Mechanism of Action of Tolvaptan

Introduction

Tolvaptan is an oral vasopressin V₂ receptor antagonist, approved for treating hyponatremia due to SIADH, heart failure, or cirrhosis, and for slowing disease progression in autosomal dominant polycystic kidney disease (ADPKD). It increases free water excretion (aquaretic effect) without significant electrolyte loss.

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Step-by-Step Mechanism of Action

1. Selective V₂ receptor antagonism
   Tolvaptan binds to and blocks vasopressin V₂ receptors located in the collecting ducts of the kidneys.
2. Inhibition of aquaporin-2 channel insertion
   This prevents vasopressin-induced insertion of aquaporin-2 water channels into the apical membrane.
3. Free water diuresis (aquaresis)
   With fewer water channels, water reabsorption decreases, leading to excretion of dilute urine.
4. Correction of serum sodium
   Loss of free water raises serum sodium concentration, correcting hyponatremia.
5. Reduced cAMP levels in ADPKD
   In polycystic kidneys, V₂ receptor inhibition reduces intracellular cAMP, decreasing cyst cell proliferation and fluid secretion.

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Pharmacokinetic Parameters

Parameter	Value
Route	Oral
Bioavailability	~40%
Time to Peak (Tmax)	2–4 hours
Protein Binding	~99%
Metabolism	Hepatic (CYP3A4)
Half-life	8–12 hours
Excretion	Mainly hepatic

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Clinical Uses

• Euvolemic and hypervolemic hyponatremia (e.g., SIADH, CHF, cirrhosis)
• Autosomal dominant polycystic kidney disease (ADPKD)

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Adverse Effects

• Thirst, dry mouth
• Polyuria and nocturia
• Risk of overly rapid correction of sodium
• Hepatotoxicity (especially in long-term use for ADPKD)
• Headache, nausea

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Comparative Analysis

Drug	Target	Effect	Key Use
Tolvaptan	V₂ receptor	Aquaretic diuresis	Hyponatremia, ADPKD
Conivaptan	V₁/V₂ receptors	Mixed vasodilation & aquaresis	ICU hyponatremia
Furosemide	NKCC2 in TAL	Natriuretic diuresis	Edema, CHF, hypertension

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MCQs

1. Tolvaptan primarily blocks:
   a) V₁ receptor b) V₂ receptor c) Aquaporin-1 d) Sodium channel
   Answer: b) V₂ receptor
2. Which type of diuresis does tolvaptan cause?
   a) Natriuresis b) Osmotic diuresis c) Aquaretic diuresis d) Glucosuria
   Answer: c) Aquaretic diuresis
3. Tolvaptan raises serum sodium by:
   a) Increasing sodium intake b) Inhibiting aldosterone c) Reducing free water reabsorption d) Promoting potassium excretion
   Answer: c) Reducing free water reabsorption
4. The aquaretic effect is due to inhibition of:
   a) Aquaporin-3 b) Sodium channel c) Aquaporin-2 insertion d) Renin release
   Answer: c) Aquaporin-2 insertion
5. In ADPKD, tolvaptan reduces:
   a) Urine osmolality b) Serum sodium c) cAMP levels d) BUN
   Answer: c) cAMP levels
6. Tolvaptan metabolism primarily involves:
   a) CYP2D6 b) CYP3A4 c) UGT1A1 d) CYP2C9
   Answer: b) CYP3A4
7. Which condition is a contraindication?
   a) Hypertension b) SIADH c) Hypovolemic hyponatremia d) Polycystic liver disease
   Answer: c) Hypovolemic hyponatremia
8. Protein binding of tolvaptan is approximately:
   a) 60% b) 75% c) 90% d) 99%
   Answer: d) 99%
9. Main side effect requiring caution:
   a) Bradycardia b) Liver injury c) Rash d) Hypokalemia
   Answer: b) Liver injury
10. Time to peak plasma concentration:
    a) 30 minutes b) 1 hour c) 2–4 hours d) 8 hours
    Answer: c) 2–4 hours

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FAQs

1. Can tolvaptan be used long-term?
Only in ADPKD under REMS monitoring. For hyponatremia, duration is limited to 30 days.

2. How quickly does it increase serum sodium?
Effect begins within hours; sodium rise must be monitored to prevent overly rapid correction.

3. Why is fluid restriction not advised initially?
Because the drug promotes free water loss; restricting fluids too early may increase sodium too quickly.

4. Is it safe in liver disease?
Use with caution—tolvaptan can be hepatotoxic and requires monitoring.

5. Is tolvaptan a loop diuretic?
No—it is a selective aquaretic that conserves electrolytes while increasing water excretion.

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References

• DrugBank: Tolvaptan
• FDA Label: Tolvaptan (Samsca)
• PubMed Review: Tolvaptan in ADPKD
• StatPearls: Tolvaptan Pharmacology