Clinical Ocular Pharmacology CH 3.1 PDF

3 Ophthalmic Drug Delivery Jimmy D. Bartlett The pharmacotherapy of eye disease generally requires high local concentrations of drug at the ocular tissues. Treatment of ocular surface infections or inflammations necessitates effective drug delivery to the eyelids, conjunctiva, or cornea. In contras...

3 Ophthalmic Drug Delivery Jimmy D. Bartlett The pharmacotherapy of eye disease generally requires high local concentrations of drug at the ocular tissues. Treatment of ocular surface infections or inflammations necessitates effective drug delivery to the eyelids, conjunctiva, or cornea. In contrast, treatment of uveitis, glaucoma, or retinitis involves therapeutic drug levels at appropriate target sites deep within the globe. Although many systems have been developed specifically for drug delivery to the eye, most of them suffer from lack of precision, and those associated with intraocular drug delivery can lead to toxicity.This chapter discusses the most clinically useful drug delivery systems developed for ocular pharmacotherapy, with emphasis on those used in primary eye care. TOPICAL ADMINISTRATION Topical application, the most common route of administration for ophthalmic drugs, is convenient, simple, and noninvasive, and patients can self-administer the medication. Topically applied anesthetics are even used as the primary anesthetic for contemporary cataract surgery. The primary source of drug loss in topical administration is diffusion into the circulating blood. Diffusion into the blood takes place through blood vessels of the conjunctiva, episclera, intraocular vessels, and vessels of the nasal mucosa and oral pharynx after drainage through the nasolacrimal system. Because of these losses of drug through the systemic circulation,topically administered medications do not typically penetrate in useful concentrations to the posterior ocular structures and therefore are often of no therapeutic benefit for diseases of the posterior segment. Solutions and Suspensions Solutions are the most commonly used mode of delivery for topical ocular medications. Solutions or suspensions are usually preferred over ointments, because the former are more easily instilled, interfere less with vision, and have fewer potential complications. Disadvantages of topically applied solutions include short ocular contact time, imprecise and inconsistent delivery of drug, frequent contamination, and the possibility of ocular injury with the dropper tip. Suspensions must be resuspended by shaking to provide an accurate dosage of drug, and the degree of resuspension varies considerably among preparations and among patients. Corticosteroid formulations, for example, are not always adequately resuspended even by the most compliant and carefully instructed patients. Some generic steroid suspensions, moreover, have been found to suspend poorly, and some generic products may develop a clogged dropper tip.These problems have been described primarily in association with 1% prednisolone acetate suspension. Packaging Most eyedrop containers consist of two parts,an eyedropper tip and a bottle containing the solution or suspension. Because it is advantageous to administer small volumes of medication to minimize systemic absorption of topically applied solutions or suspensions, some manufacturers have attempted to reduce eyedrop volume by modifying or redesigning dropper tips. Traditionally, commercial eyedrops have ranged in size from 50 to 70 mcl.The typical volumes now delivered by commercial glaucoma medications are in the range of 25 to 56 mcl. To help reduce confusion in labeling and identification among various topical ocular medications, drug packaging standards are in use. The standard colors for drug labeling and bottle caps are yellow, blue, or both for beta blockers; red for mydriatics and cycloplegics; green for miotics; orange for carbonic anhydrase inhibitors; gray for nonsteroidal anti-inflammatory drugs; pink for steroids; brown or tan for anti-infective agents; and teal for prostaglandin analogues. Storage Solutions of drugs should be stored in the examination room in a manner allowing easy identification of labels (Figure 3-1). Containers of solutions often differ little in size, shape, or labeling. The drug name should be 39 40 CHAPTER 3 Ophthalmic Drug Delivery Figure 3-1 Drug storage tray allows easy identification of packaging labels. confirmed by inspection each and every time a medication is used. Although refrigeration of solutions may help to prolong shelf life,there appears to be little difference in local ocular irritation caused by eyedrops stored in the refrigerator or at room temperature. Cold drops, however, often can serve to reinforce proper eyedrop self-administration technique for patients who have difficulty ascertaining when the drops have been properly instilled. Expiration dates of solutions should be respected. Office staff should periodically survey ophthalmic preparations in the office and discard solutions that have reached the expiration date.The use of old solutions can increase liability as well as introduce the risk of potential drug toxicity or iatrogenic infection. Some commonly used ophthalmic solutions, such as proparacaine, may change color, which indicates oxidation (Figure 3-2), whereas others show no visible signs of deterioration. Techniques of Instillation Two methods are commonly used to instill topical ocular solutions: 1. With the patient looking down and the upper lid retracted, a drop of solution is applied to the superiorly exposed bulbar conjunctiva. 2. With the patient’s head inclined backward so that the optical axis is as nearly vertical as possible, the lower lid is retracted and the upper lid stabilized.The patient should be instructed to elevate the globe to move the cornea away from the instillation site to minimize the blink reflex. The solution is instilled, and the dropper tip is kept at least 2 cm from the globe to avoid contact contamination (Figure 3-3). After the lids are gently closed, the patient should be cautioned to avoid lid squeezing. Pressure should be applied with the fingertips over the puncta and canaliculi to minimize nasolacrimal drainage (Figure 3-4).This position, known as nasolacrimal occlusion, should be maintained for 2 to 3 minutes. Several investigators have shown that simple eyelid closure alone significantly retards medication drainage and thereby minimizes potential side effects associated Figure 3-2 Change in color of proparacaine solution (left) indicates deterioration of the formulation. CHAPTER 3 Ophthalmic Drug Delivery 41 Box 3-1 Recommended Procedure for Instilling Topical Ocular Solutions Figure 3-3 Traditional technique for instillation of topical ocular solutions.The patient’s head is inclined backward, the lower lid is retracted, the globe is elevated, and the dropper tip is kept at least 2 cm from the globe. with systemic drug absorption. However, when nasolacrimal occlusion is used in conjunction with eyelid closure, intraocular drug absorption may be enhanced. The same maximal drug effect can be achieved with many ocular hypotensive drugs at lower concentrations and with lower dosage frequencies than those generally recommended.This is true at least for use of pilocarpine and timolol. In the long-term treatment of glaucoma with topical drugs, silicone punctal plugs may be used as a 1. Tilt patient’s head backward. 2. Instruct patient to direct gaze toward ceiling. 3. Gently grasp lower outer eyelid below lashes and pull eyelid away from globe. 4. Without touching lashes or eyelids, instill one drop of solution into conjunctival sac. 5. Continue to hold eyelid in this position for a few seconds to allow solution to gravitate into deepest portion of lower fornix. 6. Instruct patient to gaze downward while lifting the eyelid upward until it contacts the globe. 7. Instruct patient to gently close eyes. 8. Patient should keep eyes closed for 2 to 3 minutes. substitute for manual nasolacrimal occlusion. It is unclear, however, whether these devices actually achieve better intraocular pressure control compared with no occlusion. Boxes 3-1 and 3-2 summarize the recommended procedures for drop instillation. Administering topical solutions to uncooperative children is often difficult. Several techniques may be used to facilitate drug administration to these patients.The child’s hand can be placed on the forehead, which proprioceptively reinforces upward gaze. In addition, the palpebral aperture can be widened for drop instillation by telling the child to open his or her mouth. A spread of the neural impulse from the mesencephalic root of the fifth cranial nerve to the nucleus of the levator may explain the effectiveness of this maneuver. Another useful method of administering drops to uncooperative pediatric patients is to instruct them to close their eyes.They usually do not resist and are unable to see the approach of the dropper bottle.Through gentle retraction of the lower lid, a small opening through the lashes into the conjunctival sac is Box 3-2 Instructions to Patients for SelfAdministration of Solutions or Suspensions Figure 3-4 Nasolacrimal drainage of solutions may be minimized by applying pressure with fingertips over the puncta and canaliculi. 1. Tilt head backward. 2. With clean hands, gently grasp lower outer eyelid below lashes and pull eyelid away from the eye. 3. Place dropper over eye by looking directly at it. 4. Just before applying a drop, look upward. 5. After applying the drop, look downward for a few seconds. 6. Lift eyelid upward until it contacts the eye. 7. Gently close eyes for 2 to 3 minutes. 42 CHAPTER 3 Ophthalmic Drug Delivery created, and the drop can be instilled. The simple placement of the drop on the eyelashes of the closed eyelids has also been shown to achieve effective mydriasis and cycloplegia in the pediatric population. The self-administration of topical solutions by elderly patients can sometimes be difficult because of arthritis, tremors, or other physically debilitating diseases. It has been shown that most patients older than age 75 have difficulty applying their eyedrops. Although some patients recognize the problem, many are observed to have difficulty but to not acknowledge their inadequacies at eyedrop instillation.Thus, simply asking patients about their eyedrop technique is not likely to reveal which patients are in need of instruction. A better approach is to actually observe the eyedrop instillation technique and to make sure that it is taught to all patients or their caregivers before patients leave the office.The instillation of ocular drugs may be facilitated in these patients by using a pair of spectacle lenses into which a hole has been drilled through the center of each lens.The patient inserts the dropper tip into the hole, gazes superiorly, and squeezes the bottle (Figure 3-5). Only polycarbonate lenses should be used because of the risk associated with drilling into a conventional glass or plastic lens. Various commercial devices are also available (Figure 3-6). Solutions characterized by significant local toxicity or staining potential (e.g., silver nitrate) can be instilled using a cotton swab as an applicator.This technique minimizes drop size and subsequent overflow onto the patient’s cheek or clothing. A Unit-Dose Dispensers Recognizing that long-term therapy with frequently applied preserved solutions can be toxic to the ocular surface, manufacturers have formulated some ophthalmic solutions in unit-dose dispensers without preservatives (Figure 3-7). B Figure 3-6 Commercial eyedrop assistance device. (A) Insertion of dropper bottle into device. (B) Device in use. Unpreserved artificial tears are available in this form, as are timolol, cyclosporine, and ketorolac. Most unit-dose dispensers accommodate solution volumes ranging from 0.1 to 0.6 ml. Because these solutions are unpreserved, they are designed for short-term use (not exceeding 12 hours), after which the unit is discarded. Figure 3-5 Modification of polycarbonate spectacle lenses to facilitate drop instillation. After a hole is drilled through the center of each lens, the patient inserts the dropper tip into the hole, gazes superiorly, and squeezes the bottle. Sprays The topical administration of solutions to the eye is often an unpleasant procedure associated with significant burning, stinging, lacrimation, and emotional trepidation, CHAPTER 3 Ophthalmic Drug Delivery 43 Figure 3-8 Ophthalmic sprays can be extemporaneously prepared for delivery of suitable mydriatics or cycloplegics. (Available from Lee Pharmacy, Inc., Fort Smith,Arkansas.) and cycloplegia comparable with those obtained with eyedrops (Figure 3-9).This occurs even when the spray is applied to the closed eyelid. especially in children.Topical sprays represent an alternative method of administering ophthalmic solutions that may be less irritating and less objectionable. Combinations of mydriatics and cycloplegics, such as phenylephrine–tropicamide or phenylephrine–tropicamide–cyclopentolate, can be used as sprays for routine mydriasis in adults or for cycloplegia in children. Ophthalmic sprays can be prepared by a compounding pharmacy (Figure 3-8) for application of appropriate mydriatic or cycloplegic combinations (see Chapter 21). The unit is held 5 to 10 cm from the eye before activating the spray. Several artificial tears are commercially available as sprays. One advantage of a mydriatic or cycloplegic spray is that the drug can be applied to closed eyelids.After drug application, patients should be instructed to blink. If the medication reaches the precorneal tear film, mild stinging is expected. After blinking several times (for 10 to 15 seconds), patients should wipe off the excess solution. If no mild burning or stinging occurs after the eye has been sprayed, it is likely that none of the drug reached the precorneal tear film from the lid margin, and another application is necessary.This may occur in patients who have tightly closed lids in which redundancy of the skin shields the lid margins from the spray. When the efficacy of sprays is compared with that of topically applied eyedrops, sprays provide both mydriasis Ointments Although solutions are the most commonly used vehicles for topical ocular medications, ointments are also frequently used for application to the eye.When applied to the inferior conjunctival sac, ophthalmic ointments melt quickly, and the excess spreads out onto the lid margins, lashes, and skin of the lids, depending on the amount instilled and on the extent of lacrimation induced by any irritation.The ointment at the lid margins acts as a reservoir and enhances drug contact time. 9.0 Drops, eyes open Drops, eyes closed Spray, eyes open Spray, eyes closed 8.0 PUPIL SIZE (mm) Figure 3-7 Unit-dose dispensers. 7.0 6.0 5.0 4.0 3.0 2.0 0 5 10 15 20 25 30 35 40 45 50 55 60 TIME (min) Figure 3-9 Mydriatic effect of ophthalmic spray applied to closed eyes is comparable with that of eyedrops applied to open eyes. (Reprinted with permission from Wesson MD, Bartlett JD, Swiatocha J, et al. Mydriatic efficacy of a cycloplegic spray in the pediatric population. J Am Optom Assoc 1993;64:637–640.) 44 CHAPTER 3 Ophthalmic Drug Delivery Techniques of Application Patients are instructed to elevate the gaze, and with the lower lid retracted, the ointment is instilled into the inferior conjunctival sac (Figure 3-10). A pressure patch can then be applied.The daytime use of ointments frequently leads to complaints of blurred vision. For bedtime use, at least 1 cm of ointment is generally applied. If the ointment is not to be applied at bedtime or used under a pressure patch, smaller volumes of ointment should be instilled. An alternative method of application involves placing the ointment on a cotton-tipped applicator and applying it to the upper lid margin and lashes as well as the medial and lateral canthi. In this way blurring of vision and drug irritation are minimized. In addition, the ointment acts as a drug reservoir and has a therapeutic effect for approximately 6 hours. This method of application may be of practical value in the treatment of ocular infections in all patients, but especially those in the pediatric and geriatric age groups. A B Figure 3-10 Technique of ointment instillation. With the globe elevated and the lower lid retracted, ointment is instilled into the inferior conjunctival sac in a sweeping fashion from lateral canthus (A) to medial canthus (B). Once the ointment has been instilled, the bioavailability of subsequently instilled solutions may be altered because the solution is blocked from contact with the ocular surface. Whenever both solution and ointment formulations are used in therapy, the solution should be instilled before the ointment is applied. Complications Contact dermatitis of the lids sometimes occurs during use of ointments containing sensitizing agents such as atropine or neomycin, because ointments are characterized by prolonged ocular contact time. Hypersensitivity to the incorporated preservatives may also occur. Blurred vision is one of the most frequent adverse effects from ophthalmic ointments. This problem can often be alleviated or minimized by simply reducing the volume of ointment instilled during the daytime.Another option involves instructing patients to apply the ointment to each eye on an alternating schedule. This allows patients to have acceptable vision with at least one eye at all times during the waking hours. The effect of ophthalmic ointments on the healing of corneal wounds has been studied. Early formulations of ophthalmic ointments contained waxy grades of petrolatum or unwashed lanolin, which interfered with corneal wound healing. Contemporary ophthalmic ointments, however, are nonemulsive and do not contain the coarse grade of white petrolatum. These ointments cause no significant inhibition of corneal wound healing. The following guidelines are suggested for the clinical use of ophthalmic ointments: • Ointments may be used immediately after intraocular surgery under a conjunctival flap or in corneal incisions with excellent wound approximation, because the risk of entrapment of ointment is minimal. Ointments should not be used, however, in any surgical wound in which there is a question of wound integrity, such as when difficulty is experienced maintaining the anterior chamber at surgery. In such cases ointment application should be delayed for several days. • Ointments should be used with caution in jagged or flap-like corneal lacerations, in eyes with impending corneal perforation, and in open conjunctival lacerations. • Ointments can be used routinely for superficial corneal abrasions. However, any abrasion involving corneal tissues deeper than the epithelium should be managed on an individual basis depending on the configuration of the wound edges. • Ointments may be applied to corneal ulcers with little risk of entrapment or inhibition of wound healing. However, they should be used with caution in ulcers with an impending perforation or large overhanging margins because there is a risk of ointment entrapment under a flap. • Ointments may be preferred in patients undergoing macular hole surgery with postoperative face-down positioning. Ointment administration CHAPTER 3 Ophthalmic Drug Delivery permits less frequent dosing of antibiotics and steroids, reducing the number of times patients must look upward during instillation. Lid Scrubs Application of solutions or ointments directly to the lid margin is especially helpful in treating seborrheic or infectious blepharitis.After several drops of the antibiotic solution or detergent, such as baby shampoo, are placed on the end of a cotton-tipped applicator, the solution is applied to the lid margin with the eyelids either opened or closed (Figure 3-11). Antibiotic ointments are applied in the same way. Although baby shampoo is frequently used for cleaning the eyelid margin, commercially available eyelid cleansers are effective, with potentially less ocular stinging, burning, or toxicity. Commercial lid scrub products are designed to aid in removal of oils, debris, or desquamated skin from the inflamed eyelid. The lid scrubs can A 45 also be used for hygienic eyelid cleansing in contact lens wearers.Although these solutions are designed to be used full strength on eyelid tissues, they must not be instilled directly into the eyes. Some of the products (Table 3-1) are packaged with presoaked gauze or cotton pads, which provide an abrasive action to augment the cleansing properties of the detergent. Patients generally express a preference for the commercially available lid scrub products because they are convenient and easy to use. Gels Pilocarpine is commercially available in a carbomer gel vehicle.The 4% pilocarpine gel is packaged in a 3.5-g tube similar to ophthalmic ointments.A practical advantage of this sustained delivery system is the once-daily dosage regimen, with the drug usually administered at bedtime. Minor side effects include superficial corneal haze, which may occur after long-term use (>8 weeks), and superficial punctate keratitis, which can affect almost one-half the treated patients but usually resolves spontaneously. Several artificial tear preparations are formulated as ophthalmic gels. Tears Again (Cynacon OCuSoft, Richmond, TX) is a sterile lubricant gel consisting of carboxymethylcellulose sodium 2% and povidone 0.1%. GenTeal Lubricant Eye Gel (Novartis Ophthalmics, East Hanover, NJ) contains carbopol 980, a gelling agent with high water-binding affinity that transforms from gel to liquid on contact with ocular tissue. These gel systems tend to minimize the blurred vision that can accompany daytime instillation of ophthalmic ointments. In situ–activated gel-forming systems are delivered to the ocular surface as eyedrops.These are then converted by temperature changes and ionic movement into a gellike viscosity that permits prolonged contact with the eye. Gellan gum (Gelrite) and a heteropolysaccharide (xanthan gum) are currently used to deliver timolol in the treatment of glaucoma. Studies have confirmed that treatment with 0.5% timolol in gel-forming solution once daily in the morning achieves intraocular pressure levels equal to twice-daily application of 0.5% timolol solution. The gel-forming solution is well tolerated and does not cause blurred vision or ocular discomfort. Solid Delivery Devices One of the significant problems with the delivery of drugs in solution is that drug administration is pulsed, with an initial period of overdosage followed by a period of relative underdosage. The development of solid drug delivery devices has been an attempt to overcome this disadvantage. B Figure 3-11 Technique of lid scrub. Drug application to the lid margin is accomplished with a cotton-tipped applicator applied to the opened (A) or closed (B) eyelids. Soft Contact Lenses Drugs penetrate soft contact lenses at a rate that depends on the pore size between the cross-linkages of the threedimensional lattice structure of the lens, the concentration 46 CHAPTER 3 Ophthalmic Drug Delivery Table 3-1 Representative Eyelid Scrub Products Trade Name (Manufacturer) Ingredients Formulation Eye Scrub (CIBA Vision, Atlanta, GA) PEG-200 glyceryl monotallowate, disodium laureth sulfosuccinate, cocoamido propyl amine oxide, PEG-78 glyceryl monococoate, benzyl alcohol, EDTA Linalool Premoistened pads SteriLid (Advanced Vision Research,Woburn, MA) OCuSOFT (Cynacon/OCuSOFT, Richmond,TX) PEG-80 sorbitan laurate, sodium trideceth sulfate, PEG-150 distearate, cocamido propyl hydroxysultaine, lauroamphocarboxyglycinate, sodium laureth-13 carboxylate, PEG-15 tallow polyamine, quaternium-15 Solution Foam and premoistened pads EDTA = ethylenediaminetetraacetic acid; PEG = polyethylene glycol. Adapted from Bartlett JD, Fiscella R, Ghormley NJ, et al., eds. Ophthalmic drug facts. St. Louis, MO: Lippincott Williams & Wilkins, 2005. of drug in the soaking solution, the soaking time, the water content of the lens, and the molecular size of the drug. Lenses with higher water content absorb more water-soluble drug for later release into the precorneal tear film. Maximum drug delivery is obtained by presoaking the lens.This produces a more sustained high yield of drug. Currently, disposable soft contact lenses can be used for drug delivery and appear to be of greatest clinical value in the treatment of bullous keratopathy, dry eye syndromes, and corneal conditions requiring protection, such as traumatic corneal abrasions or erosions.The most significant disadvantage of this mode of therapy, however, is the rapid loss of most drugs from the lens. Drug-impregnated hydrogel lenses are characterized by first-order kinetics, so they only occasionally offer any significant advantage over topically applied solutions or ointments. Collagen Shields Shaped like contact lenses, collagen shields are thin membranes of porcine or bovine scleral collagen that conform to the cornea when placed on the eye.They are packaged in a dehydrated state and require rehydration before application (Figure 3-12). When a shield is rehydrated in a solution containing a water-soluble drug, the drug becomes trapped in the collagen matrix. Collagen shields have been studied extensively for their potential usefulness as drug delivery devices because the drug is released as the shield dissolves.They have been evaluated for the delivery of antibacterial, antifungal, antiviral, antiinflammatory, and immunosuppressive drugs, as well as anticoagulants. Currently available collagen shields have variable dissolution rates of 12, 24, or 72 hours depending on the amount of collagen cross-linking induced by ultraviolet radiation during the manufacturing process. Shields dissolve as a result of proteolytic degradation by the tear film. Their oxygen permeability is comparable with that of a hydroxyethyl methacrylate lens of similar water content. Before insertion, the shields must be rehydrated for at least 3 minutes in saline, lubricating solution, antibiotic, or steroid. Because the shields can be uncomfortable Figure 3-12 Rehydrated collagen shield on eye. (Courtesy Bausch & Lomb, Inc.) CHAPTER 3 Ophthalmic Drug Delivery 47 when first placed on the cornea, use of a topical anesthetic may be required. Filter Paper Strips Three staining agents—sodium fluorescein, lissamine green, and rose bengal—are commercially available as drug-impregnated filter paper strips (Figure 3-13). This form of drug delivery allows these agents to be more easily administered to the eye in dosage amounts adequate for their intended clinical purpose. Administration of excessive drug is eliminated, so that unintentional staining of lid tissues or patients’ clothing is avoided. Note, however, that the concentration of rose bengal delivered to the ocular surface can be relatively low and depends on the strip soak time and technique. The availability of fluorescein-impregnated paper strips eliminates the risk of solution contamination with Pseudomonas aeruginosa. For administration, the drug-impregnated paper strip is moistened with a drop of normal saline or extraocular irrigating solution, and the applicator is gently touched to the superior or inferior bulbar conjunctiva or to the inferior conjunctival sac.To avoid the risk of cross-contamination between eyes, practitioners should use separate applicators for dye delivery to eyes with suspected infection. Cotton Pledgets Cotton pledgets saturated with ophthalmic solutions can be of value in several clinical situations. These devices allow prolonged ocular contact time with solutions that are normally topically instilled into the eye. A pledget is constructed by simply teasing the cotton tip of an applicator to form a small (approximately 5 mm) elongated body of cotton. After placing one or two drops of the ophthalmic solution on the pledget, the device is placed into the inferior conjunctival fornix (Figure 3-14). Figure 3-13 Drug-impregnated filter paper strips. Rose bengal (top), lissamine green (center), and sodium fluorescein (bottom). Figure 3-14 Cotton pledget positioned in the inferior conjunctival fornix. The clinical use of pledgets is usually reserved for administration of mydriatic solutions such as phenylephrine. This method of drug delivery allows maximum mydriasis in attempts to break posterior synechiae or dilate sluggish pupils. Mydriasis of the inferior pupillary quadrant for intentional sector dilation of the pupil can also be achieved (see Chapter 20). Continuous Flow Devices When relatively small amounts of drug are required for delivery to the eye, the use of solutions, ointments, or gels is usually satisfactory. However, when large volumes of fluids are required, such as in the treatment of acute chemical burns, other drug delivery systems are necessary. Various methods for delivering large volumes of fluids continuously to the eye have been developed. Conventional Irrigating Systems Extraocular irrigation is often used in the initial treatment of ocular foreign bodies or chemical burns in an effort to dislodge foreign material. It is also used to remove excessive drug from the eye after fluorescein or rose bengal staining or after gonioscopic procedures in which viscous lens-bonding solutions have been used. The conventional delivery system for irrigation fluids consists simply of the container of irrigating solution and a means, usually a tissue, towel, or emesis basin, with which to collect the fluid after bathing the eye. Patients should be in a supine position with head tilted toward the side to be irrigated (Figure 3-15).The irrigating solution should be at room temperature to minimize patient discomfort during the procedure. With the upper and lower lids retracted, the clinician gently bathes the extraocular surfaces with the solution, taking care to collect the fluid in the tissue, towel, or emesis basin and to avoid staining the patient’s clothing. In most cases no topical anesthesia is required, 48 CHAPTER 3 Ophthalmic Drug Delivery Figure 3-16 Morgan lens and tubing are attached to an intravenous line for continuous delivery of saline irrigation to the external eye. PERIOCULAR ADMINISTRATION When higher concentrations of drugs, particularly corticosteroids and antibiotics, are required in the eye than can be delivered by topical administration, local injections into the periocular tissues can be considered. Periocular drug delivery includes subconjunctival, subTenon’s, retrobulbar, and peribulbar administration. Subconjunctival Injection Figure 3-15 Conventional irrigation system. The head is tilted toward the side to be irrigated, and the irrigation solution is collected in a tissue or towel after it has bathed the extraocular tissues. unless patients, because of severe pain or ocular involvement, are unable to open the eye. The obvious limitation of the conventional irrigating system is the need to have an attendant administer the fluid. However, this method represents the most costeffective means of administering fluids continuously to the eye. Continuous Irrigating Systems To circumvent the need for an attendant to administer the irrigating fluid or drug, various methods have been developed that enable the continuous delivery of fluid on a long-term basis. Most methods that have been devised for continuous ocular irrigation are suitable for use for relatively short periods in nonambulatory patients. The Morgan lens (Figure 3-16) is the most convenient commercially available system. This system is capable of delivering a continuous flow of saline to every surface of the eye and conjunctival sac. Fluid flow acts as a cushion and allows the lens to float above the cornea and below the eyelid, avoiding contact with damaged ocular tissues. Although repeated topical applications of most ocular drugs result in intraocular drug levels comparable with those achieved with subconjunctival injections, subconjunctival injections offer an advantage in the administration of drugs, such as antibiotics, with poor intraocular penetration. This mode of drug delivery offers the following advantages: • High local concentrations of drug can be obtained with the use of small quantities of medication, so that adverse systemic effects are avoided. • High tissue concentrations can be obtained with drugs that poorly penetrate the epithelial layer of the cornea or conjunctiva. This method is useful in patients who do not reliably use topical medication. • Drugs can be injected at the conclusion of surgery to avoid the necessity of topical or systemic drug therapy. Subconjunctival injection involves passing the needle between the anterior conjunctiva and Tenon’s capsule (Figure 3-17). This can be performed through the eyelid or directly into the subconjunctival space. Tenon’s capsule lies between the injected drug and the globe, so the amount of drug absorbed across the sclera is minimized. However, at least for corticosteroids, a subconjunctivally administered drug may penetrate the underlying sclera, which suggests a rationale for placing the drug directly adjacent to the site of inflammation rather than injecting it randomly. Probably the greatest clinical benefit associated with the subconjunctival route of drug administration is in the treatment of severe corneal disease, such as bacterial ulcers. Much higher concentrations of antibiotics can be achieved in the affected corneal tissues with subconjunctival CHAPTER 3 Ophthalmic Drug Delivery 49 Conjunctiva C Lid A Tenon's capsule B Figure 3-17 Relative positions of periocular injections.A, Subconjunctival; B, sub-Tenon’s; C, retrobulbar. injection than can be obtained by systemic drug administration. Subconjunctival antibiotic administration is also useful as an initial supplement to the systemic or intravitreal antibiotic treatment of bacterial endophthalmitis. A variety of ocular diseases are treated with subconjunctival corticosteroids. Subconjunctival injection of 5-fluorouracil, an antifibroblast agent, is sometimes used after high-risk trabeculectomy surgeries for glaucoma. Subconjunctival anesthesia is now used as an alternative to peribulbar or retrobulbar anesthesia for trabeculectomy or cataract surgery. Sub-Tenon’s Injection Anterior sub-Tenon’s injection offers no significant advantages over subconjunctival drug administration. In fact, sub-Tenon’s injection delivers lower quantities of drug to the eye and is associated with a greater risk of perforating the globe. Despite these disadvantages, however, anterior sub-Tenon’s injections of corticosteroids are occasionally used in the treatment of severe uveitis. Posterior sub-Tenon’s injection of corticosteroids is most often used in the treatment of chronic equatorial and mid-zone posterior uveitis, including inflammation of the macular region. Cystoid macular edema after cataract extraction and diabetic macular edema are treated occasionally with sub-Tenon’s repository steroids. Anecortave acetat (Retaane), a synthetic derivative of cortisol, has been delivered as a posterior juxtascleral depot to exert an angiostatic effect in patients with exudative age-related macular degeneration. The drug is administered with a specially designed curved cannula at 6-month intervals. Retrobulbar Injection Drugs have been administered by retrobulbar injection since the 1920s.The procedure was originally developed to anesthetize the globe for cataract extraction and other intraocular surgeries, and this remains its principal clinical use. However, antibiotics, vasodilators, corticosteroids, and alcohol have also been administered through this route. Currently, retrobulbar anesthetics are frequently used, retrobulbar corticosteroids are used occasionally (although their clinical value remains controversial and unproved), and retrobulbar alcohol or phenol is rarely administered for intractable ocular pain in blind eyes. Although retrobulbar anesthesia has been used routinely for cataract surgery, many surgeons are now using topical anesthetics for most contemporary cataract extractions. Peribulbar Injection Because of the risks associated with retrobulbar injections, the peribulbar technique was introduced during the mid-1980s.The procedure consists of placing one or two injections of local anesthetic around the globe but not directly into the muscle cone (Figure 3-18). Because the fascial connections of the extraocular muscles are incomplete, the anesthetic injected around the globe eventually infiltrates the muscle cone to provide anesthesia and akinesia. Although neither the retrobulbar nor the peribulbar procedure allows visualization of the injection site, the retrobulbar technique intentionally aims for the muscle cone, which contains vital structures.This can be accomplished only by placing the needle extremely close to the globe. In contrast, the peribulbar procedure 50 CHAPTER 3 Ophthalmic Drug Delivery Box 3-3 Complications of Retrobulbar or Peribulbar Injections Figure 3-18 Peribulbar injection technique, in which the needle avoids the intraconal space. (Adapted from Fry RA, Henderson J. Local anaesthesia for eye surgery.The periocular technique.Anaesthesia 1989;45:14–17.) intentionally avoids the globe and the muscle cone, which makes it safer. Compared with the retrobulbar technique, peribulbar anesthesia provides similar anesthesia and akinesia for both anterior segment and vitreoretinal surgical procedures, but some patients may have inadequate akinesia and require additional injections. In addition, the onset time of blockade is not as rapid as with retrobulbar injection. Nevertheless, peribulbar anesthesia reduces the potential for inadvertent globe penetration, retrobulbar hemorrhage, and direct optic nerve injury.Although serious problems with retrobulbar and peribulbar injections are uncommon, numerous complications have been reported (Box 3-3). INTRACAMERAL ADMINISTRATION Intracameral administration involves delivering a drug directly into the anterior chamber of the eye. The most common clinical application is the injection of viscoelastic substances into the anterior chamber during cataract extraction and glaucoma filtering surgeries to protect against corneal endothelial cell loss and flat anterior chamber. Ethacrynic acid and tissue plasminogen activator have also been administered intracamerally. More recently, a 1-mm pellet incorporating 60 mcg dexamethasone consists of a biodegradable polymer that is inserted into the eye at the conclusion of cataract or other intraocular surgery. This sustained-release pellet (Surodex) provides high intraocular steroid levels for 7 to 10 days. Use of intracameral lidocaine has been introduced as a method of supplementing topical anesthesia during cataract surgery. Unpreserved 1% lidocaine is injected into the anterior chamber immediately after the paracentesis incision before injection of viscoelastic agent. Retrobulbar hemorrhage Conjunctival and eyelid ecchymosis Proptosis Exposure keratopathy Elevated intraocular pressure Contralateral amaurosis Respiratory arrest Bradycardia Central retinal artery/vein occlusion Optic atrophy Transient reduction in visual acuity Extraocular muscle palsies Ptosis Pupillary abnormalities Chemosis Eyelid swelling Pain Cardiovascular or central nervous system drug toxicity Accidental perforation or explosion of the globe Retained intraorbital needle fragment The lidocaine anesthetizes the iris and ciliary body and can reduce patient discomfort during the surgical procedure. INTRAVITREAL ADMINISTRATION Many drugs have been injected directly into the vitreous. These include antibacterial and antifungal agents for treatment of bacterial and fungal endophthalmitis, respectively, and antivirals for treatment of viral retinitis. The treatment of many intraocular diseases using systemically administered drugs is hampered because of poor drug penetration into the eye.The tight junctional complexes of the retinal pigment epithelium and retinal capillaries serve as the blood–ocular barrier, which inhibits penetration of antibiotics into the vitreous. Patients with endophthalmitis can be successfully treated using intravitreal and subconjunctival rather than systemically administered antibiotics. Although systemic antibiotics are often used to treat bacterial endophthalmitis, the systemic route of administration has limited efficacy as well as potential side effects that limit therapeutic success. Intravitreal triamcinolone has been used to treat diffuse diabetic macular edema. Also, an intravitreal implant delivering fluocinolone acetonide (Retisert) is effective in the treatment of patients with noninfectious posterior uveitis who have failed to respond to conventional treatment. Antiviral agents are sometimes injected intravitreally for treatment of cytomegalovirus (CMV) retinitis in patients CHAPTER 3 Ophthalmic Drug Delivery with acquired immunodeficiency syndrome. High doses of intravitreal foscarnet, cidofovir, or ganciclovir can effectively suppress CMV retinitis and preserve vision without adverse systemic effects. To circumvent the need for repeated intravitreal injections, an intraocular sustainedrelease ganciclovir implant (Vitrasert) was developed.The device is intended only for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome. The implant is a nonerodible drug delivery system consisting of a pellet containing a minimum of 4.5 mg of ganciclovir compressed into a 2.5-mm disc. The disc is coated with a thin film of polyvinyl alcohol and a discontinuous film of ethylene vinyl acetate. The device is then coated again with polyvinyl alcohol, and a suture tab made from polyvinyl alcohol is attached (Figure 3-19).The ethylene vinyl acetate and polyvinyl alcohol coatings provide a barrier for drug diffusion and therefore control the rate of drug delivery inside the eye. The Vitrasert is designed to release ganciclovir at the rate of 1 mcg/hr for 5 to 8 months.The device is surgically implanted into the vitreous cavity through the pars plana, and after the implant is depleted of ganciclovir,as evidenced by progression of the CMV retinitis, the device can be removed and replaced with a fresh implant. The average time before a second implant is needed is approximately 6 months. The Vitrasert has proved to be safe and effective for treatment of CMV retinitis as an adjunct to continued systemic therapy. Although use of the Vitrasert is relatively safe, it is not free of complications.Adverse events can occur in 10% to 20% of patients and can result in significant loss of vision. Acute and long-term complications associated with the Vitrasert or its surgical procedure include retinal detachment, vitreous hemorrhage, and endophthalmitis. Age-related macular degeneration is the leading cause of legal blindness in the United States. Choroidal vessels invade Bruch’s membrane for unknown reasons, possibly stimulated by vasoproliferative substances such as vascular endothelial growth factor (VEGF). New blood vessels penetrate the inner collagenase layer of Bruch’s membrane, spreading laterally underneath and within the plane of the drusen. This leads to an increased risk of discrete leakage of blood and serous fluid, detaching both the retinal pigment epithelium and overlying retina. Anti–VEGF compounds represent the newest approach to treatment of exudative age-related macular degeneration, and several such agents are now commercially available. Ethylene Vinyl Acetate Suture Tab Ganciclovir Polyvinyl Alcohol Figure 3-19 Cross-section of ganciclovir implant. (Modified from Charles NC, Steiner GC. Ganciclovir intraocular implant. A clinicopathologic study. Ophthalmology 1996;103:416–421.) 51 These include pegaptanib sodium (Macugen) and ranibizumab (Lucentis).These drugs are injected invitreally at specified intervals (see Chapter 31). PHOTODYNAMIC THERAPY Choroidal neovascularization associated with age-related macular degeneration is difficult to treat with conventional laser procedures because normal retinal tissues can be destroyed, which results in loss of central vision. Photodynamic therapy offers the opportunity to selectively eradicate neovascular membranes while producing minimal damage to normal retinal and choroidal tissues. The procedure involves intravenous administration of verteporfin (Visudyne) for 10 minutes. Verteporfin is a potent photosensitizing dye.Five minutes after the conclusion of dye administration, during which time the drug selectively accumulates in the neovascular tissue, nonthermal light at 689 nm is applied to the abnormal tissues for 83 seconds. When activated by light, verteporfin causes the production of singlet oxygen and free radicals that produce cell death and occlusion of abnormal vessels. Photodynamic therapy appears to be a safe procedure. Infrequent complications include reactions at the injection site, transient reduction in vision, and photosensitivity lasting less than 24 hours. No interactions between verteporfin and other medications have been reported. The use of verteporfin in the photodynamic therapy of neovascular age-related macular degeneration has been shown to be effective in stabilizing the disease.Although retreatments are usually needed for recurring vessel leakage, this therapeutic modality has proved to be an important treatment for patients with the neovascular form of age-related macular degeneration. It has also proved beneficial in treating choroidal neovascularization not associated with age-related macular degeneration, such as pathologic myopia, ocular histoplasmosis, angioid streaks, and that due to idiopathic causes. SELECTED BIBLIOGRAPHY Ariturk N, Oge I, Erkan D, et al.The effects of nasolacrimal canal blockage on topical medications for glaucoma. Acta Ophthalmol Scand 1996;74:411–413. Augustin AJ, D’Amico DJ, Mieler WF, et al. 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