopolamine (e.g., Isopto Hyoscine) Cyclopentolate (e.g., AK-Pentolate and Cyclogyl)

CYCLOPLEGIA

Concentration

Peak

Recovery

Peak

Recovery

0.5-3%

30-40 min

7-12 days

60-180 min

6-12 days

0.5-1%

20-40 min

6 hr

20-35 min

6 hr

2-5%

40-60 min

1-3 days

30-60 min

1-3 days

0.25% 0.5-2%

20-30 min 30-60 min

3-7 days 1 day

30-60 min 25-75 min

3-7 days 8 hr

Atropine is also used systemically as part of cardiopulmonary resuscitation. The use of atropine in this circumstance can produce fixed dilation of pupils that can be mistaken for a sign of brain death and has been reported to cause acute angle closure glaucoma.v" Scopolamine and homatropine have similar onsets of action (30 min), with full recovery of visual function in 3 to 7 days and 1 to 3 days, respectively. Tropicamide has an onset of action of 20 to 30 min and duration of action of 4 to 6 hr. Cyclopentolate produces cycloplegia and mydriasis in approximately 30 to 60 min and lasts up to 24 hr. One drop of 1% tropicamide produces variable cycloplegic results. Adding a second drop 5 min later provides reasonable cycloplegia, with less than 2.00 D of residual accommodation approximately 20 to 25 min afterwards. After 35 min, the cycloplegia is no longer reliable." Hiatt and Jenkins" showed that tropicamide is not as effective as atropine as a cycloplegic for preschoolers with esotropia. Cyclopentolate produces a greater degree of cycloplegia than homatropine and has a more rapid onset and shorter duration of action. 57 The accommodative paralysis is not complete; there is 1.50 D remaining in the vast majority of patients. 19 Retinoscopic refraction is best performed 40 to 60 min after installation. A second drop of cyclopentolate should be administered if no effect on accommodation is observed after 15 min." Mydriasis due to cyclopentolate is maximal after 30 to 60 min, with recovery requiring 24 to 48 hr." The prolonged recovery period makes cyclopentolate a less than desirable choice for routine dilation. McGregor 45 found that pupils dilated with cyclopentolate did not constrict when exposed to prolonged intense light. McGregor 4 5 suggested that practitioners used cyclopentolate to dilate when examining patients for long periods of time or when examining patients with retinal detachments or patients requiring extensive fundus photography.

Patients' ability to read will return about 6 to 12 hr after the last administration of cyclopentolate." Anticholinergics are associated with a number of common side effects, including: blurred vision; loss of near vision; photophobia; mydriasis; dry eye; possible lOP elevation; and, in some cases, acute angle closure glaucoma.P:" Tropicamide can cause a small elevation, usually less than 10 mmHg, in IOP.61 Cyclopentolate has been shown to elevate lOP by about 8 mmHg in glaucomatous eyes." The risk and consequences of increased lOP and angle closure are greater for patients known to have glaucoma and patients with shallow anterior chambers. Systemic effects are rare but include flushing, dry mucous membranes, and tachycardia. The incidence of adverse effects from cycloplegic drugs is related to the duration of action. Because of its long duration of action, atropine has the greatest incidence of untoward effects. The agent with the shortest duration of action, tropicamide, has the fewest untoward effects. It has been recognized since the middle of the nineteenth century that accommodation can interfere with the assessment of the true refractive state. Amos" pointed out that cycloplegic agents are necessary in the determination of the true refractive status of some patients with accommodative esotropia, pseudomyopia, and latent hyperopia and noncommunicative patients. The poor reliability of subjective refractive findings from children increases the importance of accurate retinoscopic findings. The accommodative system is quite vigorous in the young eye, and the fluctuating contraction of the ciliary muscle makes the masking of the full hyperopic refractive error a common problem. Children are often unable to relax accommodation during retinoscopy. The clinician can circumvent the unreliable subjective responses due to accommodative fluctuations during retinoscopy by using a cycloplegic agent. Cycloplegic refraction could benefit many chil-

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dren with strabismus. It is critical to determine the full amount of hyperopia present in children with suspected accommodative esotropia, so that the correct plus lenses can relieve the stress placed on the accommodative-convergence system. A cycloplegic refraction can also be beneficial in diagnosis and correction of refractive error for patients with other types of strabismus." Other patients who might benefit from cycloplegic refraction are those with high heterophoria, pseudomyopia, and accommodative astenopic symptoms. Correct diagnosis and treatment in these conditions depend on an accurate determination of the refractive error. 19 Other groups who might benefit from cycloplegic refraction are all children under age 3, patients whose subjective responses during the manifest refraction are inconsistent or unreliable, malingerers, hysterical patients with amblyopia, patients whose vision does not correct to 20/20, and patients who have visual signs or symptoms that do not correlate with the nature and degree of their manifest refractive error. Once the decision to cycloplege the patient is made, the following information should be obtained: • Medical and ocular history • Visual acuity (near and distance) • Pupil reflex • Ocular motility • Manifest refraction • Cover test at distance and near • Accommodation function tests • Biomicroscopy with anterior chamber depth estimation • Tonometry Atropine is the cycloplegic agent that is used to determine the maximum refractive plus power present to provide the best management of accommodative esotropia. The only patients for whom atropine is the drug of choice for this are children under the age of 4 years, in whom the effects of atropine can last up to 2 weeks. For this indication, atropine is available in a I % solution or ointment (the ointment is associated with fewer systemic effects). Normally the I % solution is administered three times/day for 3 days before refraction. The 0.5% ointment is administered two times/day for 3 days before refraction. It is suggested that atropine not be used on the day of refraction, because the unabsorbed ointment may interfere with refractive procedures.?" The patient should return for re-examination several months after initial correction, because more hyperopia will usually manifest. Refraction of nonstrabismic children and adults is best done with cyclopentolate, rather than atropine." With the exception of accommodative esotropia, the full plus cycloplegic refraction is not usually prescribed. Nonstrabismic patients, children, and adults who are used to accommodating 2.00 to 3.00 D more than necessary, will not accept full cycloplegic plus correction,

because their vision will be blurred; therefore, prescribing the maximum plus (not under cycloplegia) that prevents a drop in acuity will usually be accepted and alleviate astenopic symptoms. Over time, the plus can usually be increased without a decrease in acuity. Prior application of topical anesthetic can shorten the time to full cycloplegia for patients with dark irides. Siu et al." found that 95% cycloplegia occurred 11 minutes sooner if a topical anesthestic was used prior to instillation of cyclopentalate. Long-term use of topical atropine might cause a change in ocular refractive components when used to induce cycloplegia in children. Changes of anterior chamber depth, lens thickness, vitreous chamber length, and ocular axial length are postulated as potential causes of the refractive changes associated with sustained atropine cycloplegia." Within therapeutics there is always the problem of substance abuse, and the anticholinergics have not escaped attention. Documented instances of abuse have shown that with prolonged use of large quantities of anticholinergics, chemical keratitis can occur. In one reported case, an IS-year-old female was using 200 to 400 drops of I % cyclopentolate/day in each eye. She reported to an emergency department with complaints of severe bilateral photophobia, tearing, and redness. Visual acuity was 20/30 in both eyes. Examination revealed severe punctate keratitis and widely dilated, unresponsive pupils. The cyclopentolate was discontinued, and the patient experienced withdrawal symptoms consisting of nausea, vomiting, weakness, and tremors." Although abuse of topical ophthalmic medications is rare, the clinician should be aware of the severe manifestations of anticholinergic toxicity, topical or systemic. With topical use, scopolamine and homatropine can produce follicular conjunctivitis, vascular congestion, edema, and dermatitis. Owens and co-workers" suggested that, in children of all ages, the clinical use of tropicamide preceded by proparacaine produces refractive errors virtually equivalent to that of cyclopentolate. Cyclopentolate did produce significantly more cycloplegia in the younger children, which was supported by phakometry measurements. However, in clinical terms, the difference between the measurements was not significant. All of the anticholinergic agents used to produce cycloplegia can produce adverse central nervous system reactions that manifest as hallucinations, restlessness, psychosis, respiratory depression, and coma. Cyclopentolate can exacerbate seizures in patients with epilepsy. The risk of systemic effects increases when the cornea is compromised or when dosing and concentrations are excessive. In one study, 10 of GG patients had systemic adverse reactions to 2% cyclopentolate." A recent study suggested that severe reactions to cycloplegia are very rare, occurring in 2 to 10 patients out of 49,000. 70 Visual

Pharmacology and Refraction • Chapter I Z

and auditory hallucinations, irritability, restlessness, insomnia, confusion, memory loss, deli rum, and paranoia have all been reported in association with cycloplegia. A 56-year-old woman was evaluated for the surgical correction of hyperopia (+3.0 D). Two drops of cyclopentolate 1% were instilled in both eyes for measurement of the cycloplegic refraction and wavefront analysis. Immediately after the second instillation, the patient reported drowsiness, dizziness, nausea, and fatigue. Ten minutes later, stimulatory central nervous system symptoms in the form of restlessness, cheerfulness, and a 20-minute-long roar of laughter were observed, interrupted by a new sedative phase. Basic medical and neurological examinations were unremarkable except for gait ataxia. Four hours later, the examination was continued uneventfully. 71 Scopolamine, used to treat motion sickness, may be applied as a topical patch behind one ear. The patch produces unilateral pupillary dilation, which can be misinterpreted as a pathological sign. Two of the more annoying short-term adverse effects from dilation and cycloplegia are the loss of near vision, and hence the ability to read, and photophobia. Recently, a new drug was introduced to reverse pharmacological mydriasis. Dapiprazole (Reveyes) is an alpha receptor antagonist that has been reported to produce miosis, reversing the effects of alpha agonists on the dilator muscle. The ability of alpha-adrenergic antagonists such as thymoxamine to reverse pupillary dilation has been documented.P:" It appears that dapiprazole produces a miotic effect of longer duration." Dapiprazole produces reversal of mydriasis induced by 2.5% phenylephrine and 1% tropicamide within 60 min of administration.":" The effects on reversing cycloplegia, if any, are not yet clear. It seems unlikely that dapiprazole would affect cycloplegia, given that the ciliary muscle is not thought to have alpha receptors." No effect on the recovery of accommodative function or near visual acuity was demonstrated in patients whose eyes were dilated with the standard phenylephrine-tropicamide combination." Considering that the recovery rates of near visual acuity and amplitude of accommodation were found to be identical for groups given dapiprazole, the therapeutic value appears to be limited to a faster recovery of pupil size." Adverse effects of dapiprazole include burning and stinging upon instillation, mild ecchymosis, lid erythema, corneal edema, and superficial punctate keratitis." The use of cycloplegics is common practice for the treatment of corneal abrasions. The cycloplegic agent is prescribed to ensure adequate dilation and paralysis of the ciliary body. Cycloplegic agents relax the ciliary body and eliminate the pulling action on the inflamed uvea, thus reducing pain. Brahma and colleagues" found the use of the cycloplegic agent may be questionable. They

443

suggest that the use of flurbiprofen 0.03% one drop BID provided better management of pain associated with a corneal abrasion than did lubricants or cycloplegics. The relatively selective M( 1) antagonist pirenzepine hydrochloride was somewhat effective and relatively safe in slowing the progression of myopia in schoolaged children during a I-year treatment period, according to researchers at the University of Oklahoma and the Dean A. McGee Eye Institute, Oklahoma City. Investigators conducted a parallel-group, placebo-controlled double-masked study of healthy children aged 8 to 12 years in 13 U.S. academic clinics and private practices. All children had a spherical equivalent of -0.75 D to -4.00 D and astigmatism of 1.00 D or less. Patients underwent a baseline complete eye examination and regular examinations during a I-year period; they were randomized in a 2:1 ratio to receive 2% pirenzepine ophthalmic gel or a placebo control twice daily for a year. At study entry, the spherical equivalent was mean +/- SD -2.098 D +/- 0.903 0 for the pirenzepine group (117 children) and -1.933 D +/- 0.825 0 for the placebo group (57 children). At 1 year, results showed a mean increase in myopia of 0.26 D in the pirenzepine group vs. 0.53 0 in the placebo group. No patients in the placebo group and 13 (11%) of 117 patients in the pirenzepine group discontinued participation in the study because of adverse effects (five children, or 4%, of 117 due to excessive antimuscarinic effects) .78

Local Anesthetics Local anesthetics prevent the generation and conduction of nerve impulses by blocking sodium influx into the neuronal membrane. Sodium is one of the main ions that propagates neuronal impulses. Local anesthetics bind to specific receptors that control the gating of sodium channels. Their interference with sodium conduction across neuronal cell membranes results in the blocking of most sensation. Local anesthetics act on any part of the nervous system and every type of nerve fiber. Smaller, nonmylenated nerve fibers are affected before larger, mylenated fibers. Sensation (afferent nerve conduction) is inhibited much more readily than motor nerve function. The action of local anesthetics is reversible, and their use is followed by complete recovery of nerve function, with no evidence of structural damage to nerve fibers or cells. The degree of block produced by a given concentration of local anesthetic depends markedly on how much and how recently the nerve has been stimulated. A resting nerve is much less sensitive to the effects of a local anesthetic than is a nerve that has been recently and repetitively stimulated. The active site for local anesthetics is the inner portion of the neuronal membrane. Because the drug

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must pass through the neuronal membrane to block the sodium channel, it must remain in its un-ionized or uncharged form. Therefore, the pH of the surrounding environment is very important to the action of local anesthetics. Once inside the neuron, the local anesthetic becomes charged or ionized. Ionized drug effectively blocks sodium channels. The duration of local anesthetic action depends in part on the drug's affinity for sodium channels. The action is significantly attenuated when the local anesthetic is administered to an area of infection. Infectious tissue contains inflammatory cells, pus, and other debris that significantly lowers the surrounding pH. This acidic pH ionizes the local anesthetic molecule so that it does not cross the cell membrane as effectively. Local anesthetics are used to produce loss of pain sensation in localized anatomical regions. The many nerves present in the cornea make it exquisitely sensitive to trauma or procedure. Local anesthetics are indicated for use in specialized surgical procedures, for relief of pain in local areas due to trauma, for pruritis (topical application), and to decrease the discomfort of some ocular medications. In addition, local anesthetics are administered for removal of ocular foreign bodies, examination of painful eyes, tonometry, punctal dilation and irrigation, cytology procedures, gonioscopy, and fitting of rigid contact lenses. The use of local anesthetics for Schirmer's test is controversial. In a study of 466 eyes anesthetized with 0.5% proparacaine, the length of the Schirmer paper strip dampened was reduced by 40%.79 The results are difficult to interpret when the test is administered under anesthesia, because tear secretion decreases in proportion to the loss of sensory stimulation." In addition, the result correlates poorly with the symptoms of dryness." Nom" stated that Schirmer's test has several other potential sources of error as well-both the quality of the paper and contact with the cornea or lashes can contribute to reflex tearing. Topical anesthetics can also influence other dry-eye tests, such as tear breakup time and rose bengal staining. Thus, these tests should be performed without anesthesia. Because the initial discomfort of rigid gas-permeable lenses causes some apprehension on the part of the doctor and the patient, Bennett and Schnider" suggested that a local anesthetic be used during the trial fit. They found no significant physiological problems as a result of the use of one drop of proparacaine before lens insertion at the fitting visit. Compared with a control group who received a placebo drop, subjects who received the anesthetic seemed to adapt more readily to their lenses. Practitioners who plan to use a local anesthetic to fit rigid gas-permeable lenses may wish to follow Bennett's" suggestions for helping the patient over the psychological hurdle to successful adaptation:

• Inform the patient that the anesthetic will reduce tearing and help you determine whether the lens fits properly. • Explain to the patient that he or she will experience sensations when first wearing the lenses but these will be temporary. • Do not use anesthetics during dispensing or adaptation. • Check the patient's history for an allergy to anesthetics and examine the ocular surface for disease before anesthetic administration. Local anesthetics can significantly increase corneal thickness, altering the measurements made by ultrasound pachometry." In addition, if corneal desquamation occurs as a response to ocular anesthetics, a decrease in visual acuity may occur." It has been reported that prior instillation of a local anesthetic affects the pupil's response to mydriatics.F":" One possible explanation is that the permeability of the corneal epithelium increases. Even mild epithelial damage produced by tonometry can increase the probability that a solution as weak as 1/8% phenylephrine will result in pupil dilation." Josephson and Caffrey"? found that 60% of patients had fluorescein staining after instillation of tetracaine, suggesting that some patients may respond with enhanced corneal permeability after local anesthetic use. Increased bioavailability is an alternative explanation for enhanced drug effect after local anesthetic use. Because the rate of tearing is reduced by anesthetics, the contact time of the agent applied after the anesthetic should increase, potentiating the effect of the agent." It appears that prior instillation of local anesthetics may enhance the effects of other ophthalmic drops. Local anesthetics are classified on the basis of on their chemical structure into two groups: esters and amides. The esters include local anesthetics such as cocaine, procaine, proparacaine, tetracaine, and benzocaine. The amides include lidocaine and bupivacaine. Ophthalmic local anesthetics are listed in Table 12-2. Most ocular local anesthetics have a rapid onset of action. Tetracaine and proparacaine have an onset of 10 to 20 sec and duration of 20 min. Patients appear to tolerate proparacaine better than tetracaine? Benoxinate is also less irritating than tetracaine. Cocaine is the only local anesthetic that has vasoconstrictive effects. It has an onset of action of 5 min and may last up to 2 hr. Adverse effects from acute use of local anesthetics are usually minor. Stinging and burning upon instillation and conjunctival injection are commonly observed. Chronic use causes epithelial erosion; punctate keratitis; loss of epithelium and impaired wound healing; opacification; scarring; and, ultimately, loss of vision. 92 - 95 Stromal infiltrates and stromal edema are also seen with chronic use. % Chronic use of cocaine on the eye results in corneal pitting and sloughing of the

Pharmacology and Refraction

TABLE 12-2

Chapter 12

445

Agents Commonly Used for Ocular Anesthesia

Drug

Tetracaine (Pontocaine) Proparacaine (AK-Taine and Ophthaine) Cocaine

Concentration

0.5% 0.5% 4% or 10%

Onset

Duration

10-20 sec 10-20 sec

20 min 20 min

5 min

corneal epithelium. In people who use crack cocaine, corneal epithelial defects associated with pain, photophobia, lacrimation, and chemosis have also been observed." Topical anesthesia disrupts the normal healing process of the corneal epithelium and, as a result, cannot be used in a prolonged manner to comfort patients with corneal trauma or chronic eye irritation. Caution is warranted when using local anesthetics in the eye. During and after use, the ocular surface is insensitive and susceptible to damage from superficial foreign bodies. The effects of other drugs are enhanced as a result of increased penetration. Healing may be retarded. Allergic reactions can occur with almost any medication, and there is often cross-sensitization of the local anesthetics. The results of fluorescein and rose Bengal may be altered. Also, local anesthetics may interfere with the results of microbial cultures.":" The mechanism for the corneal toxicity of local anesthetics is not well understood. It has been postulated that these drugs cause membrane damage, change cellular morphology, damage the cell cytoskeleton, or affect cellular metabolism"'?" Nonetheless, local anesthetics are known to be corneal toxic and should not be used on a chronic basis. In a case reported by Duffin and Olson." a 51-year-old woman lost most vision in one eye after being prescribed 0.5% tetracaine ointment for ocular pain associated with a traumatic corneal abrasion. The patient consequently used tetracaine for a 2month period, which resulted in dense scarring of the cornea that reduces her visual acuity to less than 20/200. Local anesthetics used for retrobulbar anesthesia usually include lidocaine, bupivacaine, and mepivacaine. There have been some reports of paretic or restricted vertical rectus muscles after use of local anesthetics in these procedures, some of which result in diplopia.Pv f" Hyperopia, diplopia, and altered visual acuities were also noted. 105,107 Animal studies have shown that local anesthetics are toxic to the ultrastructure of extraocular muscle fibers. Although some of these muscle fibers do regenerate, toxicity can be demonstrated within minutes of exposure to the local anesthetic and can persist for up to 14 days after iniection.?" Other adverse effects associated with retrobulbar

2 hr

Notes

Dose

1-2 gtt 1 gtt

Vasoconstrictor; sloughs corneal epithelium

1 gtt

anesthesia include optic nerve damage, hemorrhage, central retinal artery occlusion, and blindness. 109 Proparacaine has antibacterial effects on the conjunctival flora.!" Anesthetics should not be used when doing corneal cultures as it will inhibit growth of the organism that one is attempting to isolate. Preservativefree anesthetic solutions seemed not to interfere with bacterial development in culture media. Benzalkonium chloride alone and associated with EDTA inhibited development of gram positive bacteria, S. aureus, but did not inhibit P. aetuginosa." It should be noted that shortterm storage of proparacaine at room temperature did not affect efficacy, but storage at room temperature for more than 2 weeks resulted in a decrease in drug effect. 112 Cross-sensitization between related topical ophthalmologic anesthetics is a rare occurrence. Two cases of allergic contact dermatitis to proparacaine and tetracaine have been reported, which suggests that allergic sensitization and possible cross-reaction to topical anesthetics can occur and may be an occupational hazard for ophthalmic personnel.l" There is a suggestion that proparacaine may be helpful after exposure to pepper spray because it would be only one to two drops being used. All subjects reported significant pain after exposure to pepper spray as well as blurring of vision, and tearing at 10 min that was much improved by 1 hour. Topical flurbiprofen 0.03% improved symptoms in 2 of 11 subjects, whereas topical proparacaine hydrochloride 0.5% improved symptoms in 16 of 29 eyes. At 1 week after exposure, corneal sensation returned to baseline, and no corneal abnormalities were noted. 114

Ocular Pharmacological Tests Punctal Dilation and Occlusion In the strictest sense, epiphora is the overflow of tears across the lower lid margin onto the face. There are many causes of epiphora, including blockage of the lacrimal drainage system and excess production of tears. It is important to remember that not all epiphora is pathological. Differential diagnosis of the symptoms is important, because most patients with epiphora do not have

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lacrimal obstruction. Melore'" pointed out that unilateral tearing is more likely a sign of blockage or pathology than is bilateral tearing. The clinical history is a key component of the differential diagnosis. Epiphora in a child with a history of tearing since birth is almost always the result of an imperfect Hasner's membrane; acquired epiphora in a child suggests a canalicular obstruction.!" If the patient has had facial trauma, a radiographic examination of the nasolacrimal bony canal should be performed.!" Epiphora associated with nasal obstruction and bleeding from the puncta or nose should lead to suspicion of a nasal, sinus, or lacrimal sac malignancy. Intermittent epiphora in the adult can be the result of allergic rhinitis. Eyelid disease can also result in epiphora, by leading to malposition of the punctum, which affects tear drainage. Entropion can cause reflex tearing due to corneal irritation, and when lid laxity is also present, punctal eversion may prevent drainage. Overall, age appears to be the most frequent cause of acquired epiphora. II? When performing an external examination of the eye, Melore'" recommends the clinician should apply external pressure and massage the tear sac. If a discharge occurs from the punctum, the blockage is a result of dacryocystitis. After the external examination is completed, dry-eye diagnostic tests should be performed. These include Schirmer's test, tear breakup time, and rose Bengal staining. Once pseudoepiphora (reflex tearing due to dry eye) has been ruled out, the clinician should test the patency of the nasolacrimal drainage. In 1961, Iones'" described a simple dye test that is now the most common procedure used to evaluate epiphora. The Jones 1 test involves instillation of a dye into the eye's cul-de-sac to determine whether the tears traverse the nasolacrimal drainage channels. Melore'" suggests one or two drops of a 2% liquid sodium fluorescein instilled into the lower cul-de-sac of the eye being tested. Each eye should be tested separately. After instillation, the patient must sit upright with his or her head straight and eyes open. The patient may blink but should not rub his or her eyes. After 5 min, the clinician notes whether the fluorescein dye has disappeared from the external eye. Because the floor of the nose slopes backward toward the throat, tears passing through the nasolacrimal drainage system are swallowed. Therefore, the clinician examines the back of the throat with a tongue depressor and Burton lamp for the presence of fluorescein. If fluorescein is present, the test is positive, and it is assumed the drainage system is normal. The clinician who prefers to examine the nose for fluorescein begins with the same instillation techniques as specified above. Five minutes after instillation, the clinician notes whether fluorescein is present in the external eye and then instructs the patient to blowout of one nostril into a white tissue. The tissue is examined for

fluorescein under a Burton lamp. Another alternative is to insert a cotton-tipped applicator against the inferior turbinate for 10 sec and examine it for the presence of fluorescein. Dutton 116 reported that false-negative results occur in 22% of normal individuals as a result of delayed transit time for the dye. A negative test alone does not necessarily indicate abnormal drainage. A negative Jones 1 test indicates delayed transit time of the dye, and the Jones 2 test can be used to determine the anatomical patency in such cases. The clinician instills one drop of 0.5% proparacaine into the eye to be tested. A cotton-tipped applicator is dampened with 0.5% proparacaine and applied over the puncta for 30 sec with pressure. To dilate the inferior punctum, the clinician gently pulls the lower lid away from the globe and inserts the dilator vertically into the punctum. The clinician gently rolls the dilator between the fingers until the punctum is penetrated about 2 mm inferiorly. The dilator is lowered to a horizontal position with a continual, gentle, forward motion. Excess pressure should be avoided. As the dilator is inserted further into the canaliculus, the ring of elastic tissue surrounding the punctum blanches, indicating that temporary dilation of the punctum has occurred. A 2-ml syringe with sterile saline attached to a 3-gauge lacrimal canula is inserted through the lower punctum into the vertical and horizontal canaliculi. The patient is inclined forward and should hold an emesis basin beneath the nose. Irrigation will produce fluorescein-stained fluid. This indicates that the obstruction is not complete and that with forced pressure, tears overcome it. If the fluid is clear, a nasolacrimal duct obstruction exists between the punctum and the lacrimal sac. Stenosis of the punctum should be ruled out. If no fluid appears, blockage is complete. 119 In an alternative to the Jones 2 test, the clinician places the patient in a reclined position and asks the patients to state whether he or she tastes the saline irrigating solution. Detection of an obstruction by the Jones 2 test, especially if it is complete, may require surgical intervention to relieve the epiphora.

Horner's Syndrome Horner's syndrome usually presents as miosis of the involved pupil and ptosis of the upper and lower eyelids. The cases of Horner's syndrome are listed in Box 12-2 in order of frequency; common physical findings are also listed. Patients with Horner's syndrome often have other findings, including narrowed palpebral fissure, ipsilateral hyperemia, and ipsilateral anhydrosis of the face and neck. Anhydrosis can be diagnosed by placing a hydroactive dye on the face, but the test has several pitfalls. 120 In one study, baseline anisocoria was 0.92 mm for 90 patients with maximum baseline anisocoria of 2.4 mm.

Pharmacology and Refraction

The average postcocaine anisocoria in the same study was 2.54 mm. Hence the cocaine test has clinical utility for separating Horner's anisocoria from physiological anisocoria. It is virtually impossible to tell the two apart solely on the basis of clinical examination.!" Cocaine interferes with norepinephrine reuptake, indirectly stimulating dilator muscles to produce mydriasis. If norepinephrine is lacking because of sympathetic nerve interruption, cocaine has no effect.':" Postcocaine anisocoria is as good as, or better than, baseline anisocoria as an indicator of Horner's syndrome. Postcocaine anisocoria greater than 1.0 mm is essentially diagnostic of Horner's syndrome. Hydroxyamphetamine is another indirectly acting sympathomimetic agent that can distinguish between lesions that are before and after the superior cervical ganglion stage. This is important clinically, because postganglionic lesions are more likely to be associated

Box 12-2

Etiologies and Findings of Homers Syndrome

Chapter 12

447

with tumors. Hydroxyamphetamine dilates the pupil more when Horner's syndrome is due to a preganglionic lesion than when it is due to postganglionic lesion (Table 12-3). It is recommended that patients with Horner's syndrome and postganglionic lesions undergo head and neck neuroimaging to rule out tumor as the cause of Horner's syndrome. Alternatives to hydroxyamphetamine include topical clonidine and pholedrine. Figure 12-7 presents a flow chart for the evaluation of Horner's syndrome. Apraclonidine may be a useful drug for the diagnosis of Horner syndrome. Morales et al., 123 using only six patients with Horner syndrome, found instillation of apraclonidine into affected eyes produced mydriasis with 1.0 to 4.5 mm of anisocoria. They explained the mydriasis as follows: apraclonidine's major site of pharmacologic action for reduction of aqueous production is on postjunctional alpha (2) receptors in the ciliary body. The upregulation of alpha receptors that occurs with sympathetic denervation unmasks apraclonidine's alpha (1) effect, which results in pupil dilation.

Myasthenia Gravis Etiologies Idiopathic disease Tumor/neoplasm Cluster headache Iatrogenic disease Trauma Cervical disk disease Congenital disease Vascular occlusion or anomaly

Myasthenia gravis (MG) is a syndrome of muscle weakness. Patients with MG have only 10% to 30% of the usual number of muscle cholinergic receptors. About 80% of patients have IgG antibodies against acetylcholine receptors in their serum. True MG is thought to be an autoimmune disease that is more common in women than in men. It generally affects women in their third decade of life and men 50 to 60 years of age. Ocular myasthenia gravis (OMG) is a syndrome with only ocular symptoms, usually ptosis and diplopia. Autoantibodies to acetylcholine receptors can be identified in only about 50% of patients with OMG. OMG is usually mild, often remits, and generally has a favorable prognosis.

Frequent Findings Miosis (98% of cases) Blepharoptosis (88% of cases) Anhydrosis (4% of cases) Anisocoria (20%-30% of cases)

TABLE 12-3

Hydroxyamphetamine (HAl Testing for Horner's Syndrome PREGANGLIONIC

Initial diameter Diameter after HA Dilation amplitude Anisocoria before HA Anisocoria after HA Change in anisocoria

POSTGANGLIONIC

Normal pupil [mm] In = 30}

Homers pupil [mm] In = 30)

Normal pupil [rnm] In = 30}

Homers pupil [mm] In = 30}

4.17 6.23 2.06

3.09 5.48 2.39 1.08 0.75 -0.33

4.38 6.29 1.91

3.46 4.02 0.56 0.93 2.26 1.34

Data arefrom Wilhelm H, Ochsner H, Kopycziok E, et al. 1992. Ger J Ophthalmol 1:96.

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BEN.JAMIN , Borishs Clinical Refraction

Horner's syndrome examination

History and general evaluation

Topical hydroxyamphetamine or topical pholedrine

Probable physiological anisocoria

Neuroimaging to rule out tumor

History and general evaluation May not need imaging

Figure 12-7 Diagnostic flow chart for Horner's syndrome.

Many conditions and drugs mimic true MG. Myasthenia-like syndromes are listed in Box 12-3. Rarely, a malignancy or other tumor can be associated with a myasthenia-like syndrome. Brainstem tumors may have unilateral ocular symptoms and cause dysphasia, but they do not produce generalized symptorns.!" Ocular, facial, and general symptoms of MG are listed in Box 12-4. Most patients with MG present with ocular symptoms. Although there are several noninvasive tests for MG that involve fatiguing various extraocular or lid muscles, the gold standard is the edrophonium (Tensilon) test. Edrophonium is a short-acting cholinesterase inhibitor that blocks the destruction of acetylcholine. For several seconds after systemic administration of edrophonium. synaptic acetylcholine levels rise and MG symptoms transiently improve. lOP also increases significantly in patients with MG after an edrophonium challenge. Several protocols exist for edrophonium administration, all of which give the drug (10 ml) in divided doses. Edrophonium is administered intravenously or intramuscularly and is available in a concentration of 10 mg/m!. The protocols are described in Box 12-5. MG

can be confirmed with electromyography if the edrophonium challenge test is equivocal. 124-126 The ice test is a simple in-office, short, specific, and relatively sensitive test for the diagnosis of myasthenic ptosis. The sensitivity of the ice test in patients with complete ptosis decreases considerably. A positive ice test result was noted in 16 of the 20 (80%) patients with MG and in none of the 20 patients without MG. The ice test exploits improved neuromuscular transmission at reduced temperatures so an ice pack is applied for about 2 minutes and the doctor observes if the ptosis decreases. 127

OCULAR EFFECTS OF SYSTEMIC MEDICATIONS As a result of the growing specialization of the health care field and the increasing number of diseases that have become treatable, the number of medications per patient is increasing. In fact, the average patient over 60 years old is being treated with more than 10 medications. A detailed review of drug interactions is beyond

Pharmacology and Refraction

Box 12-3

Chapter 12

449

Syndromes that Resemble Myasthenia Gravis

Paraneoplastic (Eaton-Lambert syndrome) Congenital myasthenia syndromes Drugs Aminoglycoside antibiotics Neomycin Kanamycin Gentamicin Streptozocin Other antibiotics Polymixin B Colistin Tetracyclines Antimalarial agents Chloroquine Quinine Antineoplastic agents Vincristine Vinblastine Beta-adrenergic antagonists Propranolol Timolol Anticholinergic agents Phenothiazine antipsychotics Antihistamines Other drugs Penicillamine Procainamide Neuromuscular blocking agents Alcohol General anesthetics Lithium Phenytoin Drugs that decrease or interfere with calcium Toxins Scorpions Ticks, wasps, spider bites/stings Bacteria Clostridium botulinum (botulism) Clostridium tetani (tetanus and lockjaw)

Includes rare ocular manifestations. Involves the pharyngeal muscles and proximal muscles of the limbs. Appears in children whose mothers have myasthenia gravis. Usually manifests with significant ocular signs and mild generalized disease. Worsen preexisting myasthenia gravis or cause a myasthenia-like weakness. Block acetylcholine receptors in high concentrations or in sensitive individuals.

the scope of this chapter. However, it should be remembered that the side effects and toxic effects of a single agent can be potentiated by other drugs added to the patient's physiological and pharmacological mix. The potential for interaction rises exponentially with the number of drugs to which an individual patient is exposed. A brief outline of drug interactions is presented in Box 12-6. Prescription polypharmacy is complicated by self-medication with GTe agents. As the number of medications per patient increases, the potential for improper dosing and adverse effects increases enor-

mously. The effects of age on the body's ability to eliminate drugs, underlying diseases, individual variations, and drug-drug interactions make the treatment of patients with multiple disease states difficult to manage without adverse pharmacological effects. Untoward effects of medications can occur for a number of reasons (Box 12-7). A change in vision may not always be a result of an underlying pathology, but may be one of the many potential untoward effects of medications. The likelihood of drug-altered visual acuity or clinical refraction

450

BENJAMIN

Box 12-4

Borishs Clinical Refraction

Clinical Findings in Myasthenia Gravis

Ocular findings (70% of presenting cases; sometime in the course of the illness in 90% of cases) Ptosis (unilateral or bilateral) Lid twitch Lid fatigue Diplopia Extraocular muscle paresis (ocular motility dysfunction) Horizontal or vertical gaze palsy Photophobia Orbiculorsis weakness Decreased pupillary constriction with repeated exposure to light Gaze-evoked nystagmus Horizontal nystagmus Decreased corneal sensitivity Hyper- or hypometric saccades Intranuclear ophthalmoplegia Face and voice changes (50%-70% of presenting cases) Change from smile to snarl Choking/throat clearing Dysphasia Nasal speech Decreased voice strength as patient continues talking Generalized weakness (10%-30% of presenting cases) Load-dependent increase in weakness throughout the day Dysarthria (20%-30% of presenting cases)

Box 12-5

Edrophonium (Tensilon) Challenge Test for Diagnosing Myasthenia Gravis

Drug: Edrophonium chloride (10 mg/ml), intramuscularly or intravenously 1. Administer 1 ml, wait 60 sec and then give 9 m!. 2. Administer 2 ml, wait 30 sec and then give 8 rnl. 3. Administer 2.5 ml every 30 sec for 4 doses. Positive test: Subjective or objective improvement in at least one symptom or increased intraocular pressure. False-positive tests: Amyotrophic lateral sclerosis, some brainstem tumors, and some drug-induced myasthenia syndromes.

is appreciated when one considers the thousands of available drugs. Changes in vision, visual acuity, or refractive error may result from drug-induced adverse effects such as: nystagmus; central nervous system toxicity; retinal or optic nerve toxicity; corneal surface changes, such as deposits; lenticular deposits; or changes in the shape, size, or opacity of the crystalline

Box 12-6

Overview of Types of Systemic Drug Interactions

Same site of action: Drugs that have similar effects or side effects at the same site of action have the ability to potentate each other. Examples: Two drugs that cause cycloplegia, two drugs that are retinal toxic, and two drugs that cause conjunctival irritation. Same physiological effect: Drugs that produce the same effect may potentiate each other. Example: Two drugs that increase intraocular pressure. Liver and renal elimination: Drugs that are metabolized by the liver may reduce each other's clearance and increase toxicity. Drugs that are primarily eliminated by the kidneys have the potential to reduce each other's clearance and potentiate toxicity. Example: Cimetadine reduces the liver metabolism of several other drugs. Plasma protein binding: Drugs bound to plasma proteins, such as albumin, have the ability to displace each other and increase toxicity. Example: Nonsteroidal antiinflammatory drugs (e.g., aspirin) can displace warfarin from albumin and cause serious bleeding.

Box 12-7

Mechanisms that Contribute to the Untoward Effects of Systemic Medications

Predictable nontherapeutic effect or "side effect." Example: Relative dehydration of the lens with diuretic therapy for congestive heart failure. Predictable overdose or toxic effects: Example: Effects of high-dose vitamin A on the eye and vision. Drug interation: Two drugs with synergistic effects or a combination that interferes with the clearance of each drug. Example: Drug A reduces the liver metabolism of drug B, resulting in toxic levels of drug B. Allergic reactions: Release of inflammatory mediators by mast cells in and around the eye. Example: Sulfacetaminde eyedrops produce immediate itching, conjunctivitis, and eyelid angioedema in sensitive (allergic) individuals. Idiopathic: Unpredictable, unwanted effect that is temporally associated with drug administration and does not occur in the absence of drug. By definition, the mechanism is unknown and the occurrence is rare.

lens. Accomodative dysfunction is also a common cause of a change in vision during drug therapy. 128 Because of its rich blood supply and relatively small mass, the eye is unusually susceptible to adverse reactions from systemic medications, even though there are

Pharmacology and Refraction

physiological barriers in place that limit the passage of drugs. When a drug is administered systemically, it can reach ocular tissues by way of the uveal or retinal vasculature or through the tear fluid. Once the drug is in the eye, it can be deposited in several sites and may linger in ocular tissues for weeks after discontinuation of therapy. For example, some metabolites can be detected in vitreous humor for weeks after administration. In fact, postmortem sampling of the vitreous is common when drug abuse is suspected as the cause of death. If enough of the drug accumulates in ocular tissues, adverse effects or toxicity can result. Box 12-8 lists some common ocular drug storage sites. Many ocular effects of systemic medications are transient and reversible, but some are not. For more severe effects, close monitoring of the patient and early discontinuation of the drug, if possible, can help limit permanent damage to vision. Not every ocular adverse effect associated with systemic administration of drugs is directly related to drug concentration in ocular tissues. In some instances, visual disturbances are a result of some aberration in systemic physiology. For example, many individuals become hyperglycemic when treated with systemic antiinflammatory steroids such as prednisone. Glucose is an osmotic particle in the blood, and hyperglycemia can cause the plasma to be hyperosmolar. Hyperosmolarity causes a relative dehydration of the lens and changes the refractive error. Hyperglycemia can also disturb electrolyte balance and further change refraction and vision. To discern the underlying cause(s) of visual dysfunction when the patient is being treated with systemic medications, the clinician must obtain a detailed history to determine whether there is a temporal relationship between the onset of visual dysfunction and a change in drug therapy. It is difficult for all ocular adverse effects of systemic drugs to be documented in clinical trials and the early postmarketing period. Most clinical trials evaluate drug effects on a limited number of subjects who are healthy or those with the active target disease. In

Box 12·8

Common Sites of Drug Storage in the Eye

Comea Epithelium: Lipophilic drugs Stroma: Hydrophilic drugs Keratocytes: Lipophilic drugs Conjunctiva: Lipophilic and hydrophilic drugs Iris: Lipophilic drugs Crystalline lens: Lipophilic drugs Aqueous humor: Hydrophilic drugs or metabolites Vitreous humor: Hydrophilic drugs or metabolites Retina: Lipophilic drugs

Chapter 12

451

drug trials, the opportunity to observe such reactions is limited. Also, because detailed ocular examinations are not routinely performed, eye care practitioners are at a distinct advantage for first noting and reporting suspected ocular adverse effects of systemic agents. The Food and Drug Administration encourages reporting of adverse or suspected adverse drug effects, but most clinicians still significantly underreport these types of reactions. Patients at risk for adverse drug effects of any type include the very young, the very old, and the very ill. Patients with impaired metabolic capacity, for example, those with liver or kidney disease, are also at risk. Dosing adjustments are warranted for these patients as well as for children and the elderly. Not all of the ocular side effects of systemic agents are well characterized. Nothing more than a temporal association has been reported for most drugs. For others, the mechanism, reversibility, and dose-response relationships are better characterized. In the following sections, we discuss specific agents for which there have been consistent reports of ocular side effects from systemic therapy. Other drugs are mentioned briefly or listed with their associated adverse effect in boxes.

Myopia, Blurry Vision, and Amblyopia Myopia Transient myopia has been frequently reported as an adverse effect of many groups of drugs. Drug-induced myopia can occur after one dose or during chronic therapy. Most of the myopic shifts are 1.00 to 5.00 D in severity and resolve within 7 days of discontinuation of the drug.':" Groups of drugs known to cause transient myopia are listed in Box 12-9. There are several postulated mechanisms for drug- induced myopic shifts. A

Box 12·9

Systemic Agents that Cause Transient Myopia

Acetazolamide Hydrochlorothiazide Tetracyclines Prochlorperazine Promethazine Corticosteroids Ampicillin Acetaminophen Arsenicals Sulfonamides Hydralazine Ethoxzolamide Oral contraceptives Nonsteroidal antiinflammatory drugs

452

BEN.JAMIN

Borishs Clinical Refraction

change in the hydration of the lens, displacement of the lens or iris, a change in the aqueous or vitreous humor components or volume, elongation of the globe, accommodative spasm, and ciliary body edema may all produce refractive error changes.": 130-133 An analog of the retinoids, including vitamin A, isotretinoin is used in the treatment of dermatological disorders such as acne. There have been several case reports of this drug's producing changes in refractive error up to 3.00 D in severity. The cause of the myopia is not known at this time, but it may be related to lenticular swelling or swelling of the ciliary body that causes displacement of the lens. In the reported cases, the myopia was fully reversed within 1 to 2 days after discontinuation of therapy. 134 Diuretics such as hydrochlorothiazide and furosemide, which are the mainstay of the treatment for congestive heart failure and hypertension, can also cause transient myopia. Diuretics alter renal fluid and electrolyte balance, resulting in a net renal loss of water that is sometimes accompanied by a loss of sodium and potassium. Increasing renal fluid loss also disrupts the fluid and electrolyte balance in the eye. The lens becomes relatively dehydrated, leading to changes in refraction. These refractive changes usually stabilize as the diuretic therapy continues over 2 to 4 weeks. The thiazide diuretics are especially prone to causing myopic shifts. These drugs not only alter the sodium, potassium, and water balance at the site of the kidney, but also may produce hyperglycemia in sensitive patients. In a diabetic patient, hyperglycemia can cause lenticular swelling and myopia. In a nondiabetic patient, it can cause excessive diuresis, dehydration, and lenticular shrinkage with resultant hyperopia.!" For the diabetic patient, changes in visual acuity and blurry vision are often signs of poor blood sugar control resulting from pharmacological factors or systemic infection. Nonsteroidal antiinflammatory drugs (NSAIDs) are pharmacologically related to aspirin. These agents are widely used for their antipyretic, antiinflammatory, and analgesic properties (Box 12-10). Four NSAIDsaspirin; ibuprofen; naproxen; and, most recently, ketoprofen-are widely available as OTe medications. Although not a classical NSAID, acetaminophen is also available as an OTe analgesic and antipyretic. Its mechanism of action is unknown, and it has no antiinflammatory properties. Many of the NSAIDs and acetaminophen are used in combination allergy and cold medications. NSAIDs have a variety of systemic and ocular effects. They exert many of their therapeutic and adverse effects by inhibiting the formation of inflammatory mediators, prostaglandins. Because prostaglandins also regulate renal sodium and water excretion, their absence in the kidney affects systemic fluid and water balance. The visual implications of this sodium and water imbalance are changes in refractive

Box 12·10

Examples of Systemic Nonsteroidal Antiinflammatory Drugs

Aspirin Diflunisal Etodolac F1urbiprofen Fenoprofen Ibuprofen Indomethacin Ketoprofen Ketorolac Naproxen Phenylbutazone Piroxicam Sulindac

error. For example, phenylbutazone, an NSAID used for arthritis, can cause a hyperopic shift of 3.00 to 4.00 D. This change in refraction is due to a change in the hydration of the lens resulting from altered renal sodium and water excretion. Some cardiovascular agents have been reported to infrequently cause transient myopia. For example, isosorbide dinitrate, a nitrate derivative used in the treatment of angina and congestive heart failure, was reported to cause a transient myopia that resolved within 6 hr after the medication was administered. HI Sulfa-containing drugs, including antibiotics and oral hypoglycemic agents, can cause reversible myopia of several diopters. This phenomenon is most likely due to increased lens thickness resulting from ciliary body edema. Topiramate (Topamax). an oral sulfamate medication used primarily for seizure treatment, induced a myopic shift. Although the mechanism for topiramate induced myopia is unknown, it may partially be caused by topirarnate's weak carbonic anhydrase inhibitor activity or by a prostaglandin mediated effect.I" Topiramate may also cause uveal effusions with resultant ciliary body swelling that causes forward rotation of the lens-iris diaphragm resulting in myopia and angle closure glaucoma. 1>6 Topiramate at lower doses does not cause recurrence of myopia.':" Three women developed acute transient myopia caused by drugs used for gynecological problems. One patient was treated with disothiazide for premenstrual edema. The second was treated with sulphonamide for acute cystitis. The third developed myopia coincident with metronidazole treatment for trichomonas vaginalis. The myopic changes were completely reversed on discontinuation of the causative agent. 13~ Recently, a hyperopic shift in refractive error was reported in

Pharmacology and Refraction

association with suramin sodium therapy for prostate cancer.139

Blurry Vision Blurry vision is a common patient complaint, and its cause can often be difficult to discern. Many drugs can produce blurry vision as an adverse effect The most common are those that have anticholinergic side effects. Anticholinergic side effects and drugs that produce them are listed in Boxes 12-11 and 12-12, respectively. Anticholinergic drugs block cholinergic, muscarinic receptors. Other adverse effects associated with drugs that produce anticholinergic side effects include elevated lOP (most common in glaucoma patients), acute angle closure glaucoma, photophobia, paralysis of accommodation, decreased lacrimation that leads to dry eye and contact lens intolerance, and mydriasis. Drugs with anticholinergic side effects have various routes of administration, and the route of administration can greatly determine the severity or spectrum of ocular side effects. For example, scopolamine, noted for its efficacy in treating motion sickness, is available in oral. parenteral, and transdermal patch forms. Although a lower, incidence of intolerable adverse effects is reported with the transdermal patch, some effects do occur.140-144 Anisocoria, changes in anterior chamber depth, blurred vision, decreased accommodation, acute angle closure glaucoma, and photophobia have all been reported with the use of the transdermal patch. When applying the patch, the clinician must take care to avoid finger-to-eye contamination.

Common Side Effects of Anticholinergic Drugs

Ocular Effects

Decreased lacrimation Mydriasis Cycloplegia Blurred vision Elevated intraocular pressure Acute angle closure glaucoma Photophobia Contact lens intolerance Other Effects

Dry mucous membranes Constipation Sedation Decreased cognitive function Urinary retention Tachycardia Predisposition to faIling in elderly patients

453

In one case of blurry vision that was drug induced, a 34-year-old male presented to an emergency department with a chief complaint of blurry vision in both eyes and a rash on his face, including the periocular area, since beginning therapy with benztropine (Cogentin). The patient was also being treated with fluphenazine (Prolixin), a phenothiazine antipsychotic. Both of these drugs are anticholinergic and could easily have produced the blurred vision. Blurred vision has been reported to be a consequence of corneal edema in patients taking phenothiazine antipsychotic drugs. Resolution of corneal edema and improvement of visual acuity were accomplished with discontinuation of the drug. 145,146 Most neuroleptic (antipsychotic) drugs decrease motor activity and decrease interest in the visual environment. Whether these drugs in fact alter the physiology of vision, they do decrease visual perception or attention that results in poorer measured visual functions. Antianxiety drugs as well as antidepressants may produce similar results.':" Blurred vision has been reported after rapid withdrawal of the SSRIs (selective serotonin reuptake inhibitors), which are frequently prescribed antidepressants. Some examples are sertraline HCI (Zoloft) and paroxetine (Paxilj.!" Flecainde, an antiarrythmic, may also cause transient blurred vision.':" Other drugs associated with blurred vision are listed in Table 12-4. There was a case report of blurred vision from Earl Grey tea intoxication. The patient consumed about one

Box 12-12

Box 12-11

Chapter 12

Systemic Drugs with Anticholinergic Properties

Anticholinergics Atropine Scopolamine Homatropine Tropicamide Antihistamines (firstgeneration) Diphenhydramine Chlorphenirarnine Bromphenirarnine

Hydroxyzine Clernastine

Antidepressants Nortriptyline Amitriptyline Imipramine Phenothiazine antipsychotics Thorazine Chlorpromazine Antinausea drugs Promethazine Dimenhydrate

BENJAMIN

454

TABLE 1 2-4

Borishs Clinical Refraction

Systemic Drugs Associated with Blurred Vision

Drug

Mechanisms

Cardiac glycosides (digoxin and digitoxin)

Oculomotor and accommodative dysfunction and toxic amblyopia

Anticholinergic agents Phenothiazine antipsychotics Antihistamines

Accommodative dysfunction and decreased lacrimation

Antidiarrheals

Atropine Class IA and IC antiarrhythmics Diuretics Beta-adrenergic antagonists Ethanol

Cannabis Opioid analgesics

Lenticulardehydration Oculomotor dysfunction and lacrimal changes Oculomotor dysfunction and central nervous system (CNS) depression Oculomotor dysfunction and CNS depression Oculomotor dysfunction, accommodative dysfunction, and CNS depression

gallon of tea per day. Earl Grey tea is composed of black tea and the essence of bergamot oil, a well-known UVAinduced photosensitiser with a strong phototoxic effect. It is thought the adverse effects of bergamot oil in this patient are explained by the effect of bergapten causing potassium channel blockade. The patient recovered by switching tea and cutting consumption to a half a gallon a day. ISO

Amblyopia In toxic amblyopia, agents such as lead, quinine, salleylates, cyanide intoxication due to tobacco, ethambutanol, rifampicin and methanol may be etiologic factors. Ethanol produces a host of adverse effects on vision. It has been estimated that more than 20,000 Americans are heavy users of alcohol, with heavy use defined as greater than three alcoholic drinks per day.!" Amblyopia associated with ethanol abuse is characterized by a loss of color vision (usually red), decreased acuity, and scotomas. Schaible and Colnik!" showed that supplementation of folate to chronic alcohol and tobacco abusers restored vision by an average of four Snellen lines, contributing to the current belief that

Box 12-13

Systemic Drugs that Produce Amblyopia

Alcohol Aldosterone Barbiturates [e.g., phenobarbital and thiopental) Nonsteroidal antiinflammatory agents (e.g., aspirin and ibuprofen) Tricyclic antidepressants (e.g., imipramine, desipramine, and nortriptyline) Hydroxychloroquine and chloroquine Antipsychotic agents (e.g.. chlorpromazine) Sulfa drugs [e.g., sulfacetamide and sulfamethoxazole) Antiinflammatory steroids (e.g., prednisone and triamcinolone)

ethanol and malnutrition both contribute to alcoholic

arnblyopia.F''!" Amblyopia of unknown mechanisms has been reported with use of ibuprofen, one of the NSAJDs available as an OTC agent. Generally, refractive error changes several weeks after the onset of therapy with ibuprofen. Visual acuity may decline to 20/80 to 20/200, and visual field defects may be present. With discontinuation of therapy, vision usually returns to norma1.1S4-IS6 There have been a few cases of permanent visual damage from chronic ibuprofen therapy. Any drug that can produce toxicity to the retina may produce amblyopia with a variety of etiologies. Close monitoring of patients' visual function and early discontinuation of the drug increases the reversibility of drug toxicity. Other drugs that have been reported to produce amblyopia are listed in Box 12-13. Toxic amblyopia overlaps with retrobulbar neuritis.

Accommodative Changes Lithium is a valuable asset in the pharmacological armentarium for the treatment of bipolar depressive disorders. However, because treatment of these disorders is often lifelong, adverse effects are common. Lithium has a narrow therapeutic index and a significant number of drug interactions. Several studies have shown that the development of adverse effects remains the primary reason for discontinuation of therapy. IS? Changes in refraction usually do not occur in healthy volunteers with short-term administration. However, in several studies, accommodation was objectively reduced in young healthy volunteers and those with bipolar disorders.ls8-16o Lithium is associated with many types of ocular effects (Box 12-14). The main complaint from patients taking lithium is that it decreases vision. There is a measurable decrease in visual acuity at both near and distance in these patients. IS? Decreased vision and change in acuity may

Pharmacology and Refraction

Box 1..·14

Ocular Effects of Lithium

Nystagmus Irritative conjunctivitis Decreased accommodation Hallucinations Exophthalmos Myasthenic blocking effect Extraocularmotor dysfunction Blurred vision Papilledema

Box 12·1 5

Systemic Drugs that Alter Accommodation

Alcohol Antianxiety medications Antibiotics Anticholinergic agents Anticoagulants Chemotherapeutic agents Antidepressants Antidiarrheals Antihistamines Antimalarial drugs Central nervous system stimulants Antiparasitic drugs Antiparkinson drugs Antipsychotics Antispasmodics Carbonic anhydrase inhibitors Corticosteroids Diuretics Narcotics Psychedelic agents Sedatives

be due to a combination of effects, such as ocular irritation and nystagmus. Most effects are reversible upon discontinuation of the drug. Ciliary spasm causes headaches, blurred distance vision, and poor accommodative amplitudes. Common drugs that cause ciliary spasm include pyridostigmine, opioids, digitalis, organophosphate poisons, and cholinomimetics such as pilocarpine and carbachol. 128 Other drugs that cause accommodative fluctuations are listed in Box 12-15.

Photophobia, Photosensitivity, and

Phototoxicity It has been well documented that prolonged exposure to very bright light can produce toxicity to both the ante-

Box 12-16

Chapter 12

455

Systemic Drugs that Produce Ocular Phototoxicity

Nonsteroidal antiinflammatory drugs Diflunisal Ibuprofen Piroxicam Sulindac Nabumetone Antidepressants Amitriptyline Amoxipine Desipramine Antipsychotics Hydrochlorothiazide Chlorpromazine Fluphenazine Haloperidol Prochlorperazine Trifluroperazine Antihypertensives Propranolol Captopril Diltiazem Minoxidil Methyldopa Nifedipine Hypoglycemics Acetohexamide Chlorpropamide Tolbutamide

Antibiotics Doxycycline Dapsone Ciprofloxacin Lomfloxacin Norfloxacin Ofloxacin Oxytetracycline Trimethoprim Antiparasitic agents Chloroquine Hydroxychloroquine Diuretics Furosemide Chlorothiazide Amiloride Antihistamines Diphenhydramine Cyproheptadine Miscellaneous Lithium Isotretinoin Tretinoin Alprazolam Amatadine Amiodarone Carbamazepine Oral contraceptives Promethazine

rior and posterior segments of the eye. The cornea normally filters out all radiation below 295 nm and the lens filters out all radiation between 295 and 400 nm. In the absence of the lens, or in the immature eye, much of this radiation is passed through to the retina. Ultimately, radiation damage can cause age-related macular degeneration, one of the most common causes of blindness in the Western world. In this regard, phototoxicity can be augmented by several classes of pharmaceutical agents. These drugs can produce photosensitivity and phototoxicity to the eye by several mechanisms, ultimately leading to decreased vision and changes in refractive index. Some agents produce mydriasis, and others produce ultrastructural changes that make tissue more prone to damage by ultraviolet radiation (UVR), leading to deposits and opacities. Some may bind to ocular tissue, altering the eye's transmission and absorption characteristics. 161 Box 12-16 lists agents that produce photosensitivity and phototoxicity. Patients being treated with these medications should wear pro-

456

BENJAMIN

Borishs Clinical Refraction

tective sunglasses, use sunscreen on exposed areas, and avoid prolonged exposure to bright light. One class of drugs that produces photosensitivity and toxicity is the phenothiazine antipsychotics. The phenothiazines produce photosensitivity and toxicity to the cornea, lens, and retina. This can ultimately lead to corneal and retinal damage as well as to the development of cataracts. Photophobia can result from any ocular irritant. Physiologically, it is a protective mechanism. It is .c~ar­ acterized by tearing and blinking in response to irntation. There have been several reports of lithium-induced photophobia, but this adverse effect does not appear to limit therapy.162-164 The cause of lithium-related photophobia is not known. It may be a result of direct irritation from high concentrations of the drug in tears.!" Lithium does alter the rod photoreceptors, which may alter dark adaptation. 164 Box 12-17 lists drugs that cause photophobia. Mydriatics may also produce photophobia, which reverses once the effects of the drugs have dissipated. Photophobia may also be caused by drugs that are cataractogenic, those that produce ocular inflammation, and those that produce optic neuritis. An HIV-infected male patient experienced photophobia after a change in dosing regimen that resulted in substantially higher indinavir plasma levels as compared with a reference population. High indinavir levels

Box 12-17

Systemic Drugs that Cause Photophobia

Acetohexamide Amitriptyline Atropine Belladonna Captopril Chloroquine Desipramine Digitalis Doxepin Fluphenazine Hydroxychloroquine Homatropine Ibuprofen Isoniazid Methyldopa Nortriptyline Phenylbutazone Tetracycline Tolbutamide Trifluroperazine Vincristine Vinblastine

were suspected to be the cause of photophobia in this patient. 166

Diplopia Lithium-induced diplopia may be related to sixth nerve dysfunction or oculomotor dysfunction.F''!" The most common muscle dysfunction is that of vertical gaze, but muscle dysfunction can be seen at almost any position. Initially it may be intermittent and noticeable only in isolated fields. Also lithium can cause a neuromuscular blocking effect (similar to MG) that can manifest as

diplopia.!" Carbarnazepine, an antiseizure medication, produces diplopia and blurred vision because of impairment of smooth pursuit movements. Given that many fine aberrations in movements may be the first sign of drug toxicity, it has been suggested that ocular movement testing is an excellent method for determining underlying drug toxicity. 167 Isolated ocular muscle paresis can be a presenting sign of toxic neuropathy associated with vincristine use. A 28-year-old male with non-Hodgkin's lymphoma presented with acute onset of diplopia three weeks after the completion of combination chemotherapy with vincristine. He had a left esotropia with marked decrease in abduction. Lymphomatous and other intracranial pathologies were excluded. Vincristine neurotoxicity was considered as the possible etiology of the abducens nerve palsy. The diplopia completely resolved four weeks after the cessation of vincristine therapy.'?" Any drug that produces a myasthenia-gravis-like effect can cause diplopia. Drugs with the potential to interfere with muscle cholinergic transmission include paralytic agents used in surgery, ganglionic blockers, and aminoglycoside antibiotics. Other agents reported to produce a myasthenia-gravis-like syndrome in the eye are listed in Box 12-18.

Box 1 2·1 8

Systemic Drug Classes that Produce a MyastheniaGravis-Like Syndrome

Neuromuscular blocking agents Antibiotics Anticholinesterase agents Antiarrhythmics Anticonvulsants Beta blockers Corticosteroids Chloroquine Lithium Magnesium

Pharmacology and Refraction

Color Vision Defects In the case of the cardiac glycosides, changes in color vision are one of the first signs of impending toxicity. Used for more than 250 years, digitalis and the related cardiac glycosides digoxin and digitoxin are some of the mainstays in the treatment ofcongestive heart failure and certain types of cardiac arrhythmias. Derived from the foxglove plant (Digitalis lanata], these drugs increase the heart's contractile (inotropic) force. They have a narrow therapeutic index, and inadvertent poisoning with digitalis is common. It has been estimated that 20% of patients who take digoxin become toxic, and of them, 95% exhibit some type ofvisual disturbance.!" Although the visual effects of the cardiac glycosides are most common when drug levels are in the toxic range, ocular findings are present even when drug levels are within the therapeutic range. Some investigators have found the use ofthe Farnsworth-MunselilOO-HueTest color vision test useful in diagnosing digoxin toxicity. 172-l7G The mechanism of action of the cardiac glycosides is well known. These drugs inhibit the sodium/potassium adenosinetriphosphatase (ATPase) pump, resulting in a net increase in myocardial intracellular calcium levels, increased myocardial contractile force, and a slowing of the heart rate. Because ATPase pumps are located in other tissues, the effects of cardiac glycosides are not cardiac selective. The mechanism of the ocular side effects of the cardiac glycosides was debated for many years. Early researchers contended that they were a direct result of the drug on the CNS.177 - 181 In later studies, electroretinogram (ERG) findings on digoxin toxicity showed aberrations in the response to the longer wavelengths of light and abnormal cone ERG and dark adaptation. 18 2 , 183 These recent findings, when combined with results from other studies that have shown that digitalis is concentrated in the retina, indicate that the ocular effects of the cardiac glycosides may be due to these drugs' effect on the retinal ATPase, impairing photoreceptor repolarization.t'"?" Ocular effects of cardiac glycosides usually occur when the plasma level of the drug is approaching the toxic range. Common signs include: xanthopsia or the perception of a yellowish tinge around objects; blue-yellow color defects; some red-green defects; decreased or dimming of vision; blurred vision; central and paracentral scotomas; decreased lOP; retrobulbar neuritis; mydriasis; snowy vision; and hallucinations. 157, 176,186-192 There has been one case report of dazzling and orbital pain temporally associated with digoxin administration.!" Although xanthopsia is the most common manifestation of cardiac glycoside toxicity, there have been several cases in which other effects occurred without xanthopsia. I 7l , 177 , 194, 195 Antiepileptic drugs, vigabatrin and carbamazepine, cause acquired color vision defects. The abnormal color

Chapter 12

457

perception seems to be associated with constricted visual fields in the vigabatrin monotherapy patients.'?" Drugs used for erectile dysfunction, such as Viagra, Levitra, and Cialis, appear to affect color vision. Both Viagra and Levitra inhibit phosphodiesterase-5 (PDE-5) an enzyme involved in the degradation of cyclic GMP. The ocular side effects for Viagra and Levitra may be a result of the role that PDE-5 plays in light excitation of visual cells. Ocular side effects include a bluish tinge to the visual field, hypersensitivity to light, and hazy vision. These effects are reversible and may last only a few minutes or hours. It has been reported that only 3% of patients have visual side-effects with the standard 50mg dose.' 97 These color vision changes are less common with Cialis, occurring in less than 0.1% of patients according to the manufacturer's package insert. Ibuprofen, an NSAID, may be associated with reversible changes in color vision. In a study by Ridder and Tomlinson.'?" contrast sensitivity was depressed in a patient taking ibuprofen. Oral contraceptive use has been associated with color vision defects in the blue-yellow spectrum. 199 Alcohol use has been reported to cause loss of red vision. A slight blue color vision defect found was found in patients on long-term amiodarone treatrnent.i" Although most drugs cause a decrease in color vision, there is one group that has been associated with enhanced color perception: the hallucinogens. For example, phencyclidine and lysergic acid diethylamide (LSD) are both associated with exaggerated color perception. 153

Cortical Blindness and Changes in Night Vision There are not many reports of drug-induced cortical blindness. Most reports are temporally related to drug use and remain unconfirmed associations. However, aspirin has been associated with a reversible cortical blindness. The mechanism of this blindness is currently unknown, and a dose-response relationship for aspirin and cortical blindness has not been found. Barbiturates can produce cortical blindness when the patient is in a barbiturate coma. Cisplatin, a chemotherapeutic agent that contains platinum, has been well described as a neurotoxic agent. It can produce cortical blindness, retrobulbar optic neuritis, and papillederna.P'r'" Blindness associated with cisplatin has occurred hours or days after administratiorr'": the mechanism is not known. Other drugs reported to have associations with cortical blindness are listed in Box 12-19. Videx, a purine analogue antiretrovirus agent used to treat HIV-related infections, has been associated with nightblindness. '?' Fenretinide, a drug used in the treatment of breast cancer has also been reported to have a

458

BENJAMIN' Borishs Clinical Refraction

Box 12·1 9

Systemic Drugs Associated with Cortical Blindness

Aspirin Cisplatin Cyclosporine Sulfacetamide Sulfisoxazole Vinblastine Vincristine

measurable effect on night vision. This drug is a vitamin A analog that may interfere with the binding of vitamin A to opsin or with the transport of the vitamin.f" Vitamin A deficiency has been connected with night blindness.i'"

Ptosis The eyelids and periocular structures are highly vascularized, delicate tissues which can become swollen and inflamed as a result of a variety of mechanical and physiologcal effects. Calcium channel blockers, or calcium channel modulators, are occasionally associated with periorbital edema and transient increases in lOP. These drugs alter calcium function in myocardial and vascular cells, resulting in a negative inotropic and chronotropic effect on the heart as well as vasodilation. The net effect is to decrease blood pressure in either hypertension or hypertension accompanied by heart failure. Because the arteriolar side of the vasculature is dilated, the postulated mechanism for periorbital edema is due to increased capillary hydrostatic pressure that forces fluid into the eyelids and periorbital area. Given that periorbital edema associated with calcium channel modulators is often accompanied by pedial edema, this mechanism seems likely.207-212 Other drugs associated with periorbital edema include acetaminophen, antibiotics, albuterol, antipsychotic agents, digitalis, enalapril, corticosteroids, NSAIDs, methotrexate, and lithium. Viagra has an effect on blood pressure and, therefore, potential for retinal vascular accidents. Praunfelder'" suggested caution for use in patients with microvascular disease. A 56-year-old man with a history of tobacco abuse was treated for erectile dysfunction. Viagra (50 mg) was taken once without adverse effect. Three weeks later, the patient took a second dose of Viagra (50 mg); 36 hours later he experienced a pupil-sparing third-nerve palsy. The patient also had ptosis with double vision. Pupil-sparing third-nerve palsy is also associated with sildenafil citrate?" Ptosis can result from underlying pathologies, such as MG neuronal lesions, or it may be congenital or the

Box 12·20

Systemic Drugs Associated with Ptosis

Alcohol Barbiturates Dexamethasone Diphtheria-pertussus-tetanus (DPT) vaccine

Digitalis Oral contraceptives Vincristine Vinblastine

result of drug therapy. It is usually unilateral; bilateral ptosis can occur but may be difficult to detect. There are a few reports of lithium-induced ptosis that resembled MG. Lithium may augment the autoimmune mechanism in MG and may exacerbate symptorns.!" Other less commonly reported drug-ptosis associations are listed in Box 12-20. The mechanisms behind these associations remain largely unknown.

Exophthalmos Lithium can produce exophthalmos of unknown etiology. It is believed that lithium may inhibit thyroid hormone secretion or produce an antithyroid effect by an autoimmune mechanism.t'Y" Lithium has also been associated with hyperthyroidism.i'"?" Although lithium-induced exophthalmos is rare, it can occur at any time during or after therapy. Most cases are reversible and do not require additional therapy. 157 Corticosteroids such as prednisone have also been associated with the development of exophthalmos. Katz and Cormodyi" presented two cases of patients on chronic, superphysiological systemic doses of corticosteroids; both patients experienced a benign form of ocular proptosis. In a retrospective study, Van Dalen and Shermarr'" reviewed 20 male patients on daily oral prednisone for severe chronic obstructive pulmonary disease. Careful history and examination of the patients did not reveal any other cause for exophthalmos. It seems that exophthalmos is a usually benign but common effect of chronic systemic glucocorticoid therapy. Other agents reported to produce exophthalmos include oral contraceptives, excess thyroid hormone (as a result of pathology or thyroid supplements), and vitamin A.

lacrimal Changes Dry eye is a manifestation of many disease states (e.g.. Sjogren's syndrome), it is a normal effect of aging, and it can certainly be an adverse effect of drug therapy. The term"dry eye" denotes an abnormality of the precorneal

Pharmacology and Refraction

tear film that can be due to a defect in the lipid, aqueous, or mucin layer. Lid dysfunction and ocular surface diseases can produce dry eye. Any drug or disease that causes drying of the eye can alter the corneal surface enough to alter visual acuity.':" The use of a medication that causes drying of the eye can augment underlying disease states that produce dry eye. In dealing with this common complaint, it is important to discern the cause in order to initiate an effective therapeutic regimen and thus preserve the health of the ocular surface. The class of drugs that most frequently produces dry eye is the anticholinergic agents (see Box 12-12). The effects of drug-induced dry eye on the overall health of the eye and on the tolerance for contact lens wear can be profound. The beta-adrenergic blockers (e.g., propranolol) can cause a syndrome that resembles keratoconjunctivitis sicca. Busulfan, NSAIDs, and quinidine have also been reported to produce a sicca-like syndrome. The betaadrenergic antagonist practolol appears to be the worst offender of the beta blockers, causing corneal scarring and ulceration if it is not discontinued. Keratoconjunctivitis sicca can cause diffuse punctate epithelial erosions over the lower third of the cornea and can be identified with rose Bengal or other diagnostic stains.f" Hydrochlorothiazide, used in the treatment of hypertension, has been shown to decrease tear production significantly and produce dry eye.?" Antihistamines, classical H I antagonists by virtue of their anticholinergic effects, can decrease tear and mucus production and change the clinical refraction.m,m Although this may not be clinically significant in all patients, it can further aggravate diseases such as keratoconjunctivitis slcca?" and produce additional surface damage. In addition, drying of the eye by antihistamines and other agents can lead to contact lens intolerance. As mentioned, isotretinoin is a vitamin A analog used for the treatment of dermatological disorders. One of the most common and intolerable adverse effects associated with isotretinoin therapy is dry eye. Symptoms disappear once the drug has been discontinued, but most clinicians discourage contact lens wear during therapy because the dry eye is so severe. New research from the Beaver Dam study suggests that treatment with certain blood pressure drugs (ACE inhibitors) seems to reduce the risk of dry eye syndrome (DES).229 During the 5-year study period, 322 of the 2500 subjects (ages 48 to 91) developed DES. It occurred in 9% of subjects taking an ACE inhibitor versus 14% among those not taking an ACE inhibitor. The authors noted that the protective effect of these drugs may involve their antiinflammatory effects. They also found that self-reported dry eye was not significantly associated with sex of the subject, blood pressure, hypertension, serum total or high-density lipoprotein

Chapter 12

459

cholesterol level, body mass index, history of arthritis, gout, osteoporosis, cardiovascular disease, thyroid disease, smoking, the use of caffeine, vitamins, antianxiety medications, antidepressants, calcium channel blockers, or anticholesterolemics. Greater risk of dry eye was associated with subjects who used antihistamines or diuretics. In a survey of nearly 39,000 women physicians who are taking part in a long-term health study, postmenopausal women taking the female hormone estrogen alone were determined to have a 70% higher risk of developing DES compared to women who had never taken the medication. Those who were taking a combination of estrogen and the hormone progestin had a 30% higher risk of developing DES. 230 Epiphora has been reported as a side effect of topical mitomycin C (MMe). Obstruction of the puncta or canaliculi is not an infrequent event after topical 0.04% MMC used to treat conjunctival neoplasia.?" Drugs known to have adverse effects on the ocular lacrimal status are listed in Box 12-21.

Box 12·21

Systemic Drugs Associated with Decreased Lacrimal Production or Alteration in the Tear Film

Alcohol Antihypertensive agents Beta-blockers (e.g., tirnolol. propranolol, and naldolol) Methyldopa Reserpine Clonidine Diuretics Phenothiazine antipsychotics Chlorpromazine Antihistamines Diphenhydramine Chlorpheniramine Clemastine Promethazine Anticholinergics Atropine Scopolamine Isotretinoin Antidepressants Desipramine Imipramine Cannabinoids Methotrexate Opioids Morphine

460

BENJAMIN

Borish's Clinical Refraction

Conjunctival Changes Nonspecific ocular irritation, conjuctivities, and hyperemia are difficult symptoms to differentiate in the absence of an obvious infection. In fact, these complaints may wax and wane in such a way that the underlying etiology is difficult to discern. Many drugs are secreted in the tears or alter the precorneal tear film in some manner that produces ocular irritation, conjunctivitis, or hyperemia and subsequent inflammatory changes. Obtaining a thorough history of all medications; including OTC drugs and possible drugs of abuse, can lead to determining the cause and resolving the symptoms. An example of a drug that can cause ocular irritation is aspirin. This well known and widely available NSAID is secreted in tears in rather high concentrations that can lead to ocular irritation and nonspecific conjunctivitis." Lithium is distributed into all body fluids-when it reaches the tears, it can cause significant ocular irritation and decreased contact lens tolerance. 157,232 Lithium has also been shown to decrease tear production and increase the salt content of the tears. 232,233-235 Dry-eye symptoms and sicca usually occur in the early weeks of therapy and can be effectively managed with artificial tears.':" No changes in refraction occurred in healthy volunteers with short-term administration; with chronic use, refractive status varied widely between patients. Changes in acinar cell morphology have been observed in rabbits treated with isotretinoin.' These changes are consistent with the alterations observed in patients undergoing isotretinoin therapy. Mathers et al.236 observed that the meibomian glands appeared to atrophy during treatment. This may be an underlying cause of dry eye and the consequent contact lens intolerance and blepharitis that occur with isotretinoin therapy.2,236,237 Irritative conjunctivitis and blepharitis occur in up to 40% of patients treated with isotretinoin.' The tear film from these patients has a lower lipid content than does the tear film from control patients and may cause faster evaporation of tears from the ocular surface.' Dry eyes and ocular irritation are the results. In addition, isotretinoin is secreted by the lacrimal apparatus into the tears, further disrupting the tear film and aggravating dry eye. Blepharitis is another common adverse effect of isotretinoin therapy. It appears that S. aureus is the usual culprit that is allowed to establish itself because of decreased keritinization and lubrication of the eyelid margins.' Long-term topical glaucoma treatment results in histopathological changes of conjunctiva. The administration of a single topical medication preserved with benzalkonium chloride, irrespective of type, for 3 months or more can induce a significant degree of subclinical inflamrnation.i" Even short-term use of glaucoma medications can have an effect: I-month

treatment with glaucoma medications contammg higher levels of benzalkonium chloride (BAK) can result in greater corneal damage and conjunctival cell infiltration than medications that are preserved with Purite or that contain lower levels of BAK. Using glaucoma medications with alternative preservatives or low levels of BAK may help preserve ocular surface health."? Other drugs associated with conjunctivitis are listed in Box 12-22. The mechanisms by which some of these drugs produce conjunctivitis are not known. Others produce changes in lacrimal status, interact with other drugs, are secreted in tears, or instigate allergic responses to produce conjunctival irritation. Drug containers may cause nonintentional conjunctival trauma and simulate severe ocular disorders. The patients presented with red, painful eyes, congested lower palpebral conjunctiva, epithelial conjunctival erosions, and episcleritis. In all patients, direct contact of

Box 12-22

Systemic Drugs Associated with Conjunctival Irritation and/or Conjunctivitis

Nonspecific Conjunctivitis Acetaminophen Allopurinol Barbiturates Benzodiazepines Carbamazepine Cephalosporin antibiotics Cimetidine Nonsteroidal antiinflammatory drugs (NSAIDs) Opioids Nifedipine Sulfa antibiotics Vitamin A Verapamil Conjunctival Hypereml. Corticosteroids Cimetidine Erythromycin Gold compounds Minoxidil Tolbutamide Nonspecific Ocular 'rrlt.tlon Benzodiazepines Antihistamines NSAIDs Methotrexate Nifedipine Verapamil Sulfa antibiotics Cannabinoids Trazodone

Pharmacology and Refraction

the tube or bottle-tip with the affected area of the conjunctiva was ascertained by inspection. Physicians should be aware of this diagnosis in any case of prolonged and unexplained ocular irritation and should instruct patients as to the proper instillation of topical ophthalmic medications."?

Keratitis Punctate corneal lesions were associated with the illicit use of methylendioxyamphetamine ("ecstasy") in several patients.?" and corneal epithelial defects following the use of crack cocaine have been reported.Yr'" McHenry et al. 242 described a condition they called "crack eye" as being characterized by pain, photophobia, lacrimation, chemosis, and hyperemia in association with corneal epithelial defects. These defects can be a result of direct irritation from the fumes from smoking crack cocaine or can result from the person's rubbing his or her eyes in response to the irritation. Regardless of the cause, these defects can lead to corneal ulceration, infectious keratitis, and corneal perforations.r'"?" Whereas crack cocaine emits toxic fumes and intense heat that can damage the corneal surface, CNS stimulants such as amphetamine and "ecstasy" can cause insomnia, and the resulting ocular damage can be attributed to lagophthalmos. Cocaine administered through the conjunctival fornices in a 32-year-old abuser was reported to have caused bilateral corneal ulcers.!" Panophthalmitis secondary to intranasal cocaine use has also been reported.?" Although topical ocular anesthetic abuse is uncommon, the associated complications include persistent corneal epithelial defect, ring-shaped stromal infiltrate, and anterior segment inflammation. This disorder can masquerade as Acanthamoeba keratitis or other infectious keratitis. Sun et al. 248 reported a suspicious case of infectious keratitis unresponsive to antibiotics. The patient had an irritable manner, low pain-control threshold, and an analgesic drug abuse history. This information, along with finding a topical ocular anesthetic bottle at bedside helped alert us to the possibility of drug abuse. After discontinuing use of the topical anesthetic and using lubricants, topical steroid, and a therapeutic soft contact lens, the condition improved. Toxic keratopathy can even be the result from abuse of topically administered anesthetics even at a very low concentration, 0.05%.249 Topical NSAIDs have been associated with corneal complications that include: keratitis, ulceration, and corneal perforation."? Corneal changes can reflect the chemical properties of the medication.i" Amphiphilic medications such as amiodarone, chloroquine, suramin, and clofazimine can produce a drug-induced lipidosis with a vortex keratopathy. Cytarabine, an antimetabolite, can result in a degeration of the epithelial cells of the basal layer

Box 12-23

Chapter 1Z

461

Systemic Drugs Associated with the Development of Keratitis

Alcohol Nonsteroidal antiinflammatory drugs Indomethacin Phenylbutazone Sulindac Corticosteroids Prednisone Betamethasone Dexamethasone F1uoromethalone Hydrocortisone Beta-adrenergic antagonists Timolol Betaxolol Atenolol Metoprolol Oxyprenolol Antihistamines Brompheniramine Chlorpheniramine Cocaine Sulfa antibiotics Tetracycline

leading the formation of microcysts. Corneal drug deposition alone rarely results in vision loss and is not typically an indication for discontinuing the drug. Because corneal changes are usually dose related, these changes can reflect potential risk to the lens and retina. Other agents known to cause keratitis are listed in Box 12-23. The mechanisms are not well characterized, but the keratitis may be reversed by discontinuation of the drug. Some data indicate that these agents may be secreted in tears and may have a direct local effect on the cornea. It should be mentioned that keratitis is also produced by topical antimicrobial agents such as antibiotics. A chemical keratitis resulting from topical antimicrobial drug use should not be confused with a worsening of the symptoms.

Pupillary Changes Many systemic agents affect the pupil's size and responsiveness. They do this by directly modulating the autonomic nervous system, by interacting with the CNS, or by causing hypoxia. As mentioned earlier, anticholinergic drugs block the effects of acetylcholine on the ciliary muscle, producing mydriasis. This effect is seen regardless of the route of administration. Occasionally, an anticholinergic agent, such as scopolamine, can produce anisocoria.i'" Costly and sometimes unnecessary

462

BENJAMIN·' Borishs Clinical Refraction

workups of neurological deficits can be prevented if the clinician takes a careful history that includes asking the patient whether he or she is wearing a scopolamine patch to prevent motion sickness. Anisocoria has also been reported with inadvertent contact with jimsonweed. In one case, a 38-year-old male with no significant medical history reported to an emergency department with a complaint of blurred vision and a dilated pupil. His right pupil was found to be fully dilated at 6 mm and nonreactive to light and pilocarpine administration. Earlier in the day, the patient had been using a weed trimmer and a piece of jimsonweed had flown into his eye.The pupil remained dilated for 2 days after removal of the foreign body.i" Sympathomimetic agents and CNS stimulants such as epinephrine, cocaine, and amphetamine can cause mydriasis as a result of interaction with the alpha receptor on the dilator muscle. One of the hallmark signs of abuse of CNS stimulants, such as cocaine or amphetamine, is dilated pupils that have a sluggish response to light. All drugs that depress the CNS have the potential to produce mydriasis, usually as a consequence of hypoxia. Anoxic signs such as these occur when the drugs are taken in toxic amounts or combined with each other to produce a synergistic effect on respiratory depression. Box 12-24 lists other agents that produce mydriasis. Miosis can result from drugs acting on the ciliary muscle or from modulation of neurotransmission in the CNS. Drugs that produce miosis are listed in Box 12-25. Ocular drugs used primarily for their effects on the pupil may cause adverse reactions to other areas of the eye. Four patients (age range 54-82, 1F, 3M) diagnosed with nonarthritic ischemic optic neuropathy experienced acute worsening of visual function after instillation of phenylephrine for dilated funduscopic examination. Phenylephrine is a mydriatic with vasoconstrictive properties, which may be absorbed through the cornea, thus yielding nonnegligible intraocular concentrations. Vasoconstriction of the watershed posterior ciliary capillary beds may result in further precipitating infarction of already compromised circulatory territories in edematous optic nerves. Because phenylephrine is a known vasoconstrictor in vivo and in vitro, it is more likely to cause deleterious vasoconstriction and an acute decline in visual function in patients with acute ischemic optic neuropathy than tropicamide. The routine practice of using phenylephrine to prepare patients for funduscopic assessment should be reexamined, particularly in patients with ischemic optic neuropathy.P"

Ocular Opacities: Deposits and Cataracts Many agents or their metabolites are capable of producing ocular deposits. These usually occur on the

Box 12·24

Systemic Drugs that Produce Mydriasis

Acetaminophen Alcohol Albuterol Barbiturates CNS stimulants Cocaine Amphetamine Ephedrine Anticholinergics Atropine Homatropine Dimenhydrinate Scopolamine Tricyclic antidepressants Amitriptyline Desipramine Doxepin Nortriptyline Imipramine Antihistamines Chlorpheniramine Clernastine Diphenhydramine Brornphenirarnine Benzodiazepines Chlordiazepoxide Flurazepam Chlorazepate Diazepam Midazolam Corticosteroids Betamethasone Fludrocortisone Prednisone Prednisolone Methylprednisolone Miscellaneous Levodopa Lidocaine Mescaline Meprobamate

Box 12-25

Barbiturates Cardisoprolol Opioids Levodopa Marijuana Neostigmine Vitamin A

Unknown Central nervous system (CNS) effect Beta-adrenergic stimulant (CNS effect) Anoxia Alpha-adrenergic agonist (dilator muscle)

Ciliary muscle

Anticholinergic, ciliary muscle

Anticholinergic, ciliary muscle

Unknown

Unknown

Alpha-adrenergic agonist

Systemic Drugs that Produce Miosis

Pharmacology and Refraction

cornea, conjunctiva, or lens. The most likely area for corneal deposits is Descernet's membrane near the corneal periphery?" Drug-induced lenticular deposits are less common. Most corneal and lenticular deposits caused by pharmacological therapy resolve once the drug is discontinued. The symptoms of lenticular deposits or cataracts vary with the severity of the deposit and consequent change in opacity. Usual complaints include decreased vision, blurred vision, or increased glare. 157 Drugs that cause corneal and lenticular deposits are listed in Box 12-26. It is thought that the majority of agents are secreted in relatively high concentrations in the tears and deposit in the cornea. Some drugs alter the sensitivity of the lens to UVR, and although they do not cause any changes in opacity directly, they make the lens more prone to damage from UVR. The majority of corneal deposits are found in the superficial corneal layers. They can be seen easily with slit lamp examination and vary in their characteristics. Chloroquine, a drug used in the prophylaxis and treatment of malaria, produces classical deposits not only on the cornea, but also on the lens, and is toxic to the retina.?" Corneal deposits associated with chloroquine are typically yellowish-white dots in the palpebral fissure area. With continuation of therapy, they become whorl-like in the epithelium. Patients often complain of a halo effect on vision that resolves once the drug is discontinued. The metabolite of chloroquine, and not the drug itself, is believed to produce the deposits."? Some of the NSAIDs, such as naproxen and indomethacin, have been reported to cause corneal

Box 12-26

Systemic Drugs that Produce Lenticular or Corneal Deposits

Corne.' Deposits Alcohol Amiodarone Auranofin Chloroquine Hydroxychloroquine Chlorpromazine Chlorprothixene Promazine Echothiophate Meperidine Epinephrine Iron supplements

Lentlcul.r Deposits Amiodarone Gold compounds Chlorprothixene

Chapter 12

463

deposits. The pattern is similar to that produced by Fabry's disease and therapy with promethazine, meperidine, chloroquine, and amiodarone."" Antiviral medications are being used with increasing frequency, partly because of their utility in treating AIDS-related diseases. By and large, these drugs produce much less pathology than the disease states for which they are used. Most of the toxicity reports are anecdotal. Amantadine has been documented to produce a white punctate corneal deposit that reverses readily when the drug is discontinued. It is thought that these deposits are a result of high tear concentrations of the drug.i" Ganciclovir and foscamet are used to treat cytomegalovirus retinitis, and both have been shown to produce little toxicity when injected directly into the vitreous in rabbits. 259,260 The phenothiazine antipsychotics produce corneal opacities with chronic use. These opacities coupled with the formation of lenticular deposits and those effects associated with the anticholinergic properties of the drug seem to be the most common adverse effects of the phenothiazines.i'"?" Among the phenothiazines, chlorpromazine seems to be the worst offender. Ocular changes occur in the majority of patients and appear to be related to the total dose administered. Patients who receive 300 mg or greater over several years seem to be more prone to developing opacification. 265 - 268 The development of lenticular opacity appears to result from drug-induced phototoxicity. Initial changes appear as a dust-like granular opacity in the pupillary area radiating out to the anterior cortex. 267 - 269 Corneal changes usually appear after lenticular opacities have already occurred. The deep layers of the cornea are the most prone to fine granular deposits that appear as a brownish haze. 265,270 Although visual acuity can be significantly decreased, diffuse opacification that does not change vision often occurS.m,2?! These changes have been shown experimentally to be due to production of superoxide radical. 272 Amiodarone has been associated with corneal deposits in more than 90% of patients being treated. 27J - 277 These corneal opacities usually present in a yellow-brown, linear whorl located on the corneal epithelium basal cell layer, the middle and lower thirds of the cornea, in a pattern that appears similar to the keratopathy of Fabry's disease. 278-282 The deposits appear to be related to the dose and the duration of treatment and can sometimes interfere with visual acuity.274,m-281 The corneal changes appear to be more frequent than those in the lens, present earlier in the course of therapy, and can persist for up to 18 months after therapy is discontinued."? The chemical structure of amiodarone includes both hydrophilic and hydrophobic moieties that can accumulate in lysosomes, and it is believed that this accumulation may result in the keratopathy that is

464

BEN.JAMIN

Barish's Clinical Refraction

so common with this agent.?" Other adverse effects of amiodarone therapy include chromatopsia, glare, halos, blurred vision, papillopathy, and pseudotumor cerebri. 283-287 Other agents known to cause corneal deposits include amodiaquine chloroquine, gentamicin, hydroquinone, hydroxychloroquine indomethacin, mombenzone, perhexiline, epinephrine, suramin, tilorone, and gold salts.288,289 Gold salts (auranofin and others) are often given on a chronic basis for the treatment of rheumatoid arthritis. Deposits on both the cornea and the lens are predictable adverse effects. They typically occur after approximately 2 g of gold has been given and appear as a gold or purple stippling in the superficial stroma near the corneal periphery?" McCormick et al. 290 found that 97% of patients receiving gold salt therapy had corneal deposits or chrysiasis. The deposits appeared to be limited to the posterior half of the inferior cornea and were related to the duration of therapy. Lenticular chrysiasis has also been associated with gold therapy. One well-known group of drugs that induce cataracts is the glucocorticoids, also known as the corticosteroids. 291,292 Posterior subcapsular cataract development has been associated with chronic use of these drugs in many routes of administration. These include systemically delivered drugs; topical ophthalmic products including drops and creams applied to the periocular area; and inhaled steroids for asthma, which were recently temporally associated with cataracts.i"?" It should be noted that cataracts secondary to inhaled glucocorticoids are extremely rare. They most often occur in individuals with a predetermined hypersensitivity. Use of inhaled steroids in respiratory disease should not be limited by the very small risk of cataract development. Glucocorticoids also produce a distinctive reticulated pattern in the anterior capsules from cataract-containing lenses with significant epithelial disruption.i" The mechanism of glucocorticoid-induced cataracts is not well known, but there is a positive correlation between length of therapy and dose in the development of the opacities. Corticosteroids affect the water transport processes in the lens, which may increase its permeability to cations. Normal water and electrolyte transport is necessary to maintain the transparency of the lens. Some animal and in vitro studies suggest that glucocorticoids may alter the lens proteins in a way that causes cross-linking or changes the structure of the lens so that it is more susceptible to oxidation and, ultimately, loss of transparency.P"?" Recently, Nakamura et al. 304 observed that the rate of steroid-induced cataracts in renal transplant patients increased with the use of cyclosporine A (CSA), despite a decrease in the total dose of systemic steroids. This suggests that the additional use of CSA may contribute to the develop-

ment of steroid-induced cataracts. Steroid pulse therapy should be considered a risk factor for the development of steroid-induced cataracts. It is advisable to monitor closely patients who are being treated with chronic steroids. Steroid-induced changes in opacity are not reversible and can develop into mature nuclear cataracts, but they can be prevented by close monitoring and discontinuation of the drug, if possible. Smoking is associated with a higher prevalence of nuclear and posterior subcapsular cataracts. Heavy smokers, (at least 1.5 packs a day) are particularly susceptible to developing age-related cataracts. The benefits of stopping smoking are still not clear. There appears to more benefit for those smoking less than 1.5 packs a day than for heavy smokers. Those smoking less than 1.5 packs a day expose the eyes to less of the damaging cigarette toxins and tobacco-related oxidant stress and are more likely to return to nonsmoking risk levels by 10 years after cessation. However, once eye damage has occurred, it is not likely it will be reversed by quitting.?" The consumption of alcohol may also increase the risk of developing cataracts. One study found that the only adverse effect of alcohol was among smokers. People who smoked and drank heavily had an increased prevalence of nuclear cataract.r" A more recent study suggests the consumption of alcoholic beverages, particularly hard liquor and wine, was positively related to nuclear opacity?" Cataracts in relatively young patents have been associated with isotretinoin therapy. Although the underlying cause of isotretinoin-induced cataracts has not been firmly established, protein assays of lenses of patients taking this drug have shown elevated absorption of UVR, leading to increased damage.?" This also indicates that not all of the ocular effects from isotretinoin therapy may be reversible. In addition to producing corneal deposits, amiodarone is known to produce anterior subcapsular cataracts. These changes occur with chronic use and are not associated with the acute use of amiodarone in bouts of life threatening ventricular tachycardia. In a 10year study, Flach et al. 286 followed 14 patients treated with amiodarone. Seven patients died during this period, three had their treatment discontinued for various reasons, and the remaining four experienced the development or acceleration of lens opacities. Snellen visual acuities were not decreased, but acuity was shown to be impaired with contrast sensitivity measurements. The mechanism of caractogenesis by amiodarone is not known at this time. The opacities have been described as loosely packed, yellowish-white deposits that cover an area larger than an undilated pupil aperture. These deposits, which look similar to those produced by phenothiazines, are usually located in the aperture, suggesting that amiodarone, a known photosensitizing

Pharmacology and Refraction

agent, may augment or accelerate the effects of lIVR. "" Illl Phenothiazine antipsychotic agents are associated with the development of posterior subcapsular cataracts with chronic, long-term use. Chlorpromazine, a prototype of this drug class, also produces corneal stromal pigrneruation.!" l.xarnplcs of drugs in this class are listed in Box 12-27. Many hypotheses for the development of cataracts with phenothiazine treatment have been offered including corneal dehydration, disruption of the lens membrane, changes in electrolyte balance, and concentration-dependent effect of the drug from the uveal circulation. >II \1-1 The incidence of cataract development seems to be higher in patients treated with the phcnothiazines than in patients treated with the butyrophenone antipsychotics, the less anticholinergic, but more selective, dopamine antagonists. One important class of therapeutic drug classes is the antihyperlipidernics. Drugs, such as simvastatin and lovastatin. are used in the treatment of lipid disorders and have been implicated in the acceleration of cataract development. w; \1" These drugs lower serum cholesterol by inhibiting liMe CoA reductase, the enzyme that catalyzes the rate-limiting step cholesterol synthesis. Ikcause the lens is isolated from circulating lipoproteins and its growth is dependent on cholesterol, the implications of lowering cholesterol synthesis by lovastatin or related drugs caused some initial concern. The cataractogenic potential of lovastatin or simvastatin was especially disturbing in light of some animal studies that showed that these drugs produced lenticular opacities. >I~.\I,' However. in subsequent animal and human studies with chronic administration of up to 5 years, no difference in corneal and lenticular opacities was found between patients treated with either drug and patients who received a placebo. il'I-\21 lraunfelder ':" has suggested the statins are associated with ocular hemorrhage. Allopurinol, a drug used to treat gouty arthritis, seems to have a cataractogenic action in some patients but not all. \2"L'~ Allopurinol binds to human lens proteins in the presence of lIVR, \'~ and once it is bound, it becomes a potent photosensitizer with a longer wave-

Box 12-27

Chlorpromazine .lhiorid.izi nl' l'luphcnazine Perphcnazinc Pror hi 0 rpcraz in e Acctophcnazinc

The Phenothiazine Antipsychotics

Chapter 12

465

length absorption spectrum. lc: The incidence of cataract development appears to be related to dose, length of therapy, and exposure to lIVR. Sponsel and Rapoza \2" found lenticular changes in the presence of drug induced hyperglycemia in an otherwise healthy male patient indaparnide, a diuretic used in the treatment of hypertension, was associated with the development of bilateral subcapsular cataracts in this patient after 3 years of treatment. The opacities did not resolve after discontinuation of the drug, and the patient subsequently underwent cataract extraction and intraocular lens implantation to correct his vision. An association between the use of phenytoi n. a hydantoin antiseizure medication, and the development of cataracts has been documented in both human and animal. \2')\\(1 The mechanism is not known, but in one patient, bi lateral cataracts developed 4 months after a toxic level of phenytoin was inadvertently reached. \\1 Other drugs with temporal associations with cataract development for which the mechanism is not well understood are listed in Box 12-28.

Changes in Intraocular Pressure If left untreated, elevated lOP can result in glaucomatous changes, decreased vision, and blindness. Independent of underlying pathology, there are several drugs that can elevate [OP and produce glaucomatous changes if therapy is not discontinued. Acute angle closure glaucoma is a potential adverse effect of several drug classes. This occurs most often in patients with a previous history of angle closure and those with narrow angles. Any drug that produces mydriasis (e.g., the antichol inergics) has the potential

Box 12·28

Systemic Drugs Associated with the Development of Cataracts

Corticosteroids Prednisone Prednisolone l Ivdrocortisonc Dexamethasone Alcohol Allopurinol

Husul fan Chloroquine Ilydroxychioroquine Ch lorpromazi ne Huphcnazinc Ch lorproth ixen« Dcferoarnine Isotrctinoin

466

BENJAMIN

~

Borishs Clinical Refraction

for angle closure glaucoma. The primary mechanism is pupillary block during pharmacological mydriasis and acute lens swelling.?" Two antihistamines have been reported to be associated with acute angle closure glaucoma-chlorpheniramine and orphenadrine.l" Both drugs are selective HI antagonists indicated for the treatment of allergic disease. Other histamine antagonists that are selective for the H2 receptor are used in the treatment of gastric ulcers and gastric reflux disease. There has been one report of H 2 antagonists such as ranitidine and cimetidine causing adverse effects on lOP in humans and one report in animal studies. m .m Both cimetidine and ranitidine were administered directly into the cerebral ventricles of rats in concentrations that would be much higher than that obtained with therapeutic dosing. Other studies in healthy volunteers have shown H2 antagonists to have no effect on IOP.336 •337 Ritch et al.338 reported four cases of acute angle closure glaucoma associated with imipramine therapy. The patients at highest risk were those with narrow angles or a previous history of angle closure glaucoma. Increased lOP with corticosteroid use seems to be a genetically predetermined phenomenon closely associated with primary open-angle glaucoma. The patient population is divided into normals, low responders, and high responders by provocative testing. The mechanism is not well understood. Glucocorticoids are to be used with caution in patients with elevated IOP.m Tetrahydrocannabinol, the active ingredient in marijuana, has been shown in animals to reduce lOP when administered topically orally, or intravenously or via smoking.34o.341.342 Other animal studies showed that with the acute use of a 2% solution, there was a minimal reduction in lOP. A greater ocular hypotensive response was seen with chronic administration, but the beneficial effects were accompanied by ocular toxicity. Hyperemia, chemosis, erythema, and opacities became evident in 3 to 5 days.343.344 In humans, the ocular hypotensive effect is accompanied by hyperemia and decreased lacrimation.l":"? Ethanol, the most common drug of abuse and recreational beverage, decreases lOP through a diuretic effect.153

Retinal Toxicity All of the phenothiazine antipsychotics produce varying degrees of retinal toxicity. This toxicity is a result of a yet unknown mechanism that may be related to signal processing in the rod pathways of the inner retinal layers or may be due to inhibition of phagocytosis.r" As discussed earlier, these drugs also produce anticholinergic side effects. Of the phenothiazines, thioridazine produces the most profound effects on the retina. Its effects have been

well characterized, and at this time it is assumed that all the drugs in this class have similar actions. Thioridazine has been shown to alter the retinal pigment epithelium and to produce a salt-and-pepper zone between the optic disc and equator, pigmentary clumping, optic atrophy, and hyperpigmentation.'29.267.348.349 Early in the course of retinopathy, there is uniform pigment clumping that progresses into nummular areas and finally large areas of atrophy?SO-1S2 Symptomatology can range from an asymptomatic state to blurred vision and nyctalopia, especially in the early stages of toxicity.267.349.352.353 Visual acuity usually decreases, as does color vision. Scotomas may also develop.?" Abnormal ERGs and e1ectroculograms are usually closely correlated with the extent of visual damage.349.353 The changes in vision may not be reflected by the appearance of the fundus."? Retinal damage may continue even after the drug has been discontinued, possibly as a result of continued degeneration of cells that were damaged with the initial exposure to the drug.l" Amiodarone, an antiarrhythmic agent, has been reported to cause optic nerve toxicity.355-357 It is characterized by optic nerve swelling that may be unilateral or bilateral, occasional intracranial swelling that produces papilledema, and visual field loss. As mentioned, isotretinoin, or 13-cis-retinoic acid, is an analog of vitamin A (retinoic acid). Vitamin A's integral role in the visual cycle is well established. Treatment with isotretinoin can often cause a temporary decrease in dark adaptation and associated problems with night vision. As an analog, isotretinoin can displace vitamin A from the visual cycle, while having no intrinsic activity of its own on cone function. Weleber et al.!" found that patients being treated with isotretinoin had abnormal ERGs. Some returned to normal after therapy was discontinued; however, one patient had an abnormal ERG 6 months after discontinuation. There are several possible reasons why isotretinoin produces retinal abnormalities. It may inhibit the binding or retinol to the retinal pigment epithelium, alter retinol storage, or alter cellular metabolism in some way that prevents activation of retinol. 192.358 It is thought that some of the visual disturbances produced by the cardiac glycosides (discussed earlier) are due to the inhibition of sodium/potassium ATPases located in the retina. Many studies have shown that patients who are intoxicated with digoxin have abnormal ERGs. The carbonic anhydrase inhibitor methazolamide was shown to be effective in reducing chronic cystoid macular edema in some patients with retinitis pigmentosa. 359.360.361 However, its use was associated with a rebound edema after 6 to 12 weeks of treatment in a few patients. In each case, there was a slight variation in visual acuity (seven letters). The cause of the rebound edema is not fully understood. Certainly, poor patient

Pharmacology and Refraction

compliance or underlying disease fluctuations may contribute.36l.362 Reversible optic neuropathy has been found in patients treated with disulfiram. This drug has been used since the late 1940s as a deterrent to ethanol consumption by alcohol abusers. Because disulfiram inhibits alcohol dehydrogenase, an enzyme responsible for one of the steps in alcohol metabolism, alcohol cannot be completely metabolized when this drug has been taken. Consequently, when the patient consumes alcohol the level of aldehydes increases and the patient becomes violently ill. The optic neuropathy associated with disulfiram has been reported in several studies.v":"" but the mechanism is not known. The accumulation of aldehydes, an elevation in CNS concentrations of dopamine, and a direct toxic effect of the drug or metabolites to the visual cortex are all possibilities.363.368 Because changes in vision occur with both this drug and alcohol abuse, it is important for the clinician to be aware of either as a possible cause of decreased vision associated with alcohol abuse. Chronically administered intranasal cocaine can produce extensive ischemic necrosis of the mucosal and bony structures of the nose. Because these structures are located close to the optic nerve, this type of damage can lead to involvement of the optic nerve and potentially to loss of vision. Swelling of the optic nerve head, scotomas, and visual field loss were found in one cocaine user who had severe intranasal necrosis'?? and it is anticipated that as long-term cocaine abuse continues to grow, more ocular complications will be reported. The benzodiazepine class of sedative hypnotics is used in the treatment of anxiety, insomnia, and seizure disorders and as an adjunct medication for anesthesia. These drugs exert their action in the CNS by binding to and augmenting the actions of the neurotransmitter, gamma-aminobutyric acid (GABA). In the retina, potentiation of GABA by benzodiazepines has been shown to depress ERG-mediated signals from both rods and cones, slowing the processing of visual information. Clinically, this translates into decreased vision and possible visual field loss, especially in patients with preexisting retinopathy.F'v'" The mechanism of decreased vision from benzodiazepines is believed to be related to the potentiation of GABA in the retina, which results in hyperpolarization of ganglion cells, or increased release of dopamine, which would attenuate a-waves via interaction with D 2 receptors.?" Chloroquine and hydroxychloroquine, used in the treatment of autoimmune diseases (e.g., lupus erythematosus, rheumatoid arthritis, and malaria), produce predictable, dose-dependent retinal toxicity.372-376 The incidence of toxicity with hydroxychloroquine is somewhat less than that of toxicity with chloroquine.374.377.378 Hydroxychloroquine usually does not, for instance, produce retinal changes within the time frame and

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dosages used in the treatment of malaria. Retinal toxicity, first reported in 1957, includes perifoveal pigment granularity associated with the loss of the foveal light reflex. This early toxicity may be asymptomatic.F''r'" With late toxicity, a bulls-eye retinopathy-tapetoretinal degeneration with diffuse pigmentary derangement, optic nerve pallor, degeneration of the blood-retinal barrier, depigmentation, arteriolar narrowing, and vascular sheathing-may be seen.381-383 With late progression, the patient complains of blurred vision, night blindness, and scotomas.l" Once the drug is discontinued, vision mayor may not stabilize.385.386 Careful following of patients being treated with this drug is recommended to circumvent irreversible visual loss. Monitoring after the drug has been discontinued is currently controversial because delayed toxicity is rare and the monitoring expensive. There have been rare reports of delayed onset of retinal toxicity whereby visual function began to deteriorate after the drug had been discontinued.?" Older people may represent a case of special concern, because their retinal pigment epithelium may be more susceptible to the effects of chloroquine and hydroxychloroquine.l" Routine tests such as Amsler grids are easy to use and correlate well with scotomas found with static and kinetic perimetry.Y"?" Others have found that the contrast sensitivity test, ERGs, pattern visual evoked potentials, and color fundus photographs are effective screening methods to monitor for chloroquine toxicity.392-394 The mechanism of chloroquine or hydroxychloroquine retinal toxicity is not known. Like the phenothiazines, these drugs can concentrate in the melanin and are concentrated in the retinal and uveal pigment epithelium.I" Toxicity may be related to progressive destruction of rods and cones or to damage to the ganglion cells.396 - 399 Some have hypothesized that because of the binding to melanin, its function is impaired and the visual cell layer degenerates.t'" The results from recent animal studies for chloroquine-induced retinal toxicity indicate that platelet-activating factor (PAF) may be an important mediator in the genesis of chloroquine toxicity. With pretreatment, selective PAF antagonists can significantly attenuate retinal toxicity."?' Further research may reveal PAF antagonists to be a significant improvement in the treatment of chloroquine toxicity and inflammatory disease, in general. Quinine, a compound chemically related to chloroquine and hydroxychloroquine, is also retinal toxic. It is an older agent, now used for the prevention of nocturnal muscle cramps, and rarely for the prevention and treatment of malaria. Many studies suggest that quinine produces a direct toxic effect to the inner and outer segments of the retina. 402,403 Quinine produces abnormal ERG, electroculuogram, and visual evoked response (VER) findings. Visual function deteriorates, producing

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nyctalopia and generalized decreased vision. 40 I ,40 4 These effects are somewhat reversible once the drug has been discontinued. With overdose and subsequent quinine toxicity, temporary or permanent blindness can result. 405,406 Indomethacin, a potent inhibitor of cyclooxygenase, produces both anterior and posterior chamber toxicity. In 35% to 50% of patients taking indomethacin at therapeutic doses, some degree of adverse effect will occur.?" Corneal deposits, vitreal hemorrhage, macular pigmentary changes, macular puckering, and central serous retinopathy have been reported. These effects are more common in patients who are on chronic indomethacin therapy than in patients who are being treated with the drug for acute exacerbations of gout. Niacin, used in the treatment of hyperlipidemias, has been shown to produce reversible retinopathy of unknown causes at various doses. Blurred vision, pericentral scotomas, metamorphopsia, and halos precede the maculopathy.':" The maculopathy itself is characterized by cystoid macular edema and wrinkling of the inner retina into a starburst configuration.t'<"'" With the advent of chemotherapeutic agents for the treatment of cancer came a group of drugs that exhibited true nonselective toxicity. These drugs interfere at some point with the division of all cells. Cells that are rapidly dividing or changing, such as epithelium and mucosal cells, are more prone to toxicity from chemotherapeutic agents than are slowly dividing cells. Vincristine, an alkaloid derivative of the Vinca rosea line, is effective in the treatment of a wide range of malignancies.t'" The vinca alkaloids inhibit cellular proliferation by interfering with the microtubule spindle function at metaphase." Vincristine causes a welldefined neurotoxicity. In the eye, it has been shown to produce nyctalopia, decreases of the b-wave of the ERG, ptosis, oculomotor defects, optic neuropathy, and irreversible blindness. These effects may be a result of the drug's interfering with neuronal transmission between the photoreceptors and second-order transmission, producing some type of inflammatory reaction or decreasing ATP transport from the inner to the outer segments. 412-41 'i Tamoxifen, used in the treatment of breast cancers, produces a well-defined retinopathy. First reported in the late 1970s, tamoxifen produces a decrease in visual acuity as severe as 20/200. The fundus examination usually reveals cystoid macular edema, punctate macular retinal pigment epithelial changes, and white refractile lesions of the inner retinal layers.?'" Although the retinopathy progresses with increasing duration of therapy, visual acuity appears to improve once the drug is discontinued even though the pigment epithelial changes and refractile lesions may be permanent.v'r'" There is some question about the relationship among ocular toxicity, the dose of tamoxifen, and the mecha-

Box 12-29

Ocular Side Effects of Oral Contraceptives or Hormonal Treatment

Corneal sensitivity Contact lens intolerance Optic neuritis Blurred vision Temporary blindness Diplopia Hemianopsia Papilledema Retinal vascular disease Macular edema Periphlebitis

nism of toxicity.'?" Tamoxifen is an amphilic compound that integrates easily into polar lipids such as those found in the retina. It may be that high concentrations accumulate and lead to retinal toxicity. Hormonal therapy has been associated with many ocular side effects, including retinal vascular changes that lead to acute loss of vision. Estrogens, progestins, and testosterone are used for pharmacological contraception, replacement therapy, treatment of infertility, and in some cases the treatment of cancer. The ocular effects of hormones are well characterized and are listed in Box 12-29. Ilormonal therapy seems to augment other risk factors, such as family history, smoking, and lipid disorders, to increase the probability of development of coagulopathies. Coagulopathies from hormonal therapy may lead to acute retinal vasculature thrombosis and loss of vision. 4l9 ,4 20 Interferon treatment for hepatitis C can cause retinopathy. The funduscopic appearance shares similarity to diabetic retinopathy suggesting that interferon retinopathy may also be the result of a micro-angiopathy.?' The suggestion has been made that the interferon retinopathy was worse in patients with diabetes. This was found to be statistically significant in another study of 63 patients with hepatitis treated with interferon where 11 /12 (92%) of patients with diabetes developed evidence of retinopathy, although it was asymptomatic in the majority."? Another study reported seven patients developed retinopathy while receiving high-dose interferon alfa-2b therapy for adjuvant treatment of high-risk melanoma. The risk was greater with higher dosage.":' Desatnik et al. 4 2 4 reported a case of systemic corticosteroid therapy for treatment of deteriorating renal failure leading to exudative retinal detachments occurring two weeks after receiving medication. The patient presented with painless bilateral vision loss. This finding may pose complications for the use systemic corticosteroid therapy.

Pharmacology and Refraction

Drugs of abuse, such as cocaine and methamphetamine, are vasoconstrictors that have been shown to cause retinal vasculitis, occlusion, necrotizing angiitis, and amaurosis fugax.425 - 429 These drugs are often selfadministered via inhalation or injection. They frequently contain contaminants that can illicit an immune response, resulting in a combination of hypersensitivity vasculitis and vasoconstriction that leads to loss of vision. 426.428,430 Other drugs associated with amaurosis fugax include ethanol and barbiturates.!" In some animal studies, therapeutic doses of lithium have been shown to cause destruction of the lipoprotein outer segment membranes of retinal photoreceptors.?' which may lead to aberrations in dark adaptation.?" Deferoxamine, an iron chelator used in the treatment of iron overdose and some diseases (e.g., beta-thalassemia major), has been associated with several adverse effects that appear to be dependent on the duration of treatment. The results of clinical trials have varied, possibly because of differences in routes of administration.tvt" Acute treatment with deferoxamine for overdose is generally associated with few ocular side effects. Optic disc edema, optic neuropathy, and in some cases permanent vision loss have been associated with the chronic administration of deferoxamine.434,436.437 In two cases, hearing loss accompanied vision changes 3 months after initiation of therapy with deferoxamine.?" The mechanism of ocular toxicity from deferoxamine is not clear. Certainly because the drug chelates metal ions, nonselective chelation of another ion important in the proper functioning of enzymes, may produces ocular toxicity. Deferoxamine-induced ocular toxicity may be a direct effect of the drug or metabolite on the eye, or it may augment the ocular toxicity of the disease for which it is being used.i" The long-term use of the antiepileptic drug clonazepam may also be associated with the development of toxic retinopathy?" Pseudotumor cerebri is a rare adverse effect of many drugs. In addition, it can occur with hypertension, obesity, and trauma. Symptoms include chronic headaches, papilledema, increased intracranial pressure, decreased vision, nausea, dizziness, vomiting, diplopia, and visual field loss. Papilledema secondary to pseudotumor cerebri was found in several patients being treated with lithium. Because lithium substitutes for intracellular sodium, it may adversely affect cellular sodium pumps, increasing intracerebral fluid."? Most cases of pseudotumor cerebri occurred in patients who had been treated with lithium for several years and had bilateral papilledema and resolved after discontinuation of therapy.441-443 In several cases, further intervention was required to maintain vision; interventions included optic nerve sheath decompression and placement of intracerebral shunts."?

Box '2-30

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Systemic Drugs Associated with Pseudotumor Cerebri

Steroid hormones Glucocorticoids Betamethasone Cortisone Dexamethasone Prednisolone Prednisone Hydrocortisone Methylprednisolone Triamcinolone Mineralocorticoids Deoxycorticosterone Aldosterone Fluprednisolone Other hormones Oral contraceptives Antibiotics Tetracyclines Gentamicin Nalidixic acid Antifungals Ketoconazole Griseofulvin Miscellaneous Demeclocycline Manganese Vitamin A

Other drugs that have been associated with pseudotumor cerebri are listed in Box 12-30. Box 12-31 summarizes the drugs that have been associated with various forms of retinopathies.

Ocular Movement Disorders Any medication that causes nystagmus may reduce visual acuity. Phenytoin, one of the most widely prescribed drugs for the control of seizure disorders, arrhythmias, and neuralgias, causes several types of oculomotor movement disorders. Gaze-evoked nystagmus and diplopia are common effects of phenytoin, even when the drug level is within the therapeutic range. Nystagmus is also a good indicator of phenytoin toxicity. The ocular motor disturbances associated with phenytoin are usually fine in nature and are horizontally oriented.?" A good example of phenytoin-induced nystagmus is the case of a 35-year-old female who was brought to the emergency department by her mother for "funny eye movements." The patient had a history of cerebral palsy and seizure disorder. Seizures had been controlled with phenytoin and phenobarbital until that day, when the patient had one seizure. Laboratory values revealed a

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Box 12-H

Borishs Clinical Refraction

Systemic Drugs Associated with Various Types of Retinopathy

Retinal Degeneration

Corticosteroids Prednisone Prednisolone Dexamethasone Methylprednisolone Hydrocortisone Chloroquine Hydroxychloroquine Retinal Edema

Acetazolamide Aspirin Corticosteroids Hydrochlorothiazide Prochlorperazine Promazine Tamoxifen Thioridazine Tritluroperazi ne Retinal Vascular Disorders

Acetaminophen Barbiturates Chloroquine Hydroxychloroquine Diltiazem Gentamicin Nifedipine Oral contraceptives Sulfa antibiotics Retinal DepositslMacular Deposits

Carbamazepi ne Chloroquine Hydroxychloroquine Chlorpromazine Chlorprothixene Cisplatin Nitrofurantoin Perphenazine Prochlorperazine Promazine Tamoxifen Thioridazine Thiothixene Tritluroperazine

high phenytoin blood level. The patient's nystagmus was resolved by discontinuing phenytoin for 1 day and then restarting it. Downbeat nystagmus is associated with carbamazepine, phenytoin, lithium, and alcohol.44s-449 The chief complaint with downbeat nystagmus is that vision blurs with reading or that the field of vision moves up and down."? The pathogenesis of nystagmus from antiseizure medications is not well known. Given that these drugs interfere with the generation of neuronal action potentials, it may be a centrally mediated phenomenon. Other hypotheses have included a loss of the vestibulocerebellar inhibition of the upward otolith-ocular reflexes, an imbalance of the vestibulocerebellar connections, and a deficit in the pursuit system.44S,4SI-4S~ Lithium therapy can produce various types of nystagmus, most commonly downbeat. Its development can occur at any time during therapy and in some cases is irreversible. 448.4S2,4S4 Lithium-induced nystagmus can be associated with a lesion at the cranial cervical junction involving the lower brainstem and can indicate cerebellar dysfunction."? Patients often complain of blurred vision or oscillopsia, reduced visual acuity, and in some cases nausea. They usually retain good acuity in primary gaze, but acuity worsens with lateral gaze. It is advisable for the clinician to look further into lithium-induced nystagmus for potential neurotoxicity. Early detection can often circumvent irreversible changes in both vision and function. 449.45S Other adverse effects associated with lithium include exophthalmos, scotomas, lid and conjunctiva edema, decreased dark adaptation, and nonspecific ocular irritation. 157,219 Cetirizine (Zyrtec) can cause oculogyric crisis, especially in the pediatric age group. Oculogyric crisis is one of the acute dystonic reactions including: blepharospasm, periorbital twitches, and protracted staring episodes usually from neuroleptic drugs. Fraunfelder and Fraunfelder''" reported nine cases of oculogyric crisis from cetirizine. Eight of the nine cases occurred in the pediatric age group. The ocular effects were seen in oral dosages ranging from 5 to 10 mg. Onset ofsymptoms ranged from 3 to 184 days. Six cases of oculogyric crisis had positive rechallenge data. Eight cases had complete neurological consultation including radiographic studies. Extensive neurological workups may be avoided if clinicians recognize this drug-induced ocular side effect. For patients who abuse intravenous drugs, there is always the risk of small vessel occlusion from the administration of adulterants. Also, many street drugs contain adulterants, such as quinine, that are retinal toXic.403,457,458 Clinically, this translates into retinopathy and nephropathy. Talc retinopathy has been well described and can lead to sudden bilateral loss of vision.?? Methylenedioxymethamphetamine ("ecstasy") abuse has been associated with otherwise unexplained bilateral 6th-nerve palsy."?

Pharmacology and Refraction

Drug-Induced Myasthenia Gravis-Like Syndrome Numerous medications can induce a syndrome similar to MG (see Box 12-18). Symptoms are similar to those seen in MG and include ptosis, accommodative weakness, and ocular muscle weakness. These symptoms respond well to the intravenous administration of edrophonium (Tensilon) and are fully reversible. Penicillamine, an immunosuppressive agent used for the treatment of rheumatoid arthritis, produces a myasthenia-gravis-like syndrome."! The propensity to develop the syndrome with penicillamine therapy is, thought to be genetically based. Most patients who exhibit this adverse effect are lacking a specific antigen. 462 A 63 Common ocular symptoms of MG that develop include diplopia, nerve palsy, blepharoptosis, and optic neuropathy" Most symptoms resolve after discontinuation of the drug. Although the most current theory is a genetic predisposition to develop these symptoms in the presence of penicillamine, there is debate whether the drug may unmask latent MG.464A65 Fluoroquinolones have been associated with peripheral sensory disorders and weakness, especially in patients with underlying myasthenia gravis or myasthenia-like Eaton-Lambert syndrome. Trovafloxacin, a fluoroquinolone, has been reported to cause diffuse weakness due to a demyelinating polyneuropathy that began after initiation of the drug in a patient without an underlying neurological disorder.t'" Interleukin-2 is an effective agent against renal cell carcinoma and melanoma, but it has been associated with autoimmune sequelae. It may induce Myasthenia gravis. A 64-year-old man with non-insulin-dependent diabetes and metastatic renal cell carcinoma developed insulin-dependent diabetes after his first cycle of therapy with high dose interleukin-2. After additional therapy with interleukin-2, the patient developed generalized myasthenia gravis (MG). This case demonstrates the importance of recognition of IL-2-induced MG.4 6 7 Parmar et al. 4 68 present a case of a 67-year-old woman who was started on atorvastatin (Lipitor) and within 3 months began to experience ocular and systemic muscle weakness. The patient had a myogenic ptosis with a variable incomitant horizontal and vertical strabismus that resolved with discontinuation of the statin. The authors suggested that an ocular myasthenic syndrome was a complication of statin use.

Other Drugs with Ocular Effects Many drugs break down the physiological and pharmacological barriers in the eye. Therefore, increased exposure to infection cannot be overlooked. Infection should be ruled out as a cause for acute changes in vision, because it has potentially devastating consequences if it is inadequately treated. The mere adrninis-

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tration of drugs to the eye may predispose the eye to infection. The clinician must be careful to keep solutions sterile, minimize trauma to the eye, and practice excellent hygiene (especially handwashing). Irritating agents may break down ocular barriers and allow usually harmless skin flora to invade the eye. Staphylococcus or Streptococcus infections can often follow chemical conjunctivitis, chemical keratitis, or epithelial sloughing, all which can be a result of drug exposure. Local anesthetics may prevent the sensation of chemical changes to the eye, allowing infection to proceed unchecked. Both topical and systemic glucocorticoids may potentiate as well as predispose the patient to viral infections such as herpes simplex. Endophthalmitis is usually associated with surgical trauma to the eye. As a result of increasing intravenous drug abuse, however, the incidence of endophthalmitis is rising.i'" Intravenous drug abuse is associated with many types of atypical fungal and bacterial infections. Even with aggressive management, enucleation is often the end result. Drug-induced toxic epidermal necrolysis (TEN), or Lyell's disease, is rare but should be mentioned because of its relation to drug administration and its potentially devastating effects on vision. This disease is characterized by the acute necrosis of large parts of the epidermis and mucosal tissue. Several drug classes have been implicated in its development of TEN, including the hydantoin class of antiseizure medications (phenytoin), NSAIDs, antibiotics (especially the sulfonamides), and the barbiturates.?" Ocular involvement is not uncommon and represents 40% to 50% of the sequelae of those who survive the disease.?" These commonly include decreased visual acuity, photophobia, keratitis, neovascularization, and ulceration. All are long-term sequelae, which sometimes never resolve. Early symptoms include conjunctival blisters, hyperemia, and ulcerations.V-"?" This progresses to fulminant conjunctivitis with injection, discharge, and rnicroulcerations, complete with the presence of inflammatory cells.i" Late in the course of the disease, a severe dry-eye syndrome develops that can often be debilitating and is thought to be responsible for the scarring, punctate ker. I 'Impairment. . 474-476 atopathy, an d permanent visua Although visual acuity can recover somewhat, it has been reported that in the most extreme cases, the acuity can be as poor as finger counting at 50 cm. 4 71 Allergic reactions in the eye can be associated with itching, redness, edema, and changes in vision. The most common allergic reactions in the eye are conjunctivitis, surrounding dermatitis, excessive tearing, and angioedema around the orbit. These reactions may be local or part of a systemic anaphylactoid reaction. The primary mediator of allergic reactions is the mast cell. Large numbers of mast cells exist in the conjunctiva and

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skin. Mast cells can release their contents directly, when certain drugs cause them to degranulate, or indirectly, through a true IgE-mediated hypersensitivity reaction. Very small amounts of drug may bind to IgE on mast cell surfaces in sensitive individuals and cause mast cell degranulation. The mast cell releases many vasoactive mediators, which result in local irritation, vasodilation, congestion, and inflammation. Topical agents may produce local allergic reactions at the site of administration. Systemic medications can be concentrated in tears and produce symptoms of ocular allergies. Ocular allergic reactions are usually readily reversible with withdrawal and avoidance of the offending agent. The most common medications that cause allergic reactions are antibiotics (mainly penicillins, cephalosporins, and sulfa antibiotics), NSAIDs (except acetaminophen), and opioid analgesics.i" Ocular hemorrhage is a potential complication of any drug that affects the hematopoietic system. The effects of aspirin and related NSAIDson inhibiting coagulation are well documented.v'
does not regulate these alternative treatment products. However, the potential for ocular side effects from these agents exists, and large segments of the population use these alternative therapies without their doctor's knowledge. For this reason, connecting adverse events to their use is difficult. Praunfelder''" reported that some herbal treatments have ocular side effects including canthaxanthine, chamomile, Datura, Echinacea purpurea, Ginkgo biloba, licorice, niacin and Vitamin A. Table 12-5 lists the specific ocular side effects reported for these agents. Clinicians need to be observant for the side effects of alternative treatments. Many of the side effects are usually result of taking excessive doses of these compounds. Previously unreported visual side effects have now been identified by the National Registry of DrugInduced Ocular Side Effects for bisphosphonates, retinoids, topirarnate, and cetirizine (Table 12-6).493 SUMMARY

Ocular pharmacology is a complex and growing field of study. The eye is a particularly useful site for drug administration, because it offers easy, relatively noninvasive delivery. The advent of new ocular delivery systems may enhance the efficacy of ocularly administered drugs while diminishing the potential for systemic adverse effects. In addition, many of these new delivery systems can eliminate the problems encountered with pulse dosing by offering a more sustained drug delivery system. Almost any drug can affect vision. Although the mechanisms of drug-altered vision are quite variable and many are not well understood, there are certain general principles that the clinician can follow to identify the potential for ocular effects of systemic agents and to minimize the likelihood that these effects will occur. These principles are outlined in Boxes 12-32 and 12-33.

TABLE 12-5

Ocular Side Effects of Herbal and Nutritional Supplements

Herbal or Nutritional Supplement

Canthaxanthine Chamomile Datura Echinacea purpurea Ginkgo biloba

Licorice Niacin Vitamin A

Ocular Side Effects

Crystalline retinopathy Conjunctivitis Mydriasis Mydriasis Retinal hemorrhage, hyphema, retrobulbar hemorrhage Transient vision loss Cystoid macular edema, blur Intracranial hypertension

Pharmacology and Refraction

TABLE 12·6

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Recently Identified Adverse Ocular Drug Reaction by the National Registry of DrugInduced Ocular Side Effects

Drug

Example of Drug Uses

Some Common Ocular Side Effects

Biphosphonates (fosamax, actonel)

• Inhibit bone resorption in postmenopausal women • Management of hypercalcemia of osteolytic bone cancer

Cetirizine (Zyrtec)

• Allergic rhinitis • Chronic urticaria

Retinoids (Retin-A)

• Treatment of severe recalcintrant nodular acne • Induce remission of leukemia

Topiramate (Topomax)

• Treatment of refractory epilepsy • Off-label treatment of migraines and weight loss medication

• • • • • • • • • • • • • • • • • • • • • • •

Scleritis Blurred vision Ocular irritation Nonspecific conjunctivitis Pain Photophobia Uveitis Expiscleritis Papillary changes Blurred vision Keratoconjunctivitis sicca Abnormal meibomian gland secretion Abnormal scotopic ERG Corneal opacities Decreased tolerance to contact lens Decreased vision Keratitis Myopia Photophobia Abnormal vision Acute secondary angle-closure glaucoma Acute myopia Suprachoroidal effusions

Adapted from Fraunfelder FIN, Fraunfelder FT: Ophthalmology 111 (7): 1275-1279.

Box 12-32

General Principles of Drug Toxicity

• The degree of toxicity is related to the dose of the drug and the duration of therapy. • Ocular toxicity from systemic medications largely reverses with discontinuation of the drug. • Use of multiple drugs increases the potential for drug toxicity. • Veryyoung and very old patients are more susceptible to adverse drug reactions. • Patients with preexisting systemic or ocular diseases should be considered at risk for adverse drug reactions and drug toxicity. • Patients with renal or hepatic diseases are more likely to manifest adverse drug reactions.

Box 12-33

General Considerations for Avoiding Adverse Drug Reactions

• Use drugs that have been tried and proven effective. • Use the lowest effective dose for the shortest period of time. • Avoid multiple drug use when possible. • If possible, avoid drug use in patients at risk for drug reactions. • Take a good history of medications, reactions to medications, allergies, and systemic and ocular illnesses. • If a patient at risk must be treated pharmacologically, start with the lowest dose. If it is necessary to increase the dose, do so slowly and monitor the patient frequently for adverse effects. • Stop medications that are temporally associated with adverse reactions.

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ACKNOWLEDGEMENTS The authors wish to acknowledge optometry student, Erin D. Iones, for her tireless effort in data collection, organization, and proofreading in the preparation of this chapter.

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