Local Treatment of Glaucoma

Currently, glaucoma therapy remains focused on mechanisms designed to decrease intraocular pressure (IOP) and this approach is considered effective also in normal tension glaucoma.

Normal values of IOP lie between 15 and 20 mmHg, that is, above the venous pressure. IOP reflects the ratio of production and outflow of aqueous humor. Aqueous humor is secreted by the epithelial cells of the ciliary body and, following passage through the trabecular meshwork, is drained via the canal of Schlemm (blue arrows in A). This route is taken by 85–90% of aqueous humor; a smaller portion enters the uveoscleral vessels and, thus, the venous system. In the socalled open-angle glaucoma, passage of aqueous humor through the trabecular meshwork is impeded so that drainage through Schlemm’s canal becomes inef - cient. The much rarer primary angle-closure glaucoma features a narrowed iridocorneal angle or a tight contact between iris and lens (‘pupillary block’). Secondarily, blockade by the iris of the trabecular meshwork may be due to various causes (e. g., synechiae). Topographical relationships in the chamber angle are shown enlarged in the red box.

For topical therapy of open-angle glaucoma, the following groups of drugs can be used: for reducing production of aqueous humor, β-blockers (e. g., timolol), α2-agonists (clonidine, brimonidine), and inhibitors of carbonic anhydrase (dorzolamide, brinzolamide).

For promoting drainage through the trabecular meshwork, parasympathomimetics (e. g., pilocarpine) are effective, and through the uveoscleral route, prostaglandin derivatives. Pilocarpine excites the ciliary muscle and the pupillary sphincter. The contraction of both muscles widens the geometrical arrangement of trabeculae, resulting in improved drainage of aqueous humor. Uveoscleral drainage is augmented by the prostaglandin derivatives lanatoprost and bimato-

prost. Both substances can be used for topical monotherapy or combined with other active principles. A peculiar side effect is notable: dark pigmentation of iris and eyelashes.

The therapy of angle-closure glaucoma involves chiefly reduction of aqueous humor production (osmotic agents, β-blockers) and surgical procedures.

The topical application of pharmaceuticals in the form of eye-drops is hampered by a pharmacokinetic problem. The drug must penetrate from the ocular surface (cornea and conjunctiva) to its target sites, namely, the smooth muscle of the ciliary body or the iris, the secretory epithelium of the ciliary body, or the uveoscleral vessels (B). The applied drug concentration is diluted by lacrimal fluid and drains via the tear duct to the nasal mucosa, where the drug may be absorbed. During permeation through the cornea, transport through blood vessels takes place. The drug concentration reaching the anterior chamber is diluted by aqueous humor and, finally, drug molecules are also transported away via Schlemm’s canal. In order to reach the required concentrations at the target site (10–8 to 10–6 M, depending on the substance), the concentration needed in the eye drops is ~ 10–2 M (equivalent to ~ 0.5 mg per droplet, depending on molecular weight). The amount of drug contained in a single drop is large enough to elicit a general reaction with systemic use. Even when applied properly, eye drops can therefore evoke side effects in the cardiovascular system or the bronchial space. This possibility leads to corresponding contraindications. Thus, in patients with severe congestive heart failure, bradycardia, or obstructive lung disease, eye drops containing β-block- ers must be avoided at all times.

A. Local pharmacotherapy of glaucoma

Conjunctiva

Increased drainage

Pilocarpine

Prostaglandin derivatives

Schlemm’s canal

Cornea

Iris

Sclera

M. ciliaris

Proc. ciliaris

Inhibitors of aqueous humor production: β -Blocker, CAH-inhibitors, α 2-agonist