Vasopressin antagonists

Vasopressin antagonists, commonly known as vaptans, are a class of pharmacological agents that block the action of vasopressin (antidiuretic hormone, ADH) at its receptors. Vasopressin is a peptide hormone that regulates water retention, vasoconstriction, and corticotropin release, acting via three main receptor types:

• V1a receptors: Found in vascular smooth muscle; mediate vasoconstriction

• V1b receptors: Present in the anterior pituitary; stimulate ACTH release

• V2 receptors: Located in the renal collecting ducts; mediate free water reabsorption via aquaporin-2 channels

Vasopressin antagonists specifically block V2, V1a, or both receptor types, depending on the agent. The primary therapeutic effect of V2 antagonism is aquaresis, which refers to the excretion of free water without electrolyte loss, making vaptans particularly effective in treating conditions such as euvolemic or hypervolemic hyponatremia, often caused by Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) or congestive heart failure (CHF).

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Mechanism of Action

• V2 receptor antagonists prevent ADH-induced insertion of aquaporin-2 water channels in the renal collecting ducts. This inhibits water reabsorption, leading to increased urine output (free water loss), and thus increases serum sodium concentration by reducing dilution.

• Dual V1a/V2 receptor antagonists also inhibit vasoconstriction and myocardial remodeling associated with V1a activation, providing additional benefit in conditions such as heart failure and cirrhosis.

The net effect is:

• ↑ Urine output (without significant electrolyte loss)

• ↓ Total body water

• ↑ Serum sodium concentration (correction of hyponatremia)

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Classification of Vasopressin Antagonists

1. Selective V2 Receptor Antagonists

   • Tolvaptan

   • Lixivaptan (investigational)

2. Dual V1a/V2 Receptor Antagonists

   • Conivaptan

   • Mozavaptan (approved in Japan)

   • Satavaptan (development discontinued)

3. Experimental Agents

   • Relcovaptan (V1a selective): Investigated for Raynaud’s disease, dysmenorrhea

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FDA-Approved Vasopressin Antagonists

1. Tolvaptan

• Generic Name: Tolvaptan

• Brand: Samsca® (oral), Jynarque® (for ADPKD)

• Receptor Selectivity: Selective V2 receptor antagonist

• Indications:

  • Hyponatremia associated with SIADH, CHF, and cirrhosis (Samsca®)

  • Autosomal Dominant Polycystic Kidney Disease (ADPKD) to slow kidney function decline (Jynarque®)

• Route of Administration: Oral tablets

• Dosing:

  • Hyponatremia: Start with 15 mg once daily; may titrate to 30–60 mg/day

  • ADPKD: Initiate with split dosing (e.g., 45 mg AM/15 mg PM)

• Contraindications: Urgent need to raise sodium acutely, hypovolemia, anuria, inability to sense/respond to thirst, concurrent CYP3A4 inhibitors (e.g., ketoconazole), liver disease (Jynarque has hepatotoxicity warning)

• Warnings:

  • Hepatotoxicity: Black Box Warning in ADPKD

  • Over-rapid correction of sodium: Risk of osmotic demyelination syndrome (ODS)

• Adverse Effects: Thirst, dry mouth, polyuria, hypernatremia, increased ALT/AST

• Monitoring:

  • Serum sodium every 6–8 hours initially

  • Liver function tests (particularly in ADPKD use)

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2. Conivaptan

• Generic Name: Conivaptan hydrochloride

• Brand: Vaprisol®

• Receptor Selectivity: Dual V1a and V2 receptor antagonist

• Indications:

  • Euvolemic and hypervolemic hyponatremia (hospitalized patients)

• Route of Administration: Intravenous infusion only

• Dosing:

  • Initial loading dose: 20 mg IV over 30 min

  • Maintenance: 20 mg continuous infusion over 24 hours, up to 4 days

• Contraindications:

  • Hypovolemic hyponatremia

  • Concurrent CYP3A4 inhibitors

  • Corn allergy (contains corn-derived excipients)

• Warnings:

  • Requires central line administration due to risk of phlebitis and infusion site reactions

  • Avoid over-rapid correction of serum sodium

• Adverse Effects: Infusion site reactions, hypokalemia, orthostatic hypotension, headache

• Monitoring:

  • Sodium every 6–8 hours

  • Potassium, fluid balance

  • Infusion site (for local irritation)

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Non-FDA Approved or Discontinued Vasopressin Antagonists

1. Mozavaptan: Approved in Japan for SIADH associated with small cell lung cancer

2. Satavaptan: Investigated for cirrhotic ascites and hyponatremia—development halted due to poor outcomes

3. Lixivaptan: Investigational oral V2 antagonist with a possibly better hepatic safety profile than tolvaptan

4. Relcovaptan: Selective V1a antagonist under investigation for vascular disorders and uterine cramps

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Therapeutic Uses

Condition	Preferred Vasopressin Antagonist
SIADH (euvolemic hyponatremia)	Tolvaptan (oral), Conivaptan (IV)
Hypervolemic hyponatremia (CHF, cirrhosis)	Tolvaptan (with caution), Conivaptan
ADPKD	Tolvaptan (Jynarque)
Hospitalized patients with symptomatic low Na⁺	Conivaptan IV
Potential for expansion	Heart failure, ascites, vasospastic conditions (under study)

Contraindications

• Hypovolemic hyponatremia

• Anuria or renal failure

• Inability to maintain adequate fluid intake (e.g., impaired thirst)

• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin)

• Liver disease (esp. with long-term tolvaptan)

• Pregnancy and lactation: Not recommended due to lack of sufficient data

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Precautions

• Fluid restriction should be avoided during vaptan therapy to allow for controlled aquaresis

• Use with caution in patients at risk for:

  • Osmotic demyelination syndrome (chronic hyponatremia >48 hours, alcoholism, malnutrition, liver disease)

  • Hypotension (due to aquaresis and natriuresis)

• Risk of dehydration, particularly in elderly patients or those with fever or diarrhea

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Adverse Effects

System	Reported Effects
Neurologic	Headache, dizziness, insomnia
Renal/Fluid balance	Polyuria, thirst, dehydration, acute kidney injury
Electrolytes	Hypernatremia, hypokalemia
Hepatic	Elevated ALT, AST; rare hepatotoxicity (esp. tolvaptan)
Cardiovascular	Hypotension, orthostatic symptoms
Infusion site (Conivaptan)	Phlebitis, pain, erythema

Drug Interactions

• Strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, ritonavir): Increase plasma concentrations of vaptans → risk of toxicity

• Diuretics: Additive volume depletion and risk of electrolyte imbalance

• Digoxin: Risk of digoxin toxicity due to hypokalemia

• NSAIDs: May reduce renal perfusion and impair aquaresis

• ACE inhibitors or ARBs: Use cautiously; monitor renal function and potassium

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Monitoring and Dosing Considerations

• Initial sodium correction should not exceed 8–10 mEq/L in 24 hours

• Serum sodium and osmolality: Monitor every 6–8 hours during initiation

• Liver function tests: Especially with tolvaptan in ADPKD

• Urine output and hydration status: Ensure euvolemia is maintained

• Adjust dose or discontinue if:

  • Serum sodium correction is too rapid

  • Liver enzymes are >3x upper normal limit

  • Patient cannot maintain adequate oral fluid intake

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Regulatory Notes and Access

• Tolvaptan (Samsca®) is FDA-approved for hospital-based treatment of hyponatremia, with Risk Evaluation and Mitigation Strategy (REMS) for Jynarque® due to liver injury risk

• Conivaptan (Vaprisol®) is approved only for IV inpatient use and limited to short duration (≤4 days)

• Both are specialty drugs—access may require authorization and close monitoring

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Comparison with Traditional Therapies

Therapy	Mechanism	Use in Hyponatremia	Limitations
Fluid restriction	Reduces dilutional hyponatremia	First-line (SIADH, CHF)	Often ineffective, poor adherence
Hypertonic saline	Direct sodium replacement	Symptomatic or severe cases	Risk of ODS if overcorrected
Vaptans	Free water clearance (aquaresis)	Euvolemic/hypervolemic states	Cost, monitoring, contraindications
Loop diuretics	Sodium + water excretion	Adjunctive in volume overload	May worsen Na⁺ unless used carefully