Glaucoma is defined as high intraocular pressure and optic neuropathy not compatible with vision. It is a complex syndrome associated with an increase in intraocular pressure subsequently resulting in damage to the ganglion cells of the optic nerve, eventually leading to blindness. Intraocular pressures can rise due to either primary (inherited and congenital) or secondary causes.
The aqueous humor occupies the anterior and posterior chambers of the eye and provides nutrition for the cornea and lens. Aqueous humor is produced by the nonpigmented ciliary epithelium of the ciliary processes. Sodium, chloride, potassium, ascorbate, and bicarbonate (enzyme is carbonic anhydrase) are actively transported from the plasma in the stroma of the ciliary process into the posterior chamber, with water and chloride following passively to maintain an electrical and osmotic balance. Production is decreased with increased intraocular pressure and inflammation.
Aqueous outflow is via one of two pathways: the conventional and unconventional. Most of the outflow (85% in the dog, 97% in the cat) is via the conventional pathway, which is via the iridocorneal angle. The iridocorneal angle is located all 360 degrees between the peripheral cornea and peripheral iris. The angle is made of the pectinate ligaments, corneoscleral trabecular meshwork, and the scleral plexus. There is both parasympathetic (mainly) and sympathetic innervation. The remaining outflow (15% in the dog and 3% in the cat) exits via the unconventional pathway (uveoscleral). This is diffusion through the iris and ciliary body to reach and be drained by the ciliary muscle veins, the suprachoroidal space, and the choroidal circulation. The uveoscleral outflow acts as an alternative route for a compromised iridocorneal outflow. In uveitis, prostaglandins produced in the inflamed eye increase uveoscleral outflow and, along with a fall in aqueous production, try to keep intraocular pressure in the normal range.
To improve efficacy via the different mechanisms of action, carbonic anhydrase inhibitors and prostaglandins are combined with timolol. Current combination products include dorzolamide/timolol, latanoprost/timolol, and travoprost/timolol.
The primary drugs used for treatment of glaucoma are topical medications, including prostaglandins, miotics, beta-blocking adrenergics, and topical carbonic anhydrase inhibitors, but these are often supplemented with systemic drugs.
Medical options include the use of various combinations of osmotic diuretics, carbonic anhydrase inhibitors, sympathomimetics, parasympathomimetics, alpha- and beta-blockers, and topical prostaglandins.
Osmotic Diuretics for Treatment of Glaucoma in Animals
Emergency treatment of acute glaucoma requires urgent reduction of intraocular pressure. This is accomplished pharmacologically using osmotic diuretics such as mannitol or glycerol in combination with other topical and systemic drugs.
Osmotic diuretics are large-molecular-weight molecules that increase the osmotic pressure of plasma relative to the aqueous and vitreous. Most of the water in the eye is in the vitreous. Dehydration of the vitreous allows the lens and iris to move posteriorly, opening the iridocorneal angle. The other effect is to decrease formation of aqueous humor. Mannitol is administered (1–1.5 g/kg, IV over 20–30 minutes), with the effect peaking in 2–3 hours and lasting up to 5 hours. Mannitol is not metabolized and thus can be used in diabetic animals. Cold glycerol (1–2 g/kg, PO) can be used but is unpalatable, and most dogs vomit. With both drugs, water should be withheld for 3–5 hours, and the animal should be offered regular opportunities to urinate. Kidney and cardiac function should be checked before treatment, and cardiac function monitored during treatment. Mannitol can be used again within 8–12 hours if initial control of intraocular pressure is not maintained; longterm control is unlikely if intraocular pressures do not stay within the normal range after two treatments.
Carbonic Anhydrase Inhibitors for Treatment of Glaucoma in Animals
Carbonic anhydrase inhibitors (CAI) are sulfonamide derivatives that inhibit the enzyme carbonic anhydrase II (CA-II) in the nonpigmented ciliary epithelium responsible for catalyzing the following reaction: CO2 + H2O ← carbonic anhydrase → H2CO3 ↔ H+ + HCO3–. The bicarbonate and sodium ions are actively transported into the anterior chamber, leading to passive movement of water. This mechanism produces 40%–60% of aqueous humor. Inhibition of CA-II inhibits a similar percentage of aqueous humor production.
Topical
Topical CAIs have fewer adverse effects than the oral formulation, but, being modified sulfonamides, can cause blepharitis, conjunctivitis, keratitis, and, in humans, a bitter, sour, or unusual taste. There is carbonic anhydrase activity in corneal endothelium and the potential for developing corneal edema in patients with low endothelial counts.
The two drugs available are brinzolamide 1% and dorzolamide 2%. They must be applied every 8 hours. To improve corneal penetration, dorzolamide is formulated with an acid pH and can sting. It is more likely to cause a contact irritation with periocular alopecia. If this occurs, brinzolamide can be used instead. Both drugs are effective in cats, although some cats are very sensitive and can become hypokalemic from acute or chronic use. Compounded dorzolamide and timolol is also efficacious in horses.
Monotherapy with CAIs is uncommon; they are formulated in combination with a beta-blocker (2% dorzolamide/0.5% timolol) or added to a regimen with a topical prostaglandin analog.
Systemic
Drugs used include methazolamide (2–4 mg/kg, PO, every 8–12 hours), acetazolamide (5–8 mg/kg, PO, every 8–12 hours), and dichlorphenamide (2–4 mg/kg, PO, every 8–12 hours). Methazolamide is the drug of choice because it has fewer adverse effects. Maximal effect occurs 3–6 hours after administration. The most common adverse effect is a metabolic acidosis that causes panting. Other effects can include vomiting, diarrhea, and hypokalemia.
Acetazolamide commonly causes anorexia. Potassium supplementation can be administered with potassium bicarbonate or citrate (1–2 g/day) added to the food. Cats are more sensitive than dogs to the adverse effects of these drugs and need careful monitoring. Systemic CAIs are not recommended for use in cats.
Prostaglandins for Treatment of Glaucoma in Animals
Prostaglandin analogs (PGF2 alpha) are used topically to increase unconventional (uveoscleral) outflow in dogs (15%). They have limited, if any, efficacy in cats because the uveoscleral pathway contributes only 3% of aqueous outflow. Enhancement of aqueous outflow involves stimulation of expression of ciliary body matrix metalloproteinases and remodelling of the extracellular matrix in the ciliary muscle and sclera. A number of PGF2 alpha analogs have been developed, including 0.004% travoprost, 0.005% latanoprost, 0.0015% tafluprost, 0.03% bimatoprost (prostamide), and 0.12% isopropyl unoprostone (synthetic docosanoid). Latanoprostene bunod 0.024% is a new nitric oxide donating PGF2 alpha analog that increases outflow by uveoscleral and trabecular pathways. These are ester prodrugs that are hydrolyzed by esterases in the cornea to the free acid (there is debate if bimatoprost is a prodrug). They are applied every 12 hours; increasing the frequency bdoes not increase efficacy. Bimatoprost can reduce intraocular pressure in humans unresponsive to latanoprost. After administration of bimatoprost in acute primary glaucoma, intraocular pressure can decrease by 15–20 mmHg in 45–60 minutes.
Adverse effects seen in dogs include an increase in conjunctivitis, uveitis, and intense miosis. These drugs should not be used with an anterior lens luxation because they can cause pupillary block and increase intraocular pressure. In posterior lens luxations, the miosis can trap the lens in the vitreous. In humans, topical prostaglandin analogs have been associated with an increase in eyelid and iris pigmentation; however, this has not been reported in dogs. Topical prostaglandin analogs can cause anterior uveitis in horses that can be ameliorated with concurrent use of topical diclofenac.
Autonomic System Drugs for Treatment of Glaucoma in Animals
Beta-Blocking Adrenergics
Beta-adrenergic antagonists act to reduce production and increase outflow. These work well in cats and can be used as a sole treatment. They are often combined with carbonic anhydrase inhibitors (dorzolamide/timolol) and prostaglandins (latanoprost, travoprost/timolol). The most common product is 0.5% timolol maleate, administered every 8–12 hours. Other products available include betaxolol and levobunolol hydrochloride. Topical beta-blockers can have a noteworthy effect on heart rate in small animals as a result of passage through the nasolacrimal duct into the mouth, extensive buccal absorption, avoidance of the first-pass effect in the liver and a direct effect on the heart. This can be a concern in animals with compromised cardiac function.
Sympathomimetics
Sympathomimetics also act to decrease intraocular pressure. The mechanism of action is not fully understood. It is thought that they may reduce production and increase outflow of aqueous humor. Their use is more academic because they are not commonly used. One option is 0.1%–0.5% dipivalyl epinephrine (epinephrine prodrug), every 6–12 hours. Another option is 1%–2% epinephrine (an alpha and a beta adrenergic agonist). This is used intraocularly 1:10,000 dilution for pupillary dilation during cataract surgery.
Parasympathomimetics
Parasympathomimetics (cholinergics) mimic the action of acetylcholine on the muscarinic receptors of the iris and ciliary body muscle. This causes miosis and increased conventional aqueous humor outflow from contraction of the ciliary body muscle and opening of the iridocorneal angle. The most common drug is 1%–2% pilocarpine applied every 8–12 hours. Parasympathomimetics start to work in 15 minutes, with the maximum effect in 4 hours. They can last up to 24 hours; however, for maximum efficacy, application every 8–12 hours is best. An alternative is a topical anticholinesterase inhibitor, 0.125%–0.25% demecarium bromide, every 12–24 hours. Parasympathomimetics also increase vascular permeability, which can reactivate latent iritis and intensify any concurrent anterior uveal inflammation.
