Compare and contrast the pharmacology of mannitol and hypertonic saline.
A structured approach is important and a table worked best for most candidates, although a few attempted this in free text. Despite attempting a structured answer very few candidates provided information in regards to preparation, dose, monitoring of osmolarity, adverse effects or contraindications. Understanding of the action of these drugs was expected and factual inaccuracies were common with many candidates suggesting hypertonic saline acts as an osmotic diuretic. Better answers mentioned other potential mechanisms of action of mannitol. Many candidates failed to appreciate the impact on raised intracranial pressure.
Osmotherapy for management of raised intracranial pressure is where this topic usually comes up, in questions from the Second Part exam (for example, in Question 8 from the first paper of 2001). From the college comments here, it is not clear that the typical ADME pharmacology structure would have won the day. "Preparation, dose, monitoring of osmolarity, adverse effects or contraindications" do not fit the normal pharmacokinetics / pharmacodynamics mould which is usually seen in questions starting with "Compare and contrast the pharmacology". This is probably why only 8% of them passed. Thus, here, two example answers are offered: one which does the typical "absorption, distribution, elimination" thing, and the other which duplicates the answer to the more mature questions from the Second Part papers:
| Name | 20% saline | 20% mannitol |
| Class | Concentrated electrolyte | Osmotherapy agent |
| Chemistry | Monovalent cation salt | Sugar alcohol |
| Routes of administration | IV only (specifically, can only be administered through CVC) | IV only (though can be taken orally for osmotic laxative effect |
| Dose | 20-40 mmol | 0.25-1.0g/kg |
| Absorption | Well absorbed in the small intestine. largely because of paracellular transport (high concentration). Good bioavailability | Zero absorption; 0% bioavailability |
| Solubility | pKa 3.09; good water 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) |
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 | 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 | Does not undergo any metabolism; excreted unchanged in the urine |
| Elimination | Eliminated renally, where specific reabsorption mechanisms in the renal tubule regulate the rate of sodium and chloride excretion | Eliminated renally; filtered in the glomerulus and does not undergo any reabsorption, which results in a profound osmotic diuresis |
| Monitoring | Serum sodium (endoint: Na+ 145-150 mmol/L) | Serum osmolality can be monitored |
| Time course of action | For control of intracranial pressure, onset of effect is very rapid (within tens of seconds of the infusion starting) | 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. | 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 | Increase in serum osmolality, which produces the desireable osmotic decrease in intracranial pressure. A smaller increase in circulating volume than with mannitol, and without the diuresis. Produced hypernatremia and hyperchloraemia, of which the latter may be associated with a metabolic acidosis |
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. |
And now, for something a bit more grown-up:
| Advantages |
|
|
| Disadvantages |
|
|
Shenkin, Henry A., et al. "The use of mannitol for the reduction of intracranial pressure in intracranial surgery." Survey of Anesthesiology 8.5 (1964): 405-406.
Francony, Gilles, et al. "Equimolar doses of mannitol and hypertonic saline in the treatment of increased intracranial pressure*." Critical care medicine 36.3 (2008): 795-800.
Lazaridis, Christos, et al. "High-Osmolarity Saline in Neurocritical Care: Systematic Review and Meta-Analysis*." Critical care medicine 41.5 (2013): 1353-1360.
Bhardwaj, Anish, and John A. Ulatowski. "Hypertonic saline solutions in brain injury." Current opinion in critical care 10.2 (2004): 126-131.