Chapter 64: Ocular Pharmacology

Anterior Segment.

Cornea. The cornea is a transparent and avascular tissue organized into five layers: epithelium, Bowman's membrane, stroma, Descemet's membrane, and endothelium (Figure 64–3B). Representing an important barrier to foreign matter, including drugs, the hydrophobic epithelial layer comprises five to six cell layers. The basal epithelial cells lie on a basement membrane that is adjacent to Bowman's membrane, a layer of collagen fibers. Constituting ~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, 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 requires penetration of 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 (1-2 mm wide) called the limbus. Limbal structures include the conjunctival epithelium, which contains the corneal epithelial stem cells, Tenon's capsule, episclera, corneoscleral stroma, canal of Schlemm, and trabecular meshwork (Figure 64–3B). Limbal blood vessels, as well as the tears, provide important nutrients and immunological defense mechanisms for the cornea. The anterior chamber holds ~250 μL 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 ~50 μL 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, and 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 80-95% 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 "Glaucoma" and Chapter 33).

The peripheral anterior chamber angle is an important anatomical structure for differentiating two forms of glaucoma: open-angle glaucoma, which is by far the most common form of glaucoma in the U.S., 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, by either laser or incision, but short-term medical management may be necessary to reduce the acute intraocular pressure (IOP) elevation and to clear the cornea prior to surgery. Long-term IOP reduction may be necessary, especially if the peripheral iris has permanently covered the trabecular meshwork. 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 change in the lens-iris relationship leads to an increase in pressure in the posterior chamber, causing the iris base to be pushed against the angle wall, thereby covering the trabecular meshwork and closing the filtration angle and markedly elevating the IOP. The result is known as an acute attack of pupillary-block angle-closure glaucoma. Unfortunately, individuals with susceptible angles usually are not aware of a risk of angle-closure glaucoma. Furthermore, 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 who need not be concerned about taking these drugs.

Iris and Pupil. The iris is the most anterior portion of the uveal tract, which also includes the ciliary 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"). 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 (Figure 64–4), 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 64–2. Figure 64–5 provides a flowchart for the diagnostic evaluation of anisocoria.

Ciliary Body. The ciliary body serves two very specialized roles in the eye:

• secretion of aqueous humor by the epithelial bilayer

• accommodation by the ciliary muscle

The anterior portion of the ciliary body, called the pars plicata, is composed of 70-80 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 zonule 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 IOP-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 ~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. Aging, in addition to certain medications, such as corticosteroids, and certain diseases, such as diabetes mellitus, cause the lens to become opacified, which is termed a cataract.

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 collagen fibers into the superficial scleral. Numerous blood vessels pierce the sclera through emissaria to both supply and 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 lie 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, 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. The unique organization and biochemistry of the photoreceptors have provided a superb system for investigating signal transduction mechanisms. The wealth of information about rhodopsin has made it an excellent model for the G protein–coupled signal transduction. Such detailed understanding holds promise for targeted therapy for some of the hereditary retinal diseases.

Vitreous. Approximately 80% of the eye's volume is the vitreous, which is a clear medium containing collagen type II, hyaluronic acid, proteoglycans, and a variety of macromolecules, including glucose, ascorbic acid, amino acids, and a number of inorganic salts. Glutamate in the vitreous has been suspected to have a possible relationship to glaucoma. The ganglion cells appear to die in glaucoma via a process of apoptosis (Quigley et al., 1995; Wax et al., 1998), and glutamate has been shown to induce apoptosis via NMDA receptor excitotoxicity (Sucher et al., 1997). Elevated glutamate levels have been noted in experimental animal models (Dreyer et al., 1996; Yoles and Schwartz, 1998) and in humans with glaucoma (Dreyer et al., 1996), although this has been questioned (Levkovitch-Verbin et al., 2002). Memantine, a noncompetitive NMDA receptor antagonist (Vorwerk et al., 1996; Seki and Lipton, 2008; Ju et al., 2008), is currently being investigated clinically as a possible treatment for glaucoma.

Optic Nerve. The optic nerve is a myelinated nerve conducting the retinal output to the central nervous system (CNS). It is composed of:

• an intraocular portion, which is visible as the optic disk in the retina

• an intraorbital portion

• an intracanalicular portion

• an intracranial portion

The nerve is ensheathed in meninges continuous with the brain. At present, pharmacological treatment of optic neuropathies usually is based on management of the underlying disease. For example, nonarteritic ischemic optic neuropathy might be treated with intravitreal glucocorticoids (Kaderli et al., 2007) and optic neuritis may be best treated with intravenous glucocorticoids (Atkins et al., 2007; Beck and Gal, 2008; Volpe, 2008). Unfortunately, these guidelines have not yet become routine clinical practice (Biousse et al., 2009). Glaucomatous optic neuropathy is medically managed by decreasing IOP.

For example, anesthetic agents commonly are administered by injection for surgical procedures, and antibiotics and glucocorticoids also may be injected to enhance their delivery to local tissues. The antimetabolite 5-fluorouracil and the DNA alkylating agent mitomycin C may be extemporaneously compounded for subconjunctival administration to retard the fibroblast proliferation related to scarring after glaucoma surgery. Mitomycin C also can be applied to the cornea to prevent scarring after corneal surgery. Intraocular (i.e., intravitreal) injections of antibiotics are considered in instances of endophthalmitis, a severe 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. Intraocular inserts are used to treat intraocular viral infections. The ganciclovir implant is indicated to treat CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).

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, frequently rabbits, are studied to provide pharmacokinetic data on ophthalmic drugs.

Absorption. After topical instillation of a drug, the rate and extent of absorption are determined by the time the drug remains in the cul-de-sac and precorneal tear film, elimination by nasolacrimal drainage, drug binding to tear proteins, drug metabolism by tear and tissue proteins, and diffusion across the cornea and conjunctiva (Lee, 1993). A drug's residence time may be prolonged by changing its formulation. Residence time also may be extended by blocking the egress of tears from the eye by closing the tear drainage ducts with flexible silicone (punctal) plugs (herrick lacrimal plug, punctum plug) or cautery. Nasolacrimal drainage contributes to systemic absorption of topically administered ophthalmic medications. Absorption from the nasal mucosa avoids first-pass metabolism by the liver, 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 64–6.

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 trilaminar "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 epithelial defects and corneal ulcers, may alter drug penetration. Medication absorption usually is increased when an anatomical barrier is compromised or removed. 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 epithelial integrity, 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 then is distributed to intraocular structures as well as potentially to the systemic circulation via the trabecular meshwork pathway (Figure 64–3B). Melanin binding of certain drugs is an important factor in some ocular compartments. For example, the mydriatic effect of α adrenergic–receptor agonists is slower in onset in human volunteers with darkly pigmented irides compared to those with lightly pigmented irides. In rabbits, radiolabeled atropine binds significantly to melanin granules in irides of non-albino animals. This finding correlates with the fact that atropine's mydriatic effect lasts longer in non-albino 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 49) causes a toxic retinal lesion known as a "bull's-eye" maculopathy, which is associated with a decrease in visual acuity.

Metabolism. Enzymatic biotransformation of ocular drugs may be significant because a variety of enzymes, including esterases, oxidoreductases, lysosomal enzymes, peptidases, glucuronide and sulfate transferases, glutathione-conjugating enzymes, catechol-O-methyl-transferase, monoamine oxidase, and 11β-hydroxysteroid dehydrogenase are found in the eye. The esterases have been of particular interest because of the development of prodrugs for enhanced corneal permeability; e.g., dipivefrin hydrochloride is a prodrug for epinephrine, and latanoprost is a prodrug for prostaglandin F_2α (PGF_2α); both drugs are used for glaucoma management. Topically applied ocular drugs are eliminated by the liver and kidney after systemic absorption, but enzymatic transformation of systemically administered drugs also is important in ophthalmology.

Toxicology. All ophthalmic medications are potentially absorbed into the systemic circulation (Figure 64–6), 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). Thimerosal is used rarely due to a high incidence of hypersensitivity reactions.

Dacryoadenitis, an infection of the lacrimal gland, is most common in children and young adults. It may be bacterial (typically Staphylococcus aureus, Streptococcus spp.) or viral (most commonly seen in mumps, infectious mononucleosis, influenza, and herpes zoster). When bacterial infection is suspected, systemic antibiotics usually are indicated.

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. In adults, dacryocystitis and canalicular infections may be caused by S. aureus, Streptococcus spp., diphtheroids, Candida spp., and Actinomyces israelii. Any discharge from the lacrimal sac should be sent for smears and cultures. Systemic antibiotics typically are indicated.

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 eyelid margins. The typical offending bacterium is S. aureus, and the usual treatment consists of warm compresses and topical antibiotic gel, drops, or ointment. Blepharitis is a common bilateral inflammatory process of the eyelids characterized by irritation and burning, and it also usually is associated with a Staphylococcus sp. Local hygiene is the mainstay of therapy; topical antibiotics frequently are used, usually in gel, drop, or ointment form, particularly when the disease is accompanied by conjunctivitis and keratitis. Systemic tetracycline, doxycycline, minocycline, and erythromycin often are effective in reducing severe eyelid inflammation but must be used for weeks to months.

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 spp., Streptococcus pneumoniae, Haemophilus spp., S. aureus, Moraxella lacunata, and chlamydial spp.). 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 with a broad-spectrum topical antibiotic without obtaining a culture.

The mild, small, more peripheral infections usually are not cultured, and the eyes are treated with broad-spectrum topical antibiotics. In more severe, central, or larger infections, corneal scrapings for smears, cultures, and sensitivities are performed, and the patient is immediately started on intensive hourly, around-the-clock topical antibiotic therapy. The goal of treatment is to eradicate the infection and reduce the amount of corneal scarring and the chance of corneal perforation and severe decreased vision or blindness. The initial medication selection and dosage are adjusted according to the clinical response and culture and sensitivity results.

Immediate vitrectomy (i.e., specialized surgical removal of the vitreous) is beneficial for patients who have light perception–only vision (Endophthalmitis Vitrectomy Study Group, 1995). Vitrectomy for other causes of endophthalmitis (e.g., glaucoma bleb related, post-traumatic, or endogenous) may be beneficial (Schiedler et al., 2004). In cases of endogenous seeding, parenteral antibiotics have a role in eliminating the infectious source, but the efficacy of systemic antibiotics with trauma is not well established.

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 type II, Epstein-Barr virus, and CMV. 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 (Herpetic Eye Disease Study Group, 1997; Herpetic Eye Disease Study Group, 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 (Herpetic Eye Disease Study Group, 1998). An ophthalmic formulation of trifluridine (viroptic) is available for treatment of keratoconjunctivitis and epithelial keratitis due to herpes simplex viruses.

Herpes zoster ophthalmicus is a latent reactivation of a varicella zoster infection in the first division of the trigeminal cranial nerve. Systemic acyclovir, valacyclovir, and famciclovir are effective in reducing the severity and complications of herpes zoster ophthalmicus (Colin et al., 2000). Currently, there are no ophthalmic preparations of acyclovir approved by the FDA, although an ophthalmic ointment is available for investigational use.

Viral retinitis may be caused by herpes simplex virus, CMV, adenovirus, and varicella zoster virus. With the highly active antiretroviral therapy (HAART; see Chapter 59), 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). Acute retinal necrosis and progressive outer retinal necrosis, most often caused by varicella zoster virus, can be treated by various combinations of oral, intravenous, intravitreal injection of, and intravitreal implantation of antiviral medications (Roig-Melo et al., 2001).

In 2005-2006, there was a worldwide epidemic of Fusarium fungal keratitis related to a specific contact lens solution, which resolved when it was removed from the market (Chang et al., 2007). When fungal infection is suspected, samples of the affected tissues are obtained for smears, cultures, and sensitivities, and this information is used to guide drug selection.

Additional risk factors for Acanthamoeba keratitis include poor contact lens hygiene, wearing contact lenses in a pool or hot tub, and ocular trauma. Treatment usually consists of a combination of topical agents. The aromatic diamidines (i.e., propamidine isethionate in both topical aqueous and ointment forms [brolene]) have been used successfully to treat this relatively resistant infectious keratitis (Hargrave et al., 1999), although it is not available in the U.S. The cationic antiseptic agent polyhexamethylene biguanide (PHMB) also is used in drop form for Acanthamoeba keratitis, although this is not an FDA-approved antiprotozoal agent. Topical chlorhexidine can be used as an alternative to PHMB. Oral imidazoles (e.g., itraconazole, fluconazole, ketoconazole, voriconazole) often are used in addition to the topical medications. Resolution of Acanthamoeba keratitis often requires many months of treatment.

Glaucoma. In the U.S., glaucoma is the second leading cause of blindness in African-Americans, the third leading cause in Caucasians, and the leading cause in Hispanic Americans (Congdon et al., 2004). African Americans have three times the age-adjusted prevalence of glaucoma compared to Caucasians (Friedman et al., 2004). Characterized by progressive optic nerve cupping and visual field loss, glaucoma is responsible for the bilateral blindness of 90,000 Americans (half of whom are African-American or Hispanic) (Congdon et al., 2004), and ~2.2 million have the disease (1.86% of the population >40 years of age). This number is expected to increase by 50% by the year 2020 (Friedman et al., 2004). Risk factors associated with glaucomatous nerve damage include increased IOP, positive family history of glaucoma, African-American heritage, and possibly myopia and hypertension. The production and regulation of aqueous humor were discussed earlier in "Aqueous Humor Dynamics and Regulation of Intraocular Pressure." Previously, an IOP of >21 mm Hg was considered abnormal. This, however, is incorrect, as IOP is not an accurate indicator of disease. Nonetheless, elevated IOP is a risk factor for glaucoma. Several randomized, controlled trials have determined that reducing IOP can delay glaucomatous nerve or field damage (Fluorouracil Filtering Surgery Study Group, 1996; AGIS Investigators, 2000; Heijl et al., 2002). Although markedly elevated IOPs (e.g., >30 mm Hg) usually will lead to optic nerve damage, the optic nerves in certain patients apparently can tolerate IOPs in the mid- to high 20s. These patients are referred to as ocular hypertensives. The Ocular Hypertension Treatment Study found that prophylactic medical reduction of IOP reduced the risk of progression to glaucoma from ~10-5% (Kass et al., 2002). Other patients have progressive glaucomatous optic nerve damage despite having IOPs in the normal range, and this form of the disease sometimes is called normal- or low-tension glaucoma. A reduction of IOP by 30% reduces disease progression from ~35-10%, even for normal-tension glaucoma patients (Collaborative Normal-Tension Glaucoma Study Group, 1998a; Collaborative Normal-Tension Glaucoma Study Group, 1998b). Despite overwhelming evidence that IOP reduction is a helpful treatment, at present the pathophysiological processes involved in glaucomatous optic nerve damage and the relationship to aqueous humor dynamics are not understood.

Current pharmacotherapies are targeted at decreasing the production of aqueous humor at the ciliary body and increasing outflow through the trabecular meshwork and uveoscleral pathways. There is no consensus on the best IOP-lowering technique for glaucoma therapy. Currently, a National Eye Institute–sponsored clinical trial, the Collaborative Initial Glaucoma Treatment Study (CIGTS), aims to determine whether it is best, in terms of preservation of visual function and quality of life, to treat patients newly diagnosed with open-angle glaucoma with filtering surgery or medication. Initial results showed no difference in disease progression rates between the two treatment groups at 5 years (Lichter et al., 2001), but after 9 years, more subjects (25.5% versus 21.3%) had visual field loss in the medicine arm than in the surgery arm of the trial (Musch et al., 2009).

The CIGTS study aside, a stepped medical approach depends on the patient's health, age, and ocular status, with knowledge of systemic effects and contraindications for all medications. Recall that:

• young patients usually are intolerant of miotic therapy secondary to visual blurring from induced myopia

• direct miotic agents are preferred over cholinesterase inhibitors in "phakic" patients (i.e., those patients who have their own crystalline lens) because the latter drugs can promote cataract formation

• in patients who have an increased risk of retinal detachment, miotics should be used with caution because 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)

The goal is to prevent progressive glaucomatous optic-nerve damage with minimum risk and side effects from either topical or systemic therapy. With these general principles in mind, a stepped medical approach may begin with a topical prostaglandin (PG) analog. Due to their once-daily dosing, low incidence of systemic side effects, and potent IOP-lowering effect, PG analogs have largely replaced β adrenergic–receptor antagonists as first-line medical therapy for glaucoma. The PG analogs consist of latanoprost (xalatan), travoprost (travatan, travatan z), and bimatoprost (lumigan, latisse). The chemical structure of latanoprost is shown below:

PGF_2α reduces IOP but has intolerable local side effects. Modifications to the chemical structure of PGF_2α have produced analogs with a more acceptable side-effect profile. In primates and humans, PGF_2α analogs appear to lower IOP by facilitating aqueous outflow through the accessory uveoscleral outflow pathway. The mechanism by which this occurs is unclear. PGF_2α and its analogs (prodrugs that are hydrolyzed to PGF_2α) bind to FP receptors that link to G_q11 and then to the PLC–IP₃–Ca²⁺ pathway. This pathway is active in isolated human ciliary muscle cells. Other cells in the eye also may express FP receptors. Theories of IOP lowering by PGF_2α range from altered ciliary muscle tension to effects on trabecular meshwork cells to release of matrix metalloproteinases and digestion of extracellular matrix materials that may impede outflow tracts. There also is less myocilin protein noted in monkey smooth muscle after PGF_2α treatment (Lindsey et al., 2001).

The β receptor antagonists now are the next most common topical medical treatment. There are two classes of topical β blockers. The nonselective ones bind to both β₁ and β₂ receptors and include timolol maleate and hemihydrate (hemihydrate is not available in the U.S.), levobunolol, metipranolol, and carteolol. There is one β₁-selective antagonist, betaxolol, available for ophthalmic use, but it is less efficacious than the nonselective β blockers because the β receptors of the eye are largely of the β₂ subtype. However, because the β₁ receptors are found preferentially in the heart while the β₂ receptors are found in the lung, betaxolol is less likely to cause breathing difficulty. In the eye, the targeted tissues are the ciliary body epithelium and blood vessels, where β₂ receptors account for 75-90% of the total population. How β blockade leads to decreased aqueous production and reduced IOP is uncertain. Production of aqueous humor seems to be activated by a β receptor–mediated cyclic AMP–PKA pathway; β blockade blunts adrenergic activation of this pathway by preventing catecholamine stimulation of the β receptor, thereby decreasing intracellular cyclic AMP. Another hypothesis is that β blockers decrease ocular blood flow, which decreases the ultrafiltration responsible for aqueous production (Juzych and Zimmerman, 1997).

When there are medical contraindications to the use of PG analogs or β receptor antagonists, other agents, such as a β₂ adrenergic– receptor agonist or topical carbonic anhydrase inhibitor (CAI), may be used as first-line therapy. The β₂ adrenergic agonists improve the pharmacological profile of the nonselective sympathomimetic agent epinephrine and its derivative, dipivefrin (propine, others). Epinephrine stimulates both α and β adrenergic receptors. The drug appears to decrease IOP by enhancing both conventional (via a β₂ receptor mechanism) and uveoscleral outflow (perhaps via PG production) from the eye. Although effective, epinephrine is poorly tolerated, principally due to localized irritation and hyperemia. Dipivefrin is an epinephrine prodrug that is converted into epinephrine by esterases in the cornea. It is much better tolerated but is still prone to cause epinephrine-like side effects (Fang and Kass, 1997). The β₂ adrenergic agonist clonidine is effective at reducing IOP but also readily crosses the blood-brain barrier and causes systemic hypotension; as a result, it no longer is used for glaucoma. In contrast, apraclonidine (iopidine) is a relatively selective β₂ adrenergic agonist that is highly ionized at physiological pH and therefore does not cross the blood-brain barrier. Brimonidine (alphagan, others) also is a selective α₂ adrenergic agonist but is lipophilic, enabling easy corneal penetration. Both apraclonidine and brimonidine reduce aqueous production and may enhance some uveoscleral outflow. Both appear to bind to pre- and postsynaptic α₂ receptors. By binding to the presynaptic receptors, the drugs reduce the amount of neurotransmitter release from sympathetic nerve stimulation and thereby lower IOP. By binding to postsynaptic α₂ receptors, these drugs stimulate the G_i pathway, reducing cellular cyclic AMP production, thereby reducing aqueous humor production (Juzych et al., 1997).

The development of a topical CAI took many years but was an important event because of the poor side-effect profile of oral CAIs. Dorzolamide (trusopt, others) and brinzolamide (azopt) both work by inhibiting carbonic anhydrase (isoenzyme II), which is found in the ciliary body epithelium. This reduces the formation of bicarbonate ions, which reduces fluid transport and, thus, IOP (Sharir, 1997).

Any of these four drug classes can be used as additive second- or third-line therapy. In fact, the β receptor antagonist timolol has been combined with the CAI dorzolamide (see the structure below) in a single medication (cosopt, others) and with the α₂ adrenergic agonist brimonidine (combigan).

Such combinations reduce the number of drops needed and may improve compliance. Other combination products involving PG analogs and β blockers are in development.

Topical miotic agents are historically important glaucoma medications but are less commonly used today. Miotics lower IOP by causing muscarinic-induced contraction of the ciliary muscle, which facilitates aqueous outflow. They do not affect aqueous production. Multiple miotic agents have been developed. Pilocarpine and carbachol are cholinomimetics that stimulate muscarinic receptors. Echothiophate (phospholine iodide) is an organophosphate inhibitor of acetylcholinesterase; it is relatively stable in aqueous solution and, by virtue of its quaternary ammonium structure, is positively charged and poorly absorbed. The usefulness of these medicines is lessened by their numerous side effects and the need to use them three to four times a day (Kaufman and Gabelt, 1997).

If combined topical therapy fails to achieve the target IOP or fails to halt glaucomatous optic nerve damage, then systemic therapy with CAI is a final medication option before resorting to laser or incisional surgical treatment. The best-tolerated oral preparation is acetazolamide in sustained-release capsules (see Chapter 25), followed by methazolamide. The least well tolerated are acetazolamide tablets.

Toxicity of Agents in the 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 IOP reduction, can cause a vasoconstriction–vasodilation rebound phenomenon leading to a red eye. Ocular and skin allergies from topical epinephrine, related prodrug formulations, apraclonidine, and brimonidine are common. Brimonidine is less likely to cause ocular allergy and therefore is more commonly used. These agents can cause CNS depression and apnea in neonates and are contraindicated in children <2 years of age.

Systemic absorption of epinephrine-related drugs and β adrenergic antagonists can induce all the side effects found with direct systemic administration. The use of CAIs systemically 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.

If posterior synechiae already have formed, an α adrenergic agonist may be used to break the synechiae by enhancing pupillary dilation. A solution containing scopolamine 0.3% in combination with 10% phenylephrine (murocoll-2) is available for this purpose. Two others, 1% hydroxyamphetamine hydrobromide combined with 0.25% tropicamide (paremyd) and 1% phenylephrine in combination with 0.2% cyclopentolate (cyclomydril) are only indicated for induction of mydriasis. Topical steroids usually are adequate to decrease inflammation, but sometimes they must be supplemented with systemic steroids.

An eye with hyperopia, or farsightedness, must constantly accommodate to focus on distant images. In some hyperopic children, the synkinetic accommodative-convergence response leads to excessive convergence and a manifest esotropia (turned-in eye). The brain rejects diplopia and suppresses the image from the deviated eye. If proper vision is not restored by ~7 years of age, the brain never learns to process visual information from that eye. The result is that the eye appears structurally normal but does not develop normal visual acuity and is therefore amblyopic. Unfortunately, this is a fairly common cause of visual disability. In this setting, atropine (1%) instilled in the preferred seeing eye produces cycloplegia and the inability of this eye to accommodate, thus forcing the child to use the amblyopic eye (Pediatric Eye Disease Investigator Group, 2002; Pediatric Eye Disease Investigator Group, 2003). Echothiophate iodide also has been used in the setting of accommodative strabismus. Accommodation drives the near reflex, the triad of miosis, accommodation, and convergence. An irreversible 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.

Intraoperatively, there are circumstances in which miosis is preferred, and two cholinergic agonists are available for intraocular use, acetylcholine (miochol-e) 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 10). For surgical visualization of the lens, trypan blue (visionblue) is marketed to facilitate visualization of the lens and for staining during surgical vitrectomy procedures to guide the excision of tissue (membraneblue).

Therapeutic Uses. Currently, the glucocorticoids formulated for topical administration to the eye are dexamethasone (dexasol, others), prednisolone (pred forte, others), fluorometholone (fml, others), loteprednol (alrex, lotemax), rimexolone (vexol), and difluprednate (durezol). Because of their anti-inflammatory effects, topical corticosteroids are used in managing significant ocular allergy, anterior uveitis, external eye inflammatory diseases associated with some infections and ocular cicatricial pemphigoid, and postoperative inflammation following refractive, corneal, and intraocular surgery. After glaucoma filtering surgery, topical steroids can delay the wound-healing process by decreasing fibroblast infiltration, thereby reducing potential scarring of the surgical site (Araujo et al., 1995). Steroids commonly are given systemically and by sub-Tenon's capsule injection to manage posterior uveitis. Intravitreal injection of steroids now is being used to treat a variety of retinal conditions including age-related macular degeneration (ARMD), diabetic retinopathy, and cystoid macular edema. Two intravitreal triamcinolone formulations, trivaris and triesence, are approved for ocular inflammatory conditions unresponsive to topical corticosteroids and visualization during vitrectomy, respectively. Parenteral steroids followed by tapering oral doses is the preferred treatment for optic neuritis (Kaufman et al., 2000; Trobe et al., 1999). An ophthalmic implant of fluocinolone (retisert) is marketed for the treatment of chronic, non-infectious uveitis.

Toxicity of Steroids. Steroid drops, pills, and creams are associated with ocular problems, as are intravitreal and intravenous steroids. Ocular complications include the development of posterior subcapsular cataracts, secondary infections (see Chapter 42), and secondary open-angle glaucoma (Becker and Mills, 1963). There is a significant increase in the risk for developing secondary glaucoma when there is a positive family history of glaucoma. In the absence of a family history of open-angle glaucoma, only ~5% of normal individuals respond to topical or long-term systemic steroids with a marked increase in IOP. With a positive family history, however, moderate to marked steroid-induced IOP elevations may occur 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 IOP is reversible once administration of the steroid ceases. However, intraocular or sub-Tenon's steroid-related pressure elevation may persist for months and may require treatment with glaucoma medication or even filtering surgery. Newer topical steroids, so-called "soft steroids" (e.g., loteprednol), have been developed that reduce, but do not eliminate, the risk of elevated IOP.

Therapeutic Uses. Currently, there are five topical NSAIDs (see Chapter 34) approved for ocular use: flurbiprofen (ocufen, others), ketorolac (acular, others), diclofenac (voltaren, others), bromfenac (xibrom), and nepafenac (nevanac). Flurbiprofen is 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., 1999; Almeida et al., 2008) and diclofenac (Asano et al., 2008) have been found to be effective in treating cystoid macular edema occurring after cataract surgery. Bromfenac and nepafenac are indicated for treating postoperative pain and inflammation after cataract surgery. In patients treated with PG analogs such as latanoprost or bimatoprost, ketorolac and diclofenac may help decrease postoperative inflammation. They also are useful in decreasing pain after corneal refractive surgery. Topical and systemic NSAIDs occasionally have been associated with sterile corneal melts and perforations, especially in older patients with ocular surface disease, such as dry eye syndrome.

Therapeutic Uses. In glaucoma surgery, both fluorouracil and mitomycin (mutamycin), which also are anti-neoplastic agents (see Chapter 61), improve the success of filtration surgery by limiting the postoperative wound-healing process. Mitomycin is used intraoperatively as a single subconjunctival application at the trabeculectomy site. Meticulous care is used to avoid intraocular penetration, because mitomycin is extremely toxic to intraocular structures. Fluorouracil may be used intraoperatively at the trabeculectomy site and/or subconjunctivally during the postoperative course (Fluorouracil Filtering Surgery Study Group, 1989). Although both agents work by limiting the healing process, sometimes this can result in thin, ischemic, avascular tissue that is prone to breakdown. The resultant leaks can cause hypotony (low IOP) and increase the risk of infection.

In corneal surgery, mitomycin has been used topically after excision of pterygium, a fibrovascular membrane that can grow onto the cornea. Mitomycin can be used to reduce the risk of scarring after certain procedures to remove corneal opacities and also prophylactically to prevent corneal scarring after excimer laser surface ablation (photorefractive and phototherapeutic keratectomy). Mitomycin also is used to treat certain conjunctival and corneal tumors. Interferon α-2b has been used in the treatment of conjunctival papilloma and certain conjunctival tumors. Although the use of mitomycin for both corneal surgery and glaucoma filtration surgeries augments the success of these surgical procedures, caution is advocated in light of the potentially serious delayed ocular complications (Rubinfeld et al., 1992; Hardten and Samuelson, 1999; Bahar et al., 2009).

Intraocular methotrexate (see Chapter 61) is used to treat uveitis and uveitic cystoid macular edema. It also has been used to treat the uncommon complication of lymphoma in the vitreous, which is an inaccessible compartment for most anti-neoplastic drugs (Taylor et al., 2009).

The liquid perfluorocarbons, with specific gravities between 1.76 and 1.94, are denser than vitreous and are helpful in flattening the retina when vitreous is present. Silicone oil (polydimethylsiloxanes; adatosil 5000) has had extensive use in both Europe and the U.S. for long-term tamponade of the retina. Complications from silicone oil use include glaucoma, cataract formation, corneal edema, corneal band keratopathy, and retinal toxicity.

Topical aminocaproic acid (caprogel) has been investigated to prevent rebleeding after traumatic hyphema (blood in the anterior chamber), but clinical trials report mixed success, and the drug is not marketed in the U.S. (Karkhaneh et al., 2003; Pieramici et al., 2003).

Depending on the intraocular location of a clot, there may be significant problems relating to IOP, retinal degeneration, and persistent poor vision. Recombinant tissue plasminogen activator (t-PA; alteplase) (Chapter 30) has been used during intraocular surgeries to assist evacuation of a hyphema, subretinal clot, or nonclearing vitreous hemorrhage. Alteplase also has been administered subconjunctivally and intracamerally (i.e., controlled intraocular administration into the anterior segment) to lyse blood clots obstructing a glaucoma filtration site. The main complication related to the use of t-PA is bleeding.

The variability in duration of paralysis may be related to the rate of developing antibodies to the toxin, upregulation of nicotinic cholinergic postsynaptic receptors, and aberrant regeneration of motor nerve fibers at the neuromuscular junction. Complications related to this toxin include double vision (diplopia) and lid droop (ptosis) and potentially life-threatening distant spread of toxin effect from the injection site (asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties) within hours to weeks after administration.

Glaucoma. The anti-seizure drug topiramate (topamax, others) frequently has been reported to cause choroidal effusions, thereby anteriorly rotating the ciliary body and causing an angle-closure glaucoma (Banta et al., 2001).

Retina. Numerous drugs have toxic side effects on the retina. The anti-arthritis and antimalarial medicines hydroxychloroquine (plaquenil, others) and chloroquine can cause a central retinal toxicity by an unknown mechanism. With normal dosages, toxicity does not appear until ~6 years after the drug is started. Stopping the drug will not reverse the damage but will prevent further toxicity (Tehrani et al., 2008). Tamoxifen is known to cause a crystalline maculopathy. The anti-seizure drug vigabatrin (sabril) causes progressive and permanent bilateral concentric visual field constriction in a high percentage of patients. The mechanism is not known, but vigabatrin is more effectively transported into the retina than into the brain, and consequently, elevations of retinal GABA concentrations may contribute to the vision loss.

Optic Nerve. The three phosphodiesterase (PDE) inhibitors, sildenafil (viagra, revatio), vardenafil (levitra), and tadalafil (cialis, adcirca), inhibit PDE5 in the corpus cavernosum to help achieve and maintain penile erection. The drug also mildly inhibits PDE6, which controls the levels of cyclic GMP in the retina. Visually, this can result in seeing a bluish haze or experiencing light sensitivity. There have been several reports of nonarteritic ischemic optic neuropathy (NAION) in patients using these drugs. Despite these reports, there is little conclusive evidence that these drugs caused this problem, but patients should stop using the medications if they experience visual problems (Laties, 2009). Multiple medications can cause a toxic optic neuropathy characterized by gradually progressive bilateral central scotomas and vision loss. There can be accompanying optic nerve pallor. These medicines include ethambutol, chloramphenicol, and rifampin (Lloyd and Fraunfelder, 2007). Systemic or ocular steroids can cause elevated IOP and glaucoma. If the steroids cannot be stopped, glaucoma medications, and even filtering surgery, often are required.

Anterior Segment. Steroids also have been implicated in cataract formation. If vision is reduced, cataract surgery may be necessary. Rifabutin, if used in conjunction with clarithromycin or fluconazole for treatment of Mycobacterium avium complex (MAC) opportunistic infections in human immunodeficiency virus (HIV)-positive persons, is associated with an iridocyclitis and even hypopyon. This will resolve with steroids or by stopping the medication.

Ocular Surface. Isotretinoin (accutane, others) has a drying effect on mucous membranes and is associated with dry eye and meibomian gland dysfunction.

Cornea Coryanghiva and Eyclids. The cornea, the conjunctiva, and even the eyelids can be affected by systemic medications. One of the most common drug deposits found in the cornea is from the cardiac medication amiodarone. It deposits in the inferior and central cornea in a whorl-like pattern termed cornea verticillata. It appears as fine tan or brown pigment in the epithelium. Fortunately, the deposits seldom affect vision, and therefore, this rarely is a cause to discontinue the medication. The deposits disappear slowly if the medication is stopped. Other medications, including indomethacin, atovaquone, chloroquine, and hydroxychloroquine, can cause a similar pattern.

The phenothiazines, including chlorpromazine and thioridazine, can cause brown pigmentary deposits in the cornea, conjunctiva, and eyelids. The deposits generally are found in Descemet's membrane and the posterior cornea. They typically do not affect vision. The ocular deposits generally persist after discontinuation of the medication and can even worsen, perhaps because the medication deposits in the skin are slowly released and accumulate in the eye.

Gold treatments for arthritis (now rarely used) can lead to gold deposition in the cornea and conjunctiva, which are termed chrysiasis and are gold to violet in color. With lower cumulative doses (1-2 g), the deposits are found primarily in the epithelium and anterior stroma. These deposits usually disappear with discontinuation of the medication. With higher doses, the gold is deposited in Descemet's membrane and posterior stroma and can involve the entire stroma. These changes can be permanent. The deposits generally do not affect vision and are not a reason to stop gold therapy.

Tetracyclines can cause a yellow discoloration of the light-exposed conjunctiva. Systemic minocycline can induce a blue-gray scleral pigmentation that is most prominent in the interpalpebral zone (Morrow and Abbott, 1998).

Anterior Segment and External Diagnostic Uses. Epiphora (excessive tearing) and surface problems of the cornea and conjunctiva are commonly encountered external ocular disorders. The dyes fluorescein, rose bengal, and lissamine green are used in evaluating these problems. Available as a 2% alkaline solution, 10% and 25% solutions for injection, and an impregnated paper strip, fluorescein reveals epithelial defects of the cornea and conjunctiva and aqueous humor leakage that may occur after trauma or ocular surgery. In the setting of epiphora, fluorescein is used to help determine the patency of the nasolacrimal system. In addition, this dye is used as part of the procedure of applanation tonometry (IOP measurement) and to assist in determining the proper fit of rigid and semirigid contact lenses. Fluorescein in combination with proparacaine or benoxinate is available for procedures in which a disclosing agent is needed in conjunction with a topical anesthetic. Fluorexon (fluoresoft), a high-molecular-weight fluorescent solution, is used when fluorescein is contraindicated (as when soft contact lenses are in place).

Rose bengal and lissamine green, available as saturated paper strips, stain devitalized tissue on the cornea and conjunctiva.

Posterior Segment Diagnostic Uses. The integrity of the blood-retinal and retinal pigment epithelial barriers may be examined directly by retinal angiography using intravenous administration of either fluorescein sodium or indocyanine green. These agents commonly cause nausea and may precipitate serious allergic reactions in susceptible individuals.

Pegaptanib (0.3 mg) is administered once every 6 weeks by intravitreous injection into the eye to be treated. Side effects are largely related to the injection. Following the injection, patients should be monitored for elevation in IOP and for endophthalmitis. Rare cases of anaphylaxis/anaphylactoid reactions have been reported. No special dosage modification is required for any of the populations that have been studied (i.e., gender, elderly).

In the eye, several diseases that involve neovascularization such as proliferative diabetic retinopathy, macular edema, retinopathy of prematurity (Hubbard, 2008), ARMD (Patel et al., 2008), and neovascular glaucoma have been treated off label with bevacizumab, while ranibizumab generally has been reserved for both classic (Brown et al., 2009) and occult (Chang et al., 2007) choroidal neovascular membranes associated with ARMD. Both drugs are delivered by intravitreal injection and often are used on a weekly or monthly basis for maintenance therapy. Aside from the risks of hemorrhage and infection from intravitreal injections, both drugs have been associated with the risk of cerebral vascular accidents (Dafer et al., 2007; Shima et al., 2008). A multicenter clinical trial evaluating the effectiveness of the two medications for treating ARMD is currently under way.

Lidocaine and bupivacaine are used for infiltration and retrobulbar block anesthesia for surgery. Potential complications and risks relate to allergic reactions, globe perforation, hemorrhage, and vascular and subdural injections. Both preservative-free lidocaine (1%), which is introduced into the anterior chamber, and lidocaine jelly (2%), which is placed on the ocular surface during preoperative patient preparation, are used for cataract surgery performed under topical anesthesia. This form of anesthesia eliminates the risks of the anesthetic injection and allows for more rapid visual recovery after surgery. General anesthetics and sedation are important adjuncts for patient care for surgery and examination of the eye, especially in children and uncooperative adults. Most inhalational agents and CNS depressants are associated with a reduction in IOP. An exception is ketamine, which has been associated with an elevation in IOP. In the setting of a patient with a ruptured globe, the anesthesia should be selected carefully to avoid agents that depolarize the extraocular muscles, which may result in expulsion of intraocular contents.

Other Agents for Ophthalmic Therapy.

Vitamins and Trace Elements.

General Considerations. Table 64–9 summarizes the current understanding of vitamins related to eye function and disease, especially the biochemistry of vitamin A.

Although vitamin A must be supplied from the environment, most actions of vitamin A, like those of vitamin D, are exerted through hormone-like receptors. Vitamin A has diverse actions in cellular regulation and differentiation that go far beyond its classically defined function in vision. Analogs of vitamin A, because of their prominent effects on epithelial differentiation, have found important therapeutic applications in the treatment of a variety of dermatological conditions and are being evaluated in cancer chemoprevention.

History. The relationship of night blindness to nutritional deficiency was definitively recognized in the 1800s. Ophthalmia brasiliana (keratomalacia), a disease of the eyes that afflicted primarily poorly nourished slaves, was first described in 1865. Later, it was observed that the nurslings of mothers who fasted were prone to develop spontaneous sloughing of the cornea. Other reports of nutritional keratomalacia soon followed from all parts of the world.

Experimental rather than clinical observations, however, led to the discovery of vitamin A. In 1913, McCollum and Davis, and Osborne and Mendel independently reported that animals fed artificial diets with lard as the sole source of fat developed a nutritional deficiency that could be corrected by the addition to the diet of a factor contained in butter, egg yolk, and cod liver oil. An outstanding symptom of this experimental nutritional deficiency was xerophthalmia (dryness and thickening of the conjunctiva). Clinical and experimental vitamin A deficiencies were recognized to be related during World War I, when it became apparent that xerophthalmia in humans was a result of a decrease in the amount of butterfat in the diet.

Chemistry and Terminology. Retinoid refers to the chemical entity retinol and other closely related naturally occurring derivatives. Retinoids, which exert most of their effects by binding to specific nuclear receptors and modulating gene expression, also include structurally related synthetic analogs that need not have retinol-like (vitamin A) activity (Evans and Kaye, 1999).

The purified plant pigment carotene (provitamin A) is a remarkably potent source of vitamin A. β-Carotene, the most active carotenoid found in plants, has the structural formula shown in Figure 64–7A. The structural formulas for the vitamin A family of retinoids are shown in Figure 64–7B.

Retinol, a primary alcohol, is present in esterified form in the tissues of animals and saltwater fish, mainly in the liver.

A number of cis-trans isomers exist because of the unsaturated carbons in the retinol side chain. Fish liver oils contain mixtures of the stereoisomers; synthetic retinol is the all-trans isomer. Interconversion between isomers readily takes place in the body. In the visual cycle, the reaction between retinal (vitamin A aldehyde) and opsin to form rhodopsin occurs only with the 11-cis isomer. Ethers and esters derived from the alcohol also show activity in vivo. The ring structure of retinol (β-ionone), or the more unsaturated ring in 3-dehydroretinol (dehydro-β-ionone), is essential for activity; hydrogenation destroys biological activity. Of all known derivatives, all-trans-retinol and its aldehyde, retinal, exhibit the greatest biological potency in vivo; 3-dehydroretinol has ~40% of the potency of all-trans-retinol.

Retinoic acid, in which the alcohol moiety has been oxidized, shares some but not all of the actions of retinol. Retinoic acid is ineffective in restoring visual or reproductive function in certain species in which retinol is effective. However, retinoic acid is very potent in promoting growth and controlling differentiation and maintenance of epithelial tissue in vitamin A–deficient animals. Indeed, all-trans-retinoic acid (tretinoin) appears to be the active form of vitamin A in all tissues except the retina, and is 10- to 100-fold more potent than retinol in various systems in vitro. Isomerization of this compound in the body yields 13-cis-retinoic acid (isotretinoin), which is nearly as potent as tretinoin in many of its actions on epithelial tissues but may be only one-fifth as potent in producing the toxic symptoms of hypervitaminosis A. Retinoic acid analogs used clinically are discussed in detail in Chapter 65.

Physiological Functions and Pharmacological Actions. Vitamin A plays an essential role in the function of the retina, is necessary for growth and differentiation of epithelial tissue, and is required for growth of bone, reproduction, and embryonic development. Together with certain carotenoids, vitamin A enhances immune function, reduces the consequences of some infectious diseases, and may protect against the development of certain malignancies. As a result, there is considerable interest in the pharmacological use of retinoids for cancer prophylaxis and for treating various premalignant conditions. Because of the effects of vitamin A on epithelial tissues, retinoids and their analogs are used to treat a number of skin diseases, including some of the consequences of aging and prolonged exposure to the sun (see Chapter 65).

The functions of vitamin A are mediated by different forms of the molecule. In vision, the functional vitamin is retinal. Retinoic acid appears to be the active form in functions associated with growth, differentiation, and transformation.

Retinal and the Visual Cycle. Vitamin A deficiency interferes with vision in dim light, a condition known as night blindness (nyctalopia).

Photoreception is accomplished by two types of specialized retinal cells, termed rods and cones. Rods are especially sensitive to light of low intensity; cones act as receptors of high-intensity light and are responsible for color vision. The initial step is the absorption of light by a chromophore attached to the receptor protein. The chromophore of both rods and cones is 11-cis-retinal. The holoreceptor in rods is termed rhodopsin—a combination of the protein opsin and 11-cis-retinal attached as a prosthetic group. The three different types of cone cells (red, green, and blue) contain individual, related photoreceptor proteins and respond optimally to light of different wavelengths.

In the synthesis of rhodopsin, 11-cis-retinol is converted to 11-cis-retinal in a reversible reaction that requires pyridine nucleotides. 11-cis-Retinal then combines with the ∊ amino group of a specific lysine residue in opsin to form rhodopsin. Most rhodopsin is located in the membranes of the discs situated in the outer segments of the rods. The protein has seven membrane-spanning domains, a characteristic shared by all receptors whose functions are transduced via G proteins.

The visual cycle (Figure 64–8) is initiated by the absorption of a photon of light, leading to the isomerization of 11-cis-retinal to the all-trans form covalently bound to rhodopsin, a G protein–coupled receptor (GPCR). Activated rhodopsin interacts with the heterotrimeric G protein transducin (G_t), initiating GDP–GTP exchange and formation of the activated α_t-GTP subunit. α_t-GTP binds to and activates a cyclic GMP phosphodiesterase, PDE6, resulting in a rapid drop in the local concentration of cyclic GMP. The decline in cyclic GMP permits dissociation of cyclic GMP from open cyclic GMP–gated ion channels (open in the dark), causing channel closure and hyperpolarization. This is followed by a stimulation of GC (guanylyl cyclase) activity, re-opening of the ion channel, and restoration of initial cellular Ca²⁺. A series of reactions involving rhodopsin kinase, arrestin, recoverin, and the GTPase activity of α_t-GTP also help to restore the system to the ground state, with re-formation of the heterotrimeric form of G_t-GDP (Cote, 2007).

Vitamin A Deficiency and Vision. Humans deficient in vitamin A lose their ability for dark adaptation. Rod vision is affected more than cone vision. Upon depletion of retinol from liver and blood, usually at plasma concentrations of retinol of <0.2 mg/L (0.70 μM), the concentrations of retinol and rhodopsin in the retina fall. Unless the deficiency is overcome, opsin, lacking the stabilizing effect of retinal, decays, and anatomical deterioration of the rod outer segment occurs. In rats maintained on a vitamin A–deficient diet, irreversible ultrastructural changes leading to blindness then supervene, a process that takes ~10 months.

Following short-term deprivation of vitamin A, dark adaptation can be restored to normal by the addition of retinol to the diet. However, vision does not return to normal for several weeks after adequate amounts of retinol have been supplied. The reason for this delay is unknown.

Vitamin A and Epithelial Structures. The functional and structural integrity of epithelial cells throughout the body is dependent on an adequate supply of vitamin A. The vitamin plays a major role in the induction and control of epithelial differentiation in mucus-secreting or keratinizing tissues. In the presence of retinol or retinoic acid, basal epithelial cells are stimulated to produce mucus. Excessive concentrations of the retinoids lead to the production of a thick layer of mucin, the inhibition of keratinization, and the display of goblet cells.

In the absence of vitamin A, goblet mucous cells disappear and are replaced by basal cells that have been stimulated to proliferate. These undermine and replace the original epithelium with a stratified, keratinizing epithelium. The suppression of normal secretions leads to irritation and infection. Reversal of these changes is achieved by the administration of retinol, retinoic acid, or other retinoids. When this process happens in the cornea, severe hyperkeratinization (xerophthalmia) may lead to permanent blindness. Common causes of vitamin A deficiency include malnutrition and bariatric surgery. Worldwide, xerophthalmia remains one of the most common causes of blindness.

Mechanism of Action. In isolated fibroblasts or epithelial tissue, retinoids enhance the synthesis of some proteins (e.g., fibronectin) and reduce the synthesis of others (e.g., collagenase, certain species of keratin), and molecular evidence suggests that these actions can be entirely accounted for by changes in nuclear transcription (Mangelsdorf et al., 1994). Retinoic acid appears to be considerably more potent than retinol in mediating these effects.

Retinoic acid influences gene expression by combining with nuclear receptors. Multiple retinoid receptors have been described. These are grouped into two families. One family, the retinoic acid receptors (RARs), designated α, β, and γ, are derived from genes localized to human chromosomes 17, 3, and 12, respectively. The second family, the retinoid X receptors (RXRs), also is composed of α, β, and γ receptor isoforms (Chambon, 1995). The retinoid receptors show extensive sequence homology to each other in both their DNA and hormone-binding domains and belong to a receptor superfamily that includes receptors for steroid and thyroid hormones and calcitriol (Mangelsdorf et al., 1994). Cellular responses to thyroid hormones, calcitriol, and retinoic acid are enhanced by the presence of RXR. Gene activation involves binding of the hormone-receptor complex to promoter elements in target genes, followed by dimerization with an RXR-ligand complex. The endogenous RXR ligand is 9-cis-retinoic acid (Heyman et al., 1992; Levin et al., 1992). No comparable receptor for retinol has been identified; retinol may need to be oxidized to retinoic acid to produce its effects within target cells.

Retinoids can influence the expression of receptors for certain hormones and growth factors and thus can influence the growth, differentiation, and function of target cells by both direct and indirect actions (Love and Gudas, 1994).

Therapeutic Uses. Nutritional vitamin A deficiency causes xerophthalmia, a progressive disease characterized by nyctalopia (night blindness), xerosis (dryness), and keratomalacia (corneal thinning), which may lead to corneal perforation; xerophthalmia may be reversed with vitamin A therapy (WHO/UNICEF/IVAGG Task Force, 1988). However, rapid, irreversible blindness ensues once the cornea perforates. Vitamin A also is involved in epithelial differentiation and may have some role in corneal epithelial wound healing. Currently, there is no evidence to support using topical vitamin A for keratoconjunctivitis sicca in the absence of a nutritional deficiency. The current recommendation for retinitis pigmentosa is to administer 15,000 IU of vitamin A palmitate daily under the supervision of an ophthalmologist and to avoid high-dose vitamin E.

The Age-Related Eye Disease Study (AREDS) found a reduction in the risk of progression of some types of ARMD for those randomized to receive high doses of vitamins C (500 mg), E (400 IU), β-carotene (15 mg), cupric oxide (2 mg), and zinc (80 mg) (Age-Related Eye Disease Study Research Group, 2001). Interestingly, zinc has been found to be neuroprotective in a rat model of glaucoma. The mechanism appears to be mediated by heat shock proteins and may represent a novel treatment strategy for glaucoma (Park et al., 2001).

Wetting Agents and Tear Substitutes.

General Considerations. The current management of dry eyes usually includes instilling artificial tears and ophthalmic lubricants. In general, tear substitutes are hypotonic or isotonic solutions composed of electrolytes, surfactants, preservatives, and some viscosity-increasing agent that prolongs the residence time in the cul-de-sac and precorneal tear film. Common viscosity agents include cellulose polymers (e.g., carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose [hypromellose], and methylcellulose), polyvinyl alcohol, polyethylene glycol, polysorbate, mineral oil, glycerin, and dextran. The tear substitutes are available as preservative-containing or preservative-free preparations. The viscosity of the tear substitute depends on its exact formulation and can range from watery to gel like. Some tear formulations also are combined with a vasoconstrictor, such as naphazoline, phenylephrine, or tetrahydrozoline. Tyloxapol (enuclene) is marketed as an over-the-counter ophthalmic preparation used to facilitate the wearing comfort of artificial eyes.

The lubricating ointments are composed of a mixture of white petrolatum, mineral oil, liquid or alcohol lanolin, and sometimes a preservative. These highly viscous formulations cause considerable blurring of vision, and consequently, they are used primarily at bedtime, in critically ill patients, or in very severe dry eye conditions. A hydroxypropyl cellulose ophthalmic insert (lacrisert) that is placed in the inferior cul-de-sac and dissolves during the day is available to treat dry eyes.

Such aqueous, ointment, and insert formulations are only fair substitutes for the precorneal tear film, which truly is a poorly understood lipid, aqueous, and mucin trilaminar barrier (see "Absorption").

Therapeutic Uses. Many local eye conditions and systemic diseases may affect the precorneal tear film. Local eye disease, such as blepharitis, ocular rosacea, ocular pemphigoid, chemical burns, or corneal dystrophies, may alter the ocular surface and change the tear composition. Appropriate treatment of the symptomatic dry eye includes treating the accompanying disease and possibly the addition of tear substitutes, punctal plugs (see "Absorption"), or ophthalmic cyclosporine (see "Immunomodulatory Agent"). There also are a number of systemic conditions that may manifest themselves with symptomatic dry eyes, including Sjögren's syndrome, rheumatoid arthritis, vitamin A deficiency, Stevens-Johnson syndrome, and trachoma. Treating the systemic disease may not eliminate the symptomatic dry eye complaints; chronic therapy with tear substitutes, ophthalmic cyclosporine, insertion of punctal plugs, placement of dissolvable collagen implants, or surgical occlusion of the lacrimal drainage system may be indicated. Ophthalmic cyclosporine (restasis) can be used to increase tear production in patients with ocular inflammation associated with keratoconjunctivitis sicca.

Osmotic Agents.

General Considerations. The main osmotic drugs for ocular use include glycerin, mannitol, and hypertonic saline. With the availability of these agents, the use of urea for management of acutely elevated IOP is nearly obsolete.

Therapeutic Uses. Ophthalmologists occasionally use glycerin and mannitol for short-term management of acute rises in IOP. Sporadically, these agents are used intraoperatively to dehydrate the vitreous prior to anterior segment surgical procedures. Many patients with acute glaucoma do not tolerate oral medications because of nausea; therefore, intravenous administration of mannitol and/or acetazolamide may be preferred over oral administration of glycerin. These agents should be used with caution in patients with congestive heart failure or renal failure.

Corneal edema is a clinical sign of corneal endothelial dysfunction, and topical osmotic agents may effectively dehydrate the cornea. Identifying the cause of corneal edema will guide therapy, and topical osmotic agents, such as hypertonic saline, may temporize the need for surgical intervention in the form of a corneal transplant. Sodium chloride is available in either aqueous or ointment formulations. Topical glycerin also is available; however, because it causes pain on contact with the cornea and conjunctiva, its use is limited to urgent evaluation of filtration-angle structures. In general, when corneal edema occurs secondary to acute glaucoma, the use of an oral osmotic agent to help reduce IOP is preferred over topical glycerin, which simply clears the cornea temporarily. Reducing the IOP will help clear the cornea more permanently to allow both a view of the filtration angle by gonioscopy and a clear view of the iris as required to perform laser iridotomy.