| Chapter 28 Hyperosmotic Agents JOHN DANIAS, JANET B. SERLE and DONNA J. GAGLIUSO Table Of Contents |
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HISTORICAL PERSPECTIVE MECHANISMS OF INTRAOCULAR PRESSURE REDUCTION PHARMACOLOGY CLINICAL USES SYSTEMIC SIDE EFFECTS AND CONTRAINDICATIONS SUMMARY REFERENCES |
| Systemically administered hyperosmotic agents are indicated in the treatment of acute, substantial elevations of intraocular pressure (IOP). They are most effective and best tolerated when used for a short time. Side effects and a limited duration of IOP-lowering response preclude chronic use in the treatment of glaucoma. Topically administered hyperosmotic agents are helpful in patients with edematous corneas. Transient dehydration of the cornea after topical administration allows for improved anterior and posterior segment visualization. |
| HISTORICAL PERSPECTIVE |
| Various hypertonic substances have been used to reduce IOP and to treat cerebral edema. Agents that were used before 1956 included orally administered sodium chloride and lactose and intravenously administered glucose, sucrose, sodium chloride, sorbitol, and gum acacia.1,2 These agents were relatively ineffective because of their rapid distribution into total body fluids or were too toxic to be used clinically. In 1956, Javid and Settlage3 reported that intravenously administered urea effectively reduced intracranial pressure. In 1959, Galin and coworkers4 reported that intravenously administered urea was effective in reducing IOP. Subsequently, intravenously administered mannitol in 1962,5,6 orally administered glycerol in 1963,7 and orally administered isosorbide in 19678 were found to be effective hyperosmotic agents. |
| MECHANISMS OF INTRAOCULAR PRESSURE REDUCTION |
| Two mechanisms are responsible for the decrease in IOP caused by hyperosmotic
agents. The primary mechanism is a reduction in vitreous volume. Administration
of hyperosmotic agents leads to hyperosmolality of the
intravascular fluid. A bloodvitreous osmotic gradient is established (as
effective drugs penetrate slowly into the avascular vitreous, and
transport into the eye of hyperosmotic agents is restricted by the blood-ocular
barrier). Fluid subsequently is drawn out of the vitreous into
the vascular space, driven by this hyperosmotic gradient. 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 a stable ocular shape and size. 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 of clinical use.9 If an osmotic gradient cannot be established or maintained, then hyperosmotic
agents cannot reduce IOP. This would occur if the blood-ocular
barrier was not intact or if the agent used was not excluded by the normal
barrier. A rebound elevation in IOP after the use of hyperosmotic
agents may occur if the blood-ocular barrier is disrupted and hyperosmotic
agents enter the intraocular space or if the osmotic pressure of
the dehydrated vitreous becomes greater than the serum osmolality (e.g., by increased water consumption). Either of these situations causes a
reversal of fluid flow from the intravascular space into the vitreous
body. Clinical and laboratory studies suggest that another secondary mechanism may play a small role in the IOP reduction seen with hyperosmotic agents. Oral or intravenous administration of low doses of hyperosmotic agents that do not increase serum osmolarity does reduce IOP.10,11 In animals with unilateral optic nerve transections, the operated eyes show reduced or absent IOP effects after low doses of hyperosmotic agents. In contrast, the eyes with intact optic nerves show IOP reductions after these low doses of hyperosmotic agents. Injection of hyperosmotic agents into the third ventricle of rabbits lowers IOP only in the eyes with intact optic nerves.10 These studies support the theory that a hypothalamic center with osmoreceptors and efferent connections to the eye mediates part of the IOP responses to hyperosmotic agents. |
| PHARMACOLOGY |
| An osmotic gradient is a function of the difference of number of molecules (not
the individual size of the molecules) in two solutions that are
partitioned by a semipermeable membrane. A thousand molecules of a
low-molecular-weight substance are just as effective as a thousand molecules
of a highmolecular-weight substance, provided that both substances
are equally excluded by the membrane. In the case of an hyperosmotic
agent, the duration and effectiveness of an osmotic gradient are inversely
dependent on the leakiness of the membrane separating the vascular
and vitreous compartments and the rate at which the osmotic agent
is cleared from the blood (by excretion or metabolism) and are directly
dependent on how rapidly the substance enters the bloodstream. The larger the number of molecules, the more hypertonic a solution. Thus, assuming all else is equal, on a per-gram basis, substances of lower molecular weight are more effective than substances of higher molecular weight (at the same dosage). Drugs with poor solubility require greater volumes of fluid for administration and are thus less effective in increasing intravascular osmolality. Ocular penetration is a function of the permeability of the blood-ocular barrier and the size of the molecule. Larger molecules usually are more restricted in penetrating the blood-ocular barrier than are smaller molecules. The blood-ocular barrier has multiple components. The pigment epithelium of the iris and ciliary body forms the blood-aqueous barrier. More posteriorly, the retinal pigment epithelium forms a barrier between the choroidal circulation and the outer visual retina. The endothelial cells of the retinal vessels and capillaries form a barrier between the retinal circulation and the vitreous cavity on one side and the inner retina on the other side. The blood-aqueous barrier typically is leakier than the blood-retinal-vitreous barriers. This difference becomes more marked as the water solubility of a molecule increases and less marked as the lipid solubility increases. Fluid moves from the compartment of lower osmolarity. Systemically administered hyperosmotic agents increase intravascular osmolarity and induce fluid to flow out of the eye. The opposite flow of fluid (into the eye) was used in the water provocative test, which is of historical interest, and was used to diagnose glaucoma. Rapidly drinking a liter of water decreased the blood osmolarity. The relatively higher intraocular osmolarity induced the flow of fluid into the eye, raising the IOP.12 Finally, the route of administration dictates the onset of action of hyperosmotic agents. Intravenous administration is the most rapid route for accession of substances into the bloodstream and provides the most rapid onset of action.13 |
| CLINICAL USES | ||||||||||||||||||||||||||||||||||||||||||||||||
SYSTEMICALLY ADMINISTERED Hyperosmotic agents that lower IOP are administered orally or intravenously in clinical practice (Tables 1 and 2). Indications for the use of hyperosmotic agents include the treatment of acute elevations in IOP and the treatment of glaucomas with critically shallow anterior chambers.
TABLE 1. Orally Administered Hyperosmotic Agents in Clinical Use
TABLE 2. Intravenously Administered Hyperosmotic Agents in Clinical Use
Elevations in IOP often are present before surgery in patients undergoing filtration surgery and the surgeon is concerned that the sudden drop in IOP occurring when the initial incision is made may cause problems such as choroidal hemorrhage. To avoid this problem, a hyperosmotic agent may be administered intravenously just before surgery. When the pressure has been reduced to a level that the surgeon considers safe for the patient to open the eye, surgery is begun. Postoperative IOP elevations occur after various types of intraocular surgery, and hyperosmotic agents may be used to temporize. Significant IOP elevations occur in up to 20% of patients undergoing anterior segment laser surgery, including laser trabeculoplasty, laser iridectomy, and laser capsulotomy.14–16 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,17–19 thereby reducing the need for hyperosmotic treatment after laser surgery. More recently, these alpha adrenergic drugs have been used in the chronic management of glaucoma.19–21 This renders them less effective in preventing and treating acute IOP elevations in patients treated with them chronically.22 The use of hyperosmotic agents after laser surgery may, therefore, increase. Hyperosmotic agents are 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 or allow for surgical intervention under more controlled circumstances. Ocular diseases that lead to critical shallowing of the anterior chamber include pupillary block angle closure glaucoma and the various types of ciliary block glaucoma. In angle closure and ciliary block glaucomas, 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. 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 scopalomine. Peripheral iridoplasty may be indicated in patients with variants of ciliary block glaucoma that are due to swelling or forward movement of the ciliary body, which may follow retinal detachment surgery, panretinal photocoagulation, and central retinal vein occlusion. TOPICALLY ADMINISTERED Topical hyperosmotic agents are used to dehydrate edematous corneas to improve the view of the anterior and posterior segments and to permit gonioscopic examination (Table 3). These agents are particularly useful in diagnosing suspected angle closure glaucoma in patients with elevated IOPs and cloudy corneas.
TABLE 3. Topically Administered Hyperosmotic Agents for Corneal Dehydration
In addition, topical hyperosmotic agents are used chronically to dehydrate corneas in patients with failing endothelial function (e.g., patients with Fuch's dystrophy, postsurgical corneal decompensation). Topical agents in the form of drops or ointments improve corneal clarity and, thus, visual acuity in the early stages of corneal decompensation, often delaying the need for surgical intervention (see Table 3). HYPEROSMOTIC AGENTS Intravenous Agents Hyperosmotic agents should be administered intravenously when the patient needs to be fasting, such as before surgery, or when the patient is nauseous or vomiting and is unable to take the agents orally. Intravenous agents have a faster onset of action than orally administered hyperosmotic agents. Urea Urea was first introduced into clinical practice in 1956 for neurosurgical use.3 Subsequently, in 1959, it was reported to be an effective ocular-hypotensive agent.4,23 Urea is administered as a 30% solution that must be freshly prepared. Stale solutions decompose to ammonia, a toxic byproduct. The recommended dosage is 2 to 7 ml/kg. IOP reductions occur within 30 to 45 minutes and peak at 1 hour after administration. Persistent reductions in IOP are observed for 5 to 6 hours. Urea is a small molecule6 and is not restricted to the extracellular or intravascular fluid compartment. It moves freely throughout total body water. Urea thus is less effective than mannitol for reducing IOP in inflammatory glaucomas. In addition, extravasation of urea during administration leads to tissue necrosis and sloughing; thus, the drug must be administered carefully. Urea is not metabolized and is excreted rapidly by the kidneys.24 The blood urea nitrogen level remains elevated for up to 6 hours after administration but returns to normal within 24 hours.25 Mannitol Mannitol was first reported to be an effective ocular-hypotensive agent in 1962.6 Mannitol is administered as a 10% or 20% solution. It is stable in solution but is soluble only up to a concentration of 15% in cold water. If crystals are observed before administration, the solution can be warmed. A blood filter should also be used to avoid the entry of crystals into 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 after administration. Persistent IOP reductions have been reported for up to 6 hours.26 Mannitol is eliminated by the kidneys and is not metabolized in the body.24 The large size of the molecule prevents it from crossing the intact blood-ocular barrier.24 Oral Agents Oral agents have the advantages of less-systemic toxicity than intravenously administered agents, and they can be administered on an outpatient basis, thus eliminating the need for obligatory hospitalization.27 However, oral administration of hyperosmotic agents may be accompanied by unpleasant gastrointestinal side effects. Glycerol Glycerol was the first oral hyperosmotic agent to be used clinically.7 Glycerol is available as a 50% solution in 0.9% saline. One milliliter of this solution contains 0.62 g of glycerol. Dosages used in clinical practice range between 1 and 1.5 g/kg of body weight. The taste is not very pleasant (extremely sweet), so orange juice or ice can be used to make glycerol more palatable. Orally administered glycerol is not as effective as intravenously administered hyperosmotic agents in lowering IOP. Absorption is variable and glycerol crosses the blood-aqueous barrier in the inflamed eye more easily than other hyperosmotic agents.25 The advantage of glycerol is that it is a component of human body fat, as it constitutes approximately 1% of body weight. Glycerol thus is readily metabolized, which makes it relatively safe. Accidental ingestion of up to 23 g/kg in a 2½-year old was tolerated.28 Experimental chronic oral administration of approximately 1 to 3 g/kg three times a day for 7 weeks in 14 humans produced no significant toxicity.29 Glycerol is metabolized through the tricarboxylic acid cycle to glucose, and hyperglycemia and glycosuria can result from its use. Thus, it is relatively contraindicated in subjects with diabetes as it can easily upset glucose control. The high concentration of glucose after metabolism of glycerol also provides a substantial caloric load in contrast to the other clinically available hyperosmotic agents. Interestingly, in the preinsulin era, glycerin was used as a source of carbohydrate in subjects with diabetes as its cellular uptake does not require insulin. The onset of the ocular-hypotensive effect of glycerol is 10 minutes after administration and the peak effect is 30 minutes to 1 hour after administration. The duration of IOP reduction is 4 to 5 hours, after which IOP returns to pretreatment values. Glycerol administration can be repeated at that time.7 As the drug is metabolized, it is less likely to produce a diuresis than a nonmetabolized drug such as isosorbide or mannitol. This may be useful for surgery in which the surgeon wishes to avoid the need for a Foley catheter. Isosorbide Isosorbide was first used for lowering IOP in 1967.8 Since then, isosorbide has quickly surpassed glycerol as the oral hyperosmotic of choice in the United States. Its main advantage is rapid and almost complete absorption from the gastrointestinal tract.30 In addition, isosorbide is more palatable than glycerol, causing less nausea. Nonetheless, it is far from tasty and is most palatable when administered with ice or orange juice. Isosorbide is available as a 45% solution. Dosages used clinically range from 1.5 to 2 g/kg and produce IOP reductions comparable to clinically administered dosages of glycerol. However, isosorbide is not metabolized and does not cause hyperglycemia. Maximum reductions in IOP occur 45 minutes to 2 hours after administration. IOP decreases by 25% to 90% and returns to pretreatment values in 3½ to 4½ hours after administration.31 Over 95% of a dose of isosorbide is excreted unchanged by the kidneys.32 Ethanol Ethanol has been investigated as an IOP-lowering agent in both normotensive and glaucomatous patients at various doses.24,33 In relatively high doses, it decreases IOP through both an osmotic action on the vitreous (as penetration into the vitreous is slow) and by inhibition of secretion of antidiuretic hormone by the posterior pituitary gland. Unfortunately, intoxication associated with the use of ethanol precludes its use in clinical practice. The effective dosage as an osmotic agent is approximately 2 to 3 ml/kg of 40% to 50% (i.e., 80 to 100 proof) alcohol. Urea Urea has been administered orally, but it is not palatable. Thus, if selected, urea should be administered intravenously. TOPICAL AGENTS Glycerol Glycerol (Ophthalgan) is used to clear the cornea to perform gonioscopy in patients with microcystic corneal edema (see Table 3). The effect on the cornea is only temporary (1 to 5 minutes). The onset of action is rapid (1 to 2 minutes). Topically applied hyperosmotic agents do not reduce IOP. They do not create a sufficient osmotic gradient, as they are quickly diluted by tears. Glycerol causes intense burning when applied to the nonanesthetized cornea; thus, topical anesthesia is indicated before its use. Sodium Chloride Sodium chloride 5% is available in both drops and ointment (see Table 3). It has no significant side effects except for occasional mild burning and irritation. When used as an ointment, sodium chloride 5% temporarily can blur the vision. Hypertonic sodium chloride in ointment form can reduce corneal thickness up to 24% in patients with compromised corneal endothelial function. The effect lasts up to 7 hours and is maximal 3 to 4 hours after application. In contrast, sodium chloride drops seem to have little effect on corneal thickness.34 Dextran Polysaccharide The colloidal dextran polysaccharide solution (Dehydrex), which has been evaluated for use in patients with recurrent corneal erosion syndrome, is not commercially available.35 This solution is a high-molecular-weight polysaccharide that is equal to or slightly hyperosmolar to corneal tissues. One small clinical trial suggests this solution, which causes epithelial dehydration and lubrication, improves vision, and reduces symptoms in patients with recurrent corneal erosion syndrome. |
| SYSTEMIC SIDE EFFECTS AND CONTRAINDICATIONS |
| The mechanism by which the systemically administered hyperosmotic agents
reduce IOP (i.e., relative dehydration of extravascular spaces) also is the reason for
the side effects of these agents. Water is drawn into the intravascular
space, thus increasing the intravascular volume. This is relatively
well tolerated in healthy individuals. However, it can be detrimental
in patients sensitive to acute changes of intravascular volume, such as
patients with chronic congestive heart failure. In these patients, the
use of systemic hyperosmotic agents can induce an acute episode of
heart failure.36 Headache is a common side effect of hyperosmotic agents. The headache
is caused by cerebral dehydration, causing reduced intracranial pressure.37 It may last for as long as 45 minutes to 1 hour after administration of
the agent. The headache is quite similar to headaches that occur after
lumbar puncture. In a few patients, cerebral dehydration has caused
confusion and disorientation.37 This is more common with intravenous agents that have a more rapid onset
of effect. Increased diuresis results from the use of systemic hyperosmotic agents as the intravascular volume expands. Many of the hyperosmotic agents are excreted in the urine, and catheterization may be necessary in anesthetized patients to avoid severe distention of the bladder.37 Urinary retention with severe bladder distention is common in older men with prostatic hypertrophy, particularly when they cannot void for extended periods such as during a surgical procedure. Renal failure is a relative contraindication to the use of hyperosmotic agents. The fluid drawn into the intravascular space by these agents is excreted by the kidneys. If renal function is compromised, the increase in intravascular free water causes plasma sodium concentration to fall. The resulting hyponatremia can lead to lethargy, seizures, and coma.28 Potassium depletion also may occur. Renal toxicity can complicate the situation as many of these agents are excreted in the urine, and compromised renal function can reduce their elimination. In this situation, hemodialysis is indicated as neurologic deterioration can be rapid.36 Thus, in patients with compromised renal function, there is an advantage to using hyperosmotic agents that are metabolized as well as excreted, such as glycerin. Nausea and vomiting are the most common side effects, particularly in patients receiving orally administered hyperosmotic agents. This side effect also has been reported in up to 30% of patients receiving urea intravenously.23 Severe vomiting can limit the usefulness of oral hyperosmotic agents in the preoperative treatment of patients. Extravasation of urea during infusion can cause local tissue damage, which can be quite painful and rarely produces necrosis.38 Mannitol extravasation causes only localized swelling.5 In addition, thrombophlebitis at the site of injection is more common with urea and occurs in up to 5% of patients. Mannitol thrombophlebitis is extremely uncommon and very mild.6 Rare events that have been reported in association with the use of hyperosmotic agents include the development of subdural hematomas with urea39 and allergic reactions with mannitol.40,41 |
| SUMMARY |
| Hyperosmotic agents reduce IOP by increasing plasma osmolarity and thus
drawing water out of the vitreous and into the intravascular space. Systemically
administered hyperosmotic agents are indicated for the short-term
management of acute elevations of IOP such as preoperative and
early postoperative IOP elevations, and pupillary block and ciliary block
glaucomas. These medications are indicated in the treatment of acute
IOP elevations in patients nonresponsive to topically administered
ocular hypotensive agents and systemically administered carbonic anhydrase
inhibitors. Orally administered hyperosmotic agents are less toxic
but may not be tolerated as well as intravenously administered agents. Intravenous
agents have a more rapid onset of effect. Elimination
of many of these agents is through the kidneys. The preferred hyperosmotic
agents are mannitol for intravenous administration and isosorbide
for oral administration. These two agents are better tolerated and induce
fewer side effects than the other drugs currently available. Hyperosmotic agents should not be administered chronically to treat glaucoma. The duration of IOP effect is relatively brief, 4 to 6 hours; thus, dosing three to four times daily would be required for chronic use. Repetitive dosing leads to decreased efficacy, as the hyperosmotic particles eventually enter the extravascular spaces. Rebound elevations of IOP have been noted after repetitive dosing. Side effects are quite common and occasionally serious. Thus, long-term use of hyperosmotic agents for the chronic management of glaucoma is not appropriate. Topical hyperosmotic agents draw water from the cornea into the tears. They are useful diagnostic tools for temporarily clearing the cornea in cases of corneal edema, and they are useful therapeutic tools for the chronic management of mild cornea edema. Side effects of these agents are limited to local ocular discomfort. |