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

Figure 1-7 The patient’s head is tilted back,the dropper tip is aimed downward, and the bottle tip is directly above the eye. At this point the patient is ready to squeeze the bottle. (From Ritch R, et al. An improved technique of eyedrop selfadministration for patients with limited vision. Am J Ophthalmol 2003;135:531–532.)

drug. These patients should also be able to use the telephone to contact their prescribing practitioner and dispensing pharmacy. Magnifiers, large-print telephone numerals, or other visual or nonoptical aids may be required and should be recommended when needed.

Patients Who Cannot Swallow Pills

Some adults, as well as most young children, have difficulty swallowing medications formulated as standard pills (tablets and capsules).When oral medications are needed, drug therapy can be more efficient, and patient compliance improved, by prescribing medications formulated as chewable tablets, solutions, or suspensions, which are usually flavored to improve taste and are easily swallowed.

Figure 1-8 Large stick-on numerals, such as those used on office charts, can indicate dosage frequency for medications used by visually impaired patients.

Most therapeutic categories of medications used for ophthalmic purposes contain such drug formulations, and these are easily administered by mouth using a teaspoon or various modifications designed for pediatric use.

Though patients vary greatly in their particular history and clinical presentation, the clinician will find that successful pharmacotherapy requires certain constant attributes: knowledge of pharmacologic mechanisms and the disease process, mastery of the art of tailored patient education and effective communication, and attention to economics and resources within the health care system. As the body of evidence-based medicine expands and new drugs are continually introduced, the clinician should anticipate applying lifelong research skills to maintain contemporary standards of patient management.

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Drugs affect ocular tissues on the basis of special pharmacokinetic properties of the eye. Pharmacokinetics is the study of the time course of absorption, distribution, metabolism, and elimination of an administered drug. Drug absorption depends on the molecular properties of the drug, the viscosity of its vehicle, and the functional status of the tissue forming the barrier to penetration. Drug distribution over time and bioavailability at the desired site of action can usually be predicted by the interrelationships of the compartments and barriers of the eye. Metabolism plays an important part in eliminating drugs and their sometimes toxic byproducts from the eye and from the body. Metabolic enzymes have recently been studied to assist in the design of prodrugs, which are molecules that are converted to an active form after tissue penetration has occurred. The other end of the spectrum includes the use of compounds that, in the eye, predictably undergo transformation by enzymes to an inactive form associated with fewer side effects than those associated with the parent form.

OCULAR TISSUE STRUCTURE AND PHARMACOKINETICS

The eye is composed of numerous tissues, each of distinct developmental origin and each with a specific role in the functioning visual system. These tissues include the smooth and striate musculature, a variety of simple and mucoid epithelia, connective tissues, sympathetic and parasympathetic nerves, and the retina.

The organization of the eye must provide a path for light through the clear tissues that form the optical imaging system while providing for the nutrition of those same tissues in the absence of a blood supply. This avascularity allows a direct route for ocular drug penetration without absorption by the systemic circulation.

Tear Structure and Chemical Properties

The tear film covering the cornea and defining the major optical surface of the eye is composed of three layers

(Figure 2-1). The outermost, oily layer is usually considered to be a lipid monolayer and is produced primarily by the meibomian glands located in the eyelids.The primary function of the oily layer is to stabilize the surface of the underlying aqueous fluid layer and to retard evaporation. Tear surface lipids are readily washed away if the eye is flushed with saline or medication, resulting in a more than 10-fold tear evaporation increase. Minor infections of the meibomian glands, particularly with staphylococci, can also decrease tear film stability due to an alteration of the chemical nature of meibum, the secretion product of the gland.

The aqueous phase of the tears comprises more than 95% of the total volume and covers the cornea with a layer that averages approximately 7 mm thick. This layer is inherently unstable, however, and begins to thin centrally at the end of each blink.The tear film in healthy subjects has a breakup time that averages between 25 and 30 seconds.

The inner, or basal, layer of the tears is composed of glycoproteins and is secreted by goblet cells in the conjunctiva. This mucinous layer is a thin hydrophilic coating (Figure 2-2A) covering the cornea and conjunctiva and, at higher magnification, is seen as thick rolls and strands (Figure 2-2B) that cleanse the tears of particulate debris at each blink.

The pH of the tears is approximately 7.4, and the tear layer contains small amounts of protein, including lysozymes, lactoferrins, gamma globulins, and other immune factors. The tears are primarily responsible for supplying the oxygen requirements of the corneal epithelium.

Tear Volume

The normal volume of the tear layer is 8 to 10 mcl, including the fluid trapped in the folds of the conjunctiva. A total volume of perhaps 30 mcl can be held for a brief time if the eyelids are not squeezed after dosing.When a single drop of medication of 50 mcl (0.05 ml) is applied, the nasolacrimal duct rapidly drains the excess, although some may be blinked out of the eye onto the lid.

Increasing drop size, therefore, does not result in penetration of more medication into the cornea. However, the systemic load is increased linearly with drop size, because after drainage through the nasolacrimal duct, the drug is usually absorbed through the nasal mucosa or is swallowed. For drugs with major systemic side effects, such as β-blockers, efforts have been made to limit drop size. Careful supervision during initial dosing and monitoring of patient compliance is important.

It is difficult to limit the volume of a drop dispensed by gravity from a dropper tip below approximately 25 mcl, three times the normal tear reservoir.The proposed theoretic optimum volume of drug solution to deliver is zero volume, because increasing the instilled volume increases the volume lost and the percentage of drug lost.Although achieving this theoretic extreme is impossible, it is practical to dispense accurately measured drops as small as 2 to 5 mcl by reducing the bore size of commercial dropper dispensers. Small drop volumes can also be dispensed from a micrometer syringe by touching a flexible polyethylene tip to the conjunctiva. For investigational purposes, this allows instillation of drugs without greatly affecting size of the tear reservoir.

Tear Flow

The normal rate of basal (unstimulated) tear flow in humans is approximately 0.5 to 2.2 mcl/min and decreases with age. Tear flow rate is stimulated by the ocular irritation resulting from many topical medications. The concentration of drug available in the tears for

transcorneal absorption is inversely proportional to the tear flow, due to the drug’s dilution and removal by the nasolacrimal duct and by eyelid spillover.Therefore both the flow rate and the tear volume influence drug absorption by the anterior segment of the eye.

To enhance corneal drug absorption, the tear film concentration can be prolonged by manually blocking the nasolacrimal ducts or by tilting the head back to reduce drainage (see Chapter 3). Another effective technique to increase corneal penetration is to administer a series of ophthalmic solutions at intervals of approximately 10 minutes. It has been determined, however, that when different drug formulations are given as drops in rapid succession, the medications first applied are diluted and do not achieve full therapeutic potential.

Patients with a flow rate near the lower limit of 0.5 mcl/min, often due to aging or atrophy of the lacrimal ducts and glands, are usually considered to have dry eye (keratoconjunctivitis sicca). This patient group includes many elderly patients, individuals with rheumatoid arthritis, some periand postmenopausal women, and persons with exposure keratitis associated with dry climate or dusty work conditions. Several factors contribute to greatly increased drug absorption in these individuals. Their total tear volume is less than normal, so that a drop of medication is not diluted as much as usual. Because lacrimation is reduced, the drug is not rapidly diluted by tears and has a prolonged residence time next to the corneal surface, where the bulk of absorption occurs. Because epithelial surface damage is usually present in

A

B

Figure 2-2 The conjunctiva shown by scanning electron microscopy with surface mucins intact (A). On higher magnification, note the strands (B) that allow the mucins to entrap particles and remove them from the tears. The tears form a reservoir for drug compounds, including those that are delivered as particulate suspensions. (Reprinted with permission from Burstein NL. The effects of topical drugs and preservatives on the tears and corneal epithelium in dry eye.Trans Ophthalmol Soc U K 1985;104:402–409.)

patients with dry eye, the final result is greatly increased ocular absorption.

Drugs (e.g., pilocarpine) that cause rapid lacrimation by stinging or by stimulation of lacrimal glands in normal individuals are formulated at high concentration to offset the dilution and washout that occur from tear flow. Patients with dry eyes that do not tear readily can absorb greatly exaggerated doses of topically applied medications. In children, who cry and lacrimate more easily than do adults, rapid drug washout can prevent adequate absorption of topically applied medications.

Cornea and Sclera

The cornea is a five-layered avascular structure (Figure 2-3). It constitutes the major functional barrier to ocular penetration, and it is also the major site of absorption for topically

TEAR FILM

EPITHELIUM

BOWMAN'S LAYER

STROMA

FIBROBLASTS

DESCEMET'S MEMBRANE

ENDOTHELIUM

CILIA

Figure 2-3 Cross-sectional diagram of the cornea. Note that the epithelium is only approximately one-tenth the total corneal mass. Nevertheless, it can be considered a separate storage depot for certain lipophilic drugs.

applied drugs. The epithelium and stroma have a major influence on pharmacodynamics, because they constitute depots or reservoirs for lipophilic and hydrophilic drugs, respectively.

The sclera is an opaque vascular structure continuous with the cornea at the limbus.The loose connective tissue overlying the sclera—the conjunctiva—is also vascularized. The conjunctiva and sclera, as routes of drug penetration, are responsible for less than one-fifth of all drug absorption to the iris and ciliary body. This limited absorption is due to the extensive vascularization of these tissues, which results in removal of most drugs. However, in recent years, the conjunctiva has been studied as a route of possible drug delivery because it contains a larger surface area than the cornea and possesses key transport processes that may allow for penetration into intraocular tissues (Figure 2-4).

Subconjunctival injections of sustained-release matrix materials or microparticles have produced significant levels in the vitreous cavity. Although the kinetics of transscleral drug delivery to the retina and choroid are

not well known, various simulation models are currently being actively developed and studied to allow for future drug delivery via this route (Table 2-1).

An elegant visualization of the route of scleral penetration was achieved by applying a piece of filter paper moistened with epinephrine to the white of the eye in a human subject. Mydriasis was obtained in an isolated sector of iris adjacent to the site of scleral application.

Studies have determined that certain compounds, including several sulfonamides, various molecular weight compounds, and many prostaglandins, exhibit good scleral penetration. Noncorneal routes of absorption may be an important consideration in some instances.

The conjunctival surface functions as a major depot for some drugs that are superficially absorbed and then re-released to the tears.Trapped particles from a suspension may allow active drug to dissolve slowly from the conjunctival sac and to saturate tear drug levels.

Corneal Epithelium

The corneal epithelium is 5 to 6 cell layers thick centrally and 8 to 10 cell layers thick at the periphery. It is composed of a basal germinative layer, intermediate wing cells, and a surface squamous layer that possesses structures that are known as zonula occludens, or tight junctions. These junctions constitute a continuing border between epithelial cells formed by the fusion of the outer plasma membrane. Mucopolysaccharides bound to the outer plasma membrane stabilize the tears. The cornea

relies on diffusion of nutrients from the aqueous humor to supply its metabolic needs.

More than one-half of the total corneal electrical resistance is contained in the uppermost squamous cell layer. Because the healthy epithelium presents a continuous layer of plasma membrane to the tear film, it largely resists the penetration of hydrophilic drugs. The anionic diagnostic agent sodium fluorescein is a good example of such a hydrophilic agent. The amount of fluorescein penetrating the intact epithelium is small. If a slight break in the outer cellular layer occurs, fluorescein can penetrate easily and is visible as a green stain for several minutes in the beam of a blue excitation filter. Epithelial erosion or the action of cationic preservatives can greatly increase the penetration of hydrophilic drugs in the same manner.

The interstices between the epithelial cell layers communicate directly by an aqueous pathway with the stroma and aqueous humor. Lipophilic drugs can readily enter the epithelium, because its barrier is composed of phospholipid membranes. Because the epithelium contains more than two-thirds of the plasma membrane mass of the cornea, it is the most significant storage depot for agents that readily partition into lipid media. The release rate of drugs from the epithelium depends on their tendency to reenter an aqueous phase.Thus, agents that are very lipophilic have a very long half-life once in the epithelium.

To penetrate the cornea effectively, a drug must possess a balance of hydrophilic and lipophilic properties

and must be able to partition between both media. This phenomenon is well known through the study of series of compounds of similar properties, such as β- blockers.A plot of partition coefficient versus corneal permeability usually results in the formation of a parabola, an example of which is shown in Figure 2-5. Molecular species with the appropriate partition coefficient at or near the peak are thus readily transferred through the cornea. Those with too low a coefficient do not penetrate well through the outer epithelial barrier. Those with too high a partition coefficient tend to remain in the epithelium and partition into the anterior chamber slowly, resulting in low but prolonged aqueous humor levels.

Corneal Stroma

Bowman’s layer is the modified anterior border of stroma in humans.This layer is 8 to 14 mm thick and is composed of clear randomly oriented collagen fibrils surrounded by mucoprotein ground substance. Numerous pores in the inner structure allow the passage of terminal branches of corneal nerves from the stroma into epithelium.The surface of Bowman’s layer adjoins the structurally distinct epithelial

basal lamina. The drug penetration characteristics of Bowman’s layer are probably similar to those of the stroma.

PARTITION COEFFICIENT (log P)

Figure 2-5 Parabolic curve of corneal penetration versus octanol–water partition diminished. Numbers refer to reagents. (Adapted from Kishida K, Otori T. Quantitative study on the relationship between transcorneal permeability of drugs and their hydrophobicity. Jpn J Ophthalmol 1980;24:251–259.)

22 CHAPTER 2 Ophthalmic Drug Formulations

The stroma occupies 90% of the corneal thickness and contains approximately one-third of the cells of the cornea in the form of keratocytes. The connective tissue of the stroma is composed of multiple layers of closely knit collagen bundles, or lamellae, arranged to distribute the stress of the intraocular pressure (IOP) evenly to the limbus, the thickened zone that joins the cornea and sclera. The collagen bundles are hexagonally packed and more ordered in the cornea than in the sclera.Their organization, together with the interspersed proteoglycans, is largely responsible for the clarity of the cornea.

The collagen fibrils occupy considerable space and thereby increase the path of diffusion. The net effect of impeding diffusion is to increase by several times the equivalent fluid layer thickness of the actual stroma. Nevertheless, the stroma is transparent to molecular species below approximately 500,000 Da. The stroma serves as the major ocular depot for topically applied hydrophilic drugs, and the keratocytes presumably provide a reservoir for lipophilic compounds as well.

The posterior border of the stroma is the endothelial basal lamina, termed Descemet’s layer. Descemet’s layer appears to pass molecular species as readily as does the stroma and is not known to act as a separate drug depot.

Corneal Endothelium

The corneal endothelium, a monolayer of polygonal cells approximately 3 mm thick, has a structure and properties unique in the body. It should not be confused with the blood vessel endothelium, which is of different developmental origin and has different characteristics. The nonregenerative property of the corneal endothelium requires that existing cells stretch to cover the space of any neighbors that are destroyed by physical damage or senescence.The endothelial cell layer has the remarkable ability to pump its own weight in fluid from the stromal side into the anterior chamber in 5 minutes. The intercellular borders form a junction that is open along its full length and allows a rapid leakage of water and solutes in the reverse direction to the fluid pump.

The fluid pump is probably a bicarbonate-based ion transport that may be coupled to Na+-K+ adenosine triphosphatase by an unknown mechanism. The leak is composed of a channel that is 12 mm long and 20 nm wide, narrowing to 5.0 nm at the edge facing the anterior chamber.This space is of a size sufficient to conduct large molecules, such as 3.5-nm diameter colloidal gold and colloidal lanthanum particles.The ultrastructure and ability to pass large molecules render the endothelial border a special type of leaky junction, rather than a tight junction (zonula occludens), as sometimes stated. Globular proteins exceeding 1 million daltons cannot pass readily, but smaller molecules are not hindered. Pinocytosis does occur in the endothelium and allows the transport of high-molecular-weight proteins. Because of the thinness

and small volume of the endothelial layer, it is not considered a major reservoir for drugs.

The cornea can concentrate certain substances from the aqueous, allowing the corneal stroma to hold more drug than would be expected from its fluid mass. This may result from the constant inward leakage of whole aqueous from the anterior chamber to the stroma, offset by the return of osmotic water by the fluid pump. Fluorescein given by mouth or vein thus accumulates rapidly in the corneal stroma from the aqueous. An alternative explanation for this accumulation is the ionic binding of substances by negative charges in stroma, reducing the diffusible pool of solute. Because fluorescein is itself an anion, however, this explanation is not fully satisfactory.

Iris

The iris functions primarily to adjust the amount of light reaching the retina, simultaneously altering the visual depth of focus without changing the field of vision. It does this by controlling the total area of the visual pathway between the two major refractive components of the eye: the cornea and the lens. Therefore, it contains pigment to absorb light.To accomplish this function, two groups of muscles—the sphincter and the dilator—work in opposition. These are supplied by cholinergic and adrenergic innervation, respectively. Miosis can be accomplished by endogenous or exogenous acetylcholine or by cholinergic stimulation. Mydriasis can be accomplished by an adrenergic stimulant, such as epinephrine (which acts on the dilator musculature), or by an antagonist to acetylcholine (which allows relaxation of the sphincter). The readily observed behavior of the iris has made its action an excellent model for the study of drug penetration in the human eye.

The pigment granules of the iris epithelium absorb light and also can absorb lipophilic drugs. This type of binding is characteristically reversible, allowing release of drug over time. It is usually termed nonspecific or lowaffinity binding, indicating that a specific high-affinity drug receptor is not involved.As a result, the iris can serve as a depot or reservoir for some drugs, concentrating and then releasing them for longer than otherwise expected.

An effective level within the eye of a single dose of a lipophilic drug can be prevented or delayed by nonspecific binding. On multiple dosing, however, a saturation equilibrium is reached when the amount of drug being bound is the same as that being released from the reservoir. Once this occurs effective dosing is achieved.

Individual iris pigmentation varies widely, and some drugs show a far greater response after the first dose in blue-eyed individuals than in patients with dark irides. Constriction of the pupil (miosis) was demonstrated after a single dose of pilocarpine continuing for 4.7 hours in darkly pigmented subjects as compared with only 2 hours in subjects with blue eyes.

Aqueous Humor

Aqueous humor is formed by the ciliary body and occupies the posterior and anterior chambers, a compartment measuring approximately 0.2 ml, although the total volume decreases with age as the lens grows.The fluid is constantly generated by the pigmented and nonpigmented epithelium of the ciliary body, which is supplied by a rich bed of capillaries. It flows from the posterior chamber through the pupil and then slowly circles in the anterior chamber, circulated by the thermal differential between the cornea and the deeper ocular tissues. The aqueous exits at the angle between the cornea and iris through the sieve-like trabecular meshwork or conventional outflow. It then enters the canal of Schlemm, which leads directly into low-pressure episcleral veins and finally into the general circulation. Aqueous humor may also exit through the walls of the iris or other tissues forming the margins of the anterior chamber, the uveoscleral route, or nonconventional routes of aqueous humor outflow. The uveoscleral route is believed to account for approximately 20% of aqueous humor outflow.

Ciliary Body

The major function of the ciliary body is aqueous humor production. Aqueous is composed of a clear ultrafiltrate of blood plasma devoid of large proteins, together with some substances actively transported across the blood–aqueous barrier.

The numerous capillaries of the ciliary body possess no tight junctions to limit the diffusion of drugs or proteins. However, drugs are usually limited by the apically tight junctions of the nonpigmented cells at the paired layers making up the ciliary epithelium. Systemic drugs enter the anterior and posterior chambers largely by passing through the ciliary body vasculature and then diffusing into the iris, where they can enter the aqueous humor.

The ciliary body is the major ocular source of drugmetabolizing enzymes responsible for the two major phases of reactions that begin the process of drug detoxification and removal from the eye. The localization of these enzymes together in a single tissue is important, because the oxidative and reductive products from phase I reactions of the cytochrome P-450 system are highly reactive and potentially more toxic than are the parent compounds. Conjugation by glucuronidation, sulfonation, acetylation, and methylation or with amino acids or glutathione in phase II reactions can then be accomplished by detoxifying enzymes. The uveal circulation provides up to 88% of the total blood flow and can rapidly remove these conjugated products from the eye. Melanin granules of the pigmented ciliary epithelium adsorb polycyclic compounds,such as chloroquine,storing them for metabolism and removal.

Crystalline Lens

The normal human lens originates from a double layer of epithelium. Its thickened outer basal lamina (the capsule) is analogous to Descemet’s layer. The lens grows to become a thick flexible tissue composed of cells densely packed with clear proteins known as crystallins. By the age of 50 years flexibility is reduced, thus diminishing accommodation. The capsule reaches a thickness of several microns anteriorly and is 10 times thinner posteriorly. The anterior lens epithelium is the most active region metabolically, conducting cation transport and cell division. This region is also the most prone to damage from drugs or toxic substances.

Hydrophilic drugs of high molecular weight cannot be absorbed by the lens from the aqueous humor, because the lens epithelium is a major barrier to entry. The capsule prevents the entry of large proteins. Lipid-soluble drugs, however, can pass slowly into and through the lens cortex. Fluorescein, a hydrophilic molecule, can penetrate the capsule and reach the nucleus in a few weeks. The lens can be viewed primarily as a barrier to rapid penetration of drugs from aqueous to vitreous humor.

The lens grows with age, and colorations or opacities may develop and interfere with vision. Cataract formation may be enhanced by some miotics, steroids, and phenothiazines. Aldose reductase inhibitors, which prevent the conversion of sugars to polyols, appear to prevent or delay diabetic cataract. Levels of glutathione and other compounds drop during the formation of some types of cataracts. The pharmacokinetics of delivery and penetration of such compounds into the crystalline lens is currently of great interest.

When cataracts necessitate lens removal to restore vision, the kinetics between aqueous and vitreous humor change. A major barrier to molecular transport is removed, and more rapid exchange can occur between aqueous and vitreous contents and various ocular components. In one experimental study the concentration of a topically applied anti-inflammatory agent, flurbiprofen, was increased in retinal tissues, vitreous humor, and choroid after lens removal.

Vitreous Humor

The vitreous humor is a viscoelastic connective tissue composed of small amounts of glycosaminoglycans, including hyaluronic acid, and of such proteins as collagen.The collagen fibrils are anchored directly to the basal lamina, which forms the boundaries of the lens, the ciliary body epithelium, and the neuroglial cells of the retina. Although the anterior vitreous is cell free, the posterior vitreous contains a few phagocytic cells, called hyalocytes, and is sometimes termed the cortical tissue layer.

At birth, the material of the vitreous is gel-like in humans and primates. A central remnant of the hyaloid artery, Cloquet’s canal (which is free of collagen fibrils),

24 CHAPTER 2 Ophthalmic Drug Formulations

runs from the posterior lens capsule to the optic disc. Because the total volume of the vitreous expands with age while the amount of hyaluronate remains constant, the gel-like material develops a central viscous fluid lake completely surrounded by the gel vitreous.These events can cause condensation and tearing of the sheath of Cloquet’s canal, forming structures termed floaters, which can interfere with vision.

The vitreous constitutes approximately 80% of the ocular mass. It may be considered an unstirred fluid with free diffusion for small molecules. Some molecular species can diffuse between the posterior chamber and the vitreous. However, very high-molecular-weight substances, such as hyaluronate, are held in place by the zonules and lens capsule and diffuse out of the vitreous only after intracapsular lens extraction. From this discussion, it is apparent that the vitreous can serve both as a major reservoir for drugs and as a temporary storage depot for metabolites. For low-molecular-weight substances, a free path of diffusion exists from the ciliary body through the posterior aqueous humor.

Hydrophilic drugs, such as gentamicin, do not cross the blood–retinal barrier readily after systemic administration. After intravitreal administration they have a prolonged half-life of 24 hours or more in the vitreous humor.Their major route of exit is across the lens zonules and into the aqueous humor and then through the aqueous outflow pathways. For the vitreous to act as a depot for these drugs, the agents must be injected, introduced by iontophoresis, or slowly released by a surgically implanted intraocular device.

Retina and Optic Nerve

Tight junctional complexes (zonula occludens) in the retinal pigment epithelium prevent the ready movement of antibiotics and other drugs from the blood to the retina and vitreous. The retina is a developmental derivative of the neural tube wall and can be viewed as a direct extension of the brain; it is not surprising that the blood–reti- nal barrier somewhat resembles the blood–brain barrier in form and function. Experimental evidence has shown that histamine does not alter the vascular permeability of the retina but does affect that of all other ocular tissues. The retina closely resembles the brain with respect to this trait.

The capillaries of the retina are lined by continuous, close-walled, endothelial cells, which are the primary determinant of the molecular selectivity that is the major function of the blood–retinal barrier. Bruch’s membrane is a prominent structure associated with the retinal–vitre- ous barrier, yet it contributes relatively little to the barrier’s filtration properties.

The barrier protects against the entry of a wide variety of metabolites and toxins and is effective against most hydrophilic drugs, which do not cross the plasma membrane. Glucose, however, can cross much more

easily than would be expected from its molecular structure. This diffusion is probably facilitated by an active transport system involving a transmembrane carrier molecule. There is more evidence of retina and retinal epithelial membrane transporters in recent years (Table 2-2).

Table 2-2

Summary of Molecular and/or Functional Evidence of Known Conjunctival and Retina/Retinal Pigmented Epithelial Membrane Transporters

BRB = blood–retinal barrier;RPE = retinal pigmented epithelium. From Hughes PM, et al.Adv Drug Deliv Rev 2005;57:2017.