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A potential ocular side effect of osmotic drugs is IOP "rebound." The creation of a blood-vitreous osmotic gradient causes transfer of water from the eye into the blood, thereby increasing the osmolality of the vitreous. During clearance of the drug from the circulation, the osmolality of the blood may decrease to a level below that in the vitreous. The hyperosmotic vitreous may then draw water into the eye, which may increase IOP. If the cause of glaucoma is not relieved after administration of the drug, IOP rebound may occur later. The osmotic drug itself may also enter the eye and then clear more slowly from the eye than from the systemic circulation. Thus, IOP rebound may be less common with glycerol and mannitol, which have poor ocular penetration compared with other osmotic drugs (e.g., urea).

A transient increased aqueous flare (aqueous protein concentration) has been observed after intravenous mannitol;19 however, the clinical significance of this finding is unknown. Severe intraocular hemorrhage has been reported following administration of urea.20

Systemic side effects ranging from mild to life-threatening may develop following treatment with osmotic drugs.15,21-23 The most frequent side effects are nausea, vomiting, and headache, which may exacerbate the symptoms of the patient with acute glaucoma. Also, these untoward side effects may be hazardous when the drugs are used perioperatively. Antiemetic drugs may reduce these symptoms when administered prior to the osmotic agent.

Hyperosmolality and electrolyte disturbances may cause various central nervous system side effects, including thirst, chills, fever, confusion, and disorientation. Subdural hematoma has been described after administration of urea.24 This potentially fatal complication probably results from brain shrinkage and retraction, causing traction and tearing of the bridging veins between the sagittal sinus or the dura and the surface of the brain.

The diuresis that follows administration of osmotic drugs may lead to urinary retention requiring catheterization, especially in men with prostatic hypertrophy. Some patients who are treated with osmotic drugs perioperatively may require a catheter to avoid the need to void during surgery. Osmotic drugs may cause severe dehydration, and glycerol, in particular, may cause hyperglycemia.25,26 Glycerol is metabolized to glucose (figure 8.2), and therefore, use of this drug should be avoided in diabetic patients, especially when multiple administrations are anticipated. Renal failure has been described in previously normal patients following infusion of mannitol.27


Glycerol kinase

Glycerol kinase


Free fatty acids + ATP

Glyceraldehyde-3-phosphate ^___Pyruvate

Glycolysis Giuconeogenesis


Free fatty acids + ATP

Glyceraldehyde-3-phosphate ^___Pyruvate

Glycolysis Giuconeogenesis

Figure 8.2. Biochemical pathway for glycerol metabolism.


Iatrogenic intoxication with osmotic drugs may occur, especially after treatment with mannitol.28,29 Because it is confined to the extracellular fluid space, mannitol may greatly increase the blood volume. The ensuing dehydration of the brain may lead to central nervous system involvement, including lethargy and disorientation. Patients with mannitol intoxication may develop severe hyponatremia, a large osmolality gap (high measured minus calculated serum osmolality), and fluid overload. The treatment for this disorder is hemodialysis or peritoneal dialysis.

Increased blood volume after administration of osmotic drugs may overload the cardiac reserve, causing congestive heart failure or pulmonary edema. Elderly patients with borderline cardiac or renal function are especially at risk for these problems. Mannitol is retained in the extracellular fluid space, which causes expansion of blood volume, and intravenous administration may be more rapid than the gastrointestinal absorption of oral osmotic drugs. Thus, patients may be at higher risk for cardiovascular complications after treatment with mannitol compared with oral osmotic drugs.

Although hypersensitivity to osmotic drugs is uncommon, serious allergic reactions have been reported after the administration of intravenous mannitol.30,31 Patients with a history of atopy and asthma may be at high risk for hypersensitivity reaction to mannitol. High-risk patients may be identified with skin testing, which can produce a positive reaction shortly after lightly scratching the skin where a drop of mannitol has been placed.30 If a reaction occurs, mannitol infusion is discontinued and supportive therapy is instituted, including, as warranted, epineph-rine, diphenhydramine, corticosteroids, or aminophylline.

Side effects of osmotic drugs are summarized in table 8.3.

Table 8.3 Side Effects of Osmotic Drugs


IOP rebound Intraocular hemorrhage


Nausea Vomiting

Abdominal cramping Diarrhea

Genitourinary Diuresis

Electrolyte abnormalities Dehydration Hypervolemia Urinary retention Anuria

Central Nervous System









Subdural hematoma

Cardiovascular Angina

Pulmonary edema Congestive heart failure


Hyperglycemia Hypersensitivity

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