Janet B. Serle
Donna J. Gagliuso
Systemically administered hyperosmotic agents have been used almost exclusively in the management of acute elevations of intraocular pressure (IOP). They are administered either orally or intravenously and are useful when intraocular pressures do not respond to topical medications or systemically administered carbonic anhydrase inhibitors. Hyperosmotic agents reduce intraocular pressure by creating an osmotic gradient between the blood and the intraocular fluid compartments that causes fluid to shift from the eye to the blood. These agents are most effective when used for a short period of time. Systemic side effects and a limited period of efficacy in maintaining a reduction in intraocular pressure preclude their chronic use in the treatment of glaucoma.
Hyperosmotic agents may also be administered topically in patients with edematous corneas. These agents cause transient dehydration of the cornea, which allows for improved anterior and posterior segment visualization. In addition, they may be used as chronic therapy to improve visual acuity in patients with corneal edema.
Various hypertonic substances have been used to reduce IOP and to treat cerebral edema. Earlier agents were relatively ineffective because of their rapid distribution into total body fluids and poorly tolerated because of their toxicity. Agents used prior to 1956 included sodium chloride, lactose, glucose, sucrose, sorbitol, and gum acacia.1,2 In 1956, Javid and Settlage3 reported that intravenously administered urea effectively reduced intracranial pressure. Subsequently, in 1959, Galin et al4 reported a similar effect on IOP with urea given intravenously. Later, intravenously administered mannitol in 1962,5,6 orally administered glycerol in 1963,7 and orally administered isosorbide in 1967,8 were found to be effective hyperosmotic agents.
MECHANISMS OF ACTION
Hyperosmotic agents reduce IOP by creating an osmotic gradient between the vitreous body and the intravascular fluid, resulting in a net loss of fluid from the vitreous and a drop in IOP. Administration of hyperosmotic agents leads to hyperosmolality of the intravascular fluid. Since transport of these agents into the eye is restricted by the blood-ocular barrier, an osmotic gradient is created. As a result of this osmotic gradient, fluid is drawn out of the vitreous into the vascular space. This loss of fluid reduces the vitreous volume. A reduction in the vitreous volume leads to a reduction in IOP as the intraocular volume decreases while the scleral wall maintains its size and shape. Studies performed in rabbits suggest that a 3% to 4% reduction in vitreous body weight occurs after administration of hyperosmotic agents in dosages comparable to those in clinical use.9
Hyperosmotic agents may paradoxically cause a rebound elevation of IOP. As these agents enter the intraocular space, the osmolality of the vitreous approaches that of the blood. As the agent is cleared from the circulation by excretion and transudation of the hyperosmolar substance into the extravascular spaces, the osmolality of the serum falls below that of the vitreous. This causes water to be drawn into the eye, resulting in an elevation of IOP. In addition, hyperosmotic agents may be ineffective as IOP-lowering drugs in situations when an osmotic gradient cannot be established or maintained. This may occur during episodes of inflammation when the blood-ocular barrier is disrupted.
A secondary mechanism of action mediated through osmoreceptors in the hypothalamic region may have a limited role in reducing IOP. Clinical and laboratory studies suggest low doses of hyperosmotic agents can reduce IOP without increasing serum osmolality.10,11 In animals studies, IOP reductions were seen after low doses of hyperosmotic agents were administered, either orally or intravenously, or injected directly into the third ventricles in eyes with intact optic nerves.10 In contrast, eyes with unilateral optic nerve transections showed reduced or absent IOP effects after the administration of low-dose hyperosmotic agents. These studies support the theory that a hypothalamic center with osmoreceptors and efferent connections to the eye mediates part of the IOP response to hyperosmotic agents.
Several factors affect the ocular osmotic gradient, which ultimately determines the reduction of IOP. These include molecular weight and concentration, dose, rate and method of administration, rate of excretion, distribution in body water, and ocular penetration.
An osmotic gradient is dependent on the number of molecules administered as opposed to the size. Therefore, low-molecular-weight molecules have a greater effect on the serum osmolality than high-molecular-weight molecules at similar dosages. Agents administered intravenously produce a more rapid and greater osmotic gradient than those administered orally as they bypass the gastrointestinal system. The more rapidly an agent is cleared from the circulation, the less effect it has on the osmotic gradient. Agents that confine themselves to the extracellular space have a greater effect on serum osmolality. Agents that have a slow or nonexistent ocular penetrance create a greater osmotic gradient. Ocular penetration is a function of the permeability of the blood-ocular barrier and the size of the molecule. Thus, larger molecules do not penetrate the blood-ocular barrier as well as smaller molecules.12,13
CLINICAL USES OF HYPEROSMOTIC AGENTS
Hyperosmotic agents are used to treat acute elevations of IOP when standard medications are ineffective. Oral and intravenous agents that have been used in clinical practice are listed in Tables 28-1 and 28-2. Hyperosmotic agents can also be used acutely to deepen anterior chamber depth in patients with critically shallow chambers. Indications for the use of hyperosmotic agents as treatment for acute elevations in IOP include episodes of pupillary block glaucoma, ciliary block glaucoma, or secondary glaucomas. Additional indications for the use of these agents include preoperative administration in patients undergoing glaucoma surgery, in patients undergoing penetrating keratoplasty, and in patients pre- or post-anterior segment laser therapy.
TABLE 28-1. Orally Administered Hyperosmotic Agents
TABLE 28-2. Intravenously Administered Hyperosmotic Agents
In pupillary and ciliary block glaucomas, critical shallowing of the anterior chamber occurs resulting in angle closure. In these cases, hyperosmotic agents not only lower the IOP but also deepen the anterior chamber. The reduction in vitreous volume allows the lens and iris to move posteriorly and the anterior chamber angle to open in patients without peripheral anterior synechiae. However, hyperosmotic agents are not the definitive treatment for these conditions. Iridectomies are indicated to prevent repeated attacks of pupillary block angle-closure glaucoma. Patients diagnosed with ciliary block glaucoma may need to be treated chronically with long-acting mydriatic agents such as atropine and scopolamine and may need laser or surgical management of the vitreous face. Peripheral iridoplasty may be indicated in patients with variants of ciliary block glaucoma that are caused by swelling or forward movement of the ciliary body, which may follow retinal detachment surgery, panretinal photocoagulation, and central retinal vein occlusion.
Extreme elevations in IOP may be present in patients undergoing glaucoma surgery. Sudden reductions in IOP occurring after an initial surgical incision may result in devastating complications, such as choroidal hemorrhages. As a precaution, a hyperosmotic agent may be administered intravenously preoperatively to reduce IOP in a slower and more controlled fashion than an incision into the eye. Intravenous hyperosmotic agents are also used preoperatively in cases of penetrating keratoplasty to decrease vitreous volume, thereby reducing posterior pressure and the risk of expulsion of ocular contents during the open sky technique.
Hyperosmotic agents are also indicated in patients with secondary glaucomas including traumatic glaucoma, uveitic glaucoma, and neovascular glaucoma during acute episodes of IOP elevations. The short-term use of these agents may help patients avoid glaucoma surgery while the underlying cause of the glaucoma is addressed or may allow for surgical intervention under more controlled circumstances at a later date.
IOP elevations may also occur after various types of intraocular laser procedures, and hyperosmotic agents may be used to reduce the IOP in this setting. Substantial IOP elevations occur in up to 20% of patients undergoing anterior segment laser surgery, including laser trabeculoplasty, laser iridectomy, and laser capsulotomy.14,15,16 The acute use of topical alpha adrenergic agonists such as apraclonidine (Iopidine) and brimonidine (Alphagan) before and after laser treatment has reduced the incidence of these IOP spikes,17,18,19 thereby almost eliminating the need for hyperosmotic treatment after laser surgery. In patients chronically administering multiple ocular hypotensive medications including a topical alpha-adrenergic agonist, limited options remain for treating postlaser IOP elevations, and hyperosmotic agents may need to be administered.