Ординатура / Офтальмология / Английские материалы / Slatter's Fundemental of Vetrinary Ophthalmology 4th edition_Maggs, Miller, Ofri_2008

damage to the globe (Figure 3-8). Severe ophthalmic inflammation, no matter how brief, or chronic inflammation, even if mild, often results in loss of vision and must be treated vigorously if irreparable damage is to be averted. In these diseases a rapid diagnosis must be made, corticosteroid therapy begun early, clinical signs of inflammation monitored closely, and therapy tapered slowly to avoid progression. If the clinical effect is less than desired, it is often better to increase the frequency of dosage rather than changing the concentration of the drug.

Corticosteroids reduce resistance to many microorganisms and should not be used in their presence without coincident use of an effective antimicrobial agent. Accurate differential diagnosis is essential whenever steroids are used. In addition to potentiating microbial infection corticosteroids increase the activity of proteases present in corneal ulcers by up to 13 times, often resulting in rapid collagenolysis (“melting”) of the cornea with rupture of the globe and prolapse of the ocular contents. Likewise, although inhibition of collagen formation and fibroblastic activity by corticosteroids is useful in reducing corneal scarring, it may be detrimental to the healing of surgical wounds, requiring that suture removal be delayed. Ocular discharge or pain in any patient undergoing corticosteroid treatment requires immediate cessation of the corticosteroid and a prompt and complete ophthalmic examination.

Topically administered corticosteroids also are known to elevate IOP. This issue has been most closely investigated in humans, in whom a familial susceptibility to ocular hypertension from topical dexamethasone use is noted. Small increases in IOP also have been recorded experimentally in beagles with inherited open-angle glaucoma and in cats in response to topical corticosteroids, but clinically significant complications resulting from such pressure elevations have not been reported.

Ocular Penetration of Corticosteroids

Dexamethasone, betamethasone, prednisolone, prednisone, triamcinolone, and hydrocortisone are used commonly in veterinary ocular therapy. A variety of other corticosteroids used in human ophthalmic therapy because they are less likely to raise IOP are not widely used in veterinary ophthalmology. Corticosteroids penetrate the cornea to varying extents when applied topically. Factors affecting the penetration and effect of a corticosteroid are as follows:

•The salt used: Acetates are more lipid-soluble and penetrate the cornea better than succinates or phosphates.

•Frequency of application: More frequent application results in higher intraocular concentration.

•Concentration of the drug: Low concentrations of a highly potent steroid may have less antiinflammatory effect than a high concentration of a less potent steroid; for instance, topical 1.0% prednisolone has an antiinflammatory effect similar to that of 0.1% dexamethasone, although dexamethasone has a greater ocular antiinflammatory potency than prednisolone (see Figure 3-2).

•Proximity to the site of inflammation: The route of administration is chosen in relation to the intended site of action (see Figure 3-1). Inflammation of the cornea, conjunctiva, or anterior uvea is usually treated topically with a penetrating corticosteroid, or occasionally with subconjunctival injection. Systemic therapy is required if involvement of adnexal, posterior uveal, retinal, optic nerve, or orbital tissues is suspected. The retrobulbar route is also effective for disorders of the choroid, retina, optic nerve, and orbit but is rarely used.

For most ocular disorders topical administration of 1.0% prednisolone or 0.1% dexamethasone is advised. Hydrocortisone, a low-potency corticosteroid, does not penetrate the cornea in any meaningful quantities. This feature renders it useless for intraocular or deep corneal disease. Its availability only in combination with three antibiotics in commercial preparations makes it an even less appropriate choice for most surface eye disease of dogs, cats, and horses.

Most injectable steroids are suitable for subconjunctival use, with periods of activity varying from 7 to 10 days (triamcinolone, dexamethasone) to 2 to 4 weeks (methylprednisolone). Care must be taken with repository forms given subconjunctivally because they may leave unsightly and sometimes inflamed subconjunctival plaques requiring surgical removal. Repository corticosteroids also have the distinct disadvantage that they cannot be removed if the disease process changes.

Long-Term Therapy

Unlike with the human eye, long-term topical therapy with corticosteroids does not predispose the canine eye to glaucoma or cataract. Occasional statements that such treatment results in fungal superinfection (infection with unusual organisms) are

not supported by research evidence. However, long-term topical usage in dogs may cause increases in liver enzymes and, especially in smaller dogs, adrenal suppression, and these effects should be taken into account in interpretation of laboratory tests and in management of patients with hepatic or endocrine disorders. Perhaps the most common clinical scenario in which the systemic effects of a topically applied corticosteroid may be important is the treatment of lensinduced uveitis due to cataracts in diabetic dogs. Although serious clinical disturbances due to such treatment occur infrequently, the lowest concentration and frequency that produce the desired clinical effect should be used, or an NSAID considered. In particularly susceptible animals on continuous therapy, occasional laboratory evaluation should be considered.

Long-term use of topical corticosteroids may cause reversible adrenocortical suppression or may disrupt management of diabetes mellitus. Clinical consequences in otherwise healthy patients are rare.

General Indications for Corticosteroid Use

General indications for use of corticosteroids are as follows:

•Immune-mediated ocular disorders (seasonal allergic conjunctivitis, drug and contact allergies, chronic superficial keratitis or “pannus,” eosinophilic keratoconjunctivitis, episcleritis, some cases of keratoconjunctivitis sicca, lensinduced uveitis, uveodermatologic (VKH-like) syndrome, etc.)

•Traumatic conditions resulting in severe inflammation (proptosis of the globe, contusion with hyphema)

•Anterior uveitis

•Postoperative immunomodulation (e.g., after corneal transplant or cataract extraction)

•Reduction of postoperative swelling and inflammation after cryosurgery (e.g., cyclocryotherapy or cryoepilation for distichiasis or eyelid tumors)

NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Numerous NSAIDs have an important place in ophthalmology because of their potency, the destructive ocular effects of uncontrolled inflammation, and the sometimes undesirable effects of corticosteroids. NSAIDs inhibit the cyclooxygenase pathway but not the lipoxygenase pathway; therefore they tend to be less potent than corticosteroids. Carprofen, which inhibits cyclooxygenase-2, represents the newer class of more selective cyclooxygenase inhibitors that are claimed to have fewer and lesser deleterious effects on prostaglandin synthesis in the gastrointestinal tract and kidneys. The original systemic agents used for ocular disorders in animals were acetylsalicylic acid (aspirin), and flunixin meglumine. Although flunixin is not approved by the U.S. Food and Drug Administration (FDA) for use in dogs, there are a number of studies describing its use in this species.

Many NSAIDs are available for human use, but, because of severe side effects, caution must be used in extrapolating their systemic use to animals. For example, ibuprofen, naproxen, and indomethacin should not be used systemically. Recently carprofen, ketoprofen, piroxicam, meloxicam, deracoxib, and

etodolac have become available for veterinary use, typically for uveitis or postoperative analgesia. Systemic nonsteroidal drugs inhibit disruption of the blood-ocular barriers (aspirin and flunixin, 70% to 80%; dexamethasone and flunixin, 61%; aspirin, 50%; carprofen, 71%). Etodolac has similar ophthalmic uses but also causes keratoconjunctivitis sicca in some dogs. When given orally these drugs sometimes result in gastric ulceration and hemorrhage. This effect is not related to hydrochloric acid production per se, and cimetidine has not been proven to have a protective effect in dogs. However, the ulcerogenic effects of orally administered NSAIDs may be reduced by the concomitant oral administration of misoprostol. All drugs in the NSAID class should be used with caution and never in association with systemic corticosteroids.

Topical NSAIDs, including indomethacin, flurbiprofen, suprofen, diclofenac, and ketorolac, are available and may be used in place of topical corticosteroids, compared with which they appear to be slightly less potent but also less likely to inhibit would healing. They are used for the same conditions that corticosteroids would be but may be preferred in diabetic or cushingoid patients owing to their lack of systemic adrenocortical effects. Topical NSAIDs inhibit breakdown of the blood-aqueous barrier by 80% to 99% in research studies. Clinical use of NSAIDs is summarized in Table 3-14.

IMMUNOMODULATING THERAPY (IMMUNOSUPPRESSANTS AND IMMUNOSTIMULANTS)

Various drugs are used to modulate (upregulate or downregulate) the host immune response. A complete discussion of these agents is beyond the scope of this book, and only those currently used for specific ocular disorders in animals are referred to.

Azathioprine

Azathioprine is an antimetabolite and T-cell suppressor used to treat severe immune-mediated diseases of dogs in which an infectious organism is not suspected, such as uveodermatologic syndrome (VKH-like syndrome), serous retinal detachments, nodular granulomatous episcleritis, and optic neuritis. It may be used alone or in combination with corticosteroids if they have failed when used alone. The immunosuppressive effects of azathioprine may not be evident or complete until 3 to 5 weeks after initiation of therapy, and additional agents may be necessary during this period. The recommended initial dose for most immune-mediated disorders in dogs is 2 mg/kg daily. This should be tapered at about 1 week to 0.5 to 1 mg/kg every second day, and reduced again to 1 mg/kg once weekly as soon as clinical signs permit it. Lower doses and shorter durations may be used if responses are rapid. Plasma hepatic enzyme concentrations, total white blood cell count, and platelet count should be monitored every 2 weeks for the first 8 weeks, then at least monthly during therapy. Elevations of liver enzymes may occur, especially if corticosteroids are used concurrently. This drug is less safe in cats, for which alternatives should be sought.

Cyclosporine

Cyclosporine suppresses production of the lymphokine interleukin-2 by helper T lymphocytes and enhances function

of suppressor T lymphocytes. Cyclosporine affects both cellmediated immunity and, possibly, humoral immunity by inhibition of helper T cells but does not affect epithelial wound healing. When applied topically it penetrates the eye poorly and is not useful via this route for treatment of intraocular inflammation. However, topical application is used for moderating immune responses involving the lacrimal gland, conjunctiva, cornea, and sclera. It is used for treatment of keratoconjunctivitis sicca, corneal graft rejection, autoimmune keratitis (especially “pannus”), and immune-mediated episclerokeratoconjunctivitis. Intraocular concentrations are achieved with the use of intravitreous or suprachoroidal implants. These devices have been used successfully for the treatment of equine recurrent uveitis in selected individuals.

Cyclosporine’s most important ophthalmic use is in treatment of canine keratoconjunctivitis sicca. It reduces autoimmune destruction of the lacrimal gland and gland of the third

eyelid (with spontaneous regeneration of these glands while treatment is continued) and directly reduces keratoconjunctivitis. The drug is also directly lacrimogenic. Finally, cyclosporine directly stimulates canine conjunctival goblet cells to secrete mucin, possibly accounting for some of its therapeutic effect in canine keratoconjunctivitis sicca and qualitative tear film disturbances. For all of these seasons, it is the most frequently used drug for canine keratoconjunctivitis sicca. Cyclosporine is absorbed systemically after topical administration in dogs, and although depressed cell-mediated immunity can be demonstrated by lymphocyte stimulation indices, clinically relevant immunosuppression has not been reported. The drug is applied as a 1% or 2% solution in corn, canola, or olive oil, or as a 0.2% ointment. An aqueous preparation can be compounded. Cyclosporine is also used orally for the treatment of canine atopic dermatitis, including blepharitis.

Tacrolimus

The mechanism of action of tacrolimus is similar to that of cyclosporine, in that it reduces T-cell activation by inhibiting calcineurin-dependent activation of lymphokine expression, apoptosis, and degranulation. However, the intracellular receptors for tacrolimus and cyclosporine are different, leading some veterinary ophthalmologists to use tacrolimus when cyclosporine is not effective for the treatment of keratoconjunctivitis in dogs. A 0.02% aqueous suspension was recently investigated in a double-masked study of 105 dogs with keratoconjunctivitis sicca. Dogs naïve to tear stimulation therapy, dogs maintained successfully on cyclosporine therapy, and dogs unresponsive to cyclosporine therapy were all included. Twice-daily tacrolimus administration was continued for 6 to 8 weeks. Schirmer tear test results improved by 5 mm/min in more than 85% of dogs never treated before and in 51% of dogs whose disease was unresponsive to cyclosporine.

In March 2005 the FDA issued a public health advisory to inform health care providers and patients about a potential cancer risk (lymphoma and “skin cancer”) associated with the commercial topical (dermatologic) preparation of tacrolimus for human use. This issue may be relevant to topical (ophthalmic) veterinary use. The FDA’s concern was based on information from animal studies, case reports in a small number of patients, and how drugs of this class work. The FDA estimates that it may take human studies of 10 years or more in duration to determine whether use of tacrolimus is linked to cancer. In the meantime the agency advises that tacrolimus should be used only as labeled and for patients whose disease is unresponsive to or who are intolerant of other treatments. The FDA also recommends avoiding use of tacrolimus in children younger than 2 years, using tacrolimus only for short periods of time rather than continuously, and using the minimum amount needed to control the patient’s symptoms. Owners of veterinary patients should be advised of these guidelines and to wear gloves when applying this medication. Additionally, tacrolimus and cyclosporine are currently not recommended for patients with active feline herpesvirus infection.

Immunostimulants

Nonspecific immune stimulants are sometimes used with variable results to treat ocular neoplasia. Perhaps the most widely used is live bacille Calmette-Guérin (BCG) vaccine or cell wall extracts of the same organism for the treatment of periocular equine sarcoid. Extracts of other organisms that stimulate the reticuloendothelial system, nonspecific immunostimulants, and staphylococcal bacterins have also been used on occasions for ophthalmic conditions, but little is published regarding their use.

MAST CELL STABILIZERS AND

ANTIHISTAMINES

Medications that stabilize mast cells are used topically to prevent release of histamine and other mediators of inflammation in humans. They have received less use in veterinary patients; however, some veterinarians recommend their use in patients with seasonal allergic conjunctivitis or eosinophilic keratoconjunctivitis, usually in association with topical corticosteroids. Examples of mast cell stabilizers are sodium cromoglycate, olopatadine, and lodoxamide.

Antihistamines are little used in ocular therapy. Systemic antihistamines may be of some use in acute allergic conjunctivitis; however, contact dermatitis and conjunctivitis, especially of the drug-induced variety, are not histamine-mediated. In almost all ocular disorders for which antihistamines have been advocated, corticosteroid or immunosuppressive therapy is more effective.

HYPEROSMOTIC AGENTS

A hyperosmotic agent increases the osmotic concentration of blood perfusing the eye when administered systemically or of the tear film when applied topically. Because of the corneal epithelial and blood-ocular barriers, little or no osmotic agent enters the aqueous humor or vitreous, and the osmotic gradient created causes withdrawal of water from the eye to the vascular system or tears. Systemic administration of osmotic agents therefore causes reduction of vitreous volume. This, in turn, reduces IOP, both directly and via posterior movement of the lens, which reduces pupillary block and increases aqueous humor outflow facility via opening of the iridocorneal angle and ciliary cleft (see Chapter 12). Mannitol is the most commonly used systemic agent. Other osmotic agents, such as urea, glycerol, and isosorbide, were used in the past but are not used now because they lower IOP less effectively, cause tissue necrosis after perivascular leakage (urea), or cause emesis (glycerol). Osmotic drugs are applied topically to clear or reduce corneal edema. Hypertonic (5%) sodium chloride is the commonly used topical agent.

Mannitol

Mannitol is a vegetable sugar that is not metabolized and is excreted in the urine, causing osmotic diuresis. However, diuresis is not the cause of reduced IOP. Mannitol is not absorbed after oral administration and therefore must be administered intravenously. After intravenous administration IOP typically falls within 30 to 60 minutes and remains low for 5 to 6 hours. Mannitol increases serum osmolality and stimulates thirst, but if the ophthalmic effect is to be maintained, water intake must be controlled by providing small amounts of water or ice cubes. Mannitol is not used for longterm treatment of glaucoma and should not be used in animals with chronic renal failure or congestive heart failure. For acute glaucoma 1 to 2 g/kg mannitol should be administered intravenously over 10 to 20 minutes. This can be used in conjunction with an oral or topical carbonic anhydrase inhibitor and a topical miotic agent such as pilocarpine (or, more recently, a synthetic prostaglandin analogue), because these agents are synergistic.

Topical Hyperosmotic Sodium Chloride

Sodium chloride prepared as 5% ointment or solution can be used for reduction of corneal edema as seen in bullous keratopathy, superficial corneal erosion, and endothelial dysfunction. In patients with more advanced corneal edema the goal of therapy should be not clearing of the corneal opacity but rather reduction of epithelial bullae. Responses are somewhat limited by the short time such applications alter tear osmolality. Therefore frequent application is necessary. Because of duration of effect, ointments are usually more successful and appear to be less irritating.

AUTONOMIC DRUGS

Many important diagnostic and therapeutic drugs used in ophthalmology act on ocular structures with autonomic innervation. The autonomic nervous system is divided into parasympathetic and sympathetic components, with antagonistic but not necessarily equal actions. Important features of the parasympathetic and sympathetic innervation of the eye, and the sites of action of commonly used drugs, are summarized in Figures 3-9 and 3-10. In both systems the neurohumoral transmitter at the ganglion is acetylcholine, which passes across the synaptic cleft and depolarizes the postsynaptic membrane. This action of acetylcholine is terminated through its cleavage by acetylcholinesterase. In the parasympathetic system the postganglionic transmitter is also acetylcholine, but in the sympathetic system, it is norepinephrine. Norepinephrine also causes depolarization of the muscle cell, but it is not dissipated as simply as acetylcholine in the parasympathetic system. After release by the postganglionic sympathetic terminal norepinephrine may enter the effector cell, may diffuse into the vascular system, may undergo enzymatic degradation, or may be reabsorbed by the postganglionic terminal (Figure 3-11). After a period of absence, sympathetic or parasympathetic effector cells that are deprived of transmitter substance become very sensitive to the effects of that transmitter if it is applied. This phenomenon,

called denervation hypersensitivity, is used to pharmacologically localize the site of denervation in Horner’s syndrome.

Autonomic drugs may upregulate or downregulate the passage of a nerve impulse in a number of ways (see Figures 3-9 and 3-10). The ocular effects of the autonomic agents commonly used in animals include mydriasis (pupil dilation), miosis (pupil constriction), cycloplegia (paralysis of the ciliary muscle), and ciliary body contraction (opening of the iridocorneal angle); they are summarized in Box 3-2. Note that pharmacologic mydriasis may be caused by paralysis of the iris sphincter muscle or stimulation of the iris dilator muscle, whereas miosis may be caused by stimulation of the iris sphincter muscle or paralysis of the dilator muscle. However, species variation occurs. The iris in birds and reptiles is composed predominantly of striated fibers, and skeletal neuromuscular blocking agents (sometimes in addition to autonomic agents) must be used to produce mydriasis because the parasympatholytic agents used in mammals have little effect (see Chapter 20).

Parasympatholytic (Anticholinergic) Agents

Atropine

Atropine is a parasympatholytic agent used as a mydriatic and a cycloplegic agent principally for treatment of anterior uveitis (iridocyclitis). In patients with anterior uveitis, mydriasis reduces

CNS C7 T1 T2

Antagonists

Preganglionic

neuron

Cranial cervical ganglion

Postganglionic

Block storage of neuron norepinephrine

Agonists

Stimulates ganglion

Acetylcholine

Release of norepinephrine from nerve endings

OH-Amphetamine

Benzedrine

Cocaine

Release of norepinephrine and direct muscle stimulation

Stimulate neuromuscular receptor

Epinephrine (Adrenaline) ( and )

Apraclonidine ( 2 )

0 - methylation

Bloodstream

FIGURE 3-11. Fate of norepinephrine. After release by the postganglionic sympathetic terminal, norepinephrine (NE) may enter the effector cell, diffuse into the vascular system, undergo enzymatic degradation, or be reabsorbed by the postganglionic terminal. (Modified from Kramer SG, Potts AM [1969]: Iris uptake of catecholamines in experimental Horner’s syndrome. Am J Ophthalmol 67:705.)

the chances of posterior synechia, whereas cycloplegia reduces the pain of ciliary body spasm. Mydriasis induced by atropine may be enhanced by addition of sympathomimetic agents (e.g., phenylephrine); however, the sympathomimetic agents do not

augment cycloplegia and therefore are not analgesic. Atropine’s duration of action may be many days in some dogs and cats, and longer than 1 week in horses. Therefore atropine (1%) drops and ointment should always be administered therapeutically to effect (i.e., until mydriasis is induced). Initially the frequency may be 2 or 3 times daily, but this can usually be reduced rapidly. The long duration of action also makes atropine an inappropriate mydriatic agent for ophthalmic examination, for which short-acting agents such as tropicamide are preferred. Atropine (and other dilating agents) may induce ocular hypertension and ultimately worsen glaucoma in susceptible breeds of dogs (e.g., basset hound, cocker spaniel). The parasympatholytic properties of atropine also decrease tear flow after conjunctival instillation. Therefore atropine is contraindicated in animals affected with lens luxation, glaucoma, and keratoconjunctivitis sicca.

Following are some important species-specific considerations for the use of atropine:

•Horses in which topical atropine is being used frequently should be carefully observed for signs of colic, including absence of borborygmi, kicking or looking at the abdomen, increased pulse rate, and sweating.

These drugs may also be used to augment mydriasis, but without coincident paralysis of the sphincter muscle with a parasympatholytic agent, they are weak mydriatic agents and so are not used alone for this purpose. Phenylephrine causes some mydriasis in dogs but is ineffective as a mydriatic in horses and cats. Repeated use of phenylephrine at short intervals and high concentrations can cause systemic hypertension.

Topical application of dipivefrin is also used for treatment of glaucoma. Following conversion to epinephrine this drug acts intraocularly to decrease production of aqueous humor without causing major changes in pupil size. It also stabilizes vascular endothelium. For this reason it has some use in treatment of glaucoma secondary to anterior uveitis in domestic animals.

Parasympathomimetic (Cholinergic) Agents

All commonly used topical parasympathomimetic agents in veterinary ophthalmology (see Box 3-2) induce miosis and/or increase the facility of outflow of aqueous humor in glaucomatous and normal eyes. This effect may be due to stimulation of portions of the ciliary muscle that insert in the area of the iridocorneal angle, resulting in increased drainage via the trabecular meshwork. Contraction of the ciliary muscle may also result in larger trabecular spaces through which fluid may exit. Therefore their clinical indication is for treatment or delaying the onset of glaucoma. It is important to note that ciliary muscle spasm is often painful, especially in patients with preexisting anterior uveitis (iridocyclitis); therefore these drugs may induce intraocular pain.

Direct-Acting Parasympathomimetic Agents

PILOCARPINE. Pilocarpine is the archetypical direct-acting parasympathomimetic agent. It acts directly on the muscle cells of the pupillary sphincter and ciliary body and is effective even in the denervated eye or after retrobulbar anesthesia when release of acetylcholine at the neuromuscular junction is blocked. Pilocarpine also stimulates secretory glands and may be used topically or systemically in patients with keratoconjunctivitis sicca, although the T cell–modulating drugs, such as cyclosporine and tacrolimus, are more effective, have fewer side effects than pilocarpine, and have largely replaced it for treatment of this disease. Overdosage of topically or systemically applied pilocarpine results in salivation, vomiting, and diarrhea, especially in cats. Pilocarpine penetrates the eye after topical instillation, and intraocular concentration depends on frequency of application and concentration of the drops. However, pilocarpine tends to be very irritating and induces breakdown of the blood-ocular barrier (and aqueous flare) when applied topically, especially at higher concentrations. As a result of these side effects and the availability of more potent, better-tolerated hypotensive agents, it is now rarely used for management of glaucoma in veterinary ophthalmology.

Indirect-Acting Parasympathomimetic Agents

Organophosphates are indirect-acting parasympathomimetic agents and may be reversible or irreversible in nature. They act by inhibition of cholinesterase, causing preservation of acetylcholine, and hence have no effect on denervated structures. Combinations of directand indirect-acting parasympathomimetic agents do not result in more profound or prolonged miosis, and

with some combinations, competitive inhibition occurs. The reversible inhibitors such as physostigmine and carbachol are not used in the control of glaucoma, because the irreversible agents such as demecarium are more effective and require less frequent administration. If treatment with any of the irreversible agents fails, the use of another member of the group is rarely useful. All drugs of this group may cause severe and even fatal systemic toxicity through excessive topical treatment (concentration or frequency of application), especially in cats. Signs of systemic toxicity include vomiting, diarrhea, anorexia, and weakness. Particular care must be taken to avoid additive effects of these drugs with other organophosphates in flea collars, washes, and systemic parasiticides.

DEMECARIUM. Demecarium is stable in aqueous solution and is usually administered once or twice daily. Demecarium bromide, given once daily in conjunction with a topical corticosteroid (also once daily), significantly prolongs the time to onset of primary glaucoma in dogs. Iridocorneal angle closure was delayed for 32 months in dogs treated with this combination, compared with 8 months in untreated dogs. This drug is no longer commercially available but can be compounded as a 0.125% or 0.25% solution.

CARBACHOL. Carbachol is a direct-acting parasympathomimetic agent. However, it is reported to also have some indirect (cholinesterase-inhibiting) action. It causes modest decreases in IOP in beagles with inherited open-angle glaucoma. It has longer duration of action than pilocarpine, requiring administration 2 to 3 times daily, but frequently has systemic side effects in dogs. Despite being a more powerful miotic than pilocarpine, carbachol (3%) is less useful in the treatment of glaucoma than the irreversible cholinesterase inhibitors. It is used intracamerally by some veterinary ophthalmologists immediately after cataract surgery to reduce transient postoperative rises in IOP.

Sympatholytic Agents (Adrenergic Antagonists)

Numerous agents have become available that block, with different selectivity, a- and/or b-receptors. b-Blockers (b-antagonists) are thought to lower IOP by reducing blood flow to the ciliary body. However, sympathetic receptors are found in the iridocorneal angle and drainage pathway and may also play a role in the action of these drugs.

An expanding array of topical sympatholytic agents is used for human glaucoma. Examples are timolol, betaxolol, levobunolol, carteolol, and metipranolol. Those that have been studied in veterinary patients (principally dogs and cats) lower IOP poorly and have limited use in therapy of overt glaucoma in these species. However, these agents may have a role in glaucoma prophylaxis in dogs. A recent study showed that betaxolol given twice daily significantly prolonged the time to onset of primary glaucoma to 32 months, compared with 8 months in untreated dogs. Care must be taken in administering these agents to animals with cardiac or respiratory disease, and therapy should be stopped 3 to 4 days before administration of general anesthesia. Timolol (0.5%) has been studied in normal horses and does lower IOP, but only by about 4 to 5 mm Hg. Its efficacy in horses with glaucoma has not been studied.

CARBONIC ANHYDRASE INHIBITORS

The enzyme carbonic anhydrase is present in ciliary body epithelium, where it is responsible, in part, for aqueous humor

production. Carbonic anhydrase inhibitors (CAIs) reduce aqueous humor production by up to 50%, thereby decreasing IOP, and their role in veterinary ophthalmology is in the management of acute glaucomatous crises as well as long-term control of IOP in some patients. When administered systemically these drugs also inhibit carbonic anhydrase in the renal tubular epithelium and may cause mild diuresis. However, just as with osmotic agents, their IOP-lowering effect is not the result of this diuresis. Similarly, other diuretics such as furosemide do not significantly reduce aqueous humor production or IOP and should not be used for this purpose. Although diuresis is usually not clinically significant with this group of agents, systemically administered CAIs may cause other undesirable side effects, such as metabolic acidosis (usually noted as panting), gastrointestinal disturbance, and, in some cases, increased urinary loss of potassium with long-term use. Occasionally, severe skin reactions or disorientation have been reported with some CAIs. If side effects occur in a particular patient, they are rapidly reversible upon discontinuation of the drug, and another CAI may be better tolerated. Topically administered CAIs are not associated with systemic side effects.

Systemic Carbonic Anhydrase Inhibitors

The archetypical CAI was acetazolamide; however, because this drug causes vomiting more frequently than more modern agents in this group, it has now been largely replaced by CAIs such as methazolamide and dichlorphenamide. These drugs are usually administered two to three times daily at 2 to 5 mg/kg. They are typically well tolerated in dogs, but side effects seem more frequent in cats.

Topical Carbonic Anhydrase Inhibitors

Dorzolamide and brinzolamide are topically applied CAIs. They lower IOP in dogs and cats when applied three times daily and are a useful part of a combined regimen to lower IOP. They may be used in patients whose glaucoma occurs secondary to uveitis and have the advantage of lack of systemic side effects. However, they occasionally sting and tend to be expensive. They are usually used to replace rather than supplement systemically administered CAIs.

PROSTAGLANDIN ANALOGUES

Latanoprost, travoprost, bimatoprost, and unoprost are synthetic prostaglandins developed for the treatment of glaucoma in human beings but with some application in canine glaucoma. Latanoprost is potent and effective in reducing IOP in canine glaucoma, and is also important in the emergency treatment of glaucoma in dogs, in which it has largely replaced pilocarpine (see Chapter 12). Travoprost lowers IOP significantly, and to a degree equivalent to that achieved by latanoprost, in normal dogs. Prostaglandin analogues are ineffective in the treatment of glaucoma in cats and horses.

LOCAL ANESTHETICS

Topical (local) anesthetics are used for ocular examinations and minor manipulative and surgical procedures, but never for therapeutic purposes. The effect on corneal sensation of a single drop of proparacaine or 2 drops separated by 1 minute

has been studied. Application of 1 drop leads to maximal anesthesia for 15 minutes and statistically (although not necessarily clinically) significant reductions in corneal sensation for 45 minutes. These times increase to 25 minutes (maximal) and 55 minutes (duration) if a second drop is applied 1 minute after the first. In addition, 2 drops applied 1 minute apart caused a significantly greater anesthetic effect than did 1 drop when measured 30 through 55 minutes after application. Again, this difference was statistically significant, but its clinical significance was not explored.

The following cautionary notes should be considered in the use of this group of drugs:

•All topical anesthetics inhibit corneal epithelialization and are toxic to normal corneal epithelium. They produce small punctate ulcerations in normal cornea.

•Some are extremely toxic systemically (5 mL of 2% tetracaine solution is a fatal human dose) and are rapidly absorbed from the conjunctival sac. This fact is of most importance in the treatment of very small (exotic) veterinary patients.

•Some anesthetics are antigenic and may cause sensitization.

•Local anesthetics should not be dispensed to owners for any reason.

•Local anesthetics placed into diseased, painful eyes abolish protective reflexes and increase the chance of further injury (e.g., entropion) in addition to causing corneal lesions themselves.

•Ophthalmic anesthetics (like all other topical drugs) are unsuitable for injection.

Local anesthetics should not be used therapeutically or included in any therapeutic regimen or preparation.

Classically it has been recommended that samples for bacterial analysis should be taken before local anesthetics are placed in the eye, because these agents and the preservatives they contain may be bactericidal. In reality this practice is often too uncomfortable for the patient, raising the risk of patient movement and globe rupture. There is also evidence to suggest that although topical anesthetic agents may alter the bacteria cultured in some circumstances, this feature is not consistent, and the change in bacteria cultured before and after anesthesia is rarely of clinical relevance. However, local anesthesia does reduce Schirmer tear test values by about 50% and should not be used before such tests. Of the many agents available 0.5% proparacaine is generally the most useful. Short-term storage of proparacaine at room temperature does not reduce efficacy, but storage at room temperature for more than 2 weeks results in a decrease in drug effect. Brownish solutions of proparacaine are inactivated and should not be used. Tetracaine may cause sensitivity reactions in dogs.

ENZYMES AND ENZYME INHIBITORS

Enzymes and enzyme inhibitors are used infrequently in veterinary ophthalmology but have a critical role when they are employed. Classically they fall into two broad categories: those agents used to catalyze dissolution of the protein within a blood clot, and those employed to retard the degradation of collagen in a cornea during “melting” or corneal malacia.

Hyaluronidase

Hyaluronidase depolymerizes hyaluronic acid, an important constituent of connective tissue, allowing faster passage of drugs through tissues. Therefore it is sometimes injected into the retrobulbar region to promote dispersion of contrast or anesthetic agents through orbital tissues. The permeability of tissues returns to normal in 1 to 2 days. The enzyme is nontoxic and does not cause inflammation or affect capillary permeability. However, it will not dissolve fibrin or inflammatory exudates.

Tissue Plasminogen Activator

Recombinant tissue plasminogen activator (TPA) is used by intracameral injection to lyse newly formed fibrin deposits and facilitate dispersion of hyphema in uveitis, especially traumatic and postoperative intraocular inflammation. Intracameral injections should be performed only by those trained in this technique. Doses of 15 to 25 mg are typically used. TPA must be kept frozen until used.

Protease Inhibitors

Tear film and corneal proteases are produced by corneal epithelial cells, stromal fibrocytes, inflammatory cells, and certain bacteria, such as Pseudomonas spp. They are important for normal wound healing, especially in the cornea. However, in some disease states, their production, activation, and deactivation become unregulated, leading to detrimental effects. One of the most dramatic examples of this is their role in the pathogenesis of melting or malacic corneal ulcers in which there is altered protease homeostasis.

There are at least four categories of proteases, but matrix metalloproteinases and serine proteases appear most important in corneal disease and health. They have been demonstrated in increased amounts in the tear films of dogs, cats, and horses with corneal ulceration, and reduction of tear film proteolytic activity has been demonstrated in horses as ulcers heal. Therefore various protease inhibitors have been explored for the treatment of corneal ulceration. Those used historically and currently include N-acetylcysteine, disodium ethylenediamine tetra-acetate (EDTA), tetracycline antibiotics, and autogenous serum. Of these only serum is believed to have broad activity against both serine proteinases and metalloproteinases. Serum also contains numerous growth factors that are believed to be helpful in corneal wound healing. These facts, along with the easy and inexpensive procurement of serum from the patient and because it is predictably well tolerated when topically applied, make autogenous serum the first-choice proteinase inhibitor for ophthalmic use.

Matrix metalloproteinase (collagenase) inhibitors are extremely important agents in the treatment of corneal ulceration. Autogenous serum is the most accessible and most broad in its therapeutic effects and is well tolerated.

TEAR REPLACEMENT PREPARATIONS (“ARTIFICIAL TEARS”)

Artificial tear preparations are used when the normal tear quality or quantity is altered or when loss of tears is increased

due to evaporation, or, in some cases, primary corneal pathology. These agents are lacrimomimetic and are not to be confused with lacrimogenic agents, such as cyclosporine. The production of endogenous tears is always preferred over the replacement of tears with “artificial” tears. Aqueous solutions such as normal saline are unsuitable for tear replacement because they do not adhere to the lipophilic corneal epithelium and have extremely brief ocular retention times. Additionally they dilute what endogenous tears are present, and the preservatives most contain may cause inflammation or worsening of primary disease. Therefore aqueous solutions must be modified by the addition of agents to bind the solution to the epithelium and/or increase viscosity of the preparation. In the normal precorneal tear film this function is performed by mucopolysaccharide molecules within the mucin layer of the tear film and having both hydrophilic and lipophilic ends. Solutions modified in this way, termed mucinomimetic, have longer contact time and better “eye feel,” and offer more antidesiccant advantages than traditional saline solutions. The inclusion of a bicarbonate-based buffer to retain pH near that of normal tears also helps corneal epithelium return to normal in the human eye.

Indications for tear replacement preparations are as follows:

•For treatment of keratoconjunctivitis sicca (“dry eye”)

•For treatment of exposure keratitis (e.g., facial nerve paralysis, buphthalmos, breed-associated lagophthalmos)

•In patients with abnormal tear film breakup time (qualitative tear film disturbances)

•During and after general anesthesia to prevent corneoconjunctival desiccation

•As a lubricant, refractive/electroconductive, and cushioning solution during gonioscopy and electroretinography

•As a diluent for compounding of some ophthalmic solutions

•In patients with primary corneal disease, such as feline corneal sequestration and canine superficial punctate keratitis

The most commonly used classes of lacrimomimetic preparations, grouped according to the viscosity agent used, are listed in Table 3-15.

MISCELLANEOUS THERAPEUTIC AGENTS

Surgical Adhesives

Tissue adhesive (isobutyl cyanoacrylate) has been advocated for treating some corneal ulcers in dogs, cats, and rabbits; however, it must not be permitted to enter the eye and so should not be used on leaking corneal wounds. Cyanoacrylate is used on a carefully dried corneal surface, where it engenders some inflammatory reaction that may be beneficial in stimulating healing in superficial nonhealing (indolent) corneal ulcers. Large amounts or long-term use of cyanoacrylate, however, results in severe inflammation.

Eye Washes (Collyria)

Sterile eye wash is used for removal of purulent exudates, foreign bodies, and irritants from the eyelids and conjunctival sac but not for long-term therapy. Many commercial formulas are available. Eye washes in examination rooms should be changed regularly to prevent overgrowth with contaminating microbial agents. Boric acid solution was commonly used in the past, but because of its weak germicidal action and systemic toxicity, it is no longer advocated.