Although the effect of hyperosmotic agents on intraocular pressure (IOP) has been known for almost a century, these agents became widely used in ophthalmology only in the past 40 years. Hyperosmotic agents are useful for the short-term management of acute glaucoma. These drugs can prevent the need for surgery in transient glaucoma conditions, such as occurs with traumatic hyphema. They also may be used for lowering IOP preoperatively. Hyperosmotic agents have reduced the risk of surgically decompressing eyes with markedly elevated IOPs. In addition, they are used in cases of acute cerebral edema and (topically) for corneal edema.
MECHANISMS OF ACTION
Hyperosmotic agents reduce IOP by increasing the osmolality of the plasma and drawing water from the eye into the circulation via the blood vessels of the retina and uveal tract. This transient effect lasts until osmotic equilibrium is re-established. Within a few hours, the hyperosmotic agent may penetrate the eye. If the agent has already cleared the plasma, reversal of the osmotic gradient occurs (i.e., plasma osmolality decreases to a level below that of the dehydrated tissues), with a rebound increase in IOP. For most agents in clinical use, effective IOP lowering is achieved when plasma osmolality is increased by 20–30 mOsm/l. Most of the fluid drawn from the eye comes from the vitreous; vitreous weight is reduced by 2.7–3.9% in experimental animals after administration of hyperosmotic agents in doses equivalent to those used clinically. Glaucomatous eyes appear to get a proportionately greater IOP-lowering effect from an osmotic challenge than do normal eyes.
Hyperosmotic agents also appear to lower IOP by a second mechanism; they decrease aqueous humor production via a central nervous system (CNS) pathway involving osmoreceptors in the hypothalamus. The evidence for this second mechanism is summarized as follows:
- 1.
After the administration of hyperosmotic agents, the decrease in IOP and the increase in plasma osmolality are not correlated closely in terms of magnitude of effect or time course.
- 2.
Small doses of hyperosmotic agents administered intravenously can reduce IOP without changing plasma osmolality.
- 3.
Intracarotid injections of hyperosmotic and hypo-osmotic solutions alter electric activity in regions of the hypothalamus that are known to affect fluid balance in the body.
- 4.
Destruction of the supraoptic nuclei abolishes the IOP response to hypo-osmotic solutions.
- 5.
Injections of hyperosmotic and hypo-osmotic agents into the third ventricle alter IOP without affecting plasma osmolality.
It has been postulated that the osmoreceptors in the hypothalamus alter aqueous humor production via efferent fibers in the optic nerve. This theory was stimulated by the observation that human eyes with optic nerve lesions develop less elevation of IOP after water loading. Furthermore, some investigators have noted that unilateral optic nerve transection in experimental animals diminishes the IOP response to hyperosmotic and hypo-osmotic agents administered intravenously or into the third ventricle. However, other researchers have failed to confirm the effect of optic nerve transection and have questioned the existence of osmoregulatory efferent fibers in the optic nerve.
Intra-arterial injections of hyperosmotic agents lead to breakdown of the blood–aqueous barrier and destruction of the non-pigmented ciliary epithelium. However, intravenous injections do not have the same effect. Thus it is unlikely that this mechanism plays a role in the clinical response to hyperosmotic agents.
Hyperosmotic agents pull water from the eye along an osmotic gradient and reduce aqueous humor formation via osmoreceptors in the hypothalamus. The specifics of this latter mechanism remain unknown.
DRUGS IN CLINICAL USE
A number of factors are important in determining the osmotic gradient induced between plasma and the ocular fluids. Because the change in plasma osmolality depends on the number of milliosmols of substance administered, agents of low molecular weight (e.g., urea) have a greater effect per gram administered than do compounds of high molecular weight (e.g., mannitol) at the same dose. Agents confined to the extracellular fluid space (e.g., mannitol) produce a greater effect on plasma osmolality than do agents distributed in total body water (e.g., urea). This latter factor has a larger effect than that associated with molecular weight. Some drugs rapidly enter the eye (e.g., alcohol), thereby producing less of an osmotic gradient than do those that penetrate slowly (e.g., glycerol). Agents administered intravenously bypass gastrointestinal absorption and produce a more rapid and a slightly greater rise in plasma osmolality.
Other factors that affect the osmotic gradient include the rate of elimination of the agent from the circulation, the production of hypo-osmotic diuresis (e.g., alcohol), the condition of the ocular vessels, and the state of the blood–aqueous and blood–retinal barriers (e.g., inflammation). It is peculiar that these many factors tend to balance each other sufficiently so that most hyperosmotic drugs in clinical use are effective in doses of 1–2 g/kg. Patients should be cautioned not to drink water or other fluids after administration of the agent because doing so may reduce the osmotic gradient.
ORAL AGENTS
Orally administered hyperosmotic agents are slightly less effective and have a slower onset of action than do the intravenous agents. Variable absorption from the gastrointestinal tract makes their effect less predictable. These differences are not great, however, and the oral agents are safer and less likely to produce volumetric overload in patients with borderline cardiac status. Oral agents are not well tolerated by patients with nausea and vomiting.
Glycerol
Glycerol (Glyrol, Osmoglyn), the most commonly prescribed hyperosmotic agent, is usually administered as a 50% solution in a dose of 1.5–3 ml/kg ( Table 28-1 ). (Glycerol is also available as a 75% solution.) It begins to lower IOP in 10–30 minutes, reaches a maximum effect in 45–120 minutes, and has a duration of effect of 4–5 hours. Glycerol has an intense, sweet taste and is more palatable when given in an iced unsweetened fruit juice or cola base. If necessary, glycerol can be administered repeatedly because it penetrates the eye and other tissues poorly and is confined to the extracellular water.
| Agents | Molecular weight | Distribution | Ocular penetration | Usual dose (gm/kg) | Excreted | Other |
|---|---|---|---|---|---|---|
| Oral | ||||||
| Glycerol | 92 | Extracellular | Poor | 1–1.5 (1.5–3 ml/kg 50% solution) | Urine and metabolized | May cause nausea and vomiting; source of calories |
| Isosorbide | 146 | Total body water | Good | 1–2 (1.5–4 ml/kg 45% solution) | Urine | May cause diarrhea |
| Ethanol | 46 | Total body water | Good | 0.8–1.5 (2–3 ml/kg 40–50% solution) | Metabolized | Hypotonic diuresis, source of calories, may cause nausea, vomiting, central nervous system and gastrointestinal effects |
| Intravenous | ||||||
| Urea | 60 | Total body water | Good | 1–2 (2–7 ml/kg 30% solution, 60 drops/min) | Urine | Unstable solution, skin slough |
| Mannitol | 182 | Extracellular | Poor | 1–2 (2.5–7 ml/kg, 20% solution, 60 drops/min) | Urine | Increases blood urea nitrogen, not very soluble, large volume of solution, dehydration |
The major disadvantage of glycerol is the relatively high frequency of associated nausea and vomiting. Glycerol is metabolized in the liver and produces 4.32 kcal/g of energy. The caloric value of glycerol and its metabolites as well as the osmotic dehydration it produces can lead to ketoacidosis and other problems in diabetic patients.
Isosorbide
Isosorbide (Ismotic, Hydronol) is a dihydric alcohol formed by the removal of two molecules of water from sorbitol. It is an effective oral hyperosmotic agent, administered as a 45% solution in doses of 1.5–4 ml/kg (see Table 28-1 ). Its time of onset and duration of action are similar to those of glycerol. Isosorbide is absorbed rapidly from the gastrointestinal tract and is excreted unchanged in the urine. It must be given in somewhat larger doses than glycerol to produce a comparable effect on IOP. Isosorbide is more expensive than glycerol.
Isosorbide is less likely to produce nausea and vomiting but more likely to produce diarrhea than is glycerol. Because isosorbide is not metabolized and is excreted unchanged in the urine, it does not produce any calories and is thus a better choice for diabetic patients. Unfortunately, because of relatively infrequent usage, isosorbide is no longer manufactured in the United States and obtaining it may be difficult or impossible. It is possible to confuse isosorbide with isosorbide dinitrate (Isordil), which is used to treat angina.
Ethyl alcohol
Ethyl alcohol may be an effective oral hyperosmotic agent when administered as straight spirits or diluted with appropriate mixers to a final dose of about 1.0–1.8 ml/kg of absolute alcohol (about 1–2 ml/kg of a 40–50% solution (80–100 proof)). Alcohol also induces hypotonic diuresis by inhibiting production of antidiuretic hormone. This prolongs and increases the osmotic gradient. Alcohol enters the eye rapidly, but vitreous penetration is sufficiently delayed to create an osmotic gradient. The effects of alcohol on the CNS as well as on the gastric mucosa limit its chronic use. It is important to know about alcohol’s effect on IOP because a low IOP after a three-martini (or even a one-martini) lunch may not be representative of other afternoon pressures. Like glycerol, ethyl alcohol is metabolized, producing calories that may be a problem for diabetic patients. Its use in this context is limited to emergency situations in which other, more appropriate agents are not available.
INTRAVENOUS AGENTS
Intravenously administered hyperosmotic agents produce a more rapid onset of action and a slightly greater effect than do agents administered orally. The intravenous drugs are usually administered over a period of 45–60 minutes.
Mannitol
Mannitol (Osmitrol) is an effective hyperosmotic drug that is currently the agent of choice for intravenous administration. The usual dose is 2.5–7.0 ml/kg of the 20% solution (see Table 28-1 ). The drug begins to lower IOP in 15–30 minutes, reaches a maximum effect in 30–60 minutes, and has a duration of action of approximately 6 hours. It is not necessary to administer the full dose of the drug; when IOP falls to the desired level, the infusion can be terminated. Mannitol is excreted unchanged in the urine (i.e., it is not metabolized). Because it penetrates the eye poorly, mannitol is especially useful as a hypotensive agent in the presence of ocular inflammation. The 20% solution is stable and less irritating to blood vessels and subcutaneous tissue than is urea.
The major disadvantages of mannitol are the greater likelihood of cellular dehydration because of its confinement to extracellular water and the larger volume of fluid required because of its limited solubility. Cellular dehydration in the CNS may produce symptoms of dementia and disorientation, especially in the elderly. Great caution should be observed in patients with renal failure because they may be unable to excrete the large quantity of fluid extracted from the cells. Similarly, the increased blood volume may place an intolerable load on patients with congestive heart failure. The 20% solution should be warmed to dissolve crystals, and a blood administration filter should be used in the intravenous line. An anaphylactic reaction to mannitol has been reported.
Urea
Urea (Urevert, Ureaphil) was the first intravenous agent used for the treatment of glaucoma. Administered intravenously as a 30% solution in a dose of 2.0–7.0 ml/kg (see Table 28-1 ), urea begins to lower IOP in 15–30 minutes, reaches a maximum effect in 60 minutes, and has a duration of action of 4–6 hours. Urea is slightly less effective than is mannitol because urea diffuses more freely through body water and penetrates the eye more readily. The latter is especially true in inflamed eyes. The drug is prepared in a 10% invert sugar solution to prevent hemolysis. Urea is not metabolized and is excreted rapidly in urine.
As urea is cleared from the circulation, the plasma osmolality may fall below that of the vitreous, resulting in a rebound increase in IOP. Only fresh urea solutions should be administered because old solutions decompose to ammonia. However, fresh solutions must be warmed to compensate for the endothermic reaction of dissolving the drug. The physician should be aware that warming the solution to 50°C or higher produces ammonia. Extravasation of urea results in thrombophlebitis and skin necrosis. Because of these side effects, urea is rarely used.
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