I. GENERAL CONSIDERATIONS.

Many drugs that are used for other organs or systems, for example, the nervous, cardiovascular, immune, and endocrine systems, are used orally or parenterally for ocular disease conditions. With few exceptions, the content of this chapter is limited to the topically administered drugs for the eye.

A. Considerations for drug delivery in topical administration

1. The blood–ocular barriers to drug penetration are complex, protective mechanisms that complicate drug delivery to the interior of the uninflamed eye. In corneal and conjunctival diseases where the epithelium is compromised or removed, resistance to drug absorption/corneal penetration is reduced or eliminated.

2. Vascular supply of the eye. The eye is a complex organ with an intricate vascular supply to nourish highly specialized neuroreceptors and unique tissues that must remain transparent to focus light on the photo receptors deep within the organ, and a system for secretion, circulation, and absorption of a fluid to nourish and maintain intraocular pressure compatible with the primary function of vision.

B. Mechanism of action. Drugs used in ophthalmic practice are generally the same as those targeted for other systems in regard to their mechanism of action. The uniqueness of ocular pharmacology is in the vehicle or formulation appropriate for delivery of these drugs for absorption and distribution to the targeted tissues or compartments of the eye at a sufficiently high concentration without creating toxic or physical damage to other ocular tissues.

C. Pharmacokinetics. In contrast to the abundance of pharmacokinetic data for systemic drugs, few data are available for ophthalmic drugs. In many analyses, the effects of the drug (change in pupil size, lowered intraocular pressure, change in corneal thickness, changes in optical transparency, or electrophysiologic or imaging recordings) are the basis for determining absorption, distribution, and metabolism. Drug concentrations in tissues or compartments of the eye cannot be done without disturbing and impairing the “system.”

II. OPHTHALMIC DRUG DELIVERY

A. Treatment of precorneal tissues and tearfilm, cornea, iris, and ciliary body

1. Topical preparations are preferred as they achieve relatively high local concentrations with only marginal drug exposure of the rest of the body.

a. Preparations are solutions, suspensions, emulsions, and lipid- or oil-based ointments for periodic application to the surface of the eye.

b. Ocular (conjunctival) inserts and impregnated soft contact lenses for slow release facilitate convenient uniform drug delivery.

c. Subconjunctival and subtenon’s injections may provide a long-lasting slow release depot of drug for the anterior segment.

d. Systemic delivery of some agents is limited by poor penetration due to the blood–ocular barriers or the paucity or absence of blood supply (cornea, sclera, lens).

B. Other local forms of delivery to other tissues or compartments

1. Intracameral injections into the vitreous or aqueous humor.

2. Retrobulbar injections

3. Implantion of various drug impregnated, slow-release polymers intravitreally or suprachoroidally.

C. When a drop is instilled into the conjunctival sac

1. Absorption of an ocular medication from the cul-de-sac begins with mixing of the drug with tears to give some unknown dilution that is exposed to the entire conjunctival and corneal surface.

2. Tear volume (in canine) is 8–12 μL; conjunctival sac is about 3–6 μL; delivery volume is about 50 μL; at most 20 μL can be retained.

3. Excess spills over the lid margin or goes down the nasolacrimal duct.

4. Tear turnover rate is 0.5–1.0 μL/min, so the t_½ of the initial drug concentration is 3–6 minutes.

5. Slower elimination is achieved with ointments.

6. Washout times are shortened with increased lacrimation due to irritation/discomfort or increased drainage induced by blinking. (Restraint of the dog increases the blink rate.)

7. The spillover or drained portion may be absorbed by the mucous membranes in the nose or digestive tract and can lead to systemic side effects.

8. The principal route into the eye is through the cornea.

a. Epithelial and endothelial cell membrane and intercellular tight junctions limit penetration to the lipophilic agents; the stroma is hydrophilic and water-soluble agents diffuse most readily.

b. Ideally, one should couple lipophilic component to a more hydrophilic drug that would cleave or dissociate after passage through the cornea.

9. Drug binding to protein in tears or to conjunctival pigment may reduce bioavailability. Degradation by enzymes within the cornea may destroy the drug enroute, and binding to protein in aqueous humor may inactivate and hasten elimination from the anterior chamber.

10. Drug molecules pass between compartments by diffusion and active transport processes.

a. Diffusion follows concentration gradient. Related inversely to molecular size and directly to temperature.

c. Active transport is affected by competition of other substrates for the transport system.

11. Binding, diffusion, and transport processes are quite variable between individuals and species, and are affected by pathologic conditions such as inflammation.

12. Penetration into the eye through the conjunctiva is generally not relevant. Conjunctival epithelium is similar to corneal epithelium. The subconjunctiva, episclera, sclera, and choroid are not significant barriers to diffusion.

13. Drugs crossing the conjunctiva and sclera are eliminated by the blood circulation in the choroid.

14. Once through the cornea, drugs diffuse in the aqueous humor and are taken up in the iris, base of the ciliary body and the lens. There is little to no flow into the posterior segment. Posterior segment diseases cannot be treated effectively with topical medications.

15. Cornea and lens can absorb drugs, then retain and release them over a prolonged time, such as corticosteroids in the lens.

16. Drugs are eliminated from the eye in the aqueous humor outflow into the aqueous veins or by diffusion through the uveal tissues, and washout by the venous blood circulation. (There are no lymphatics in the eye.)

17. Breakdown and metabolism of drugs applied to the eye may begin in the tears and the conjunctival and corneal epithelium as well as other ocular tissues, although these processes in the eye are somewhat limited. Enzymes for oxidizing, reducing, and conjugating are present in ocular tissues (esterases, oxidases, reductases, lysosomal enzymes, peptidases, transferases, catechol-O-methyl transferase, monoamine oxidase, corticosteroid hydroxylase).

18. Many of the topically applied drugs, particularly antibiotics and corticosteroids, are not broken down in the eye, but leave the eye unchanged and enter the general circulation.

19. Eyelids and orbital tissue are best treated with systemically administered drugs as ophthalmic preparations applied to the surface of the eye do not reach these areas.

III. PRACTICAL TOPICAL DRUG THERAPY

A. Eye drops

1. Delivery volume should not exceed 50 μL; 20 μL is ideal for small animals.

2. Repeat or continuous dosing increases the pharmacologic effect. Frequent dosing can be facilitated with subpalpebral lavage or reverse nasolacrimal lavage, especially in horses.

3. A 5-minute interval between drops reduces irritation and is consistent with the average washout period of 3–6 minutes.

4. Punctal occlusion prolongs clearance time from tears and reduces systemic side effects.

B. Ointments. Prolonged contact time due to delayed melting, dilution, and breakdown, and punctual occlusion.

C. Suspensions have no advantages; only result from poorly soluble drugs.

D. Inactive ingredients

1. They are added to adjust pH, prevent oxidation, and increase absorption. Increased lipid solubility results from pH buffering with acetic acid, boric acid, hydrochloric acid or bicarbonate, phosphates, citrates, or borates.

2. Controlling the pH (7.2–7.4) and tonicity (0.9%) of the preparation to match the tears increases the comfort of the patient.

3. Methyl, hydroxyl, and hydoxypropyl methylcellulose polyvinyl alcohol, polyvinylpyrrolidone, Dextran 70, polysorbate 80, and PEG400 are viscous substances used as tear substitutes as well as drug delivery vehicles to increase corneal contact time (see XV Tear Substitutes).

IV. AUTONOMIC DRUGS

A. Introduction (see Chapter 2 for detailed information)

1. These are drugs that act primarily on the smooth muscles of the iris (sphincter and dilator) and the ciliary body (muscles of accommodation) and the smooth muscles of the arteriolar vessels.

2. Miotic agents constrict the pupil.

3. Mydriatic agents dilate the pupil.

B. Miotics: Cholinergic stimulants (parasympathomimetics). There are direct and indirect acting cholinergic stimulants to constrict the pupil and contract ciliary muscles to facilitate outflow of aqueous humor.

1. Direct acting cholinergic stimulants

a. Mechanism of action. These drugs have the muscarinic effects of acetylcholine (ACh). In the eye they activate the muscarinic receptors of the iris sphincter and ciliary muscles at the postganglionic parasympathetic neuroeffector junction. They can act on denervated structures.

b. Agents

(1) Pilocarpine (1–8% solution, 4% ointment)

(a) Chemistry. Pilocarpine is a naturally occurring lipid-soluble alkaloid.

(b) Ocular effects

i. Topical pilocarpine induces slowly increasing contraction of the iris sphincter and ciliary muscles. Miosis begins within 10 minutes, peaks in 30 minutes, and slowly decreases over 6 hours.

ii. The effect of ciliary muscle contraction on decreasing outflow resistance in the ciliary cleft is unclear, but intraocular pressure (IOP) decreases with decreased outflow resistance in the conventional trabecular meshwork pathway.

iii. The iris sphincter contraction pulls the peripheral iris from the drainage angle to minimize obstruction to outflow if the angle is narrow or closed, but the state of contraction or relaxation of the iris does not necessarily affect outflow facility.

iv. IOP is reduced 30–40% for up to 6 hours in the beagle dog. This drug is most useful in open angle glaucoma, but is usually not effective when used alone. The high IOP and structural changes in closed angle glaucoma limit the effectiveness of miotic drugs in lowering IOP in dogs.

v. Other drugs, β-blockers, carbonic anhydrase inhibitors, and prostaglandin analogs are more effective in lowering IOP than pilocarpine.

(c) Pharmacokinetics. Pilocarpine is absorbed readily into the eye primarily through the cornea after topical administration. It is degraded in the cornea but the small portion of the administered dose that reaches the anterior chamber is taken up by uveal tissue. The drug does not enter the posterior segment of the eye in significant quantities.

(d) Therapeutic uses. The principal uses for pilocarpine are the treatment of primary glaucoma, and to stimulate lacrimation through activation of muscarinic receptors in the lacrimal gland when administered orally for neurogenic keratoconjunctivitis sicea. It is also useful for closing the pupil to keep a luxated lens from obstructing the pupil, to facilitate resolution of hyphema by increasing outflow, and in localization of parasympathetic denervation of the iris sphincter (along with physostigmine).

(e) Administration. Usually, 1–2% solution four times a day.

(f) Adverse effects include local irritation, salivation, lacrimation, nausea, vomiting, and diarrhea. Transient breakdown of blood–aqueous barrier and aqueous flare may occur. Miosis will decrease vision in low light. Cholinergic agents decrease uveoscleral outflow (most significant in the horse), so these agents are less effective in lowering IOP. Pilocarpine alone is not effective for reducing high IOP.

(2) Carbachol (0.75–3% solution)

(a) Chemistry. Carbachol is a carbamyl ester of choline that is a combination of the molecules of ACh and physostigmine, thus it also has some indirect action by inhibition of cholinesterase. It is not lipid soluble, but is stable in water solution.

(b) Mechanism of action. Carbachol enhances outflow facility and reduces IOP the same as pilocarpine. Miosis is maximal in 5 minutes and may last up to 2 days in a normal canine eye. Carbachol is more potent and has longer duration of action than pilocarpine.

(c) Pharmacokinetics. This drug is not lipid soluble so it penetrates the corneal epithelium poorly unless combined with a wetting agent such as benzylalkonium chloride.

(d) Therapeutic uses. When administered intraocularly at the conclusion of cataract surgery, the induced miosis can prevent postsurgical elevation of IOP, and may remove iris from the area of the corneal incision and decrease the potential for peripheral anterior synechia. By constricting the pupil an implanted prosthetic lens is stabilized.

(e) Administration. It is applied topically 2–4 times a day, or one time in the anterior chamber at the conclusion of cataract surgery.

(f) Adverse effects are similar to pilocarpine. There is no systemic toxicity from topical application.

(3) ACh. Topical application is of no value as cholinesterase destroys the drug before it can penetrate the cornea. The drug is used intraocularly during surgery to briefly but rapidly constrict the pupil (10 minutes).

2. Indirect acting cholinergic stimulants

a. Introduction. Cholinesterase inhibitors allow ACh to persist at the nerve ending by inhibiting the enzymatic hydrolysis of the neurotransmitter. Therefore, there will not be any effect on denervated tissues where there is no production of ACh.

b. Agents

(1) Demecarium bromide (0.125 and 0.25% solutions)

(a) Chemistry. It is synthesized by connecting two neostigmine molecules. It is water soluble and stable in aqueous solution.

(b) Mechanism of action. It reversibly inhibits cholinesterase. It is potent and long-acting. Miosis occurs within 2–4 hours and may persist for several days.

(c) Therapeutic uses. It is used in the management of primary glaucoma. It is administered prophylactically in the unaffected eye after an acute primary glaucoma attack in the first eye.

(d) Pharmacokinetics. It is readily absorbed through the cornea and taken up in the anterior uveal tissues.

(e) Administration. Apply topically once or twice daily.

(f) Adverse effects/contraindications.

i. Do not use a miotic in secondary glaucoma (usually due to uveitis) as it may increase pupillary block. As with other miotics, it is not effective for high IOP—first reduce IOP with IV mannitol.

ii. Salivation, vomiting, and diarrhea are common when the drug is first administered.

iii. Do not use on animals concurrently treated with antiparasitic products containing cholinesterase inhibitors.

(2) Echothiophate (0.03, 0.125, and 0.25% solution)

(a) Chemistry. It is phospholine iodide, a hygroscopic powder that is stable indefinitely but must be tightly capped. It has a short shelf-life in solution and must be refrigerated. It loses potency within a month; discard after 2 months.

(b) Mechanism of action. It irreversibly binds cholinesterase permitting ACh to persist at neuroeffector junction for prolonged action.

(c) Pharmacokinetics. It readily penetrates the eye through the intact cornea and the conjunctiva–sclera. Echothiophate has prolonged action with maximum effect in 4–6 hours and maintained for 24 hours.

(d) Therapeutic uses. It is for control of primary glaucoma. It is seldom used due to the inconveniences in handling: powder to be dissolved, need to refrigerate, short shelf-life, and toxicity to people handling it.

(e) Administration. It is applied topically once or twice daily.

(f) Adverse effects. It is very toxic when ingested. With prolonged topical use, corneal clouding, iritis, and iris cysts may occur; cataracts not reported for dogs as in humans.

(3) Physostigmine

(a) It is short acting and reversible.

(b) It may be used as a diagnostic agent in a normotensive eye with unexplained mydriasis and normal retinas. See pilocarpine.

(c) There are no proprietary preparations, but USP powder is available for generic compounding.

(d) Adverse effects are similar to demecarium.

Note: Pralidoxime (Protopam®) can reverse the effects of toxic doses of anticholinesterase drugs. (See Chapter 2 for more information.)

C. Mydriatics dilate the pupil (parasympatholytics and sympathomimetics)

1. Parasympatholytics (Cholinergic antagonists)

a. Introduction. These drugs compete with ACh to reversibly block cholinergic receptors of iris sphincter muscle and ciliary muscles (cycloplegia). The pupil dilates due to tone in the unopposed iris dilator muscle. They also paralyze accommodation but that is of little significance in animals.

b. Agents

(1) Atropine (0.5–2% solution)

(a) This mydriatic agent has slow onset, but prolonged action. Maximum dilation occurs in the dog in 60 minutes and may last for 4–5 days; and 10–48 hours to maximum in horse and last up to 14 days.

(b) Therapeutic uses

i. Atropine is used in acute inflammatory conditions of the iris or uveal tract to relieve the pain of sphincter muscle and ciliary muscle spasms.

ii. Dilating the pupil will minimize the possibilities of posterior synechia, pupillary block, and secondary glaucoma.

iii. Pupil dilation facilitates surgery of the lens and posterior segment, and may improve vision when opacities of the lens or cornea partially obstruct vision.

iv. Because of the large alternative uveoscleral outflow of aqueous humor in the horse, atropine is beneficial in treating primary glaucoma.

(c) Administration. Topically as needed to achieve effect, up to hourly.

(d) Adverse effects include salivation due to bitter taste, predisposition to glaucoma if there is a preexisting narrow angle or inflammatory infiltrates in the angle. GI stasis and colic may be induced in horses. Systemic toxicity with behavior changes may occur in small animals. Less commonly, diminished tear production may predispose to dry eyes and keratoconjunctivitis. Luxated lens may fall into anterior chamber.

(2) Tropicamide (0.5–1% solution)

(a) Pharmacokinetics. It has a rapid onset, short duration of action. Maximum dilation in 20 minutes, lasts for 3 hours.

(b) Therapeutic uses. Mostly to dilate pupil to facilitate examination of lens and posterior segment of the eye. Also, because it reduces blood–aqueous barrier permeability it is a good choice for intraocular surgery.

(3) Other parasympatholytics that are seldom used include homatropine, scopolamine, and cyclopentolate.

2. Adrenergic agents. Drugs with α₂-agonistic activity or β₂-blocking activity to decrease cAMP levels, which decrease aqueous humor formation.

a. Adrenergic agonists stimulate adrenergic receptors (α₁, α₂, β₁, β₂).

(1) Epinephrine (1–2% sol) decreases aqueous production through vasoconstriction in the ciliary body. Increased facility of aqueous outflow is mediated by α₂-receptors and is correlated with increased cAMP production by the trabecular meshwork.

(2) Dipivalyl epinephrine (0.1% solution). It is a lipophilic prodrug that is metabolized by corneal esterases to two epinephrine molecules.

(3) Phenylephrine (2–10% solution). A direct acting α₁-agonist with little effect on β-adrenergic receptors that is used diagnostically for Horner’s syndrome and therapeutically as an adjunct to atropine. Ten percent phenylephrine will dilate the dog’s pupil in 2 hours and it persists for 12–18 hours. Because of the time to complete mydriasis, this drug is not useful as a mydriatic when used alone. It does not dilate the pupil of the cat, horse, or cow. It is used topically for its local vasoconstrictive effect.

b. Selective α₂-agonists

(1) Preparations. Apraclonidine (1% solution) and brimonidine (0.2% solution).

(2) Therapeutic uses. It is used to treat complications related to postoperative IOP spikes and augment other glaucoma medications. These agents are not an important group for veterinary medicine due to their limited effectiveness and significant side effects of vomiting and bradycardia.

(3) Mechanism of action. Aqueous humor secretion is decreased by:

(a) Activation of presynaptic α₂-receptors, which inhibits norepinephrine (NE) release, thereby blocking the tonic adrenergic stimulation of the secretory ciliary epithelium by endogenous NE.

(b) Stimulation of postsynaptic α₂-receptor in the ciliary body suppresses adenylyl cyclase and thus decreases cAMP synthesis, which results in decreased aqueous humor formation.

(c) Constriction of the afferent arterioles of the ciliary body reduces ciliary body blood flow that may also account for reduced aqueous secretion.

(d) Enhanced uveoscleral outflow may also contribute to lowered IOP.

(e) In the dog, apraclonidine causes mydriasis through interaction with inhibitory prejunctional α₂-receptors on adrenergic nerves to the iris sphincter. In the cat, apraclonidine produces miosis, but the mechanism is uncertain.

(4) Adverse effects. Apraclonidine may reduce heart rate and blood pressure so systemic β-blockers should be used with caution.

c. Indirect-acting adrenergic stimulants stimulate the release of NE. Hydroxyamphetamine is used for diagnosis of first-order Horner’s syndrome. It causes pupillary dilation in eyes with preganglionic sympathetic disruption but not in eyes with a postganglionic lesion.

d. β-Adrenergic blockers

(1) Mechanism of action

(a) Nonspecific agents block both β₁– and β₂-receptors in the epithelium of the ciliary processes. The subsequent inhibition of cAMP production leads to diminished aqueous humor production. The major receptor in the anterior segment is β₂.

(b) β-Blockers do not affect carbonic anhydrase (CA) nor aqueous humor outflow.

(2) Therapeutic uses. These agents are useful in combination with other ocular hypotensive drugs such as CA inhibitors or parasympathomimetics for treating glaucoma and prophylactically in preglaucomatous eyes in the dog and cat. β-Agonists used with CA inhibitors or parasympathomimetics can achieve 50–60% reduction in IOP.

(3) Nonselective β-blockers. Timolol (0.25–0.5% solution), levobunolol (0.25–0.5% solution), carteolol (1% solution), metipranolol (0.3% solution):

These drugs have significant hypotensive effect for cats at 0.5%, but 4–8% solution is required for dogs. They have variable hypotensive effects in different animals possibly due to variations in β-receptors. Betaxol (0.25–0.5% sol) is a selective β₁-blocker.

(4) Administration. They are used topically, twice daily.

(5) Adverse effects. Bradycardia is the most significant side effect.

V. ANTIMICROBIALS

Antimicrobials (for chemistry, mechanism of action, and spectrum of activity refer to Chapter 15). Intraocular inflammation accompanying infections reduces or eliminates blood–ocular barriers to drug penetration so choices of antibiotics are similar to selection of antimicrobials for treatment of soft tissue infections.