Antidiuretic hormones

Introduction

Antidiuretic hormones, primarily arginine vasopressin (AVP) and its synthetic analogs, are critical regulators of water balance, osmolality, and vascular tone. They act through vasopressin receptors (V1, V2, V3/oxytocin receptors) located in vascular smooth muscle, renal collecting ducts, and the central nervous system.

Pharmacologic preparations of ADH analogs are used for the treatment of diabetes insipidus (central/neurogenic type), nocturnal enuresis, bleeding disorders (von Willebrand disease, hemophilia A), esophageal variceal bleeding, septic shock, and perioperative hypotension. Conversely, ADH antagonists are used in conditions such as syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia.

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Physiology and Mechanism of Action

• V1 Receptors (V1a): Located on vascular smooth muscle → mediate vasoconstriction.

• V2 Receptors: Located in renal collecting ducts → stimulate insertion of aquaporin-2 water channels, promoting water reabsorption and urine concentration.

• V3 Receptors (V1b): Located in the pituitary → regulate ACTH release.

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Pharmacological Agents

1. Vasopressin (Arginine Vasopressin, ADH)

• Mechanism: Non-selective agonist at V1 and V2 receptors.

• Uses:

  • Central diabetes insipidus (short-term).

  • Vasodilatory shock (septic shock, post-cardiotomy shock).

  • Esophageal variceal bleeding (reduces portal pressure).

• Adverse Effects: Hyponatremia, water intoxication, vasoconstriction (risk of ischemia in heart, gut, skin), headache.

• Precautions: Avoid in chronic nephrogenic diabetes insipidus, coronary artery disease, or peripheral vascular disease.

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2. Desmopressin (DDAVP)

• Mechanism: Synthetic analog of vasopressin with strong V2 receptor selectivity (renal and endothelial), minimal V1 activity.

• Uses:

  • Central diabetes insipidus (first-line).

  • Primary nocturnal enuresis (reduces nighttime urine output).

  • Hemophilia A and von Willebrand disease (type 1) – increases release of factor VIII and von Willebrand factor.

  • Uremic bleeding (improves platelet function).

• Routes: Oral, intranasal, subcutaneous, IV.

• Adverse Effects: Hyponatremia, seizures (from water intoxication), headache, nasal irritation (intranasal form).

• Contraindications: Hyponatremia, moderate-to-severe renal impairment, history of SIADH.

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3. Terlipressin

• Mechanism: Synthetic vasopressin analog, prodrug converted to lysine-vasopressin, with potent V1 receptor activity.

• Uses:

  • Esophageal variceal hemorrhage (first-line in many regions).

  • Hepatorenal syndrome (HRS) in advanced cirrhosis.

• Adverse Effects: Hypertension, ischemia (cardiac, intestinal, peripheral), abdominal cramps, headache.

• Contraindications: Ischemic heart disease, uncontrolled hypertension, peripheral vascular disease.

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4. Lypressin (Lysine Vasopressin)

• Mechanism: Older synthetic ADH analog, V1 and V2 agonist.

• Uses: Diabetes insipidus (historical use, largely replaced by desmopressin).

• Adverse Effects: Similar to vasopressin; less commonly used today.

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5. ADH Antagonists (Vaptans)

• Mechanism: Selective vasopressin receptor antagonists (V2 or dual V1a/V2) → promote free water excretion (aquaretic effect).

• Generic Names: tolvaptan, conivaptan, lixivaptan, mozavaptan.

• Uses:

  • Euvolemic or hypervolemic hyponatremia (e.g., SIADH, heart failure, cirrhosis).

  • Tolvaptan is also used to slow progression of autosomal dominant polycystic kidney disease (ADPKD).

• Adverse Effects: Polyuria, thirst, hypernatremia, hepatotoxicity (tolvaptan, long-term), infusion reactions (conivaptan).

• Contraindications: Hypovolemic hyponatremia, inability to access water, anuria, severe liver disease (tolvaptan with caution).

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Therapeutic Indications

1. Central Diabetes Insipidus: Desmopressin (preferred), vasopressin (short-term).

2. Nocturnal Enuresis: Desmopressin (oral, intranasal).

3. Bleeding Disorders: Desmopressin in mild hemophilia A, von Willebrand disease (type 1), uremic bleeding.

4. Esophageal Variceal Hemorrhage: Terlipressin, vasopressin.

5. Vasodilatory Shock (Septic Shock): Vasopressin (IV infusion, adjunct to norepinephrine).

6. Hepatorenal Syndrome (HRS): Terlipressin with albumin.

7. Hyponatremia (SIADH, HF, Cirrhosis): Vaptans (tolvaptan, conivaptan).

8. Autosomal Dominant Polycystic Kidney Disease: Tolvaptan (slows cyst growth and renal decline).

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Contraindications

• Vasopressin/Terlipressin: Coronary artery disease, chronic nephrogenic diabetes insipidus, uncontrolled hypertension, ischemic bowel.

• Desmopressin: Hyponatremia, severe renal impairment, SIADH.

• Vaptans: Hypovolemic hyponatremia, inability to sense/respond to thirst, severe hepatic impairment (tolvaptan caution).

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Adverse Effects

• Vasopressin: Hyponatremia, ischemia (cardiac, gut, skin), headache, abdominal cramps.

• Desmopressin: Water intoxication, seizures, hyponatremia, nasal irritation (spray).

• Terlipressin: Vasoconstriction-related ischemia, hypertension, headache.

• Vaptans: Polyuria, thirst, hypernatremia, hepatotoxicity (tolvaptan).

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Clinical Considerations

1. Monitoring:

   • Electrolytes (sodium, potassium) and fluid balance are critical.

   • Liver function (tolvaptan, desmopressin).

   • Cardiac monitoring (vasopressin, terlipressin in shock).

2. Administration:

   • Desmopressin is available orally, intranasally, IV, or subcutaneously.

   • Vasopressin and terlipressin are administered parenterally (IV).

   • Vaptans are oral (tolvaptan) or IV (conivaptan).

3. Long-Term Risks:

• Osteopenia and fractures possible with chronic hyponatremia if ADH antagonists not appropriately used.

• Tolvaptan requires frequent liver monitoring due to hepatotoxicity risk.