HYPEROSMOTIC AGENTS

Hyperosmotic agents, administered orally or intravenously, are used to treat acute, substantial elevations of intraocular pressure (IOP) that do not respond to topical ocular hypotensive medications and systemic carbonic anhydrase inhibitors. Because hyperosmotic agents are best tolerated for a limited duration, they are generally used to help control IOP prior to glaucoma surgery, for IOP elevations following surgery or laser procedures, and for pupillary block and ciliary block glaucoma.

Systemically administered hyperosmotic agents are not indicated for the chronic management of glaucoma. The duration of their IOP effect is relatively brief (4 to 6 hours) necessitating frequent dosing. Repetitive use leads to decreased efficacy because the hyperosmotic particles eventually enter the extravascular spaces. Repeat dosage can also increase the incidence and severity of side effects, which range from mildly annoying to significant and even life threatening.

When topically applied, hyperosmotic agents dehydrate the cornea by increasing the osmolarity of the tear film. In this form, these medications improve anterior and posterior segment visualization and are useful diagnostic tools. Long-acting, topically applied hyperosmotic agents can be administered chronically to improve vision in patients with mild corneal edema.

BACKGROUND

Numerous hypertonic substances have been and continue to be used to reduce IOP and to treat cerebral edema. Early hypertonic agents were either ineffective, due to their rapid distribution into total body fluids, or they were too toxic. These included oral sodium chloride and lactose, and intravenous glucose, sodium chloride, sorbital, and gum acacia.1,2 In 1956, it was reported that intravenous administration of urea reduced

intracranial pressure.3 Three years later, Galin reported a similar effect on IOP.4 Subsequently, mannitol5,6 administered intravenously, and oral glycerol7 and isosorbide8 were all found to effectively reduce IOP (Table 37–1).

MECHANISMS OF ACTION

Hyperosmotic agents reduce IOP through two different mechanisms: (1) a reduction in vitreous volume; and (2) a secondary effect on osmoreceptors in the hypothalamic center of the central nervous system.

Systemic hyperosmotic agents increase the osmolality of the intravascular fluid compared with the extravascular fluid. Because these drugs penetrate very slowly into the avascular vitreous, and the blood–ocular barrier restricts their transport into the eye, this produces an osmotic gradient that draws fluid out of the vitreous into the intravascular space. This loss of fluid shrinks the vitreous and reduces IOP.

Studies in rabbits show that administration of hyperosmotic agents in doses comparable to clinical use reduces vitreous body weight by 3 to 4%.9 However, these studies also suggest that a rebound elevation in IOP can occur if the blood–ocular barrier is not intact and hyperosomotic agents enter the intraocular space, or if the osmotic pressure of the dehydrated vitreous becomes greater than the serum osmolality. Either of these situations will encourage movement of fluid from the intravascular space into the vitreous body.

The secondary mechanism, which may have a limited role in IOP reduction, is thought to be mediated through osmoreceptors in the hypothalamic center of the central nervous system. This theory is supported by studies performed in animal models and in patients. Hyperosmotic agents in doses too low to increase serum osmolarity,

administered either orally or intravenously, or injected into the third ventricle of rabbits, were found to reduce IOP in eyes with intact optic nerves.10,11 In contrast, similar doses had minimal or no IOP effect in the eyes following unilateral optic nerve transections, suggesting a possible central effect.

PHARMACOLOGY

The ocular osmotic gradient, which governs the IOP reduction, relies on several factors. These include the number of molecules administered (not their size), how rapidly the agent enters the bloodstream, how completely the agent is confined to the extracellular fluid space, how poorly it penetrates into the eye, and how rapidly it is removed by excretion or metabolism.

The greater the number of molecules, the more hypertonic the solution. Thus, substances of lower molecular weight are more effective than similar dosages of substances with higher molecular weight, assuming that all other parameters are equal. Drugs with poor solubility require greater volumes of fluid for administration and are less effective in increasing intravascular osmolality. Because ocular penetration is a function of the permeability of the blood–ocular barrier and the size of the molecule, larger molecules are more effectively kept out of the eye by the blood–ocular barrier. Intravenous administration is the most rapid route for accession of substances into the bloodstream and provides the most rapid onset of action.12

PEARL… The ocular osmotic gradient is a function of the number of molecules, not their size.

CLINICAL USES OF HYPEROSMOTIC

AGENTS

SYSTEMIC HYPEROSMOTIC AGENTS

Hyperosmotic agents are used to treat acute IOP elevations that do not respond to standard medical therapy (see Table 37–1). They can also be used to acutely increase anterior chamber depth in patients with critically shallow chambers. Clinical indications for hyperosmotic agents include the treatment of acute elevations in IOP prior to filtration surgery, following anterior segment laser surgery, during episodes of pupillary block glaucoma, during an attack of ciliary block glaucoma, and following injection of air or silicone oil during vitreoretinal surgery.

Filtering surgery in an eye with highly elevated IOP can produce a marked, rapid pressure lowering that can result in severe complications such as a suprachoroidal hemorrhage. Hyperosmotic agents, administered intravenously just prior to or at the time of surgery, can reduce the IOP to a safe level prior to opening the eye, reducing the extent of the pressure drop. A hand-held tonometer, such as a Schiøtz, Perkins, pneumatonometer, or Tonopen, can be used to measure IOP in the operating room.

Transient IOP elevations may also occur following intraocular surgery. In this situation, hyperosmotic agents are indicated if topical hypotensive agents and systemic carbonic anhydrase inhibitors are ineffective.

Anterior segment laser surgery can produce clinically significant elevations of IOP in up to 20% of patients that have not been pretreated with ocular hypotensive medications.13 In recent years, the use of the alpha-adrenergic agonists apraclonidine (Iopidine) and brimonidine (Alphagan) at the time of laser surgery has considerably decreased the

incidence of postlaser IOP spikes and lessened the need for treatment with hyperosmotic agents in this situation.14,15 However, these agents are now widely used in the chronic management of glaucoma.16,17 Because the chronic use of these drugs may limit their benefit in preventing and treating acute IOP elevations,18 the need for hyperosmotic agents following laser surgery may once again increase.

Hyperosmotic agents are also used to treat acute IOP elevations in patients with many forms of secondary glaucoma, including neovascular glaucoma and traumatic and uveitic glaucoma. Their short-term use in these situations may help to avoid glaucoma surgery entirely, or at least allow for surgical intervention under more controlled circumstances.

PEARL… Hyperosmotic agents may be used to temporize prior to glaucoma surgery.

Hyperosmotic agents can also help reduce IOP and deepen the anterior chamber in ocular conditions associated with shallowing of the anterior chamber, such as angle-closure glaucoma and ciliary block glaucoma. Because they reduce the vitreous volume, these agents allow the lens and iris to move posteriorly and deepen the anterior chamber. If used before the formation of peripheral anterior synechiae, this effect can also open the anterior chamber angle. However, hyperosmotic agents are not the definitive treatment for these conditions. They should not replace a laser iridotomy for repeat attacks of pupillary block or chronic administration of long-acting cycloplegic agents for patients with ciliary block glaucoma.

TOPICAL HYPEROSMOTIC AGENTS

Topical hyperosmotic agents are often used acutely to dehydrate edematous corneas, which improves examination of the anterior and posterior segments (Table 37–2).

They are particularly useful for performing gonioscopy and diagnosing suspected angle-closure glaucoma in patients with elevated IOP and cloudy corneas.

Used chronically, mild topical hyperosmotic agents can dehydrate corneas with compromised endothelial cell counts. These agents, in the form of drops or ointments, can improve corneal clarity and visual acuity in the early stages of corneal decompensation, often delaying surgical intervention.

SIDE EFFECTS

The majority of side effects from hyperosmotic agents are systemic, some of which can be severe and even life threatening (Table 37–3). These effects, combined with their short duration of action, contraindicate the use of these drugs for chronic glaucoma therapy.

Nausea and vomiting are the most common side effects of hyperosmotic agents, particularly when given orally. Orally administered hyperosmotics must be used cautiously, if at all, immediately prior to surgery.

TABLE 37–3 SIDE EFFECTS OF SYSTEMICALLY

ADMINISTERED HYPEROSMOTIC AGENTS

Nausea

Vomiting

Cardiac failure

Headache

Cerebral dehydration

Confusion

Disorientation

Urinary retention

Electrolyte imbalance

Increased diuresis

Subdural hematomas

Thrombophlebitis

Allergy

Systemically administered hyperosmotic agents reduce IOP by causing relative dehydration of the extravascular spaces. This dehydration and the increased intravascular volume are responsible for many of the side effects of these agents. Whereas healthy individuals can tolerate an increased intravascular volume, a systemic hyperosmotic agent can induce acute cardiac failure in patients with chronic congestive heart failure.19 Headache, a common side effect of hyperosmotic agents, results from cerebral dehydration and reduced intracranial pressure20 and is quite similar to the headache that occurs following lumbar puncture. Cerebral dehydration may also cause confusion and disorientation,20 and both are more common following intravenous administration, due to the rapid onset of their effects.

PEARL… Hyperosmotic agents should be used cautiously, if at all, in patients with reduced cardiac function.

Hyperosmotic agents can also induce diuresis. This results from expansion of the intravascular volume, as well as the urinary excretion of the agents themselves. Anesthetized patients, particularly older men with prostatic hypertrophy, may require catheterization to avoid severe bladder distention.20

Renal failure is another contraindication to the use of hyperosmotics. When used in patients with compromised renal function, these agents may lead to hyponatremia and hypokalemia (because the kidneys are unable to excrete in sufficient quantities the free water that is drawn into the intravascular space by hyperosmotic agents). The resulting imbalance in electrolytes can lead to lethargy, seizures, and coma.21 Renal toxicity can follow, as many of the hyperosmotic agents are excreted in the urine, and poor renal function can further compromise their elimination. This situation requires hemodialysis, since neurological deterioration can be rapid.19

PITFALL… Hyperosmotic agents are contraindicated in patients with renal failure.

Intravenous administration of urea must be carefully monitored, as extravasation during infusion can cause painful, local tissue necrosis.22 Thrombophlebitis has been reported in up to 5% of patients. In contrast, extravasation of mannitol during intravenous administration causes only localized swelling,5 and thrombophlebitis is uncommon and very mild, when it does occur.6 Other, infrequently reported complications include subdural hematomas with urea23 and allergic reactions with mannitol.24

CHAPTER 37 HYPEROSMOTIC AGENTS • 409

CURRENT FORMULATIONS

INTRAVENOUS AGENTS

Intravenous hyperosmotic agents are indicated in patients who are fasting, such as before surgery, and in patients who are nauseated and vomiting. Intravenous agents have a faster onset of action than those administered orally.

Urea

Urea is administered intravenously in a 30% solution at a dosage of 2 to 7 mL/kg. The solution must be freshly prepared because stale solutions decompose to ammonia, a toxic byproduct. IOP reductions occur within 30 to 45 minutes, and peak 1 hour following administration. Persistent reductions in IOP last for 5 to 6 hours.

Because urea is a small molecule,6 it is not restricted to the extracellular fluid compartments and moves freely throughout total body water. This makes it less effective than mannitol for reducing IOP in eyes with inflammatory glaucoma and breakdown of the blood–aqueous barrier. Urea is not metabolized and is rapidly excreted by the kidneys.25 The blood urea nitrogen (BUN) level remains elevated for up to 6 hours following administration but returns to normal within 24 hours.26

Mannitol

Mannitol has been used as an ocular hypotensive agent since 1962.6 Mannitol is administered as a 10 or 20% solution. Although it is stable in solution, it is soluble only up to a 15% concentration in cold water. If crystals are observed the solution should be warmed and a blood filter used to keep crystals from entering the bloodstream.

The recommended dosage is 1 to 1.5 g/kg of body weight administered at a rate of 3 to 5 mL/min. IOP reductions occur within 30 to 45 minutes, and peak 1 to 2 hours following administration. Persistent IOP reductions have been reported for up to 6 hours.27 Mannitol is not metabolized and is eliminated by the kidneys. Because it is a large molecule, mannitol does not readily cross an intact blood–ocular barrier, and this improves its ability to lower IOP.25

PEARL… Mannitol is the preferred hyperosmotic agent for intravenous administration.

ORAL AGENTS

The advantages of orally administered hyperosmotic agents compared with intravenous agents include more convenient, outpatient administration and less systemic toxicity. However, in addition to the side effects encountered with intravenous administration, oral hyperosmotic agents often produce unpleasant gastrointestinal side effects.

410 • SECTION V MEDICAL THERAPY OF GLAUCOMA

Glycerol

Glycerol, the first clinically useful oral hyperosmotic agent,7 is available as a 50% solution in 0.9% saline, which contains 0.62 g of glycerol per mL. The recommended dose is 1 to 1.5 g/kg of body weight. Glycerol is extremely sweet, and it should be given with orange juice or over ice to make it more palatable.

Glycerol is less effective in reducing IOP than intravenously administered hyperosmotic agents. This is due to variable absorption from the gastrointestinal tract and the small size of the molecules, which cross the blood– aqueous barrier relatively easily, particularly in patients with inflamed eyes.26 The onset of the ocular hypotensive effect of glycerol occurs 10 minutes after administration, with the peak effect at 30 minutes to 1 hour. IOP reduction generally lasts for 4 to 5 hours, before returning to baseline.7

Glycerol is a component of body fat, constituting approximately 1% of body weight, and it is readily metabolized. In clinical subjects, chronic oral administration and an accidental overdose of glycerol was without side effects.21,28 However, glycerol is metabolized to glucose, which can lead to hyperglycemia, glycosuria, and a substantial caloric load in diabetic patients. For these reasons, glycerol is contraindicated in diabetic patients. Because glycerol is metabolized, it has less of a diuretic effect than many of the other hyperosmotic agents.

PITFALL… Glycerol is metabolized to glucose, which can upset glucose control in diabetics.

Isosorbide

Isosorbide was initially used to lower IOP in 19678 and became the oral hyperosmotic of choice in the United States. It is rapidly and almost entirely absorbed from the gastrointestinal tract.29 It is not metabolized, does not cause hyperglycemia, and is excreted primarily by the kidneys.30,31 Isosorbide is not as sweet as glycerol and is less likely to produce nausea. Unfortunately, this drug is currently unavailable due to production difficulties.

Ethanol

Historically, ethanol has been evaluated for use as an ocular hypotensive agent in both normal and glaucomatous patients.25,32 In sufficiently high doses, ethanol decreases IOP both through a hyperosmotic action and by inhibiting central nervous system secretion of antidiuretic hormone. Intoxication associated with the use of ethanol limits its clinical use as an ocular hypotensive agent.

TOPICAL HYPEROSMOTIC AGENTS

Glycerol

Topically applied glycerol (Ophthalgan, Wyeth-Ayerst) is used to clear corneas with epithelial edema to help establish a diagnosis. This is a particularly useful diagnostic tool in patients with an acute angle-closure glaucoma attack, clearing the cornea sufficiently to permit visualization of the angle by gonioscopy. Whereas the effect of glycerol on the cornea occurs rapidly, within 1 to 2 minutes, its dehydrating effect only lasts 1 to 5 minutes. Several drops of topical anesthetic are required prior to application because glycerol causes intense burning. Topically applied hyperosmotic agents do not reduce IOP.

PEARL… A topical anesthetic must be administered prior to applying glycerol because glycerol causes intense burning when in contact with the nonanesthetized cornea.

Sodium Chloride

Sodium chloride 5% is commercially available as a topical solution and an ointment (Table 37–2). This drug is administered chronically to dehydrate edematous corneas. The ointment formulation can reduce corneal thickness up to 24%. The effect is maximal 3 to 4 hours after application and can last up to 7 hours. Whereas the sodium chloride solution has little effect on corneal thickness,33 it is less likely to blur vision than the ointment formulation. Side effects are minor, limited to occasional mild burning and irritation.

REFERENCES

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32.Obstbaum SA, Podos SM, Kolker AE. Low-dose oral alcohol and intraocular pressure. Am J Ophthalmol 1973;76:926–928.

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