What is the mechanism of action of desmopressin (synthetic analogue of vasopressin)?

Mechanism of Action of Desmopressin

Desmopressin is a synthetic vasopressin analogue that works primarily by activating vasopressin V2 receptors on endothelial cells and renal collecting duct cells, producing both hemostatic and antidiuretic effects through distinct pathways. 1

Primary Mechanisms

Hemostatic Effects

• Desmopressin activates V2 receptors on vascular endothelial cells, triggering the release of stored von Willebrand factor (VWF) and factor VIII from Weibel-Palade bodies 2
• After intravenous administration of 0.3 μg/kg, circulating VWF and factor VIII levels increase 3- to 6-fold within 30 to 90 minutes 2
• The response is rapid, with effects evident within 30 minutes and reaching maximum at 90 minutes to 2 hours 1
• The hemostatic effect lasts approximately 8-12 hours, corresponding to the half-life of factor VIII 1, 3
• Desmopressin also increases tissue plasminogen activator levels and enhances platelet adhesiveness by 2- to 6-fold 3

Antidiuretic Effects

• Desmopressin stimulates V2 receptors in the renal collecting ducts, increasing water reabsorption and thereby reducing urine production 1, 4
• This mechanism reduces urinary output, increases urine osmolality, and decreases plasma osmolality 1
• The antidiuretic effect is mediated through aquaporin-2 water channel insertion in collecting duct principal cells 5, 6

Structural Advantages Over Natural Vasopressin

• The structural modification from arginine vasopressin to desmopressin (1-deamino-8-D-arginine vasopressin) results in markedly decreased vasopressor activity and reduced effects on visceral smooth muscle while maintaining enhanced antidiuretic activity 1, 4
• This allows clinically effective antidiuretic doses to remain below threshold levels for vascular or visceral smooth muscle effects 1, 7
• Desmopressin has increased duration of action compared to natural vasopressin, with a biphasic half-life of 7.8 and 75.5 minutes for intranasal administration versus 2.5 and 14.5 minutes for lysine vasopressin 4
• The terminal half-life after intravenous administration is approximately 2.8 hours in patients with normal renal function 1

Receptor Selectivity

• Desmopressin primarily targets V2 receptors while having minimal activity at V1a (vasoconstriction), V1b (ACTH release), and oxytocin receptors 2
• This selectivity distinguishes it from natural vasopressin, which activates multiple receptor subtypes 2
• The V2 receptor selectivity explains why desmopressin produces antidiuretic and hemostatic effects without significant pressor effects 7, 8

Important Pharmacokinetic Considerations

• Desmopressin is not metabolized by the human CYP450 system 1
• After intravenous administration of 2 mcg, 52% of the dose is recovered unchanged in urine within 24 hours 1
• The drug is primarily excreted via the kidneys, with terminal half-life increasing from 2.8 hours in normal renal function to 8.7 hours in severe renal impairment 1, 4

Clinical Limitations

• Tachyphylaxis may occur after 3 to 5 doses due to exhaustion of VWF storage in endothelial cells 2
• Shear-induced proteolysis of released VWF by ADAMTS-13 may contribute to the transient effect of desmopressin 2
• In conditions where endothelial VWF stores are depleted (such as COVID-19-associated ARDS), desmopressin may be ineffective at increasing VWF levels 2
• The intranasal route has approximately one-tenth the antidiuretic potency of an equivalent intravenous dose 4