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 (Gt), initiating GDP–GTP exchange and formation of the activated αt-GTP subunit. αt-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 αt-GTP also help to restore the system to the ground state, with re-formation of the heterotrimeric form of Gt-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.
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.