Osmotic Diuretics

Osmotic diuretics increase tubular fluid osmolarity, pulling water into the collecting tubules and preventing water reabsorption, which results in osmotic diuresis. The primary osmotic diuretic used clinically is mannitol. The primary indication for mannitol is to treat cases of increased intracranial or intraocular pressure, which can have significant effects on fluid volume and sodium concentration, so caution must be exercised when using these agents.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Chemistry and Pharmacodynamics

Definition

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.

Chemical structure

Mannitol is a nonabsorbable 6-carbon simple sugar alcohol.

Chemical structure of mannitol Osmotic diuretics

Chemical structure of mannitol

Image: “Chemical Structure of Mannitol” by Edgar181. License: Public Domain

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
Mechanism of action Osmotic diuretics

Mechanism of action of osmotic diuretics

Image by Lecturio. License: CC BY-NC-SA 4.0

Physiologic effects

  • 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+.

Pharmacokinetics

  • Absorption: 
    • 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  
  • Distribution:
    • 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
  • Excretion:
    • Approximately 80% excreted renally as unchanged drug
    • Mannitol clearance approximately equal to GFR
    • Half-life: 
      • 0.5–2.5 hours with normal renal function
      • 6–36 hours in renal failure

Indications

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

Adverse effects

  • Hyperkalemia
  • Initially:
    • Hypervolemia
    • Decompensation in heart failure patients
    • Hyponatremia in patients receiving high doses or in those with renal failure
  • Over time: 
    • Dehydration
    • Hypovolemic hypernatremia (because over time water losses exceed Na+ losses in patients with normal renal function)
  • Other symptoms:
    • Pruritus
    • Localized erythema, rash, or skin necrosis at the site of injection (mannitol is a vesicant)
    • Myalgias and/or arthralgias

Contraindications

  • Anuria
  • Severe hypovolemia
  • Active intracranial bleeding
  • Pulmonary edema

Precautions

  • 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).

Table: Comparison of diuretics
MedicationMechanismPhysiologic effectIndication
Thiazide diuretic: Hydrochlorothiazide↓ Reabsorption of NaCl in the DCT through the inhibition of Na+/Cl cotransporter
  • ↓ Blood pressure
  • ↓ Edema
  • Hypertension
  • Edema
Loop diuretic: FurosemideInhibits the luminal Na+/K+/Cl cotransporter in the thick ascending limb of the loop of Henle
  • ↓ Edema
  • ↓ Blood pressure
  • Edema/ascites
  • CHF
  • Hypertension
Potassium-sparing diuretic: Spironolactone
  • ↓ Reabsorption of Na through the ENaC channels in the CD
  • Inhibition of aldosterone receptors in the CD
  • ↓ Blood pressure
  • ↓ Edema
  • Does not cause ↑ excretion of K+
  • Anti-androgenic effects
  • CHF
  • Edema/ascites
  • Hypertension
  • Hirsutism in females
  • Primary hyperaldosteronism
Carbonic anhydrase inhibitor: AcetazolamideInhibits 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
  • ↑ Urinary excretion of HCO3 → metabolic acidosis
  • ↓ Intraocular pressure
  • Edema in patients with metabolic alkalosis
  • Altitude sickness
  • ↑ Intraocular pressure
  • Off label: normal pressure hydrocephalus
Osmotic diuretics: Mannitol↑ Osmotic pressure in the glomerular filtrate → ↑ tubular fluid and prevents water reabsorption
  • ↓ Free water
  • ↓ Cerebral blood volume
  • Increased intracranial pressure
  • Increased intraocular pressure
PCT: proximal convoluted tubule
DCT: distal convoluted tubule
CHF: congestive heart failure
Diuretics

The sites of action within the nephron for the diuretic drug classes

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. Lexicomp drug topic pages: mannitol (systemic). (0000). UpToDate. Retrieved June 16, 2021, from https://www.uptodate.com/contents/mannitol-systemic-drug-information 
  2. 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.
  3. 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/
  4. 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/
  5. 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/
  6. Wakai, A., et al. (2013). Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev 8:CD001049. https://pubmed.ncbi.nlm.nih.gov/23918314/
  7. 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/
  8. 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/
  9. 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/
  10. American Society of Health-System Pharmacists. Mannitol. Retrieved January 8, 2015, from https://www.drugs.com/monograph/mannitol.html
  11. 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/

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details