Drug class: Osmotic Diuretics
- Diuretics, Osmotic

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Urea is an osmotic diuretic.

Uses for Urea

Reduction of Intracranial Pressure

Urea is used to reduce elevated intracranial and/or CSF pressure in the control of cerebral edema which may occur during surgery, trauma, disease, or drug intoxication. Urea is especially indicated when there is evidence of herniation and developing brainstem compression. The drug may be used preoperatively, during surgery, or postoperatively. A rebound increase in intracranial pressure may occur after about 12 hours; this tends to occur more frequently with urea than with mannitol. In patients with acute elevations of intracranial pressure in Reye’s syndrome, urea has produced profound reduction of intracranial pressure; in some instances urea was effective after mannitol had failed. IV administration of urea to hydrocephalic children has produced an initial rapid fall in ventricular fluid pressure which persisted for 3–4 hours; however, the pressure then returned to and exceeded pretreatment levels.

Reduction of Intraocular Pressure

Urea is used to reduce elevated intraocular pressure when the pressure cannot be lowered by other means. Urea may be used alone or with miotics and/or carbonic anhydrase inhibitors such as acetazolamide. Urea is useful for treating acute episodes of angle-closure glaucoma, infantile glaucoma, and some secondary glaucomas, such as those caused by dislocation of the lens. Because urea penetrates the eye, it is not recommended when irritation is present, such as in glaucoma secondary to anterior uveitis. Urea may be used to lower intraocular pressure prior to intraocular surgery; it is more effective than acetazolamide, glycerin, or a combination of the 2 drugs in those cases of cataract extraction in which vitreous loss or displacement is likely. In many institutions, mannitol has supplanted urea for general use in lowering intraocular pressure because of its relative lack of toxicity and its greater stability in solution.

Other Uses

Orally^{† [off-label]} administered urea has been used to prevent or reduce the frequency of severe migraine attacks^{† [off-label]}, possibly by reducing cerebral edema. Urea has been administered orally^{† [off-label]} as a diuretic^{† [off-label]}; however, it is rarely used for that purpose because of the large doses required, unpleasant taste, and relative ineffectiveness as compared with newer diuretics. Oral^{† [off-label]} or IV urea has been used effectively in conjunction with sodium chloride supplementation and water restriction to rapidly correct hyponatremia in patients with the syndrome of inappropriate secretion of antidiuretic hormone^† (SIADH). With this combination therapy, neurologic manifestations of hyponatremia may be rapidly improved and serum sodium concentration may be normalized within 12–24 hours. In patients with SIADH, normalization of serum sodium concentration is secondary to osmotic diuresis and sodium retention induced by urea.

Urea has been administered IV for the management of acute sickle cell crises^†. One investigator has reported a reduction in the number of circulating sickled cells, but others have concluded that urea was not effective in shortening the time of crisis when compared with a control solution. Urea has also been administered orally for the prophylaxis of sickle cell crises^†. Although beneficial results were obtained in one study, other investigators have reported no decrease in the frequency of crises or improvement in hematocrit in patients treated prophylactically with urea.

Urea has also been used as a 4% solution in the prevention of acute renal failure^† and as an adjunct in the management of oliguria and edema^† that may occur during or following extensive surgery, burns, or trauma; however, substantial evidence of the effectiveness of the 4% solution for these uses is lacking. The usefulness of more concentrated solutions of urea for these purposes has not been studied, and urea has been replaced by mannitol for this type of therapy.

Urea has been used to promote the urinary excretion of toxins such as meprobamate and some barbiturates^†. Concomitant administration of sodium bicarbonate may be needed to alkalinize the urine in the management of barbiturate poisoning.

Urea has also been used as a mucolytic agent^†. When solutions of urea were injected through the tympanic membrane^† in anesthetized patients with otitis media, liquefied mucus drained through the puncture and the patients’; hearing improved. Solutions of urea have also been administered by inhalation^† to patients with bronchial diseases^†. Good response, as indicated by increased expectoration, was obtained, especially in patients with cystic fibrosis and bronchiectasis. However, the drug was found to cause an acute deterioration of ventilatory capacity in asthmatic patients, possibly because of bronchoconstriction, and is therefore not recommended for inhalation therapy in these patients.

For topical uses of urea, see 84:28.

Urea Dosage and Administration

Reconstitution and Administration

Urea is administered by slow IV infusion. The drug has also been administered orally^†.

For IV infusion, urea is usually administered as a 30% solution in 5 or 10% dextrose or 10% invert sugar injection. The rate of injection should not exceed 4 mL of a 30% solution per minute. Infusions of the drug should not be stopped abruptly. Injection of urea into veins of the lower extremities of geriatric patients is contraindicated. Extravasation of the solution at the injection site must be avoided, since local reactions ranging from mild irritation to tissue necrosis may occur. An indwelling catheter should be inserted in comatose patients receiving the drug to ensure emptying of the bladder and to facilitate measurement of urinary output.

For IV infusion, 105 mL of 5 or 10% dextrose injection or 10% invert sugar injection is added to the container labeled as containing 40 g of urea to provide solutions containing 300 mg/mL (30% solution). Solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit; reconstituted solutions of the drug should be used only if they are clear. Urea powder for injection should not be used unless the container is undamaged with seal intact.

To mask the unpleasant taste of the drug when administered orally^†, urea crystals may be administered as a 40% solution in juices or carbonated beverages or mixed with jelly or jam.

Dosage

Dosage of urea depends on the condition being treated and the patient’s physical condition, especially the state of hydration, electrolyte balance, and renal function. No more than 1.5 g/kg or 120 g should be given IV in a 24-hour period.

Reduction of Intracranial or Intraocular Pressure

To reduce elevated intracranial or intraocular pressure and produce diuresis in adults, the usual dose is 1–1.5 g/kg generally given over 1–2.5 hours; however, as little as 0.5 g/kg has been recommended by some clinicians. The usual dose for children older than 2 years of age is 0.5–1.5 g/kg or 35 g/m² in 24 hours. For children younger than 2 years of age, as little as 0.1 g/kg may be sufficient. When used in intraocular surgery, urea should be administered 1–2 hours preoperatively to achieve the maximum reduction in pressure before surgery is begun. When used during intracranial surgery, the urea infusion should be adjusted so that two-thirds of the dose is absorbed during the time the dura is exposed, with the remainder to be infused at a controlled rate as indicated.

Other Uses

As an oral^† diuretic, urea has been given to adults in a dosage of 20 g 2–5 times daily. The usual pediatric oral dosage is 0.8 g/kg or 25 g/m² in 24 hours, divided into 3 doses daily.

For rapid correction of hyponatremia in the syndrome of inappropriate antidiuretic hormone^† (SIADH), urea has been given, in conjunction with sodium chloride supplementation and water restriction, in a dosage of 80 g IV infused over 6 hours (as a 30% solution) or as 2 or 3 30-g oral doses administered during a 24-hour period. For oral^† administration, 30 g of urea crystals and 10 mL of an aluminum and magnesium hydroxides antacid (Maalox) have been dissolved in 100 mL of water.

When used for the prophylaxis of migraine^†, 1.5, 2, or 2.25 g of urea has been administered orally^† 3 times daily. Dosages were reduced after one week according to the patient’s response.

The IV dosage of urea employed in the management of acute sickle cell crises^† has varied widely. One investigator reported using enough 30% solution to elevate the BUN to 150–200 mg/dL, maintaining the BUN in this range until the pain stopped. Another investigator reported administering up to 320 g as a 16% solution in 10% invert sugar; most patients reportedly needed 120 g or less. In a third study, up to 6 g/kg was administered as a 15% solution in 10% invert sugar at a rate of 4.5 mL/kg per hour over 12–16 hours.

When administered orally^† for the prevention of acute sickle cell crises^†, 1, 2, or 2.3 g/kg has been given daily in 3 or 4 divided doses.

When used as a mucolytic agent^†, 1–1.5 mL of an 8 mol/L (approximately 50%) solution of urea was injected through the anteroinferior quadrant of the tympanic membrane^† in patients with otitis media. Two to 14 g of urea daily for 2–6 weeks has been administered by inhalation^† as 2 or 4 mol/L (12.5 or 25%, respectively) solutions to patients with bronchial diseases^†.

Cautions for Urea

Adverse Effects

The most frequent adverse reactions of urea are headache, nausea, and vomiting. Syncope, disorientation, dizziness, agitation, mental confusion, nervousness, hypotension, tachycardia, cardiotoxicity resulting in ECG changes, hyperthermia, and skin blebs may also occur.

Extravasation of the infusion must be avoided; local reactions ranging from mild irritation to necrotic sloughing of tissues may result. Pain, phlebitis, and venous thrombosis may occur at the site of injection. Thrombosis may occur independently of extravasation and is most likely to occur in the superficial and deep veins of the lower extremities, especially in geriatric patients. Use of large veins other than those in the lower extremities for infusion may lessen the possibility of thrombosis and phlebitis. The risk of venous thrombosis, as well as of hemoglobinuria, is increased when hypothermia is employed simultaneously with urea infusions. The simultaneous use of hypothermia and urea may have contributed to cardiac arrest which occurred in one patient during surgery.

Rapid IV administration of hypertonic urea solutions may cause hemolysis which may be minimized by using 5 or 10% dextrose or 10% invert sugar injection as diluents. The drug may also have a direct effect on cerebral vasomotor centers, resulting in increased capillary bleeding. Rapid infusion of urea has produced intraocular hemorrhage in patients with absolute glaucoma. Arterial oozing and bleeding have occurred during intracranial surgery in patients treated with urea, but this has not been a substantial problem. In addition, the reduction of cerebral edema may precipitate or reactivate intracranial bleeding. Seizures and death from subdural hemorrhage have occurred following administration of the drug, including the death of one patient with hypertension and cerebrovascular disease following administration of 90 g of urea in 1 L of 0.9% sodium chloride injection during a diagnostic procedure. It has been postulated that intracranial bleeding may occur more readily in patients with normal initial intracranial pressure and atherosclerotic blood vessels than in those with cerebral edema and normal blood vessels. The drug may have a fibrinolytic action which may cause an increase in prothrombin time.

Prolonged IV administration of urea to patients with sickle cell crisis has resulted in drowsiness and somnolence; this may be beneficial by permitting sleep in spite of severe pain and reducing the need for analgesics. Somnolence has occurred rarely after prolonged oral administration of urea to patients with impaired renal function. Oral administration of urea may also cause gastric irritation, nausea, and vomiting.

Precautions and Contraindications

Many of the adverse effects of intravenously administered urea on the GI tract, CNS, and blood are the result of infusing solutions of the drug too rapidly and may be avoided or minimized by not exceeding an infusion rate of 4 mL of a 30% solution per minute. Maintenance of adequate hydration and keeping the patient horizontal may also aid in minimizing adverse effects.

Urea solutions may maintain circulatory volume and blood pressure temporarily even when there is considerable blood loss. Blood replacement should be adequate and simultaneous with the administration of urea, especially when excessive blood loss occurs within a short period of time. Urea solutions should not be administered through the same administration set through which blood is being transfused.

Since a transient expansion of plasma volume may result during infusion of urea, the possibility of fulminating congestive heart failure and circulatory overload must be kept in mind, especially in patients with borderline cardiac or renal reserve. Pulmonary edema has occurred during urea administration. The drug should be administered cautiously to patients with cardiac disease. Long-term urea therapy may produce excessive diuresis which can result in dehydration, hyponatremia, and hypokalemia. Early signs of electrolyte depletion, such as muscle weakness or lethargy, may indicate the need for electrolyte supplementation before serum concentrations are reduced. Patients receiving urea should be monitored for signs of fluid and electrolyte imbalance, and corrective therapy should be instituted if necessary. Blood ammonia concentrations may rise in patients with liver impairment, and urea should be used with caution in these patients.

Because urea causes increased excretion of lithium, patients receiving lithium therapy should be observed for possible impairment of clinical response to that drug if urea is administered concomitantly. Concomitant use of hypothermia and urea may increase the risk of venous thrombosis and hemoglobinuria.

Urea should be used with caution in patients with renal disease, and kidney function studies should be performed frequently to determine if kidney function is adequate to eliminate the infused urea as well as that produced endogenously. Satisfactory elimination of urea is generally maintained in patients exhibiting a temporary decrease in urine volume; however, if blood urea nitrogen rises to 75 mg/dL or more or if diuresis does not occur within 1–2 hours after urea is administered, dosage should be reduced or the drug withheld pending further evaluation of the patient.

Urea is contraindicated in patients with severely impaired renal function, marked dehydration, or frank liver failure. The drug is also contraindicated in patients with active intracranial bleeding unless such use is preliminary to prompt surgical intervention to control hemorrhage. Patients with sickle cell disease should not receive the drug if signs and symptoms of CNS involvement are present. Solutions prepared with invert sugar are contraindicated in patients with fructose intolerance due to aldolase deficiency.

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed with urea. It is also not known whether urea can cause fetal harm when administered to pregnant women. Urea should be used during pregnancy only when clearly needed.

Fertility

It is not known whether urea can affect fertility in humans.

Lactation

Since it is not known whether urea is distributed into milk, the drug should be used with caution in nursing women.

Pharmacology

When administered in large doses, urea induces diuresis by elevating the osmotic pressure of the glomerular filtrate to such an extent that tubular reabsorption of water and solutes is hindered. Excretion of sodium, potassium, chloride, and lithium are increased.

The osmotic effect of urea causes water to be drawn from cells, including the brain and CSF, into the blood. This results in reduction of intracranial and/or CSF pressure, brain mass, and cerebral edema; however, a rebound increase in intracranial pressure may occur approximately 12 hours after the administration of urea. Fluids are also withdrawn from the anterior chamber of the eye, resulting in a reduction of intraocular pressure. Unlike mannitol, urea penetrates the eye; a rebound increase in intraocular pressure may occur if plasma concentrations of the drug fall below the concentrations of the drug in the vitreous humor.

Urea prevents and reverses sickle cell formation in vitro, presumably by interfering with the intermolecular hydrophobic bonding between interacting molecules of hemoglobin S and preventing the resultant polymerization and gel formation.

In vitro, urea liquefies purulent or mucoid sputum when the final concentration of urea in the sputum reaches 180 mg/mL or more. The drug may act as a mucolytic agent by breaking intrachain and interchain hydrogen or disulfide bonds.

Urea Pharmacokinetics

Absorption

Following IV administration of urea, the maximum reduction of intraocular and intracranial pressure and the diuretic effect occur within 1–2 hours. Diuresis and reduction of intracranial pressure may persist for 3–10 hours after the infusion is stopped; intraocular pressure usually returns to pretreatment levels in 5–6 hours. When administered orally, urea is rapidly absorbed from the GI tract.

Distribution

Urea is distributed into extracellular and intracellular fluids including lymph, bile, CSF, and blood in approximately equal concentrations. The drug crosses the placenta, penetrates the eye, and probably appears in the milk of lactating women. Highest concentrations of urea occur in the kidneys.

Elimination

It appears that a portion of urea (even when administered parenterally) is hydrolyzed in the GI tract, presumably by bacterial urease. The products of hydrolysis (ammonia and carbon dioxide) may be resynthesized into urea. Urea is excreted by the kidneys.

Chemistry and Stability

Chemistry

Urea, the diamide salt of carbonic acid, is an osmotic diuretic. The drug occurs as colorless to white prismatic crystals or as a white crystalline powder. Urea is freely soluble in water and in alcohol. Urea has a cooling, saline, unpleasant taste; it is practically odorless but may gradually develop a slight ammoniacal odor. The commercially available powder for injection also contains citric acid as a buffer; sodium hydroxide may be added during manufacture to adjust pH. When reconstituted with 5% dextrose, 10% dextrose, or 10% invert sugar injection, a 30% solution of urea has a calculated osmolarity of 5253, 5506, or 5555 mOsm/L, respectively. A 1.63% aqueous solution of urea is theoretically isotonic (as determined by freezing point depression).

The endothermic reaction that occurs on dissolution of urea may prolong reconstitution time. The diluent may be warmed in a water bath to a temperature not exceeding 50°C immediately before mixing with urea; the solution should be cooled to body temperature before administration. Following reconstitution of urea powder for injection with 5 or 10% dextrose or 10% invert sugar injection, solutions of the drug have a pH of 5.5–7.

Stability

Solutions of urea are unstable and cannot be sterilized by heat. Upon standing, heating, or exposure to acids or alkali, urea is hydrolyzed to ammonia and carbon dioxide. Ureaphil solutions (no longer commercially available in the US) were stable for 48 hours when stored at 2–8°C; the manufacturer stated that unused portions of reconstituted solutions should be discarded within 24 hours. Solutions of urea should not be administered through the same administration set through which blood is being transfused. Ureaphil powder for injection (no longer commercially available in the US) had an expiration date of 3 years following the date of manufacture.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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