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  3. Section XV - Ophthalmology

Section XV - Ophthalmology

This chapter focuses on specific pharmacodynamic, pharmacokinetic, and drug delivery issues relevant to ocular therapy and imparted by the unique anatomy and function of this sensory organ, introduced at the outset of this chapter. Many of the pharmacological agents discussed here have been discussed in earlier chapters. Autonomic agents have several uses in ophthalmology, including diagnostic evaluation of anisocoria and myasthenia gravis, as adjunctive therapy in laser and incisional surgeries

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  1. Section XV. Ophthalmology Chapter 66. Ocular Pharmacology Overview This chapter focuses on specific pharmacodynamic, pharmacokinetic, and drug delivery issues relevant to ocular therapy and imparted by the unique anatomy and function of this sensory organ, introduced at the outset of this chapter. Many of the pharmacological agents discussed here have been discussed in earlier chapters. Autonomic agents have several uses in ophthalmology, including diagnostic evaluation of anisocoria and myasthenia gravis, as adjunctive therapy in laser and incisional surgeries, and in the treatment of glaucoma. These agents are discussed in detail in Chapters 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, 7: Muscarinic Receptor Agonists and Antagonists, 8: Anticholinesterase Agents, 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia, and 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists. The antimicrobial agents employed for chemotherapy of orbital cellulitis, conjunctivitis, keratitis, endophthalmitis, retinitis, and uveitis also are discussed in Chapters 43: Antimicrobial Agents: General Considerations, 44: Antimicrobial Agents: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections, 45: Antimicrobial Agents: Penicillins, Cephalosporins, and Other -Lactam Antibiotics, 46: Antimicrobial Agents: The Aminoglycosides, 47: Antimicrobial Agents: Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents, 48: Antimicrobial Agents: Drugs Used in the Chemotherapy of Tuberculosis, Mycobacterium avium Complex Disease, and Leprosy, 49: Antimicrobial Agents: Antifungal Agents, and 50: Antimicrobial Agents: Antiviral Agents (Nonretroviral). The vitamins and trace elements used in adjunctive eye therapy are discussed in Chapters 63: Water-Soluble Vitamins: The Vitamin B Complex and Ascorbic Acid and 64: Fat- Soluble Vitamins: Vitamins A, K, and E, and immunomodulatory agents important in treating vitreoretinopathy, retinitis, and uveitis are discussed in Chapter 53: Immunomodulators: Immunosuppressive Agents, Tolerogens, and Immunostimulants. Also included in this chapter are the wetting agents and tear substitutes used to treat dry eye syndrome, as well as drugs and osmotic agents affecting ocular electrolyte metabolism (see also Chapter 29: Diuretics). The chapter concludes with a prospectus on the future of ocular therapeutics, including gene transfer, immunomodulation, molecular- and cellular-based therapies including inhibitors of protein kinase C for diabetic retinopathy, and neuroprotection. Ocular Pharmacology: Introduction History Records from Mesopotamia (ca. 3000–4000 B.C.) reveal that mysticism—combined with vegetable, animal, and mineral matter—was used to treat spirits and devils causing eye disease. During the classical Greek era (ca. 460–375 B.C.) when Hippocrates revolutionized the therapeutics of disease, several hundred remedies were described for afflictions of the eye. Galen and Susruta categorized eye diseases on an anatomical basis and applied medicinal as well as surgical remedies advocated by Hippocrates (see Duke-Elder, 1962; Albert and Edwards, 1996). With this empirical approach to treat disease, ophthalmic therapeutics took root from remedies
  2. discovered for systemic diseases. For instance, silver nitrate was used medicinally in the early seventeenth century. Credé later instituted the use of silver nitrate in newborns as prophylaxis against neonatal conjunctivitis, a potentially blinding condition, which during his time was primarily caused by Neisseria gonorrhoeae. In the nineteenth century, numerous organic substances were isolated from plants and introduced to treat eye diseases. The belladonna alkaloids were used as poisons, for asthmatic therapy, and for cosmetic effect; hyoscyamus and belladonna were used to treat iritis in the early 1800s. Atropine was isolated and used therapeutically in the eye in 1832. In 1875, pilocarpine was isolated; the therapeutic effect of lowering intraocular pressure was recognized in 1877, providing the basis for a safe and effective treatment of glaucoma that is stillbreak efficacious. Overview of Ocular Anatomy, Physiology, and Biochemistry The eye is a specialized sensory organ that is relatively secluded from systemic access by the blood- retinal, blood-aqueous, and blood-vitreous barriers. Because of this anatomical isolation, the eye offers a unique, organ-specific pharmacological laboratory to study, for example, the autonomic nervous system and effects of inflammation and infectious diseases. No other organ in the body is so readily accessible or as visible for observation; however, the eye also presents some unique opportunities as well as challenges for drug delivery (see Robinson, 1993). Extraocular Structures The eye is protected by the eyelids and by the orbit, a bony cavity of the skull that has multiple fissures and foramina that conduct nerves, muscles, and vessels (Figure 66–1). In the orbit, connective (i.e., Tenon's capsule) and adipose tissues and six extraocular muscles support and align the eyes for vision. The area behind the eye (or globe) is called the retrobulbar region. Understanding ocular and orbital anatomy is important for safe periocular drug delivery, including subconjunctival, sub-Tenon's, and retrobulbar injections. The eyelids serve several functions. Foremost, their dense sensory innervation and eyelashes protect the eye from mechanical and chemical injuries. Blinking, a coordinated movement of the orbicularis oculi, levator palpebrae, and Müller's muscles, serves to distribute tears over the cornea and conjunctiva. In human beings, the average blink rate is 15 to 20 times per minute. The external surface of the eyelids is covered by a thin layer of skin; the internal surface is lined with the palpebral portion of the conjunctiva, which is a vascularized mucous membrane continuous with the bulbar conjunctiva. At the reflection of the palpebral and bulbar conjunctiva is a space called the fornix, located superiorly and inferiorly behind the upper and lower lids, respectively. Topical medications usually are placed in the inferior fornix, also known as the inferior cul-de-sac. Figure 66–1. Anatomy of the Globe in Relationship to the Orbit and Eyelids. Various routes of administration of anesthesia are demonstrated by the blue needle pathways. (Adapted from Riordan-Eva and Tabbara, 1992, with permission.)
  3. The lacrimal system consists of secretory glandular and excretory ductal elements (Figure 66–2). The secretory system is composed of the main lacrimal gland, which is located in the temporal outer portion of the orbit, and accessory glands, also known as the glands of Krause and Wolfring (see Figure 66–1), located in the conjunctiva. The lacrimal gland is innervated by the autonomic nervous system (see Table 66–1 and Chapter 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems). The parasympathetic innervation is clinically relevant since a patient may complain of dry eye symptoms while taking medications with anticholinergic side effects, such as antidepressants (see Chapter 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders), antihistamines (see Chapter 25: Histamine, Bradykinin, and Their Antagonists), and drugs used in the management of Parkinson's disease (see Chapter 22: Treatment of Central Nervous System Degenerative Disorders). Located just posterior to the eyelashes are meibomian glands (see Figure 66–1), which secrete oils that retard evaporation of the tear film. Abnormalities in gland function, as in acne rosacea and meibomitis, can greatly affect tear film stability. Figure 66–2. Anatomy of the Lacrimal System. (Adapted from Riordan-Eva and Tabbara, 1992, with permission.) Conceptually, tears constitute a trilaminar lubrication barrier covering the conjunctiva and cornea.
  4. The anterior layer is composed primarily of lipids secreted by the meibomian glands. The middle aqueous layer, produced by the main lacrimal gland and accessory lacrimal glands (i.e., Krause and Wolfring glands), constitutes about 98% of the tear film. Adherent to the corneal epithelium, the posterior layer is a mixture of mucins produced by goblet cells in the conjunctiva. Tears also contain nutrients, enzymes, and immunoglobulins to support and protect the cornea. The tear drainage system starts through small puncta located on the medial aspects of both the upper and lower eyelids (Figure 66–2). With blinking, tears enter the puncta and continue to drain through the canaliculi, lacrimal sac, nasolacrimal duct, and then into the nose. The nose is lined by a highly vascular mucosal epithelium; consequently, topically applied medications that pass through this nasolacrimal system have direct access to the systemic circulation. Ocular Structures The eye is divided into anterior and posterior segments (see Figure 66–3A). Anterior segment structures include the cornea, limbus, anterior and posterior chambers, trabecular meshwork, Schlemm's canal, iris, lens, zonules, and ciliary body. The posterior segment comprises the vitreous, retina, choroid, sclera, and optic nerve. Figure 66–3. A. Anatomy of the Eye. B. Enlargement of the Anterior Segment Revealing the Cornea, Angle Structures, Lens, and Ciliary Body. (Adapted from Riordan-Eva and Tabbara, 1992, with permission.)
  5. Anterior Segment The cornea is a transparent and avascular tissue organized into five layers: epithelium, Bowman's membrane, stroma, Descemet's membrane, and endothelium (see Figure 66–3B). Representing an important barrier to foreign matter, including drugs, the epithelial layer is composed of five to six layers of epithelial cells. The basal epithelial cells lie on a basement membrane that is adjacent to Bowman's membrane, a layer of collagen fibers. Constituting approximately 90% of the corneal thickness, the stroma, a hydrophilic layer, is uniquely organized with collagen lamellae synthesized by keratocytes. Beneath the stroma lies Descemet's membrane,
  6. the basement membrane of the corneal endothelium. Lying most posteriorly, the endothelium is a monolayer of cells adhering to each other by tight junctions. These cells maintain corneal integrity by active transport processes and serve as a hydrophobic barrier. Hence, drug absorption across the cornea necessitates penetrating the trilaminar hydrophobic-hydrophilic-hydrophobic domains of the various anatomical layers. At the periphery of the cornea and adjacent to the sclera lies a transitional zone (1 to 2 mm wide) called the limbus. Limbal structures include the conjunctival epithelium, which contain the stem cells, Tenon's capsule, episclera, corneoscleral stroma, Schlemm's canal, and trabecular meshwork (Figure 66–3B). Limbal blood vessels, as well as the tears, provide important nutrients and immunological defense mechanisms for the cornea. The anterior chamber holds approximately 250 l of aqueous humor. The peripheral anterior chamber angle is formed by the cornea and the iris root. The trabecular meshwork and canal of Schlemm are located just above the apex of this angle. The posterior chamber, which holds approximately 50 l of aqueous humor, is defined by the boundaries of the ciliary body processes, posterior surface of the iris, and lens surface. Aqueous Humor Dynamics and Regulation of Intraocular Pressure Aqueous humor is secreted by the ciliary processes and flows from the posterior chamber, through the pupil, into the anterior chamber, and leaves the eye primarily by the trabecular meshwork and canal of Schlemm. From the canal of Schlemm, aqueous humor drains into an episcleral venous plexus and into the systemic circulation. This conventional pathway accounts for 80% to 95% of aqueous humor outflow and is the main target for cholinergic drugs used in glaucoma therapy. Another outflow pathway is the uveoscleral route (i.e., fluid flows through the ciliary muscles and into the suprachoroidal space), which is the target of selective prostanoids (see Chapter 26: Lipid- Derived Autacoids: Eicosanoids and Platelet-Activating Factor and later in this chapter). The peripheral anterior chamber is an important anatomical structure for differentiating two forms of glaucoma: open-angle glaucoma, which is by far the most common form of glaucoma, and angle- closure glaucoma. Current medical therapy of open-angle glaucoma is aimed at decreasing aqueous humor production and/or increasing aqueous outflow. The preferred management for angle-closure glaucoma is surgical iridectomy, either by laser or by incision, but short-term medical management may be necessary to reduce the acute intraocular pressure elevation and to clear the cornea prior to laser surgery. As mentioned in other chapters, acute angle-closure glaucoma may be induced rarely in anatomically predisposed eyes by anticholinergic, sympathomimetic, and antihistaminic agents. Interestingly, however, individuals with those susceptible angles do not know they have them. As far as they know, they do not have glaucoma and are not aware of a risk of angle-closure glaucoma. Yet, drug warning labels do not always specify the type of glaucoma for which this rare risk exists. Thus, unwarranted concern is raised among patients who have open-angle glaucoma, by far the most common form of glaucoma in the United States, and who need not be concerned about taking these drugs. In any event, in anatomically susceptible eyes, anticholinergic, sympathomimetic, and antihistaminic drugs can lead to partial dilation of the pupil and a change in the vectors of force between the iris and the lens. The aqueous humor then is prevented from passing through the pupil from the posterior chamber to the anterior chamber. The result can be an increase in pressure in the posterior chamber, causing the iris base to be pushed against the angle wall, thereby closing the filtration angle and markedly elevating the intraocular pressure. Iris and Pupil looseness1The iris is the most anterior portion of the uveal tract, which also includes the ciliary
  7. body and choroid. The anterior surface of the iris is the stroma, a loosely organized structure containing melanocytes, blood vessels, smooth muscle, and parasympathetic and sympathetic nerves. Differences in iris color reflect individual variation in the number of melanocytes located in the stroma. Individual variation may be an important consideration for ocular drug distribution due to drug-melanin binding (see"Distribution," below). The posterior surface of the iris is a densely pigmented bilayer of epithelial cells. Anterior to the pigmented epithelium, the dilator smooth muscle is oriented radially and is innervated by the sympathetic nervous system (see Figure 66–4) which causes mydriasis (dilation). At the pupillary margin, the sphincter smooth muscle is organized in a circular band with parasympathetic innervation which, when stimulated, causes miosis (constriction). The use of pharmacological agents to dilate normal pupils (i.e., for clinical purposes such as examining the ocular fundus) and to evaluate the pharmacological response of the pupil (e.g., unequal pupils, or anisocoria, seen in Horner's syndrome or Adie's pupil) is summarized in Table 66–2. Figure 66–5 provides a flowchart for the diagnostic evaluation of anisocoria. Figure 66–4. Autonomic Innervation of the Eye by the Sympathetic (a) and Parasympathetic (b) Systems. (Adapted from Wybar and Kerr Muir, 1984, with permission.) Figure 66–5. Anisocoria Evaluation Flowsheet. (Adapted with permission from Thompson and Pilley, 1976.) Ciliary Body
  8. The ciliary body serves two very specialized roles in the eye: secretion of aqueous humor by the epithelial bilayer and accommodation by the ciliary muscle. The anterior portion of the ciliary body, called the pars plicata, is composed of 70 to 80 ciliary processes with intricate folds. The posterior portion is the pars plana. The ciliary muscle is organized into outer longitudinal, middle radial, and inner circular layers. Coordinated contraction of this smooth muscle apparatus by the parasympathetic nervous system causes the zonules suspending the lens to relax, allowing the lens to become more convex and to shift slightly forward. This process, known as accommodation, permits focusing on near objects and may be pharmacologically blocked by muscarinic cholinergic antagonists, through the process called cycloplegia. Contraction of the ciliary muscle also puts traction on the scleral spur and, hence, widens the spaces within the trabecular meshwork. This latter effect accounts for at least some of the intraocular pressure-lowering effect of both directly acting and indirectly acting parasympathomimetic drugs. Lens The lens, a transparent biconvex structure, is suspended by zonules, specialized fibers emanating from the ciliary body. The lens is approximately 10 mm in diameter and is enclosed in a capsule. The bulk of the lens is composed of fibers derived from proliferating lens epithelial cells located under the anterior portion of the lens capsule. These lens fibers are continuously produced throughout life. Posterior Segment Because of the anatomical and vascular barriers to both local and systemic access, drug delivery to the eye's posterior pole is particularly challenging. Sclera The outermost coat of the eye, the sclera, covers the posterior portion of the globe. The external surface of the scleral shell is covered by an episcleral vascular coat, by Tenon's capsule, and by the conjunctiva. The tendons of the six extraocular muscles insert into the superficial scleral collagen fibers. Numerous blood vessels pierce the sclera through emissaria to supply as well as drain the choroid, ciliary body, optic nerve, and iris. Inside the scleral shell, the vascular choroid nourishes the outer retina by a capillary system in the choriocapillaris. Between the outer retina and the choriocapillaris lies Bruch's membrane and the retinal pigment epithelium, whose tight junctions provide an outer barrier between the retina and the choroid. The retinal pigment epithelium serves many functions, including vitamin A metabolism (see Chapter 64: Fat-Soluble Vitamins: Vitamins A, K, and E), phagocytosis of the rod outer segments, and multiple transport processes. Retina The retina is a thin, transparent, highly organized structure of neurons, glial cells, and blood vessels. Of all structures within the eye, the neurosensory retina has been the most widely studied (see Dowling, 1987). The unique organization and biochemistry of the photoreceptors have provided a superb model for investigating signal transduction mechanisms (see Stryer, 1987). Rhodopsin has been intensely analyzed at the level of its protein and gene structures (see Khorana, 1992). The wealth of information about rhodopsin has made it an excellent model for the G protein–coupled receptors (see Chapter 2: Pharmacodynamics: Mechanisms of Drug Action and the Relationship
  9. Between Drug Concentration and Effect). Such detailed understanding holds promise for targeted therapy for some of the hereditary retinal diseases. Vitreous The vitreous is a clear medium that makes up about 80% of the eye's volume. It is composed of 99% water bound with collagen type II, hyaluronic acid, and proteoglycans. The vitreous also contains glucose, ascorbic acid, amino acids, and a number of inorganic salts (see Sebag, 1989). Optic Nerve The optic nerve is a myelinated nerve conducting the retinal output to the central nervous system. It is composed of (1) an intraocular portion, which is visible as the 1.5-mm optic disk in the retina; (2) an intraorbital portion; (3) an intracanalicular portion; and (4) an intracranial portion. The nerve is ensheathed in meninges continuous with the brain. At present, pharmacological treatment of some optic neuropathies is based on management of the underlying disease. For example, optic neuritis may be treated best with intravenous methylprednisilone (Beck et al., 1992, 1993); glaucomatous optic neuropathy is medically managed by decreasing intraocular pressure. Pharmacokinetics and Toxicology of Ocular Therapeutic Agents Drug Delivery Strategies Factors that affect the bioavailability of ocular drugs include pH, salt form of the drug, various structural forms of a given drug, vehicle composition, osmolality, tonicity, and viscosity. Properties of varying ocular routes of administration are outlined in Table 66–3. A number of delivery systems have been developed for treating ocular diseases. Most ophthalmic drugs are delivered in aqueous solutions. For compounds with limited solubility, a suspension form facilitates delivery. Several formulations prolong the time a drug remains on the surface of the eye. These include gels, ointments, solid inserts, soft contact lenses, and collagen shields. Prolonging the time in the cul-de- sac facilitates drug absorption. Ophthalmic gels (e.g., pilocarpine 4% gel) release drugs by diffusion following erosion of soluble polymers. The polymers used include cellulosic ethers, polyvinyl alcohol, carbopol, polyacrylamide, polymethylvinyl ether-maleic anhydride, poloxamer 407, and puronic acid. Ointments usually contain mineral oil and a petrolatum base and are helpful in delivering antibiotics, cycloplegic drugs, or miotic agents. Solid inserts, such as OCUSERT PILO-20 and PILO-40, provide a zero-order rate of delivery by steady-state diffusion, whereby drug is released at a more constant rate to the precorneal tear film over a finite period of time rather than as a bolus. Although membrane-controlled drug delivery has advantages and is effective in some patients, the inserts have not gained widespread use, likely due to their cost and the fact that patients often have difficulty placing and retaining a solid insert in the cul-de-sac. Pharmacokinetics Classical pharmacokinetic theory based on studies of systemically administered drugs (see Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination) does not fully apply to all ophthalmic drugs (see Schoenwald, 1993; DeSantis and Patil, 1994). Although similar principles of absorption, distribution, metabolism, and excretion determine the fate of drug disposition in the eye, alternative routes of drug administration, in addition to oral and intravenous routes, introduce other variables in compartmental analysis (see Table 66–3 and Figure 66–6).
  10. Ophthalmic medications are applied topically using a variety of formulations. Drugs also may be injected by subconjunctival, sub-Tenon's, and retrobulbar routes (see Figure 66–1 and Table 66–3). For example, anesthetic agents are administered commonly by injection for surgical procedures and antibiotics and glucocorticoids also may be injected to enhance their delivery to local tissues. 5- Fluorouracil, an antimetabolite and antiproliferative agent, may be administered subconjunctivally to retard the fibroblast proliferation related to scarring after glaucoma surgery. Intraocular (i.e., intravitreal) injections of antibiotics are considered in instances of endophthalmitis, an intraocular infection. The sensitivities of the organisms to the antibiotic and the retinal toxicity threshold may be nearly the same for some antibiotics; hence, the antibiotic dose injected intravitreally must be carefully titrated. Figure 66–6. Possible Absorption Pathways of an Ophthalmic Drug Following Topical Application to the Eye. Solid black arrows represent the corneal route; dashed blue arrows represent the conjunctival/scleral route; the black dashed line represents the nasolacrimal absorption pathway. (Adapted from Chien et al., 1990, with permission.) Unlike clinical pharmacokinetic studies on systemic drugs, where data are collected relatively easily from blood samples, there is significant risk in obtaining tissue and fluid samples from the human eye. Consequently, animal models are studied to provide pharmacokinetic data on ophthalmic drugs. Commonly, the rabbit is used for such studies (see McDonald and Shadduck, 1977, for comparison of toxicity, anatomy, and physiology of human and rabbit ocular systems). Absorption After topical instillation of a drug, the rate and extent of absorption are determined by the following: the time the drug remains in the cul-de-sac and precorneal tear film (also known as the residence time); elimination by nasolacrimal drainage; drug binding to tear proteins; drug metabolism by tear and tissue proteins; and diffusion across the cornea and conjunctiva (see Lee, 1993). A drug's residence time may be prolonged by changing its formulation. Nasolacrimal
  11. drainage contributes to systemic absorption of topically administeredbreak ophthalmic medications. Absorption from the nasal mucosabreak avoids so-called first-pass metabolism by the liver (see Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination ), and consequently significant systemic side effects may be caused by topical medications, especially when used chronically. Possible absorption pathways of an ophthalmic drug following topical application to the eye are shown schematically in Figure 66–6. Transcorneal and transconjunctival/scleral absorption are the desired routes for localized ocular drug effects. The time period between drug instillation and its appearance in the aqueous humor is defined as the lag time. The drug concentration gradient between the tear film and the cornea and conjunctival epithelium provides the driving force for passive diffusion across these tissues. Other factors that affect a drug's diffusion capacity are the size of the molecule, chemical structure, and steric configuration. Transcorneal drug penetration is conceptualized as a differential solubility process; the cornea may be thought of as a trilamellar "fat-water-fat" structure corresponding to the epithelial, stromal, and endothelial layers. The epithelium and endothelium represent barriers for hydrophilic substances; the stroma is a barrier for hydrophobic compounds. Hence, a drug with both hydrophilic and lipophilic properties is best suited for transcorneal absorption. Drug penetration into the eye is approximately linearly related to its concentration in the tear film. Certain disease states, such as corneal ulcers and other corneal epithelial defects or stromal keratitis, also may alter drug penetration. Experimentally, drugs may be screened for their potential clinical utility by assessing their corneal permeability coefficients. These pharmacokinetic data combined with the drug's octanol/water partition coefficient (for lipophilic drugs) or distribution coefficient (for ionizable drugs) yield a parabolic relationship that is a useful parameter for predicting ocular absorption. Of course, such in vitro studies do not account for other factors that affect corneal absorption, such as blink rate, dilution by tear flow, nasolacrimal drainage, drug binding to proteins and tissue, and transconjunctival absorption; hence, these studies have limitations in predicting ocular drug absorption in vivo. Distribution Topically administered drugs may undergo systemic distribution primarily by nasal mucosal absorption and possibly by local ocular distribution by transcorneal/transconjunctival absorption. Following transcorneal absorption, the aqueous humor accumulates the drug, which is then distributed to intraocular structures as well as potentially to the systemic circulation via the trabecular meshwork pathway (see Figure 66–3B). Melanin binding of certain drugs is an important factor in some ocular compartments. For example, the mydriatic effect of -adrenergic receptor agonists is slower in onset in human volunteers with darkly pigmented irides compared to those with lightly pigmented irides (Obianwu and Rand, 1965). In rabbits, radiolabeled atropine binds significantly to melanin granules in irides of nonalbino animals (Salazar et al., 1976). This finding correlates with the fact that atropine's mydriatic effect lasts longer in nonalbino rabbits than in albino rabbits, and suggests that drug–melanin binding is a potential reservoir for sustained drug release. Another clinically important consideration for drug–melanin binding involves the retinal pigment epithelium. In the retinal pigment epithelium, accumulation of chloroquine (see Chapter 40: Drugs Used in the Chemotherapy of Protozoal Infections: Malaria) causes a toxic retinal lesion known as a "bull's-eye" maculopathy, which is associated with a decrease in visual acuity. Extraretinal manifestations of chloroquine toxicity include corneal and crystalline lens opacities and motility disturbances.
  12. Metabolism Enzymatic biotransformation of ocular drugs may be significant since local tissues in the eye express a variety ofenzymes, including esterases, oxidoreductases, lysosomal enzymes, peptidases, glucuronide and sulfate transferases, glutathione-conjugating enzymes, catechol-O-methyl- transferase, monoamine oxidase, and corticosteroid -hydroxylase (see Lee, 1992). The esterases have been of particular interest because of the development of prodrugs for enhanced corneal permeability; for example, dipivefrin hydrochloride (Mandell et al., 1978) is a prodrug for epinephrine, and latanoprost is a prodrug for prostaglandin F2 (Stjernschantz and Resul, 1992); both drugs are used for glaucoma management. Topically applied ocular drugs are eliminated by the liver and kidney after systemic absorption. Toxicology From the compartmental analysis given in Figure 66–6, it is apparent that all ophthalmic medications are potentially absorbed into the systemic circulation, so undesirable systemic side effects may occur. Most ophthalmic drugs are delivered locally to the eye, and the potential local toxic effects are due to hypersensitivity reactions or to direct toxic effects on the cornea, conjunctiva, periocular skin, and nasal mucosa. Eyedrops and contact lens solutions commonly contain preservatives such as benzalkonium chloride, chlorobutanol, chelating agents, and thimerosal for their antimicrobial effectiveness. In particular, benzalkonium chloride may cause a punctate keratopathy or toxic ulcerative keratopathy (Grant and Schuman, 1993). Therapeutic and Diagnostic Applications of Drugs in Ophthalmology Chemotherapy of Microbial Diseases in the Eye Antibacterial Agents General Considerations A number of antibacterial antibiotics have been formulated for topical ocular use (Table 66–4). The pharmacology, structures, and kinetics of individual drugs have been presented in detail in preceding chapters. Appropriate selection of antibiotic and route of administration is dependent on clinical examination and culture/sensitivity results. Specially formulated antibiotics also may be available for serious eye infections such as corneal ulcers or keratitis and endophthalmitis. Preparation of fortified solutions requires a pharmacist familiar with sterile preparation of ocular drugs. Therapeutic Uses Infectious diseases of the skin, eyelids, conjunctiva, and lacrimal excretory system are encountered regularly in clinical practice. Periocular skin infections are divided into preseptal and postseptal or orbital cellulitis. Depending on the clinical setting (i.e., preceding trauma, sinusitis, age of patient, relative immunocompromised state), oral or parenteral antibiotics are administered. Dacryocystitis is an infection of the lacrimal sac. In infants and children, the disease usually is unilateral and secondary to an obstruction of the nasolacrimal duct. The physician should be aware of the changing microbiological spectrum for orbital cellulitis, for example, the sharp decline in the involvement of Haemophilus influenzae after the introduction in 1985 of the H. influenzae vaccine
  13. (Ambati et al., 2000). In adults, dacryocystitis and canalicular infections may be caused by Staphylococcus aureus, Streptococcus species, Candida species, and Actinomyces israelii. Infectious processes of the lids include hordeolum and blepharitis. A hordeolum, or stye, is an infection of the meibomian, Zeis, or Moll glands at the lid margins. The typical offending bacterium is S.aureus, and the usual treatment consists of warm compresses and topical antibiotic ointment. Blepharitis is a common bilateral inflammatory process of the eyelids characterized by irritation and burning, and it also is usually caused by a Staphylococcus species. Local hygiene is the mainstay of therapy; topical antibiotics frequently are used, usually in ointment form, particularly when the disease is accompanied by conjunctivitis and keratitis. Conjunctivitis is an inflammatory process of the conjunctiva that varies in severity from mild hyperemia to severe purulent discharge. The more common causes of conjunctivitis include viruses, allergies, environmental irritants, contact lenses, and chemicals. The less common causes include other infectious pathogens, immune-mediated reactions, associated systemic diseases, and tumors of the conjunctiva or eyelid. The more commonly reported infectious agents are adenovirus and herpes simplex virus, followed by other viral (e.g., enterovirus, coxsackievirus, measles virus, varicella zoster virus, vaccinia-variola virus) and bacterial sources (e.g., Neisseria species, Streptococcus pneumoniae, Haemophilus species, S.aureus, Moraxella lacunata, chlamydial species). Rickettsia, fungi, and parasites, in both cyst and trophozoite form, are rare causes of conjunctivitis. Effective management is based on selection of an appropriate antibiotic for suspected bacterial pathogens. Unless an unusual causative organism is suspected, bacterial conjunctivitis is treated empirically without obtaining a culture. Keratitis, or corneal ulcer, may occur at any level of the cornea, e.g., epithelium, subepithelium, stroma, or endothelium. Numerous microbial agents have been isolated, including bacteria, viruses, fungi, spirochetes, and cysts and trophozoites. In aggressive forms of bacterial keratitis, immediate empirical and intensive antibiotic therapy is essential to prevent blindness from corneal perforation and secondary corneal scarring. Results of culture and sensitivity tests should guide the final drug of choice. Endophthalmitis is a potentially severe and devastating inflammatory, and usually infectious, process of the intraocular tissues. When the inflammatory process encompasses the entire globe, it is called panophthalmitis. Endophthalmitis usually is caused by bacteria, by fungi, or rarely by spirochetes. The typical case occurs during the early postoperative course (e.g., after cataract, glaucoma, cornea, or retinal surgery), following trauma, or by endogenous seeding in the immunocompromised host or intravenous drug user. Prompt therapy usually includes vitrectomy (i.e., specialized surgical removal of the vitreous) and empirical intravitreal antibiotics to treat suspected bacterial or fungal microorganisms (see Peyman and Schulman, 1994; Meredith, 1994). In cases of endogenous seeding, parenteral antibiotics have a role in eliminating the infectious source. In trauma or in the postoperative setting, however, the efficacy of systemic antibiotics is not well established. Antiviral Agents General Considerations The various antiviral drugs currently used in ophthalmology are summarized in Table 66–5 (see Chapter 50: Antimicrobial Agents: Antiviral Agents (Nonretroviral) for additional details about
  14. these agents). Therapeutic Uses The primary indications for the use of antiviral drugs in ophthalmology are viral keratitis (Kaufman, 2000), herpes zoster ophthalmicus (Liesegang, 1999; Chern and Margolis, 1998), and retinitis (Cassoux et al., 1999; Yoser et al., 1993). There are currently no antiviral agents for the treatment of viral conjunctivitis caused by adenoviruses, which usually has a self-limited course and typically is treated by symptomatic relief of irritation. Viral keratitis, an infection of the cornea that may involve either the epithelium or stroma, is most commonly caused by herpes simplex type I and varicella zoster viruses. Less common viral etiologies include herpes simplex II, Epstein-Barr virus, and cytomegalovirus. Topical antiviral agents are indicated for the treatment of epithelial disease due to herpes simplex infection. When treating viral keratitis topically, there is a very narrow margin between the therapeutic topical antiviral activity and the toxic effect on the cornea; hence, patients must be followed very closely. The role of oral acyclovir and glucocorticoids in herpetic corneal and external eye disease has been examined in the Herpetic Eye Disease Study (Anonymous, 1996, 1997a, 1998). Topical glucocorticoids are contraindicated in herpetic epithelial keratitis due to active viral replication. In contrast, for herpetic disciform keratitis, which predominantly is presumed to involve a cell- mediated immune reaction, topical glucocorticoids accelerate recovery (Wilhelmus et al., 1994). For recurrent herpetic stromal keratitis, there is clear benefit from treatment with oral acyclovir in reducing the risk of recurrence (Moyes et al., 1994; Anonymous, 1998). Herpes zoster ophthalmicus is a latent reactivation of a varicella zoster infection in the first division of the trigeminal cranial nerve. Systemic acyclovir is effective in reducing the severity and complications of herpes zoster ophthalmicus (Cobo et al., 1986). Currently, there are no ophthalmic preparations of acyclovir approved by the United States Food and Drug Administration (FDA), although an ophthalmic ointment is available for investigational use. Viral retinitis may be caused by herpes simplex virus, cytomegalovirus (CMV), adenovirus, and varicella zoster virus. With the highly active antiretroviral therapy (HAART; see Chapter 51: Antiretroviral Agents: Antiretroviral Agents), CMV retinitis does not appear to progress when specific anti-CMV therapy is discontinued, but some patients develop an immune recovery uveitis (Jacobson et al., 2000; Whitcup, 2000). Treatment usually involves long-term parenteral administration of antiviral drugs. Intravitreal administration of ganciclovir has been found to be an effective alternative to the systemic route (Sanborn et al., 1992). Antifungal Agents General Considerations The only currently available ophthalmic antifungal preparation is a polyene, natamycin (NATACYN), which has the following structure: Other antifungal agents may be specially preparedbreak for topical, subconjunctival, or intravitreal routes of administration (see Table 66–6). The pharmacology andbreak structures of available antifungal agents are given inbreak Chapter 49: Antimicrobial Agents: Antifungal Agents.
  15. Therapeutic Uses As with systemic fungal infections, the incidence of ophthalmic fungal infections has risen with the growing number of immunocompromised hosts. Ophthalmic indications for antifungal medications include fungal keratitis, scleritis, endophthalmitis, mucormycosis, and canaliculitis (see Behlau and Baker, 1994). Drug selection is based on identifying the pathogenic fungi and, if available, sensitivity data. Antiprotozoal Agents General Considerations Parasitic infections involving the eye usually manifest themselves as a form of uveitis, an inflammatory process of either the anterior or posterior segments, and less commonly as conjunctivitis, keratitis, and retinitis. Therapeutic Uses In the United States, the most commonly encountered protozoal infections include Acanthamoeba and Toxoplasma gondii. In contact-lens wearers who develop keratitis, physicians should be highly suspicious of the presence of Acanthamoeba (McCulley et al., 2000). Treatment usually consists of a combination topical antibiotic, such as polymyxin B sulfate, bacitracin zinc, and neomycin sulfate (e.g., NEOSPORIN), and sometimes an imidazole (e.g., clotrimazole, miconazole, or ketoconazole). In the United Kingdom, the aromatic diamidines (i.e., propamine isethionate in both topical aqueous and ointment forms, BROLENE) have been used successfully to treat this relatively resistant infectious keratitis (Hargrave et al., 1999). Another treatment for Acanthamoeba is the cationic antiseptic agent polyhexamethylene biguanide, although this is not an FDA-approved antiprotozoal agent (Lindquist, 1998). Toxoplasmosis may present as a posterior (e.g., focal retinochoroiditis, papillitis, vitritis, or retinitis) or occasionally as an anterior uveitis. Treatment is indicated when inflammatory lesions encroach upon the macula and threaten central visual acuity. Several regimens have been recommended with concurrent use of systemic steroids: (1) pyrimethamine, sulfadiazine, and folinic acid; (2) pyrimethamine, sulfadiazine, clindamycin, and folinic acid; (3) sulfadiazine and clindamycin; (4) clindamycin; and (5) trimethoprim–sulfamethoxazole with or without clindamycin (see Engstrom et al., 1991; Opremcak et al., 1992). Other protozoal infections (e.g., giardiasis, leishmaniasis, and malaria) and helminths are less common eye pathogens in the United States (see DeFreitas and Dunkel, 1994). Systemic pharmacological management as well as vitrectomy may be indicated for selected parasitic infections. Use of Autonomic Agents in the Eye General Considerations General autonomic pharmacology has been discussed extensively in Chapters 6: Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, 7: Muscarinic Receptor Agonists and Antagonists, 8: Anticholinesterase Agents, 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia, and 10: Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor
  16. Antagonists. The autonomic agents used in ophthalmology as well as the responses (i.e., mydriasis and cycloplegia) to muscarinic cholinergic antagonists are summarized in Table 66–7. Therapeutic Uses Autonomic drugs are used extensively for diagnostic and surgical purposes and for the treatment of glaucoma, uveitis, and strabismus. Glaucoma In the United States, glaucoma is the leading cause of blindness in African Americans and the third leading cause in Caucasians. Characterized by progressive optic nerve cupping and visual field loss, glaucoma is responsible for visual impairment of 80,000 Americans, and at least 2 million to 3 million have the disease (see Tielsch, 1993). Risk factors associated with glaucomatous nerve damage include increased intraocular pressure, positive family history of glaucoma, African- American heritage, myopia, and hypertension. The production and regulation of aqueous humor have been discussed in an earlier section of this chapter. Although particularly elevated intraocular pressures (e.g., greater than 30 mm Hg) usually will lead to optic nerve damage, certain patients' optic nerves appear to be able to tolerate intraocular pressures in the mid-to-high twenties. These patients are referred to as ocular hypertensives; a prospective, multicenter study is being conducted to determine whether or not early medical treatment to lower intraocular pressure will prevent glaucomatous optic nerve damage. Other patients have progressive glaucomatous optic nerve damage despite having intraocular pressures in the normal range, and this form of the disease is sometimes called normal- or low-tension glaucoma. However, at present, the pathophysiological processes involved in glaucomatous optic nerve damage and the relationship to aqueous humor dynamics are not understood. Current medical therapies are targeted to decrease the production of aqueous humor at the ciliary body and to increase outflow through the trabecular meshwork and uveoscleral pathways. There is no consensus on the best therapy for glaucoma. Currently, a National Eye Institute–sponsored clinical trial, the Collaborative Initial Glaucoma Treatment Study (CIGTS), aims to determine whether it is best to treat patients newly diagnosed with open-angle glaucoma with filtering surgery or with medication in terms of preservation of visual function and quality of life (Musch et al., 1999). This study aside, a stepped medical approach depends on the patient's health, age, and ocular status. Some general principles prevail in patient management: (1) asthma and chronic obstructive pulmonary emphysema having a bronchospastic component are relative contraindications to the use of topical -adrenergic receptor antagonists because of the risk of significant side effects from systemic absorption via the nasolacrimal system; (2) some cardiac dysrhythmias (i.e., bradycardia and heart block) also are relative contraindications to -adrenergic antagonists for similar reasons; (3) history of nephrolithiasis, or kidney stones, is sometimes a contraindication for carbonic anhydrase inhibitors; (4) young patients usually are intolerant of miotic therapy secondary to visual blurring from induced myopia; therefore, if a miotic agent is needed in a young patient, the OCUSERT delivery system usually is preferable; (5) direct miotic agents are preferred over cholinesterase inhibitors in "phakic" patients (i.e., those patients who have their endogenous lens), since the latter drugs can promote cataract formation; and (6) in patients who have an increased risk of retinal detachment, miotics should be used with caution, since they have been implicated in promoting retinal tears in susceptible individuals; such tears are thought to be due to altered forces at the vitreous base produced by ciliary body contraction induced by the drug. With these general principles in mind, a stepped medical approach may begin with a -adrenergic
  17. receptor antagonist, with the main goal of preventing progressive glaucomatous optic-nerve damage with minimum risk and side effects from either topical or systemic therapy. When there are medical contraindications to the use of -receptor antagonists other agents, such as latanoprost (XALATAN), a prostaglandin F2 prodrug, or an 2-adrenergic receptor agonist may be used as first- line therapy. The chemical structure of latanoprost is shown below. Second- and third-line agents include topical carbonic anhydrase inhibitors, epinephrine-related drugs, and miotic agents. Ironically, epinephrine-related drugs may be used concomitantly with a - adrenergic receptor antagonist. Epinephrine's main intraocular pressure-lowering effect is to enhance uveoscleral outflow, but it also may alter trabecular meshwork function and ciliary body blood flow. If combined topical therapy fails to achieve the target intraocular pressure or fails to halt glaucomatous optic nerve damage, then systemic therapy with carbonic anhydrase inhibitors (CAIs) is a final medication option before resorting to laser or incisional surgical treatment. Of the oral preparations available (see Chapter 29: Diuretics), the best tolerated is acetazolamide in sustained-release capsules, followed by methazolamide. The least well tolerated are acetazolamide tablets (Lichter et al., 1978). To reduce side effects, topical CAIs have been developed— dorzolamide hydrochloride (TRUSOPT), and brinzolamide (AZOPT), whose structures are shown below. These topical CAIs do not reduce the intraocular pressure as much as do the oral agents. Toxicity of Agents in Treatment of Glaucoma Ciliary body spasm is a muscarinic cholinergic effect that can lead to induced myopia and a changing refraction due to iris and ciliary body contraction as the drug effect waxes and wanes between doses. Headaches can occur from the iris and ciliary body contraction. Epinephrine-related compounds, effective in intraocular pressure reduction, can cause a vasoconstriction-vasodilation rebound phenomenon leading to a red eye. Ocular and skin allergies from topical epinephrine,
  18. related prodrug formulations, and apraclonidine are common. Systemic absorption of epinephrine- related drugs can have all the side effects found with direct systemic administration. The - adrenergic antagonists, while effective in intraocular pressure reduction, can produce systemic side effects readily through direct absorption in the tissues and via the nasolacrimal system. The use of CAIs systematically may give some patients significant problems with malaise, fatigue, depression, paresthesias, and nephrolithiasis; the topical CAIs may minimize these relatively common side effects. These medical strategies for managing glaucoma do help to slow the progression of this disease, yet there are potential risks from treatment-related side effects, and treatment effects on quality of life must be recognized. Uveitis Inflammation of the uvea, or uveitis, has both infectious and noninfectious causes, and medical treatment of the underlying cause (if known) is essential in addition to the use of topical therapy. Cyclopentolate, or sometimes an even longer-acting antimuscarinic agent such as atropine, frequently is used to prevent posterior synechia formation between the lens and iris margin and to relieve ciliary muscle spasm that is responsible for much of the pain associated with anterior uveitis. If posterior synechiae have already formed, an -adrenergic agonist may be used to break the synechiae by enhancing pupillary dilation. Topical steroids usually are adequate to decrease inflammation, but sometimes they must be supplemented by systemic steroids. Strabismus Strabismus, or ocular misalignment, has numerous causes and may occur at any age. In children, strabismus may lead to amblyopia (reduced vision). Nonsurgical efforts to treat amblyopia include occlusion therapy, orthoptics, optical devices, and pharmacological agents. The eyes of children with hyperopia, or farsightedness, must accommodate to focus distant images. In some cases, the synkinetic accommodative-convergence response leads to excessive convergence and a manifest esotropia (turned-in eye). This deviated eye does not develop normal visual acuity and is therefore amblyopic. In this setting, atropine (1%) instilled in the preferred seeing eye every five days produces cycloplegia and the inability of this eye to accommodate, thus forcing the child to use the amblyopic eye. Echothiophate iodide also has been used in the setting of accommodative strabismus. Accommodation drives the near reflex, the triad of miosis, accommodation, and convergence. A reversible cholinesterase inhibitor such as echothiophate causes miosis and an accommodative change in the shape of the lens; hence, the accommodative drive to initiate the near reflex is reduced, and less convergence will occur. Surgery and Diagnostic Purposes For certain surgical procedures and for clinical funduscopic examination, it is desirable to maximize the view of the retina and lens. Muscarinic cholinergic antagonists and 2-adrenergic agonists frequently are used singly or in combination for this purpose (see Table 66–7). Intraoperatively, there are circumstances when miosis is preferred, and two cholinergic agonists are available for intraocular use, acetylcholine and carbachol. Patients with myasthenia gravis may first present to an ophthalmologist with complaints of double vision (diplopia) or lid droop (ptosis); the edrophonium test is helpful in diagnosing these patients (see Chapter 8: Anticholinesterase Agents). Use of Immunomodulatory Drugs for Ophthalmic Therapy
  19. Glucocorticoids Glucocorticoids have an important role in managing ocular inflammatory diseases; their chemistry and pharmacology are described in Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones. Therapeutic Uses Because of their antiinflammatory effect, topical corticosteroids are used in managing anterior uveitis, external eye inflammatory diseases associated with some infections and ocular cicatricial pemphigoid, and postoperative inflammation following intraocular surgery. After glaucoma filtering surgery, topical steroids are particularly valuable in delaying the wound-healing process by decreasing fibroblast infiltration, which reduces the potential scarring of the surgical site. Steroids are commonly given systemically and by sub-Tenon's capsule injection to manage posterior uveitis. Parenteral steroids followed by tapering oral doses are the preferred treatment for optic neuritis (Kaufman et al., 2000; Trobe et al., 1999). Toxicity of Steroids Extensive discussion has been directed to the toxic effects to the eyes of topical and systemic corticosteroids. These include the development of posterior subcapsular cataracts and secondary infections (see Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones) and secondary open-angle glaucoma (Becker and Mills, 1963; Armaly, 1963a, 1963b). There is a significant increase in potential risk for developing secondary glaucoma when there is a positive family history of glaucoma. If there is no family history of open-angle glaucoma, only about 5% of normal individuals respond to topical or long-term systemic steroids with a marked increase in intraocular pressure. With a positive family history, however, moderate to marked steroid-induced intraocular pressure elevations may be seen in up to 90% of patients. The pathophysiology of steroid-induced glaucoma is not fully understood, but there is evidence that the GLCIA gene may be involved (Stone et al., 1997). Typically, steroid-induced elevation of intraocular pressure is reversible once administration of the steroid ceases. Nonsteroidal Antiinflammatory Agents General Considerations Nonsteroidal drug therapy for inflammation is discussed in Chapter 27: Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout. The nonsteroidal antiinflammatory drugs (NSAIDs) are now being applied to the treatment of ocular disease. Therapeutic Uses Currently, there are four topical NSAIDs approved for ocular use: diclofenac (VOLTAREN), flurbiprofen (OCUFEN), ketorolac (ACULAR), and suprofen (PROFENAL). Diclofenac and flurbiprofen are discussed in Chapter 27: Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout; the chemical structures of ketorolac, a pyrrolo-pyrolle derivative, and suprofen, a phenylalkanoic acid, are shown below:
  20. Flurbiprofen and suprofen are used to counter unwanted intraoperative miosis during cataract surgery. Ketorolac is given for seasonal allergic conjunctivitis. Diclofenac is used for postoperative inflammation. Both ketorolac (Weisz et al., 1999a) and diclofenac (Anonymous, 1997b) have been found to be effective in treating cystoid macular edema occurring after cataract surgery. Antihistamines and Mast-Cell Stabilizers Pheniramine (see Chapter 25: Histamine, Bradykinin, and Their Antagonists) and antazoline, both H1-receptor antagonists, are formulated in combination with naphazoline, a vasoconstrictor, for relief of allergic conjunctivitis. The chemical structure of antazoline is: Newer topical antihistamines include emedastine difumarate (EMADINE), olopatadine hydrochloride (PATANOL), levocabastine hydrochloride (LIVOSTIN), and ketotifen fumarate (ZADITOR). Cromolyn sodium (CROLOM), which prevents the release of histamine and other autacoids from mast cells (see Chapter 28: Drugs Used in the Treatment of Asthma), has found limited use in treating conjunctivitis that is thought to be allergen-mediated, such as vernal conjunctivitis. Iodoxamide tromethamine (ALOMIDE), another mast-cell-stabilizing agent, and pemirolast (ALAMAST), a mast-cell stabilizer that also has other antiinflammatory effects, also are available for ophthalmic use. Immunosuppressive and Antimitotic Agents General Considerations The principal application of immunosuppressive and antimitotic agents to ophthalmology relates to the use of 5-fluorouracil and mitomycin C in corneal and glaucoma surgeries. Certain systemic diseases with serious vision-threatening ocular manifestations—break such as Behçet's disease, Wegener's granulomatosis, rheumatoid arthritis, and Reiter's syndrome—require systemic
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