Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

between the severity of keratopathy and the dosage or duration of drug therapy, doses of <400 mg/day of hydroxychloroquine generally show no keratopathy. At higher doses (800 mg/day), however, 6% developed keratopathy within 6 months of therapy, 32% during the second 6 months, and all patients had keratopathy after 4 years. A rapid rise in the incidence of keratopathy was noted when the total drug dosage exceeded 150 g. On reducing dosage or discontinuing the drug, the corneal opacities decreased or disappeared within an average of 8 months.

Less than half of patients affected with corneal changes have visual symptoms, but the most common complaints relate to halos around lights, glare, and photophobia, whereas visual acuity usually remains unchanged. On drug discontinuation, both subjective symptoms and objective corneal signs disappear.

Etiology

Vortex keratopathies are generally associated with an intralysosomal accumulation of lipids.This mechanism is similar to that noted in Fabry’s disease, a genetic disorder of sphingolipid metabolism. Once the amphiphilic drugs penetrate the lysosomes, they bind with cellular lipids, causing them to accumulate in the tissues. The changes are limited to the corneal epithelium, which the drug may reach by deposition via the tear film or by the limbal vasculature. The “whorl” appearance occurs due to a centripetal migration of limbal epithelial cells that have accumulated these lipid deposits.

Management

Patients taking hydroxychloroquine (or chloroquine) should receive careful baseline and periodic slit-lamp examinations, with pupils dilated. Early identification of the corneal changes is facilitated by using retroillumination. The practitioner should be careful to distinguish early chloroquine keratopathy from the normal development of Hudson-Stähli lines, which it can resemble.

Keratopathy due to Fabry’s disease is another important condition in the differential diagnosis. The verticillate corneal findings are quite similar to those induced by chloroquine or hydroxychloroquine, but the systemic implications in this metabolic disease warrant consultation with an internist.

Because the condition is relatively benign and only rarely results in visual symptoms, the development of chloroquine keratopathy does not contraindicate continued use of the medication. If,however,symptoms of glare, halos, or reduced vision bother the patient, consideration may be made to reduction of drug dose in consultation with the prescribing physician.

Amiodarone

Amiodarone, a highly lipid-soluble iodine-containing drug, has been used for several decades to treat a variety of cardiac abnormalities, including atrial and ventricular arrhythmias. It is highly variable in its bioavailability after ingestion and is affected by food and other drugs. Amiodarone has been noted to cause intracytoplasmic lamellar deposits in the cornea, lens, retina, and optic nerve.The most common symptom noted in 1.4% to 40% of patients is colored rings around lights, attributed to amiodarone-related keratopathy.

Clinical Signs and Symptoms

Keratopathy is the most common ocular sign found in 69% to 100% of patients.The onset of keratopathy may be as early as 6 days after initiation of therapy, although it more commonly appears after 1 to 4 months of treatment. The corneal deposits are bilateral but are often asymmetric, and they are observed easily with the slit lamp. The development of keratopathy can be divided into four grades (Table 35-3). The development of each grade of keratopathy is shown in Figure 35-1, and a clinical photograph of amiodarone keratopathy is shown in Figure 35-2.

The severity of the keratopathy appears to be significantly correlated with total drug dosage and duration of treatment. In general, patients taking low dosages of drug (100 to 200 mg daily) retain clear corneas or demonstrate only mild keratopathy regardless of duration of treatment or cumulative dosage.Patients taking higher dosages (400 to 1,400 mg daily) demonstrate more advanced keratopathy depending on the duration of treatment. Once the keratopathy becomes fully developed, it remains relatively stationary until the drug dosage is reduced or the drug is discontinued. The keratopathy gradually resolves within 3 to 20 months after discontinuation of drug therapy.

Amiodarone-induced lens opacities have also been reported. Fine anterior subscapular lens deposits occur in approximately 50% of patients taking amiodarone in moderate to high dosages (600 to 800 mg daily) after 6 to 18 months of treatment.The deposits first appear as small golden brown or white-yellow punctate opacities located just below the anterior lens capsule. Unlike the lenticular deposits associated with chlorpromazine therapy, which develop before corneal changes, the lens opacities

Figure 35-2 Clinical photograph of grade III amiodarone keratopathy. (Courtesy Jerry Pederson, O.D.)

associated with amiodarone develop in the presence of marked keratopathy. Differentiation from epicapsular stars can also be made readily as these congenital darkly pigmented spots have a characteristic appearance and extend into the lens surface.Amiodarone-induced lenticular opacities generally cause no visual symptoms.

Etiology

As an amphiphilic drug like chloroquine, amiodarone binds to polar lipids and accumulates within lysosomes. The presence of such complex lipid deposits within the corneal epithelium has led investigators to conclude that amiodarone keratopathy is probably similar to a lipid storage disease. Light exposure may be a factor in the corneal and lenticular changes, because amiodarone is a photosensitizing agent and the observed lens changes are primarily localized to the pupillary aperture.The whorl-like pattern of the keratopathy may result from an effect at the limbus on the epithelial cells that are migrating centripetally.

Management

Because the corneal and lenticular changes associated with amiodarone therapy are benign, special follow-up of affected patients is not required unless the opacities have induced visual symptoms. If visual symptoms are annoying or incapacitating, reduction or discontinuation of drug dosage usually resolves the corneal findings, though it is unusual for ocular side effects to necessitate discontinuation of drug therapy. Occasionally, however, treatment must be discontinued because of drug intolerance or other side effects such as diarrhea, vomiting, pulmonary fibrosis, or liver damage.The use of ultraviolet (UV)-filtering lenses may be a preventive measure. Because the early stages of amiodarone keratopathy can mimic a Hudson-Stähli line, a drug history relative to amiodarone use should be elicited carefully. More advanced stages of amiodarone keratopathy may resemble the corneal changes of Fabry’s disease or chloroquine toxicity. Because of the systemic implications of this disease, patients with no history of amiodarone or chloroquine use should be evaluated by an internist. Also, rare reports of optic neuropathy have occurred with amiodarone, so dilated fundus examinations and attention to patient symptoms are important (see Appendix 35-1).

Atovaquone

Atovaquone, an antiparasitic drug used to treat pneumonia in patients intolerant of trimethoprim-sulfamethoxa- zole, has been reported to cause verticillate keratopathy in susceptible patients. The clinical manifestations are similar to other drug-induced vortex keratopathies. Slitlamp examination discloses bilateral whorl-like patterns involving the inferior-central corneal epithelium, with normal stroma and endothelium. It has been proposed that the keratopathy has a pathophysiologic mechanism similar to other drug-induced verticillate conditions. The vortex pattern is probably a result of growth and repair of the corneal epithelium, with the flow of cells from peripheral to central cornea creating the whorl-like pattern. The keratopathy subsides once drug therapy is discontinued,and there is minimal risk of long-term visual impairment.

Chlorpromazine

Chlorpromazine is a phenothiazine derivative used in the treatment of various psychiatric disorders. Often, high prolonged doses of medication are required, and these have led to well-documented phototoxic changes in the cornea and lens as well as pronounced skin discoloration. It is now generally accepted that chlorpromazine is the only phenothiazine to cause such ocular changes.

Clinical Signs and Symptoms

Although phenothiazine use is associated with an increased prevalence of nuclear cataract, the most widely recognized toxicities are anterior subcapsular cataract, corneal endothelial pigment deposition, and skin pigmentation changes. The ocular conditions, however, rarely reduce visual acuity,although glare,halos around lights,or hazy vision may be reported.

Corneal pigmentary changes almost invariably occur only in patients who have concomitant lens opacities in the higher grades (Table 35-4).There is often little or no corneal involvement with mild lens changes (grades I and II),

but patients with moderate to severe lens changes (grades III and higher) have detectable corneal pigmentation ranging from light to heavy. The pigmentation is white, yellow-white, brown, or black and occurs at the level of the endothelium and Descemet’s membrane (rarely the stroma) and is located primarily in the interpalpebral fissure area (Figure 35-3).

The lenticular changes associated with chlorpromazine have been described to occur in five stages from fine dotlike opacities on the anterior lens surface,through a stellate pattern in the anterior subcapsular region (Figure 35-4) and finally to a central, pearl-like, opaque mass surrounded by smaller clumps of pigment (see Table 53-4).

Figure 35-3 Heavy pigment deposits on corneal endothelium, caused by chlorpromazine administration. (Courtesy Jerome Thaler, O.D.)

Figure 35-4 Stellate pattern of anterior subcapsular cataract associated with chlorpromazine administration. (Courtesy Jerome Thaler, O.D.)

Usually, the corneal and lenticular pigmentary changes are dose related but progress to an endpoint beyond which no further changes are observed and reduction or discontinuation of drug therapy does not reverse the effects.This is not surprising because the deposits associated with chlorpromazine therapy are located in avascular tissues. Corneal toxicity has been reported to occur within 6 months of therapy in 12% of patients receiving 2,000 mg of chlorpromazine daily but in only 1% of patients receiving 300 mg of chlorpromazine daily. Lenticular pigmentation is rarely evident when the total dosage is less than 500 g, and the prevalence of pigmentary changes increases with total dosages between 1,000 and 2,000 g, until 90% of patients demonstrate pigmentation when the total dosage exceeds 2,500 g. Because some psychiatric conditions may require daily dosages exceeding 800 mg, lenticular pigmentation can appear in as early as 14 to 20 months of therapy. Dosages consisting of 2,000 mg daily have caused lenticular changes in as little as 6 months of therapy.

Etiology

The precise nature of the pigmentary granules in the cornea and lens is unknown. An accepted hypothesis, however, is that the pigmentary changes are a result of drug interaction with UV radiation as it passes through the cornea and lens, causing exposed proteins to denature, opacify,and accumulate in the anterior subcapsular region of the lens as well as in corneal stroma. This explains

why the keratopathy is localized to the interpalpebral fissure area.

Management

Patients receiving high-dose or long-term low-dose chlorpromazine therapy should be monitored annually by careful slit-lamp examination.If corneal and lens changes occur but visual acuity is not affected and the patient is asymptomatic,the drug dosage can be continued without modification. If the patient becomes symptomatic, however, dosage changes should be considered,including reducing the dose or changing therapy to a nonphenothiazine drug.

Indomethacin

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for their analgesic, anti-inflammatory, and antipyretic actions in the treatment of arthritis, musculoskeletal disorders, dysmenorrhea, and acute gout. Although these drugs are widely administered and are often used for prolonged periods, ocular side effects are rare and have been poorly described. Indomethacin therapy has been associated with corneal opacities and blurred vision, optic neuritis, retinal changes, conjunctival and retinal hemorrhages, and intracranial hypertension.

Clinical Signs and Symptoms

The prevalence of corneal toxicity associated with indomethacin therapy has been reported to be 11% to 16% and is most common with long-term therapy. The corneal lesions appear either as fine stromal speckled opacities or have a whorl-like distribution resembling chloroquine keratopathy. Corneal opacities have been noted in patients taking indomethacin for 12 to 18 months, with the daily dosage ranging from 75 to 200 mg and the total dosage ranging from 20 to 70 g.These corneal changes diminish or disappear within 6 months of discontinuing indomethacin.

Symptoms associated with the corneal opacities can range from mild light sensitivity to frank photophobia. Corneal sensitivity, however, is unaffected. In general, the only possible OADRs of this drug that might warrant discontinuation are optic neuritis and intracranial hypertension (see Appendix 35-1).

Etiology

The mechanism of these ocular changes is unknown.

Management

Because the corneal opacities associated with indomethacin are benign and represent no significant threat to vision, patients taking this drug can be monitored annually for evidence of corneal changes. Patients who develop evidence of keratotoxicity should be reassured regarding the benign nature of these changes,and the prescribing physician should be notified.The appearance of the corneal opacities does not necessitate reduction or

discontinuation of drug therapy, except if severe corneal toxicity causes visual symptoms that are annoying or incapacitating.

Gold Salts

Both parenteral and oral gold salts are used in the treatment of rheumatoid arthritis.After prolonged administration, gold can be deposited in various tissues of the body, a condition known as chrysiasis.

Clinical Signs and Symptoms

Ocular chrysiasis can involve generally asymptomatic deposition in the conjunctiva, cornea, and lens. Corneal chrysiasis consists of the presence of numerous minute gold particles, appearing as yellowish brown to violet or red particles distributed irregularly in the posterior onethird of the stroma. The deposition of gold generally spares the peripheral 1 to 3 mm as well as superior onefourth to one-half of the cornea. There is typically no involvement of the epithelium, Descemet’s membrane, or endothelium. Figure 35-5 shows the general distribution of gold deposits in a typical case of corneal chrysiasis. Reported corneal deposition rates have been variable, with 45% to 97% noted in patients receiving continuous long-term gold therapy for rheumatoid arthritis consisting of a cumulative dosage of 1 g. Although no correlation exists between the density of corneal deposits and the cumulative dosage, there is a positive correlation between the duration of gold therapy and the density of corneal deposits.

Lenticular chrysiasis appears as fine, dust-like, yellowish, glistening deposits in the anterior capsule or in the anterior suture lines (Figure 35-6).There is no significant correlation between corneal chrysiasis and lenticular chrysiasis,and deposits of gold in either tissue do not cause symptoms.

Etiology

The available evidence suggests that gold is deposited in the cornea and lens by circulation in the aqueous fluid in the anterior chamber.

Figure 35-5 General distribution of gold deposits in corneal chrysiasis. The deposits spare the peripheral and superior cornea and are denser inferiorly. (Modified from McCormick SA, DiBartolomeo AG, Raju VK, Schwab IR. Ocular chrysiasis. Ophthalmology 1985;92:1432–1435.)

ANTERIOR POSTERIOR

Figure 35-6 Lenticular chrysiasis. Gold deposits can diffusely involve the axial anterior capsule or can involve the anterior suture line. (Modified from McCormick SA, DiBartolomeo AG, Raju VK, Schwab IR. Ocular chrysiasis. Ophthalmology 1985;92:1432–1435.)

Management

Because ocular chrysiasis does not lead to visual impairment, inflammation, or corneal endothelial changes, gold therapy does not need to be reduced or discontinued. This benign process requires only routine follow-up.The deposits often disappear within 3 to 6 months after cessation of therapy; occasionally, they are found years after therapy has been discontinued.

Isotretinoin

An analogue of vitamin A, isotretinoin (Accutane), or 13-cis-retinoic acid, is used for control of severe recalcitrant cystic acne and other keratinizing dermatoses. Oral administration of 1 to 2 mg/kg body weight daily temporarily suppresses sebaceous gland activity, changes surface lipid composition of the skin, and inhibits keratinization. The therapeutic effect is resolution of lesions and, in most patients, prolonged remission of the disease.

Clinical Signs and Symptoms

Adverse ocular effects affecting the cornea include abnormal meibomian gland secretion/gland atrophy, increased tear film osmolarity, ocular discomfort, blepharoconjunctivitis, keratitis, corneal opacities, and decreased vision. Corresponding symptoms of ocular discomfort, photophobia, and decreased tolerance to contact lens wear are related to ocular dryness. Ocular complications generally manifest within 4 weeks of drug treatment and begin to wane approximately 4 weeks after therapy cessation. Epithelial keratitis has been reported in patients treated with an average dose of 2 mg/kg. Symptoms are dose related, with 20% of patients taking 1 mg/kg/day noting blepharoconjunctivitis and 43% of patients taking 2 mg/kg/day experiencing the same. Subepithelial corneal opacities may occur in both the peripheral and central cornea, and if the visual axis is involved, vision may be impaired.

Of interest is that decreased color vision and decreased dark adaptation are also “certain” OADRs, whereas corneal ulceration, diplopia, eyelid edema, and intracranial hypertension are also associated but considered “possible” OADRs.

A number of other OADRs are associated with this drug but are listed as “unlikely” (corneal neovascularization, activation of herpes simplex) or “unclassifiable” (cataracts, decreased accommodation, iritis).

Etiology

Because the meibomian glands are modified sebaceous glands, suppression of sebaceous gland activity can also cause deficiency of the normal lipid layer of the preocular tear film.This can lead to evaporation of the aqueous layer and subsequent drying of the ocular surface, followed by epithelial and subepithelial defects.

Management

Decreasing or discontinuing the drug usually alleviates the side effects in most patients approximately 1 month after discontinuation, but several months may be required before significant clinical improvement is obtained. Topically applied artificial tears can be used as needed to improve ocular signs and symptoms of dry eye. Although most of the symptoms related to this ocular dryness resolve when treatment is discontinued, rarely the meibomian glands may show irreversible atrophy and therefore symptoms may be prolonged.

Photosensitizing Drugs

Photosensitizing drugs are compounds that absorb optical radiation (UV and visible) and undergo a photochemical reaction, which results in chemical modifications in nearby molecules of the tissue.The psoralen compounds are photosensitizing drugs and are used by dermatologists to treat psoriasis and vitiligo. Commonly referred to as psoralen plus UV-A therapy, this treatment involves the administration of 8-methoxypsoralen or related compounds, followed by exposure to UV radiation (320 to 400 nm) for short periods. The most common photosensitizing reactions involve the skin and eye. Cataract formation is now well documented in patients having psoralen plus UV-A therapy, but visual acuity is usually unaffected.

Etiology

The eye and the skin are susceptible to damage from nonionizing wavelengths of optical radiation (280 to 1400 nm). The crystalline lens can absorb varying amounts of UV radiation and photobind susceptible drugs present in that tissue. Because the adult crystalline lens effectively filters most UV radiation, the source for most of the ocular damage from photosensitizing drugs, there is minimal risk of photobinding susceptible drugs in the retina. UV radiation, however, can penetrate to the retina in aphakic and some pseudophakic individuals and in young persons, causing potential photosensitizing damage to the retina.

Management

Free 8-methoxypsoralen can be found in the lens for at least 12 hours after administration. Thus, to prevent

permanent photobinding of this drug, dermatologists usually provide UV-filtering lenses to be used both indoors and outdoors for at least 12 hours. For children, patients with preexisting cataract, and those at increased risk of cataract development, such as patients with atopic dermatitis, protection for 24 hours is recommended.

Crack Cocaine

Cocaine, particularly the alkaline smoke from the crack form, can be associated with severe ocular problems, including corneal complications.The two forms are infectious corneal ulcers that are usually painless, or sterile epithelial defects associated with vigorous eye rubbing, which are painful. The ocular signs may be associated with periocular, oral, or facial burns from homemade metal crack pipes.These may be caused by a direct toxic effect on the structural and functional integrity of the corneal epithelium, or be due to decreased corneal sensation, neurotrophic changes, mechanical causes due to eye rubbing, and subclinical alkali burn of crack cocaine. Each of these mechanisms, alone or in combination, could lead to chronic ocular surface disease and predispose to epithelial defects and subsequent corneal infection. Although intranasal cocaine has not been detected in tears using high-performance liquid chromatography, the observed decrease in corneal sensitivity can be an indication that cocaine may travel retrograde through the nasolacrimal duct to reach the ocular tissues.Therapy should be consistent with the clinical signs and symptoms present. Because patient compliance may be poor, aggressive initial therapy is recommended to prevent subsequent more serious complications.

DRUGS AFFECTING THE

CONJUNCTIVA AND EYELIDS

Drug effects on the conjunctiva and lids can be irritative or allergic or can involve pigmentary inclusions. Some of the most common OADRs of systemic medication use are listed in Table 35-5.

Isotretinoin

An analogue of vitamin A, isotretinoin (Accutane), or 13-cis-retinoic acid, is used for control of severe recalcitrant cystic acne and other keratinizing dermatoses (also see Isotretinoin under Drugs Affecting the Cornea and Lens, above).

Clinical Signs and Symptoms

The mucous membranes, including the conjunctiva, are sites associated most frequently with adverse effects of isotretinoin therapy. Therefore it is not surprising that blepharoconjunctivitis is not only considered a “certain” ocular ADR associated with oral isotretinoin use, it is also the most common, occurring in 20% to 50% of patients.

Symptoms can vary from slight irritation associated with dry eyes to significant discomfort and discharge. Examination of the eyes may reveal scaly crusty eyelids, dilated vessels at the lid margins,and conjunctival injection along with punctate keratitis. Schirmer testing and tear break-up time results are usually decreased. As with the corneal effects, the conjunctival and lid ADRs associated with isotretinoin are dose dependent. Isotretinoin dosages of 2 mg/kg body weight daily result in blepharoconjunctivitis in 43% of patients, whereas dosages of 1 mg/kg body weight daily show a 20% incidence of blepharoconjunctivitis.Most ocular complications of isotretinoin therapy occur within 4 weeks after drug treatment is begun and disappear within 1 month after discontinuation of therapy.

Etiology

Isotretinoin treatment alters meibomian gland function. The glands appear atrophic, and gland expressions increase in thickness and decrease in volume.The decreased meibomian gland function consequently increases tear evaporation and tear osmolarity, with subsequent ocular surface disease.

Management

Because as many as half the patients who develop blepharoconjunctivitis have ocular symptoms before the

start of therapy, the drug may aggravate preexisting conditions. Decreasing the dosage or discontinuing the drug usually alleviates the side effects, although a few months may be required before significant relief is obtained in some individuals.Although most of the symptoms related to ocular dryness resolve when treatment is discontinued,the meibomian glands may show irreversible atrophy. Topically applied artificial tears can be used as needed to improve ocular signs and symptoms of dry eye.

Chlorpromazine

A slate-blue discoloration of the conjunctiva, sclera, and exposed skin can occur with administration of phenothiazine derivatives. The skin of the face and lids can be equally pigmented, whereas the palpebral folds can contain an area of nonpigmented skin deep within the creases. Melanin-like granules have been observed in the superficial dermis of the skin.The oculoskin syndrome is usually associated with pigmentary deposits in the exposed interpalpebral area of the bulbar conjunctiva, especially near the limbus, but the palpebral conjunctiva is uninvolved. Patients exposed to dosages of chlorpromazine ranging from 500 to 3,000 mg daily for 1 to 6 years may develop discoloration of the exposed skin, lids, and bulbar conjunctiva.

Sulfonamides

Ocular complications are rare with systemic use of this class of drugs. Lid edema, conjunctivitis, chemosis, anterior uveitis, and scleral reactions have been reported with highdose administration of sulfanilamide. The observed reactions appear to be analogous to systemic hypersensitivity reactions, such as urticaria and edema, seen in some patients who are allergic to sulfonamides. Several cases of Stevens-Johnson syndrome have been reported in patients of Japanese or Korean descent who were given oral methazolamide, a sulfonamide used to decrease IOP. StevensJohnson syndrome tends to show acute ocular involvement in 69% of affected individuals.This is stratified into mild ocular involvement in 40%, moderate in 25%, and severe in 4%. Late complications can occur and are usually in the form of severe ocular surface disease and trichiasis.

Gold Compounds

Chrysiasis, or gold deposition in various tissues of the body, can occur in the conjunctiva after gold injection for rheumatoid arthritis and appears as irregular brownish deposits in the cornea and superficial layers of the conjunctiva. No deposits are found in the skin of the lid. Conjunctival changes associated with gold treatment are generally benign. Discontinuation of therapy usually eliminates these effects.

cause conjunctivitis as well as eyelid and periorbital edema. Corticosteroids have been noted to cause subconjunctival hemorrhage, eyelid edema, and ptosis. Conjunctival hyperemia and chemosis is a rare OADR of barbiturates. Dermatitis, lid swelling, and ptosis have also been related to long-term barbiturate use. The reaction can persist for months after the drug is discontinued. Patients taking niacin for hyperlipidemia have shown a higher incidence of lid edema than a similar group not taking niacin.

Salicylates may cause allergic conjunctivitis, which may be associated with urticaria of the lids. Subconjunctival hemorrhage has been reported in association with high-dose use of aspirin and oral anticoagulant therapy with warfarin. Chloroquine has been reported to cause ptosis,and phenytoin may cause chronic conjunctivitis. Drugs of abuse, such as marijuana, may lead to conjunctival injection, sometimes with eyelid edema. Although reported rarely, cocaine abuse during pregnancy has been associated with a prolonged and vision-threatening eyelid edema in newborn infants.

High-dose therapy with certain chemotherapeutic agents, including cytosine arabinoside, cyclophosphamide, methotrexate, and 5-fluorouracil, has been implicated in conjunctivitis. However, it appears that lowdose therapy with the anticancer agent tamoxifen is infrequently associated with anterior segment toxicity.

Tetracyclines

Tetracycline and its derivative, minocycline, are used for control of acne vulgaris. Conjunctival deposits similar to those seen in epinephrine-treated glaucoma patients have been observed in patients treated orally with these compounds. Dosages ranged from 250 to 1,500 mg daily of tetracycline and at least 100 mg daily of minocycline.

The deposits appear as dark brown to black granules in the palpebral conjunctiva, located nasally and temporally in the upper tarsus and temporally in the lower tarsus. The granules vary in size and are located in conjunctival cysts,surrounded by minute,gray-white,noncrystalline soft spots. Under UV radiation microscopy, the brown pigment concentrations give a yellow fluorescence characteristic of tetracycline. Along with pigment, calcium is also present in the cysts. It has been hypothesized that either tetracycline or its metabolites form an insoluble chelation complex that results in the pigmentation.Large numbers of patients have received these drugs for prolonged periods for acne, and these findings are rarely reported.

Miscellaneous Drugs Affecting

the Conjunctiva and Lids

A variety of other systemic drugs can cause irritative or allergic reactions in the conjunctiva or lids.The bisphosphonates, pamidronate, and others have been reported to

DRUGS AFFECTING

THE LACRIMAL SYSTEM

Human lacrimal fluid consists of a combination of secretions from the lacrimal gland, meibomian glands, goblet cells of the conjunctiva, and accessory lacrimal glands. Aqueous tear secretion from the lacrimal gland is controlled by the autonomic nervous system. The lacrimal gland is innervated by cholinergic fibers from the seventh cranial nerve as well as by adrenergic fibers from the pericarotid plexus. Chemically, the tears are 98.2% water and 1.8% solids. Thus, drugs that directly or indirectly affect the autonomic nervous system may cause hypersecretion or, more commonly, reduced secretions, leading to lacrimal keratoconjunctivitis, or “dry eye.”

Several classes of drugs can affect aqueous tear secretion, influence tear constituents, or appear in the tears after systemic administration. Patients complaining of watery or dry eyes,eye infections,or uncomfortable contact lens wear could be exhibiting symptoms relating to actions on the tears from a variety of prescription and over-the-counter drugs.

Drugs reported to affect aqueous tear secretion are listed in Table 35-6. Among the agents that frequently reduce tear secretion are the anticholinergics and antihistamines. These classes of drugs are also present in numerous over-the-counter products such as sedatives, sleep aids, cold preparations, antidiarrheals, and nasal decongestants.

Table 35-6

Drugs That Can Affect Aqueous Tear Secretion

Drugs That Decrease Aqueous Tears

The number of drugs known to decrease the aqueous tears and cause symptoms or signs of dry eye and/or ocular surface disease is too extensive to list. Instead, the following categories of drug effects are listed as the most common examples.

Antimuscarinic Agents

Dryness of mucous membranes is a common side effect of anticholinergic drug use and is due to dose-dependent inhibition of glandular secretion. In one study, oral administration of atropine caused tear secretion to fall from 15 to 3 mcl/min.A similar dose of atropine given subcutaneously gave a nearly 50% reduction in lacrimal secretion. Scopolamine at a dose of 1 to 2 mg orally reduced tear secretion from 5 to 0.8 mcl/min.Atropine combined with diphenoxylate (Lomotil) has been reported to cause severe keratoconjunctivitis sicca in susceptible individuals.

H1 Antihistamines

Agents blocking H1 receptor types are commonly used to treat symptoms associated with colds,hay fever,and other

allergies and to prevent motion sickness. In addition to receptor-blocking effects, H1 antihistamines have varying degrees of anticholinergic actions, including the ability to alter tear film integrity. A significant reduction in tear flow was observed when 4 mg of chlorpheniramine maleate was administered daily to a group of young volunteers. Ocular dryness is less of a problem with the newer generation nonsedating antihistamines, such as loratadine and fexofenadine. Systemic use of antihistamines can aggravate existing keratitis sicca.

Isotretinoin

Dry eye symptoms and significant ocular surface disease frequently occur in patients taking isotretinoin.The associated symptoms may be accompanied by blepharoconjunctivitis. The presence of isotretinoin in tear fluid decreases stability (and tear break-up time) of the lipid layer of the tear film but may also cause a decrease in aqueous production, leading to ocular surface dryness. These effects could be responsible for the dry eye symptoms, contact lens intolerance, superficial punctate keratitis, and conjunctival irritation accompanying isotretinoin therapy. Use of artificial tear preparations may help to alleviate the associated discomfort.

β-Adrenoceptor Blocking Agents

Drugs classified as β-adrenoceptor blocking agents are important in the treatment of systemic hypertension, ischemic heart disease, cardiac arrhythmias, and migraine headache. Reduced tear secretion is a reported side effect of oral beta-blocking drugs. Although most of the reported cases deal with practolol, other beta-blockers, such as propranolol and timolol, have also been implicated in dry eye syndrome. Ocular side effects of practolol have been described as an oculomucocutaneous syndrome in which patients suffer from symptomatic lesions of the outer eye. Because the ocular side effects of practolol can be so serious,this drug is no longer marketed for clinical use. Atenolol, metoprolol, oxprenolol, and pindolol have been implicated as causative agents in dry eye symptoms.

Oral Contraceptives and Hormone Replacement Therapy

In addition to birth control, oral contraceptives are used for many conditions (dysmenorrhea, amenorrhea, menopausal symptoms, uterine bleeding). These agents have been reported to cause reduced tear production and problems associated with contact lens wear. The literature, however, is generally devoid of well-documented studies showing a definite cause-and-effect relationship. Among patients who wear hydroxyethyl methacrylate contact lenses, symptoms of dryness and irritation are more likely to occur in those who use oral contraceptives than in nonusers of these medications. A significant decrease in goblet-cell count was also noted in subjects using oral contraceptives, suggesting a likely reproductive

hormonal influence on conjunctival goblet-cell count. A study of various sex hormones in patients with Sjögren’s syndrome found an androgenic deficiency.

Estrogenic and androgenic receptors on the corneal and conjunctival cells and meibomian glands are involved in ocular surface homeostasis. Chronic inflammation in ocular surface dryness is more common in women and increases in both genders with age. An imbalance in estrogens and androgens appears to worsen the disease and symptoms in postmenopausal women, and the incidence of dry eye increases with duration of menopause and use of hormone replacement therapy. Dryness was measured by Schirmer scores in three groups of women on hormone replacement therapy, and these scores worsened in a 1-year follow-up interval in all groups. The most significant decrease among three groups on hormone replacement therapy was in the estrogen-only group compared with combinations of estrogen with progesterone alone or progesterone and androgens.

Women who are taking or considering hormone replacement therapy should be informed of the potential increased risk of dry eye syndrome with this therapy. Women on oral contraceptives who complain of dry eye or in whom ocular surface disease is noted should be advised of the potential causative aspects of their medication. In either case, therapies for dry eye are usually based on topical administration of tear substitutes, lid treatments, environmental modification, and immunomodulatory agents for inflammatory-related ocular surface disease. Hormone-based eyedrops are being studied with respect to targeting postmenopausal women with dry eye.

Miscellaneous Agents Causing Decreased Tears

Other drugs with possible anticholinergic actions,such as phenothiazines, antianxiety agents, tricyclic antidepressants, and niacin, have been associated with dry eye syndromes. Diuretics such as hydrochlorothiazide and chemotherapeutic agents such as carmustine and mitomycin can also cause both qualitative and quantitative changes in the tear film.Many drugs can have ocular surface drying effects, including stimulant drugs for attention deficit and hyperactivity disorder and most antidepressant medications.

Management of Aqueous Deficiencies

A good drug history is essential for every patient to determine if the drugs taken fit into the categories of agents that cause dry eye.As with many other symptomatic but not lifeor vision-threatening adverse effects, the risks and benefits of the drug must be weighed against the patient’s symptoms and ocular surface signs and considerations made to both ocular surface therapies as well as drug dosage reduction or discontinuation. Regardless of the cause of the deficiency, management of the symptoms and ocular surface signs is important. Guidelines for treatment are discussed in Chapters 14 and 24.

Drugs That Increase Aqueous Tears

Several studies indicate that systemic administration of certain cholinergic, adrenergic, and antihypertensive agents may stimulate lacrimation (see Table 35-6). Oral pilocarpine has been reported to improve radiotherapyinduced dry eye signs and symptoms and can improve symptoms in patients with Sjögren’s syndrome. Neostigmine, given subcutaneously or intramuscularly, also induces lacrimation. Among the adrenoceptor agonists, ephedrine has been reported to increase tear production. Several antihypertensive agents can increase tear production, including reserpine, hydralazine, and diazoxide, and at therapeutic dosages can induce lacrimation in humans. There is some evidence that the oral immunosuppressant cyclosporine can significantly enhance tear flow in kidney transplant recipients.

A pyrimidine analogue that inhibits DNA synthesis, 5-fluorouracil is commonly used to treat carcinomas of the breast, gastrointestinal tract, and genitourinary tract. Excessive tearing associated with fluorouracil therapy can occur due to punctal and canalicular stenosis and fibrosis. Long-term excretion of the drug into tears may cause inflammation, scarring, and stenosis of the lacrimal drainage system, leading to permanent epiphora. The excessive lacrimation usually resolves spontaneously within 1 to 2 weeks after drug therapy is discontinued. Topically applied antibiotics and steroids may help prevent complete punctal or canalicular stenosis, but in patients with persisting epiphora, surgical intervention may be necessary.

Long-term use of marijuana has been reported to increase tear secretion. Tear samples have shown the presence of small amounts of 9-tetrahydrocannabinol. Some authors, however, have reported a reduction in tear secretion after marijuana use, along with a subjective feeling of dryness.

Management of Tearing

If the risk-to-benefit ratio for treating a concomitant systemic condition does not allow for withdrawal of the drug causing the tearing, appropriate management of tearing depends on whether there is an increase in secretion or a blockage of drainage.

DRUGS AFFECTING THE EPISCLERA, SCLERA, AND UVEA

Until recently, very few systemic drug therapies were implicated in ocular adverse effects in the episclera,sclera, and uvea. Topical ocular medications such as beta-block- ers, latanoprost, and corticosteroids as well as other topical ocular medications have been associated with uveitis.

Some systemic therapeutic agents implicated in “probable” uveitis include cidofovir, pamidronic acid, and sulfonamides. Other medications, such as cobalt, diethylcarbamazepine, interleukins-3 and -6, oral contraceptives,