Mannitol

Mannitol

Drug Nomenclature

Date of monograph revision: 12-Aug-1997; 07-Aug-1998; 04-Oct-2000; 29-Oct-2001; 27-May-2004; 13-Jul-2006
Synonyms: Cordycepic Acid; E421; Manita; Manitol; Manitolis; Manna Sugar; Mannit; Mannite; Mannitol; Mannitoli; Mannitolum
Chemical name: d-Mannitol
Molecular formula: C6H14O6 =182.2
CAS: 69-65-8
ATC code: A06AD16; B05BC01; B05CX04
Read code: y07k0
Chemical Structure of Mannitol

Chemical Structure of Mannitol

NOTE:

Description. Mannitol is a hexahydric alcohol related to mannose (C6H12O6 = 180.2). It is isomeric with sorbitol (Go to Sorbitol).

Use in Sport. Mannitol may be restricted in certain sports, see Go to Drugs in Sport, as it is considered to be a member of a prohibited group (Diuretics); competitors should check with the appropriate sports authorities.

Pharmacopoeias:

In Chin., Eur. (see Go to European Pharmacopoeia Convention Signatories), Int., Jpn, Pol., US, and Viet.

Ph. Eur. 5.5 (Mannitol). A white or almost white crystalline powder or free-flowing granules. It exhibits polymorphism. Freely soluble in water; very slightly soluble in alcohol.

USP 29 (Mannitol). A white odourless crystalline powder or free-flowing granules with a sweet taste. Soluble 1 in 5.5 of water; very slightly soluble in alcohol; practically insoluble in ether; slightly soluble in pyridine; soluble in alkaline solutions.

Physicochemical Characteristics

Incompatibility.

Mannitol should never be added to whole blood for transfusion or given through the same set by which blood is being infused. For details of the adverse effects of mannitol on red blood cells, see Effects on the Blood under Adverse Effects, Go to Effects on the blood..

Supersaturated solutions.

Supersaturated aqueous solutions are prepared with the aid of heat. Any crystals that form during storage of the injection should be dissolved by warming before use; this may be a particular problem with the 20 and 25% injections which are supersaturated. A 5.07% solution in water is iso-osmotic with serum.

Adverse Effects

The most common adverse effect associated with mannitol therapy is fluid and electrolyte imbalance including circulatory overload and acidosis at high doses. The expansion of extracellular volume can precipitate pulmonary oedema and patients with diminished cardiac reserve are at special risk. The shift of fluid from the intracellular to extracellular compartment can cause tissue dehydration; dehydration of the brain, particularly in patients with renal failure, may give rise to CNS symptoms.

When given by mouth, mannitol causes diarrhoea. Intravenous infusion of mannitol has been associated with nausea, vomiting, thirst, headache, dizziness, chills, fever, tachycardia, chest pain, hyponatraemia, dehydration, blurred vision, urticaria, and hypotension or hypertension. Large doses have been associated rarely with acute renal failure. Hypersensitivity reactions have occurred.

Extravasation of the solution may cause oedema and skin necrosis; thrombophlebitis may occur.

Effects on the blood.

Agglutination and irreversible crenation of erythrocytes occurred when blood was mixed with varying proportions of a 10% mannitol solution.1 It was suggested that intravenous infusions should be carefully controlled and given at a slow rate. This observation could have particular relevance to patients with sickle-cell disease.2,3 Although agglutination and crenation had been observed in vitro, dilutional effects would make in-vivo interaction with blood cells less likely.4

  1. 1. Roberts BE, Smith PH. Hazards of mannitol infusions. Lancet 1966; ii: 421–2.
  2. 2. Konotey-Ahulu FID. Hazards of mannitol infusions. Lancet 1966; ii: 591.
  3. 3. Roberts BE, Smith PH. Hazards of mannitol infusions. Lancet 1966; ii: 591.
  4. 4. Samson JH. Hazards of mannitol infusions. Lancet 1966; ii: 1191.

Effects on the gastrointestinal tract.

Potentially explosive intracolonic concentrations of hydrogen gas have been measured in patients given mannitol before colonoscopy,1,2 and cases of colonic explosion, including fatalities, have been reported in patients undergoing colonoscopic electrocautery, who had received mannitol bowel preparation. However, the risk of explosion was considered to be small when air or carbon dioxide insufflation and suction were used during the colonoscopy procedure.2,3

Colonic perforation and subsequent death has been attributed to the use of mannitol for the treatment of constipation.4

  1. 1. La Brooy SJ, et al Potentially explosive colonic concentrations of hydrogen after bowel preparation with mannitol. Lancet 1981; i: 634–6. PubMed
  2. 2. Avgerinos A, et al. Bowel preparation and the risk of explosion during colonoscopic polypectomy. Gut 1984; 25: 361–4. PubMed
  3. 3. Trotman I, Walt R. Mannitol and explosions. Lancet 1981; i: 848. PubMed
  4. 4. Moses FM. Colonic perforation due to oral mannitol. JAMA 1988; 260: 640. PubMed

Effects on the kidneys.

Focal osmotic nephrosis occurred in a patient who received mannitol 20% intravenously.1

Acute oliguric renal failure has been associated with the administration of large doses of mannitol to patients with previously normal renal function,2-4 and acute renal failure developed5 in a patient with diabetes mellitus complicated by nephropathy after he received 420 g of mannitol intravenously over 4 days.

  1. 1. Goodwin WE, Latta H. Focal osmotic nephrosis due to the therapeutic use of mannitol: a case of perirenal hematoma after renal biopsy. J Urol (Baltimore) 1970; 103: 11–14. PubMed
  2. 2. Whelan TV, et al. Acute renal failure associated with mannitol intoxication. Arch Intern Med 1984; 144: 2053–5. PubMed
  3. 3. Goldwasser P, Fotino S. Acute renal failure following massive mannitol infusion: appropriate response of tubuloglomerular feedback? Arch Intern Med 1984; 144: 2214–16. PubMed
  4. 4. Rabetoy GM, et al. Where the kidney is concerned, how much mannitol is too much? Ann Pharmacother 1993; 27: 25–8. PubMed
  5. 5. Matsumura M. Mannitol-induced toxicity in a diabetic patient receiving losartan. Am J Med 2001; 110: 331. PubMed

Overdosage.

Severe mannitol intoxication was reported in 8 patients with renal failure who had received large, and sometimes enormous, amounts of mannitol intravenously over 1 to 3 days.1 These patients had CNS involvement out of proportion to uraemia, severe hyponatraemia, a large osmolality gap, and fluid overload. Six patients were treated with haemodialysis and this was considered to be more effective than peritoneal dialysis, which was used in 1 patient.

  1. 1. Borges HF, et al Mannitol intoxication in patients with renal failure. Arch Intern Med 1982; 142: 63–6. PubMed

Precautions

Mannitol is contra-indicated in patients with pulmonary congestion or pulmonary oedema, intracranial bleeding (except during craniotomy), heart failure (in patients with diminished cardiac reserve, expansion of the extracellular fluid may lead to fulminating heart failure), and in patients with renal failure unless a test dose has produced a diuretic response (if urine flow is inadequate, expansion of the extracellular fluid may lead to acute water intoxication).

Mannitol should not be given with whole blood.

All patients given mannitol should be carefully observed for signs of fluid and electrolyte imbalance and renal function should be monitored.

Pharmacokinetics

Only small amounts of mannitol are absorbed from the gastrointestinal tract. After intravenous injection mannitol is excreted rapidly by the kidneys before any very significant metabolism can take place in the liver. Mannitol does not cross the blood-brain barrier or penetrate the eye. An elimination half-life of about 100 minutes has been reported.

Uses and Administration

Mannitol is an osmotic agent. Although an isomer of sorbitol, it has little energy value, since it is largely eliminated from the body before any metabolism can take place.

Mannitol is mainly used, with adequate rehydration, to increase urine flow in patients with acute renal failure and to reduce raised intracranial pressure (Go to Raised intracranial pressure) and treat cerebral oedema. It is also used in the short-term management of glaucoma (Go to Glaucoma and ocular hypertension), especially to reduce intra-ocular pressure prior to ophthalmic surgery, and to promote the excretion of toxic substances by forced diuresis.

Other indications include bladder irrigation during transurethral resection of the prostate in order to reduce haemolysis and as an oral osmotic laxative for bowel preparation. Mannitol is used as a diluent and excipient in pharmaceutical preparations and as a bulk sweetener. It is under investigation for use in bronchiectasis and cystic fibrosis.

When given parenterally, mannitol raises the osmotic pressure of the plasma thus drawing water out of body tissues and producing an osmotic diuresis. Reduction of CSF and intra-ocular fluid pressure occurs within 15 minutes of the start of a mannitol infusion and lasts for 3 to 8 hours after the infusion is discontinued; diuresis occurs after 1 to 3 hours.

When used as an osmotic diuretic, mannitol is given by intravenous infusion. Careful monitoring of fluid balance, electrolytes, renal function, and vital signs is necessary during infusion to prevent fluid and electrolyte imbalance, including circulatory overload and tissue dehydration. Solutions containing more than 15% of mannitol may crystallise during storage, particularly at low temperatures; crystals may be redissolved by warming before use; the administration set should include a filter.

Mannitol may be used to treat patients in the oliguric phase of renal failure or those suspected of inadequate renal function after correction of plasma volume, provided a test dose of about 200 mg/kg given by rapid intravenous infusion of a 15 to 25% solution over 3 to 5 minutes produces a diuresis of at least 30 to 50 mL/hour during the next 2 to 3 hours; a second test dose is permitted if the response to the first is inadequate. The usual adult dose of mannitol ranges from 50 to 100 g in a 24 hour period, given by intravenous infusion of a 5 to 25% solution. The rate of administration is usually adjusted to maintain a urine flow of at least 30 to 50 mL/hour.

For children, a dose of 0.25 to 2 g/kg has been used.

The total dosage, the concentration, and the rate of administration depend on the fluid requirement, the urinary output, and the nature and severity of the condition being treated. Mannitol infusion has also been used to prevent acute renal failure during cardiovascular and other types of surgery, or after trauma.

To reduce raised intracranial or intra-ocular pressure mannitol may be given by intravenous infusion as a 15 to 25% solution in a dose of 0.25 to 2 g/kg over 30 to 60 minutes. Rebound increases in intracranial or intra-ocular pressure may occur but are less frequent than with urea.

During transurethral prostatic resection a 2.5 to 5% solution of mannitol has been used for irrigating the bladder.

Ciguatera poisoning.

Ciguatera poisoning occurs as a result of the consumption of certain fish contaminated with ciguatoxin found throughout the Caribbean and Indopacific; it is increasingly seen in Europe, in travellers returning from these areas, or as a result of eating imported fish. Symptoms can be severe, including a bizarre reversal of hot and cold sensation. Some neurological symptoms, pruritus, arthralgia, and fatigue, may persist for years.1 Treatment is usually symptomatic since there is no specific antidote. Dramatic reversal of neuromuscular symptoms with slower resolution of gastrointestinal upset has been reported after giving mannitol 1 g/kg by intravenous infusion over 30 to 45 minutes in the acute phase of the illness.2-4 Mannitol may also be beneficial up to a week after poisoning.5 However, a double-blind trial6 found mannitol to be no better than normal saline at relieving symptoms at 24 hours. Amitriptyline has been found on several occasions7-9 to relieve neurological symptoms (dysaesthesias and paraesthesias) and pruritus. Gabapentin has also been reported to be of benefit.10

For further information on the substances mentioned above, see:

  • Amitriptyline, Go to Amitriptyline
  • Gabapentin, Go to Gabapentin
  • Mannitol, Go to Mannitol
  1. 1. Lehane L. Ciguatera update. Med J Aust 2000; 172: 176–9. PubMed
  2. 2. Palafox NA, et al. Successful treatment of ciguatera fish poisoning with intravenous mannitol. JAMA 1988; 259: 2740–2. PubMed
  3. 3. Pearn JH, et al. Ciguatera and mannitol: experience with a new treatment regimen. Med J Aust 1989; 151: 77–80. PubMed
  4. 4. Williamson J. Ciguatera and mannitol: a successful treatment. Med J Aust 1990; 153: 306–7. PubMed
  5. 5. Fenner PJ, et al. A Queensland family with ciguatera after eating coral trout. Med J Aust 1997; 166: 473–5. PubMed
  6. 6. Schnorf H, et al. Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy. Neurology 2002; 58: 873–80. PubMed
  7. 7. Bowman PB. Amitriptyline and ciguatera. Med J Aust 1984; 140: 802. PubMed
  8. 8. Davis RT, Villar LA. Symptomatic improvement with amitriptyline in ciguatera fish poisoning. N Engl J Med 1986; 315: 65. PubMed
  9. 9. Calvert GM, et al. Treatment of ciguatera fish poisoning with amitriptyline and nifedipine. J Toxicol Clin Toxicol 1987; 25: 423–8. PubMed
  10. 10. Perez CM, et al. Treatment of ciguatera poisoning with gabapentin. N Engl J Med 2001; 344: 692–3. PubMed

Gastrointestinal disorders.

Bowel preparation.

Mannitol, 1000 mL of a 10% solution or 500 mL of 10 or 20% solution by mouth, has been used to prepare the bowel for surgical and diagnostic procedures.1,2 The potential for formation of explosive gas in the bowel should be borne in mind (see under Adverse Effects, Go to Effects on the gastrointestinal tract.).

  1. 1. Palmer KR, Khan AN. Oral mannitol: a simple and effective bowel preparation for barium enema. BMJ 1979; 2: 1038. PubMed
  2. 2. Newstead GL, Morgan BP. Bowel preparation with mannitol. Med J Aust 1979; 2: 582–3. PubMed

Diagnosis and testing.

Mannitol has been used with lactulose1,2 and with cellobiose3,4 in the detection of abnormal small bowel permeability, particularly that occurring in coeliac disease. For further information on the use of differential sugar absorption tests, see Lactulose, Go to Diagnosis and testing..

  1. 1. Pearson ADJ, et al. The gluten challenge—biopsy v permeability. Arch Dis Child 1983; 58: 653.
  2. 2. Cooper BT. Intestinal permeability in coeliac disease. Lancet 1983; i: 658–9. PubMed
  3. 3. Juby LD, et al. Cellobiose/mannitol sugar test—a sensitive tubeless test for coeliac disease: results on 1010 unselected patients. Gut 1989; 30: 476–80. PubMed
  4. 4. Hodges S, et al. Cellobiose: mannitol differential permeability in small bowel disease. Arch Dis Child 1989; 64: 853–5. PubMed

Preparations

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Australia: Mede-Prep; Osmitrol; Austria: Osmofundin 20%¤; Canada: Osmitrol; Czech Republic: Ardeaosmosol MA; Mannisol; Osmofundin 15% N; France: Manicol¤; Germany: Eufusol M 20¤; Mannit-Losung; Osmofundin 15% N; Osmosteril 20%; Thomaemannit; Hungary: Mannisol; Italy: Isotol; Mannistol; Mexico: Osmorol¤; New Zealand: Mede-Prep; Resectisol¤; Portugal: Osmofundina; Spain: Osmofundina Concentrada; Switzerland: Mannite; Thailand: Maniton¤; United States: Osmitrol; Resectisol;

Multi-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Austria: Osmofundin 10%; Resectal; Chile: Gelsolets; Denmark: Pharmalgen Albumin; Finland: Somanol + Ethanol; France: Doulax¤; Dyschelax¤; Lycaon¤; Lyptocodine¤; Rectolax¤; Tonitensyl¤; Germany: Freka-Drainjet Purisole; Osmofundin 10%¤; Osmofundin 20%¤; Osmosteril 10%; Hong Kong: Lederscon¤; Italy: Levoplus; Malto Mannite Magnesiaca¤; Naturalass; Mexico: Jarabe de Manzanas; Portugal: Purisole¤; Xarope de Macas Rainetas; Spain: Jorkil¤; Osmofundina¤; Salcedogen¤; Salcemetic; Salmagne; Verkolax¤; Sweden: Somanol¤; Switzerland: Bigasan¤; Cital¤; Purisole¤;



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