FIGURE 1 Mechanisms involved in pharmacological regulation of intraocular pressure.

1. b Blockers

b Blockers, such as betaxolol, carteolol, levobunolol, metipranolol, and timolol, are some of the most commonly used drugs in glaucoma therapy (Novack, 1987). They are competitive antagonists of b adrenergic receptors. These agents block the binding of endogenous adrenergic neurotransmitters, i.e., norepinephrine and epinephrine, to the receptors in the ciliary processes and prevent their activation. The b adrenergic receptors are coupled to adenylyl cyclase. Blockade of receptor activation prevents activation of the adenylyl cyclase, and thus a reduction in cyclic AMP levels in the ciliary epithelial cells, which subsequently suppresses the formation of aqueous humor. The cellular pathway(s) involved in the regulation of aqueous formation by cyclic AMP is still unclear. However, b blockers are known to inhibit Na–K–Cl cotransport and the Na–K–ATPase in the ciliary epithelium. Moreover, this class of drugs can also reduce the blood–aqueous flux of ascorbate and inhibit plasma flow to the ciliary processes. All of these biological eVects of b blockers can contribute, at least partly, to their reduction in aqueous humor production.

2. Carbonic Anhydrase Inhibitors

For many years, oral administration of CAIs, such as acetazolamide, lowered IOP eVectively. Unfortunately, their neurological, gastrointestinal, and metabolic untoward eVects limit their acceptance by patients. The discovery and development of topically active CAIs, such as brinzolamide and dorzolamide, have minimized the systemic side eVects and revitalized the use of this class of compounds in glaucoma treatment (Sugrue, 2000; Herkel and PfeiVer, 2001). CAIs inhibit carbonic anhydrase, mainly isozyme II, in the ciliary epithelium and reduce the production of bicarbonate ion, which is a

critical component for active ion transport in aqueous formation. A reduction in bicarbonate by CAIs diminishes sodium and fluid transport across the ciliary epithelium, and decreases aqueous humor production.

3. a2 Agonists

a2 Adrenergic agonists, e.g., apraclonidine and brimonidine, are eVective IOP lowering agents for both open and closed angle glaucomas (Robin, 1997; Adkins and Balfour, 1998). They selectively activate the a2 adrenergic receptor of the ciliary epithelium. Activation of this receptor activates an inhibitory GTP binding protein, which then inhibits the adenylyl cyclase. This leads to a reduction in intracellular cyclic AMP levels and eventually suppressed aqueous humor production. Studies also demonstrated that apraclonidine increases trabecular outflow and brimonidine stimulates uveoscleral outflow. The molecular and cellular mechanisms of these outflow eVects are uncertain, but speculated to involve changes in contractility of the TM and ciliary muscle.

I. Aqueous Outflow Increasing Agents

Drugs that increase aqueous outflow include the cholinergics, epinephrine analogs, and prostaglandin analogs (PGAs). They encompass the oldest and the most recent clinically approved compounds: physicians have been treating glaucoma with pilocarpine, a cholinergic agonist, for more than 100 years, whereas, the PGAs were approved for glaucoma treatment in recent years.

1. Cholinergics

The cholinergics are safe and eVective IOP lowering compounds (Hoyng and van Beek, 2000). They include muscarinic cholinergic agonists, such as pilocarpine and carbachol, and cholinesterase inhibitors, such as physostigmine and echothiophate iodide. These compounds activate the muscarinic cholinergic receptor, either directly as receptor agonists (e.g., pilocarpine and carbachol), or indirectly by reducing the enzymatic degradation of the endogenous agonist acetylcholine (e.g., physostigmine and echothiophate iodide). How receptor activation leads to reduction in IOP is still not clear. It has been hypothesized that activation of the muscarinic receptor causes contraction of certain ocular smooth muscles, notably the ciliary muscle and iris sphincter. Contraction of the longitudinal ciliary muscle pulls the scleral spur and TM posteriorly, enlarges the extracellular space in TM, and enhances trabecular outflow.

2. Epinephrine and Analogs

Epinephrine binds to and activates various adrenergic receptor subtypes in the eye. It and its prodrug dipivefrin lower IOP by both suppressing aqueous production and increasing aqueous outflow (Hoyng and van Beek, 2000). The multiple, complex cellular mechanisms involved in these pharmacological actions are yet to be fully delineated.

3. Prostaglandin Analogs

PGAs, such as latanoprost, travoprost, and bimatoprost, are very eYcacious in lowering IOP, and therefore are popular compounds for the treatment of glaucoma (Hejkal and Camras, 1999; Linden, 2001). Latanoprost, travoprost, and bimatoprost are prodrugs. Their metabolic products activate the FP prostaglandin receptor with high aYnity. In contrast, whether the fourth PGA, unoprostone, activates the FP receptor is still controversial (GriYn et al., 1997; Bhattacherjee et al., 2001). When compared with other PGAs, this compound is less eYcacious with mean IOP reduction consistently less than latanoprost. Latanoprost and travoprost stimulate uveoscleral outflow without significantly aVecting trabecular outflow or aqueous production. Bimatoprost slightly increases both the trabecular outflow and aqueous production, in addition to enhancing uveoscleral outflow.

Agonists of the FP receptor have been shown to cause changes in two biological functions in ocular structures related to aqueous outflow. First, FP receptor activation induces relaxation of the TM and ciliary muscle (Thieme et al., 2006). This eVect reduces tension and changes the topography of outflow pathways, which theoretically can improve uveoscleral outflow. Second, FP receptor agonists also upregulate the expression of MMPs, enzymes responsible for the hydrolysis of excessive ECM, in cultured human and monkey ciliary muscle cells. Activation of MMPs augments the rate of ECM degradation, which should open up extracellular space and decrease resistance to aqueous humor traveling through these spaces. After receiving PGA treatment for a year, monkey ciliary muscle had significant expansion in optically empty spaces between muscle bundles compared to untreated or vehicle treated control animals (Richter et al., 2003). These cellular and morphological changes likely play a role in the PGAs’ eVect on uveoscleral outflow.

J. Surgical Therapy

Surgical therapy for POAG is usually performed when medications have failed or are poorly tolerated and progressive glaucoma damage is still occurring. Results from the CIGTS show that both initial medical therapy

and initial surgical therapy are valuable in lowering IOP and delaying progression of glaucomatous damage. There are many glaucoma surgical procedures, most of which are designed to improve aqueous outflow. They can be classified as incisional or laser surgical techniques. The incisional techniques, such as trabeculectomy and its variations, non penetrating filtration procedures, and drainage tube implants, etc, aim to create new physical outflow pathways for aqueous humor. In contrast, the laser techniques, also known as laser trabeculoplasty, do not produce holes in the TM or burn into the lumen of Schlemm’s canal. Instead, laser treatment releases cytokines, especially interleukin 1b and tumor necrosis factor a, from TM cells. These cytokines modify various TM cell functions, including induction of MMP expression and degradation of ECM (Bradley et al., 2000). Furthermore, laser treated TM cells were observed to be more active in their phagocytic, migratory, and proliferative activities (Bylsma et al., 1988; Alexander et al., 1989). These cellular eVects of laser treatment may be responsible, at least partly, for the increase of aqueous outflow and reduction in IOP. In addition, laser induced scars may cause contraction of treated areas and consequently stretching of adjacent regions. This may produce enlarged extracellular spaces in the TM and improve aqueous outflow.

III. NEW APPROACHES FOR IOP LOWERING

A. Cytoskeleton Disrupting Agents

Cells within the aqueous outflow pathway, such as the TM cells and the endothelial cells lining the Schlemm’s canal, have an extensive cytoskeleton. The cytoskeleton is a complex network of protein filaments that extends throughout the cytoplasm. It can be classified into three principal types of protein filaments: actin microfilaments, microtubules, and intermediate filaments. Each type of cytoskeleton is formed by a diVerent protein monomer and can be arranged into various structures according to its associated proteins. For example, certain associated proteins regulate the assembly of actin filaments and microtubules by controlling the rate and direction of polymerization. Other associated proteins connect filaments to one another or to other cell components, such as the plasma membrane, thus forming unique cytoskeletal architecture. Still other associated proteins interact with filaments to allow movements.

The ability of eukaryotic cells to preserve and perform their many coordinated cell functions depends on the cytoskeleton. It is responsible for the maintenance of cell shape, cell–cell junctions, cell–matrix interaction, adhesion, contraction, movement, as well as transport of intracellular organelles