Desmopressin mechanism of action diabetes insipidus

The mechanism of action of desmopressin and its clinical application in the management of central diabetes insipidus will be reviewed.

Physiology of Antiduretic Hormone Action

Antidiuretic hormone and regulation of serum osmolarity 

Arginine vasopressin (AVP) is synthesized in the nuclei of paired hypothalamohypophyseal neurons originating from supraoptic and paraventricular nuclei of the hypothalamus and terminating in the posterior pituitary gland(1).

Neurosecretory granules containing AVP are transported along axons that terminate in fenestrated capillaries in the neurohypophysis (posterior pituitary)(2). The osmolarity sensing center (osmostat), located in the hypothalamus, regulates the release of AVP via relay neurons projecting to the cell bodies of the supraoptic and paraventricular nuclei(3).

There is a linear relationship between plasma osmolarity and plasma AVP levels, such that significant increases in plasma osmolarity cause a corresponding increase in plasma AVP(4). In the setting of dehydration, AVP, also known as antidiuretic hormone (ADH), increases water conservation at the level of the collecting duct, a process that increases urine osmolarity and leads to the restoration of normal plasma osmolarity(5) (see Fig. 1.0).

Key Message
Based on the results of this study, the frequency of significant hyponatremia (<130 mmol/L) was 4.2% when subjects were on intranasal desmopressin, compared to 1.3% when on oral desmopressin. This was statistically significant. Normal water and sodium balance are better achieved with oral DDAVP compared to intranasally administered DDAVP(16).

Fig. 1.0 Schematic representation of AVP mediated water conservation at the principal cell of the renal collecting duct

AVP binds to V2 receptors on G-protein coupled V2 receptors on the basolateral membrane (BM) of the principal cell(6). This initiates a cascade of intracellular processes involving adenylyl cyclase mediated cyclic adenosine monophosphate (cAMP) production and subsequent activation of protein kinase A (PKA). Afterwards, PKA will promote the liberation of aquaporins from endocytic vesicles. Aquaporin-2 (AQP2) released from vesicles inserts into the apical membrane (AM) of the collecting duct. This promotes the translocation of free water from the collecting duct into the cytoplasm of the principal cell(7). Aquaporin-3 (AQP3) and aquaporin-4 (AQP4) water channels, which are integral components (i.e., they are not released from endocytic vesicles) of the BM, facilitate the final transfer of water from the cytoplasm to the peritubular capillaries(5).

Mechanism of action of Desmopressin

Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is an analog of arginine vasopressin (AVP)(8) with a prolonged plasma half-life of approximately 55 minutes (comparatively, endogenous AVP has a half-life of 5 to 10 minutes) (9).

It is worthy to note that substitution of D-arginine for L-arginine at position number 8 of the AVP amino acid chain eliminates the vasopressor effects of this synthetic analog of AVP(10).

Desmopressin promotes water conservation by binding to V2 receptors in renal collecting ducts(8). (See figure 1.0). During periods of significant dehydration, the central thirst mechanism allows the consumption of free water, which results in the restoration of intravascular volume and osmolarity(5,11).

Desmopressin Practice Guide

  • Desmopressin can be administered safely through various routes (including intravenous, subcutaneous, oral, intranasal, and intramuscular). A simple rule of thumb is to use a conversion factor of 1:10 when converting between routes of administration(8).

Desmopressin conversion via the route of administration

Intravenous/Subcutaneous : Intranasal : Oral = 1mcg : 10mcg : 100mcg

  • Co-administration of NSAIDs and desmopressin can lead to life-threatening hyponatremia(12). In normal physiology, prostaglandin E2 (PgE2) impairs the liberation of AQP2 from their endocytic vesicles after AVP to V2 receptor interaction. Cyclooxygenase inhibitors impair the synthesis of PgE2, thus increasing the availability of AQP2 (water intoxication) (13).
  • Consider a “DDAVP holiday” intermittently to reduce the likely risk of hyponatremia. Patients can be advised to delay administration of a scheduled dose of DDAVP once a week until 2 or 3 successive episodes of breakthrough polyuria(14).
  • Gastrointestinal peptidases denature oral desmopressin; as such, patients should be counseled on the importance of taking this medication either on an empty stomach or at least 90 minutes after a meal(15).
  • Pituitary adenomas seldom present with central diabetes insipidus(CDI). CDI in the setting of a sellar mass is more suggestive of an alternative differential diagnosis, such as craniopharyngiomas or a granulomatous process(14).

Clinical Trial Evidence

In this retrospective study, the incidence of hyponatremia in patients with central diabetes insipidus was evaluated between intranasal and oral desmopressin routes of administration.  Thirty-two subjects who had previously been well controlled on stable doses of intranasal DDAVP were switched to an oral route of administration for a maximum duration of 18months(16).

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