The three primary methods of delivery of ocular medications to the eye are topical, local ocular (ie, subconjunctival, retrobulbar, intracameral, intravitreal), and systemic. The most appropriate method of administration depends on the area of the eye to be medicated. The conjunctiva, cornea, anterior chamber, and iris usually respond well to topical treatment. The eyelids can be treated topically but more frequently require systemic treatment. The posterior segment always requires systemic or intravitreal treatment, because most topical medications do not penetrate to the posterior segment. Retrobulbar and orbital tissues are treated systemically.
Topical Application of Ocular Drugs in Animals
Topical administration has the benefit of applying the drug directly to the tissue being treated and in doing so improving bioavailability and therapeutic effect. Multiple topical formulations are available, including:
solutions
suspensions
gels
ointment
solid inserts
Topical Vehicles
Drug vehicle factors that affect the kinetics of corneal and conjunctival penetration include partitioning behavior of the drug, pH, osmolality, and viscosity.
Partitioning behavior of the drug is the ability to move between the aqueous and lipid phases of the vehicle, tears, cornea and conjunctiva. More viscous formulations have a longer residence time, which in turn affects the rate and extent of absorption.
The pH of the vehicle is important for chemical and physical stability of the drug. Optimal pH is as close as possible to the drug’s dissociation constant (pKa) to maximize the ratio of ionized and non-ionized drug. Low pH and hypo- or hyperosmolality can cause increased discomfort, tearing, and excessive washout of the drug. Most topical ophthalmic drug formulations deliver drugs at rates that follow first-order kinetics. Here, the drug transfer process is proportional to the drug concentration, and drug half-life is constant regardless of the amount of drug administered.
Solutions are the most common topical formulation. The drug is immediately available for absorption. Low viscosity allows faster drainage from the conjunctival sac, resulting in less corneal and conjunctival contact time.
Suspensions are a dispersion of a poorly soluble drug in a very finely divided form. The surface area of the drug particles influences rate of dissolution of the drug in tears and determines the drug retention time in the conjunctival sac. Large particles can cause irritation, resulting in excessive tearing and drug washout.
Gels are aqueous, polymer based, and used as an alternative to ointments. Examples include methylcellulose and polyvinyl alcohol.
Ointments are usually composed of anhydrous lanolin in a mineral oil and petrolatum base. They result in increased absorption of drug in the eye because of increased retention time in the cul-de-sac.
Solid conjunctival fornix inserts and soft contact lenses can also be used as drug vehicles.
Volume
Volume of the applied drug is another important factor. The average dropper volume is between 25–50 mcL. In humans, the conjunctival cul-de-sac has a standard volume of 7 mcL and can expand up to 30 mcL; in horses, the volume can expand up to 230 mcL. The volume of medication delivered can also affect absorption and elimination of topical ocular drugs. The average commercial eyedropper volume is 25–50 mcL.
Immediately after application, there is reflex blinking and tearing. Blinking mechanically forces drug out through the nasolacrimal system. This results in up to 80% of the drug draining down the nasolacrimal duct and unavailable to enter the eye. The drug can then be absorbed systemically across the highly vascularized nasopharyngeal mucosa. Drugs absorbed via this route are carried first to the heart and lungs and bypass the liver. This avoids the hepatic first-pass metabolism that normally occurs when drugs are absorbed from the GI tract. This can increase the potential for adverse effects with some drugs.
Topically applied beta-blockers used in treatment of glaucoma can cause heart block, atrial tachycardia, congestive heart failure, bronchospasm, dyspnea, and decreased exercise tolerance. These drugs should be used carefully in older animals or in animals with cardiac or respiratory disease. Cushing syndrome can be induced in small or medium-sized dogs with chronic use of potent topical steroids. The addition of more than one drop increases the possibility for delivering a larger systemic volume, with an increased risk in adverse effects, without increased drug efficacy.
Reflex lacrimation caused by stinging on instillation can produce a higher loss rate due to a dilution effect of the tears. Normal tear turnover is ~16% per minute. Applying one drop increases tearing to 30%. This will result in most of the drug being washed out from the conjunctival sac within 5 minutes. A 5-minute interval between topical drugs is recommended to minimize washout from administration of the second drug. Solutions and suspensions should be applied before gels and ointments. More viscous formulations have a longer contact time and will limit the absorption of previously applied aqueous formulations.
Evaporation, binding, and metabolism all lead to drug loss. They tend to limit the amount of drug entering the eye to only a small fraction of the instilled dose (1%–10%). After topical application, the time for drug concentrations to peak in aqueous humor is a relatively narrow range of 20–60 minutes. This time can be impacted by the drug chosen and its particular characteristics. Most drugs are eliminated from the anterior chamber mainly by bulk flow of aqueous humor. The distribution of drugs from the anterior and posterior segment is hindered by the presence of barriers such as the iris, ciliary body, and lens, as well as bulk flow of aqueous humor through the pupil. The blood-ocular barriers also limit the amount of drug that penetrate the intraocular structures. These barriers, however, are less effective in the face of inflammation and many drugs have increased access to the intraocular structures when the eye is inflamed.
Local Ocular Routes for Administration of Drugs in Animals
Local ocular routes include:
subcutaneous
subconjunctival
sub-Tenon
intracameral
intravitreal
retrobulbar
Subcutaneous injections are used for targeted sensory and motor nerve blocks. They have also been used to deposit viscous formulations as subcutaneous fillers to help correct entropion. Local anesthetic splash blocks can be used during lid surgery, mass removal, or after removal of the globe during enucleation surgery.
Subconjunctival or sub-Tenon injection, although not a true form of systemic medication administration, has the potential to increase both drug absorption and contact time. Medications both leak onto the cornea from the entry hole of injection and diffuse through the sclera into the globe. Drugs with low solubility such as corticosteroids may provide a repository of drug lasting days to weeks. Appropriate amounts of medication must be used. Large amounts, especially of long-acting salts, can cause a notable inflammatory reaction. For sub-Tenon injections, 0.5 mL per site is usually safe and effective in small animals, and ≤1 mL can be used in large animals such as horses and cows. Suprachoroidal implants of cyclosporine are used for slow-release implants in the treatment of canine keratoconjunctivitis sicca and equine recurrent uveitis.
Intracameral injection is used to place very small volumes (≤0.1 mL) of drugs into the anterior chamber, eg, tissue plasminogen activator to break down fibrin, antimicrobials administered after surgery or for infectious anterior uveitis, and steroids after cataract surgery. Because the vitreal chamber is larger, an increased volume can be used (≤0.5 mL).
Intravitreal injections are used to place repository steroids for inflammation or noninfectious retinal detachments, antimicrobials for infectious uveitis, or for chemical ablation of the ciliary body epithelium in the treatment of chronic glaucoma. When performing intravitreal chemical ablation, gentamicin toxicity can occur in small animals or those with compromised kidney function. Care needs to be taken when using either of these routes to avoid pathologic postinjection increases in intraocular pressure.
Retrobulbar medications are used infrequently for therapeutics. They are mainly used for local anesthesia before surgical procedures such as cataract surgery in small animals, or enucleation in mammalian species. Different techniques can be used. Blocks in small animals are performed under general anesthesia and can be intra- or extraconal. In cattle and horses, under heavy sedation or general anesthesia, the retrobulbar tissues can be anesthetized with local anesthetic (lidocaine/bupivicaine) for enucleation using either a Peterson block (15–20 mL) or a 4-point block of the orbit (5–10 mL/site). In any species whenever any medication is placed into the orbit, extreme care must be taken to ensure that the medication is not inadvertently injected into a blood vessel, the optic nerve, or one of the orbital foramen. Retrobulbar injection has a high risk of adverse effects and should not be administered unless the clinician is experienced and the patient is appropriately restrained.
Systemic Routes for Administration of Ocular Drugs in Animals
Systemic medication is required for posterior segment treatment and to complement topical treatment for the anterior segment. The blood-ocular barriers can limit absorption of less lipophilic drugs, but inflammation will initially allow greater drug concentrations to reach the site. As the eye starts to heal, these barriers will again become more effective and can limit further drug penetration. This should be considered when treating posterior segment disease, eg, blastomycosis in small animals with hydrophilic drugs such as itraconazole.
