Chemistry and Pharmacodynamics
An osmotic diuretic is an osmotically active agent that is filtered into the renal tubules but not reabsorbed. The presence of this substance in the renal tubules keeps water in the tubules, resulting in diuresis.
- The only significant osmotic diuretic used clinically is mannitol.
- Glucose can also act as an osmotic diuretic when levels are high enough to exceed the kidneys’ capacity for glucose reabsorption.
Mannitol is a nonabsorbable 6-carbon simple sugar alcohol.
Mechanism of action
- Osmotic diuretics are filtered into the renal tubules, but not reabsorbed → ↑ tubular fluid osmolarity
- Because of this higher tubular fluid osmolarity, water that normally would be reabsorbed remains in the tubules.
- Primary sites of impact in the nephron: areas that are freely permeable to water
- Proximal convoluted tubule (PCT)
- Descending limb of the loop of Henle
- Initially, ↑ plasma osmolarity:
- Results in initial volume expansion → may precipitate pulmonary edema in heart failure patients
- Pulls water into the vasculature from cerebral parenchyma and the ocular space → ↓ intracranial and intraocular pressures
- ↑ Osmolarity of the tubule fluid: osmotic diuresis
- Effects on sodium concentration:
- ↑ Urinary flow causes ↑ Na+ excretion.
- Water loss exceeds Na+ losses, which over time, results in hypernatremia.
- At very high doses or in patients with renal failure, the mannitol may not be effectively cleared → ↑ osmolarity of the plasma:
- This will pull fluid into the intravascular fluid space and may result in hyponatremia.
- Important to recognize because treatment should be aimed at the ↑ osmolarity rather than the ↓ Na+.
- Poor oral absorption
- Typically administered IV as a hypertonic solution
- When given orally, can cause osmotic diarrhea
- Onset of action:
- Diuresis: 1–3 hours
- Reduction in intracranial pressure (ICP): 15–30 minutes
- Poor oral absorption
- Confined to the extracellular fluid (ECF) compartment
- Does not penetrate the blood–brain barrier (BBB)
- Freely filtered through the glomerulus
- Not reabsorbed or secreted in the kidneys
- Volume of distribution (VD): 17 L
- Metabolism: minimal hepatic metabolism to glycogen
- Approximately 80% excreted renally as unchanged drug
- Mannitol clearance approximately equal to GFR
- 0.5–2.5 hours with normal renal function
- 6–36 hours in renal failure
The primary indications for the use of mannitol include:
- Increased ICP due to:
- Cerebral edema
- Brain masses
- Increased intraocular pressure (e.g., acute glaucoma)
- Nephrotoxicity related to rhabdomyolysis (works by maintaining urinary flow)
- As an irrigation fluid during transurethral procedures (e.g., prostatic resection)
- To improve kidney function during kidney transplantation while blood flow is reduced (off-label use):
- Given to the donor prior to nephrectomy
- Given to the recipient prior to revascularization
- Can also be given to promote diuresis in order to ↑ excretion of toxic substances and/or metabolites
Adverse Effects and Contraindications
- Decompensation in heart failure patients
- Hyponatremia in patients receiving high doses or in those with renal failure
- Over time:
- Hypovolemic hypernatremia (because over time water losses exceed Na+ losses in patients with normal renal function)
- Other symptoms:
- Localized erythema, rash, or skin necrosis at the site of injection (mannitol is a vesicant)
- Myalgias and/or arthralgias
- Severe hypovolemia
- Active intracranial bleeding
- Pulmonary edema
- Mannitol may accumulate in the brain, leading to rebound ↑ in ICP
- Use with caution in patients with renal impairment.
- Use with caution in pregnancy and lactation.
Comparison of Medications
Some of the other most common diuretics include thiazide diuretics (e.g., hydrochlorothiazide), loop diuretics (e.g., furosemide), potassium-sparing diuretics (e.g., spironolactone), and carbonic anhydrase inhibitors (e.g., acetazolamide).
|Thiazide diuretic: Hydrochlorothiazide||↓ Reabsorption of NaCl in the DCT through the inhibition of Na+/Cl– cotransporter||
|Loop diuretic: Furosemide||Inhibits the luminal Na+/K+/Cl– cotransporter in the thick ascending limb of the loop of Henle||
|Potassium-sparing diuretic: Spironolactone||
|Carbonic anhydrase inhibitor: Acetazolamide||Inhibits both the hydration of CO2 in the PCT epithelial cells and the dehydration of H2CO3 in the PCT lumen; results in ↑ HCO3– and Na+ excretion||
|Osmotic diuretics: Mannitol||↑ Osmotic pressure in the glomerular filtrate → ↑ tubular fluid and prevents water reabsorption||
DCT: distal convoluted tubule
CHF: congestive heart failure
- Lexicomp drug topic pages: mannitol (systemic). (0000). UpToDate. Retrieved June 16, 2021, from https://www.uptodate.com/contents/mannitol-systemic-drug-information
- Ives, H.E. (2012). Diuretic agents. In Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.) Basic and Clinical Pharmacology, 12th ed. pp. 263‒264. Trevor AJ, Katzung BG, & Masters SB: McGraw-Hill.
- Mesghali, E., et al. (2019). Safety of peripheral line administration of 3% hypertonic saline and mannitol in the emergency department. J Emerg Med 56:431–436. https://pubmed.ncbi.nlm.nih.gov/30745195/
- Alnemari, A.M., et al. (2017). A comparison of pharmacologic therapeutic agents used for the reduction of intracranial pressure after traumatic brain injury. World Neurosurg 106:509–528. https://pubmed.ncbi.nlm.nih.gov/28712906/
- Pasarikovski, C.R., et al. (2017). Hypertonic saline for increased intracranial pressure after aneurysmal subarachnoid hemorrhage: a systematic review. World Neurosurg 105:1–6. https://pubmed.ncbi.nlm.nih.gov/28549643/
- Wakai, A., et al. (2013). Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev 8:CD001049. https://pubmed.ncbi.nlm.nih.gov/23918314/
- Weber, A.C., et al. (2018). Effect of mannitol on the globe and orbital volumes in humans. Eur J Ophthalmol 28:163–167. https://pubmed.ncbi.nlm.nih.gov/28777386/
- Mc Causland, F.R., et al. (2012). Preservation of blood pressure stability with hypertonic mannitol during hemodialysis initiation. Am J Nephrol 36:168–174. https://pubmed.ncbi.nlm.nih.gov/22846598/
- Wakai, A., et al. (2013). Mannitol for acute traumatic brain injury. Cochrane Database of Systematic Reviews 8:CD001049. https://pubmed.ncbi.nlm.nih.gov/23918314/
- American Society of Health-System Pharmacists. Mannitol. Retrieved January 8, 2015, from https://www.drugs.com/monograph/mannitol.html
- Rapoport, S. (2020). Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol 20:217–230. https://pubmed.ncbi.nlm.nih.gov/10696511/