From the Guidelines
Tolvaptan is a selective vasopressin V2 receptor antagonist that works by blocking the action of vasopressin (antidiuretic hormone) in the kidneys, leading to increased free water excretion (aquaresis) without significantly affecting electrolyte excretion, as described in the study by 1. The mechanism of action of tolvaptan involves competitively binding to V2 receptors in the collecting ducts of the kidneys, preventing the action of vasopressin, which normally promotes water reabsorption by increasing water permeability through aquaporin-2 water channels.
- By blocking V2 receptors, tolvaptan increases urine volume and decreases urine concentration, effectively reducing serum sodium concentration.
- Tolvaptan is primarily used to treat hyponatremia in conditions like syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cirrhosis, as mentioned in the study by 1.
- The medication is typically started at lower doses (15-30 mg once daily) and may be titrated upward based on serum sodium levels and clinical response, as recommended in the study by 1. Some key points to consider when using tolvaptan include:
- Patients taking tolvaptan must maintain adequate fluid intake to prevent excessive dehydration and rapid correction of sodium levels, which could lead to osmotic demyelination syndrome, as warned in the study by 1.
- Liver function monitoring is essential during treatment due to potential hepatotoxicity, as noted in the study by 1.
- Tolvaptan may be used to treat patients with resistant hyponatraemia, as suggested in the study by 1.
From the FDA Drug Label
Tolvaptan is a selective vasopressin V 2-receptor antagonist with an affinity for the V 2-receptor that is 1. 8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2-receptor is 29 times greater than for the V 1a-receptor When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations.
The mechanism of action of tolvaptan is as a selective vasopressin V2-receptor antagonist. It works by:
- Antagonizing the effect of vasopressin
- Increasing urine water excretion
- Increasing free water clearance (aquaresis)
- Decreasing urine osmolality
- Increasing serum sodium concentrations 2 2
From the Research
Mechanism of Action of Tolvaptan
- Tolvaptan is an orally administered, nonpeptide, selective arginine vasopressin V(2) receptor antagonist that increases free water clearance, thereby correcting low serum sodium levels 3, 4, 5.
- It blocks the binding of arginine vasopressin (AVP) to V(2) receptors in the collecting duct of the kidney, inducing water diuresis (aquaresis) without losing electrolytes 6.
- Tolvaptan inhibits the AVP-induced production of cyclic AMP in human V(2)-receptor-expressing cells, and has no intrinsic V(2) receptor agonistic effect 4.
- The drug also suppresses cyst growth by inhibiting AVP-induced cAMP production, and delays the onset of end-stage renal disease in animal models of autosomal dominant polycystic kidney disease (ADPKD) 6.
Effects on Signaling Pathways
- Tolvaptan activates the MAPK kinase (ERK1/ERK2) pathway in collecting duct cells, which is essential for the regulation of various cellular and physiological processes 7.
- The effect of tolvaptan on ERK1/ERK2 phosphorylation is PKA-dependent and is not due to an off-target effect of the drug 7.
- Vasopressin decreases ERK1/ERK2 activation, while tolvaptan increases ERK1/ERK2 activation in the presence of vasopressin 7.
Clinical Implications
- Tolvaptan is effective in increasing serum sodium concentrations in patients with euvolemic or hypervolemic hyponatremia, and is approved for the treatment of hyponatremia and ADPKD 3, 4, 6, 5.
- The drug is generally well tolerated, with common adverse events including thirst, dry mouth, and increased urination 3, 5.