Mannitol (20% concentrate)

This chapter is relevant to Section I2(i) of the 2023 CICM Primary Syllabus, which expects the exam candidates to develop or at least fake that they "understand the pharmacology of colloids and crystalloids". The material being explored here is20% mannitol, or 500ml of water with 100g of mannitol in it. This substance becomes a lo more relevant in the Second Part Exam, as osmotherapy for management of raised intracranial pressure is a common topic for questions there. In the CICM First Part the questions involving mannitol are essentially limited to Question 10 from the first paper of 2015, where the candidates were expected to compare it to hypertonic saline.

Name 20% mannitol
Class Osmotherapy agent
Chemistry Sugar alcohol
Routes of administration IV only (though can be taken orally for osmotic laxative effect
Absorption Zero absorption; 0% bioavailability
Solubility pKa 12.59, reasonable water solubility (but precipitates at low temperatures)
Distribution VOD=0.2L/kg, basically confined to the extracellular fluid
(thus: 25% remains intravascular, 75% becomes interstitial)
Target receptor Mechanism of action does not involve receptor binding; you might say the target is the blood brain barrier
Metabolism Does not undergo any metabolism; excreted unchanged in the urine
Elimination Eliminated renally; filtered in the glomerulus and does not undergo any reabsorption, which results in a profound osmotic diuresis
Time course of action For control of intracranial pressure, onset of effect is very rapid (within tens of seconds of the infusion starting)
Mechanism of action Increases the osmolality of the extracellular fluid, and therefore decreases the volume of the intracellular compartment by producing an osmotic shift of intracellular water of of the cells. This produces the desirable clinical effect of decreasing the volume of brain tissue, and therefore reducing the intracranial pressure.
Also increases the osmolality of renal tubular fluid, which prevents the reabsorption of water via the countercurrent multiplier mechanism, and produces diuresis - which is usually an undesirable effect
Clinical effects Initally, circulatory volume expansion, with the potential to create circulatory overload and pulmonary oedema.
Later, increase in serum osmolality, which produces the desireable osmotic decrease in intracranial pressure
Subsequently, decreased circulating volume due to massive diuresis.
Also, this leads to electrolyte depletion.

This is 20% mannitol m is 100g of six-carbon sugar alcohol, delivered in fresh water.

It is an inert alcohol, closely resembling mannose, but without the aldehyde group which would make it a sugar.

If one were strongly inclined to dive deep into the terrifying rabbithole of carbohydrate chemistry, one would find this picture, which relates the chemical formulae of mannose and mannitol.

Sugar alcohol, you say.

Yes, it is the reduced daughter product of glucose, reduced commercially in huge vats. Alternatively it can be made when fructose is hydrogenated over a nickel catalyst (which forms a mixture of sorbitol and mannitol).

properties and contents of 20% mannitol

Humans are probably rather unique in not being able to metabolise it. Indeed, even when sorbitol - another hexose alcohol - is administered to humans and rats, some of it is deposited in the liver as glycogen, giving the impression that it is being metabolised. Not so for the mannitol, which (even when given in an inventive variety of ways) does not undergo any metabolism.

Chemical properties

Baxter confess that in their Osmitrol solution the pH is adjusted with sodium hydroxide and hydrochloric acid. The mannitol itself has a pKa is 13.5 so pretty much in all physiologically relevant situations it will not dissociate.

In a way, it is attractively inert, much like a noble gas. The human body simply neglects this substance, and it exerts its effects by virtue of its osmotic effects. There is about 182.2g to every mole, which gives the 100g contents of a half-litre bag an osmolality of about 1100 mOsm/L. Each molecule, having such a small mass and remaining non-polar, is capable of penetrating the junctions between cells rather easily, and so this substance is able to distribute rapidly between extracellular fluid compartments.

Mannitol exerts its most useful effects by remaining in the extracellular fluid exclusively. Its entry into the cell is frustrated basically by an absence of a uptake pump. Human cells are just not that into mannitol. This results in a fairly restricted volume of distribution, roughly parallel to the volume of extracellular fluid (0.47-0.5 L/kg)

The clearance of mannitol is renal, wherein lies its other most significant advantage. The molecule, being freely filtered in the urine, is a powerful antagonist to normal urinary concentration mechanisms, and drags torrential diuresis out with itself, robbing the body of lots of sodium and water. There is no tubular mechanism for mannitol resorption.

It has a rather short serum half-life. First, the dose given into the bloodstream distributes very rapidly into the extracellular fluid, and the intravascular mannitol content fairly rapidly filters though the glomerulus and out into the urine. After 3 hours, 80% of the administered mannitol dose makes its way out of the patient.

What if I drank it?

It would be deliciously sweet. But one would be foolish to drink too much mannitol.

Firstly, anything more than 20g will act as an osmotic laxative. That is about 100ml.

And, one must recall that all those colonic bacteria are perfectly capable of metabolising it into H2, CO2 and water. The gases they produce will work to anger the bowel, causing distension and unpleasantness.

References

Ellis, Fred W., and John C. Krantz. "Sugar alcohols XXII. Metabolism and toxicity studies with mannitol and sorbitol in man and animals." Journal of Biological Chemistry 141.1 (1941): 147-154.

Baxter helpfully provide a fact sheet for their Osmitrol brand of mannitol solution.

Lin, K., et al. "The early response of mannitol infusion in traumatic brain injury."Acta Neurologica Taiwanica 17.1 (2008): 26.

Cloyd, JAMES C., et al. "Mannitol pharmacokinetics and serum osmolality in dogs and humans." Journal of Pharmacology and Experimental Therapeutics236.2 (1986): 301-306.