Vasopressin is a nine-amino-acid peptide synthesized in hypothalamic neurons and transported down axons to the posterior pituitary, where it is stored in secretory granules until released into the systemic circulation. Two stimuli trigger vasopressin release. The primary stimulus is a rise in plasma osmolality, sensed by osmoreceptors in the anterior hypothalamus; even a 1 to 2 percent increase above the normal set point of approximately 285 mOsm/kg triggers vasopressin secretion. The secondary stimulus is a fall in blood pressure or blood volume, sensed by baroreceptors in the carotid sinus and aortic arch; this stimulus requires a larger drop (approximately 10 to 15 percent) to activate vasopressin release but produces a larger vasopressin surge when activated. Nausea, pain, and several drugs including nicotine and opioids also stimulate vasopressin release.

Vasopressin acts through two main receptor subtypes with distinct locations and effects. V1 receptors are located on vascular smooth muscle cells throughout the systemic and pulmonary circulation. V1 receptor activation triggers vasoconstriction — an effect exploited clinically when vasopressin is used as a vasopressor in septic shock and cardiac arrest, where it raises systemic vascular resistance without the tachycardia associated with catecholamines.

V2 receptors are located on the principal cells of the renal collecting duct. V2 receptor activation triggers insertion of aquaporin-2 water channels into the luminal membrane of collecting duct cells, dramatically increasing water permeability. As tubular fluid passes through the collecting duct, water moves osmotically into the hypertonic medullary interstitium, producing concentrated urine and reducing water excretion. This is vasopressin's primary physiological role: conserving free water when plasma osmolality rises or blood volume falls.

Normally, vasopressin secretion is suppressed when plasma osmolality falls below the set point (approximately 280 to 285 mOsm/kg), allowing the kidney to excrete dilute urine and correct any free water excess. In the syndrome of inappropriate antidiuretic hormone secretion, vasopressin continues to be secreted despite low plasma osmolality, driving continued water reabsorption in the collecting duct. The result is dilutional hyponatremia — plasma sodium falls not because sodium is lost but because water is retained in excess. Because water distributes throughout total body water, there is no volume overload; patients are euvolemic, which is the key clinical distinguishing feature from hyponatremia caused by heart failure or cirrhosis.

The most common causes of the syndrome of inappropriate antidiuretic hormone secretion fall into four categories. Central nervous system disorders — including meningitis, encephalitis, stroke, and head trauma — stimulate hypothalamic vasopressin release through neural pathways that override osmotic suppression. Pulmonary disorders, particularly pneumonia and positive-pressure ventilation, activate thoracic baroreceptors that signal volume depletion and drive vasopressin release. Malignancies, most commonly small cell lung cancer, can produce ectopic vasopressin directly. Drugs are a frequent cause: the most important include selective serotonin reuptake inhibitors, carbamazepine, cyclophosphamide, and thiazide diuretics. A helpful mnemonic is SIADH causes: CNS, Pulmonary, Ectopic (tumor), Drugs.

The diagnosis of the syndrome of inappropriate antidiuretic hormone secretion requires demonstrating that urine is inappropriately concentrated despite low plasma osmolality. The key laboratory findings are low plasma sodium (hyponatremia) with low plasma osmolality, urine osmolality greater than 100 mOsm/kg (inappropriately concentrated), urine sodium greater than 40 mEq/L (sodium wasting because total body sodium is normal), and euvolemia on clinical examination. Thyroid function and adrenal function must be confirmed as normal because hypothyroidism and adrenal insufficiency can mimic the syndrome independently.

The treatment approach depends on severity. Mild to moderate hyponatremia (sodium above 125 mEq/L, no neurological symptoms) is treated with fluid restriction to 1 to 1.5 liters per day. When fluid restriction is insufficient, vaptans (tolvaptan or conivaptan) can be added to block V2 receptors and promote free water excretion. Severe symptomatic hyponatremia — manifesting as seizures, coma, or respiratory arrest — requires cautious correction with hypertonic saline.

The rate of sodium correction is one of the most clinically consequential pharmacological rules in medicine. Correcting chronic hyponatremia too rapidly causes osmotic demyelination syndrome — a devastating neurological injury caused by rapid osmotic shifts that demyelinate central pontine and extrapontine white matter, producing locked-in syndrome or death. The maximum safe correction rate is 8 to 10 mEq/L per 24 hours in most patients, and no more than 18 mEq/L in the first 48 hours. In patients at high risk — those with severe hyponatremia, malnutrition, alcoholism, or hypokalemia — the limit is even lower. This rule applies regardless of which treatment modality is used.

Tolvaptan is an orally administered selective V2 receptor antagonist approved for euvolemic and hypervolemic hyponatremia associated with the syndrome of inappropriate antidiuretic hormone secretion, heart failure, and cirrhosis. By blocking V2 receptors, tolvaptan prevents vasopressin-driven water reabsorption, producing free water excretion and raising plasma sodium. Unlike diuretics, tolvaptan does not cause hypokalemia or worsen sodium balance.

Tolvaptan carries a black box warning for hepatotoxicity based on data from the TEMPO 3:4 trial in autosomal dominant polycystic kidney disease, where high doses taken for extended periods caused serious liver injury. As a result, tolvaptan is contraindicated in patients with liver disease (including cirrhosis), must not be used for more than 30 days, and should be initiated only in a hospital setting where the rate of sodium correction can be monitored. Tolvaptan is a substrate and inhibitor of cytochrome P450 3A4, producing interactions with strong cytochrome P450 3A4 inhibitors (which raise tolvaptan levels) and inducers (which reduce efficacy).

Conivaptan blocks both V1 and V2 receptors and is available only as an intravenous formulation for in-hospital use. It is approved for euvolemic and hypervolemic hyponatremia in non-cirrhotic patients. The V1 blockade component produces some degree of vasodilation, which limits its use in patients who are already hypotensive. Like tolvaptan, conivaptan is a potent cytochrome P450 3A4 inhibitor and raises plasma levels of co-administered cytochrome P450 3A4 substrates. Hospital-only administration allows close monitoring of the sodium correction rate, reducing the risk of overcorrection.

Central diabetes insipidus results from deficient vasopressin production by the hypothalamus, most commonly due to head trauma, neurosurgery, pituitary tumors, or infiltrative diseases such as sarcoidosis. Without vasopressin, aquaporin-2 channels are not inserted in the collecting duct, and the kidney cannot concentrate urine — patients produce massive volumes (5 to 20 liters per day) of dilute urine (osmolality below 200 mOsm/kg) and become profoundly thirsty and hypernatremic if fluid intake cannot keep pace with losses. Desmopressin replaces the missing vasopressin, restoring V2 receptor activation and urine concentration. It can be administered intranasally, orally, or subcutaneously depending on the clinical context.

Desmopressin is ineffective in nephrogenic diabetes insipidus, in which the kidney is resistant to vasopressin because the V2 receptor itself is absent (X-linked inherited form) or blocked (lithium, demeclocycline) or the aquaporin-2 system is dysfunctional. In nephrogenic diabetes insipidus, adding more V2 receptor agonist cannot overcome the downstream resistance. Treatment of nephrogenic diabetes insipidus uses thiazide diuretics and low-sodium diet to create mild volume contraction that indirectly reduces urine output.

In primary nocturnal enuresis (bedwetting in children without an anatomical cause), desmopressin given intranasally or orally at bedtime reduces nocturnal urine production by activating V2 receptors in the collecting duct, allowing the bladder to remain within its functional capacity overnight. The effect is temporary — it suppresses enuresis on nights it is taken but does not cure the underlying condition. Hyponatremia is a risk if excessive fluid is consumed before the evening dose, particularly with the intranasal preparation; the oral tablet has a more predictable dose-response. Fluid restriction after the evening dose is standard practice.

Desmopressin has a distinct hemostatic mechanism unrelated to its antidiuretic effect. V2 receptor activation on vascular endothelial cells triggers exocytosis of Weibel-Palade bodies, releasing stored von Willebrand factor and factor VIII into the circulation within 30 to 60 minutes of administration. This transient surge of clotting factors is sufficient to cover minor surgical procedures, dental extractions, and bleeding episodes in patients with mild hemophilia A (factor VIII activity above 5 to 10 percent) and type 1 von Willebrand disease (the most common subtype, characterized by a quantitative reduction in normally functioning von Willebrand factor).

Desmopressin is ineffective in severe hemophilia A (where factor VIII activity is too low for a relative increase to be clinically meaningful) and in type 2B von Willebrand disease (where desmopressin-induced release of abnormal von Willebrand factor can paradoxically worsen thrombocytopenia). Repeated doses within 24 to 48 hours cause tachyphylaxis as Weibel-Palade body stores are depleted.