Arginine vasopressin (AVP), also designated antidiuretic hormone (ADH), is a cyclic nonapeptide synthesized in magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei. Its controlled release in response to plasma osmolality and hemodynamic perturbations forms the central axis of mammalian water homeostasis, and a precise understanding of this axis is prerequisite for rational use of both vasopressin analogs and vasopressin antagonists in clinical medicine.1
Synthesis begins with the translation of a precursor prohormone, prepro-AVP, which is co-packaged in neurosecretory granules with neurophysin II and copeptin (C-terminal glycopeptide). During axonal transport from hypothalamic cell bodies to nerve terminals in the posterior pituitary (neurohypophysis), enzymatic cleavage yields the mature AVP nonapeptide, neurophysin II, and copeptin as equimolar co-products. Copeptin has gained clinical traction as a surrogate marker of AVP release because it is more stable in plasma and is more easily measured by immunoassay; however, AVP itself mediates all physiological and pharmacological effects discussed in this module.1
The principal stimulus for AVP release is an increase in effective plasma osmolality, detected by specialized osmoreceptor neurons in the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ, both of which lie outside the blood-brain barrier and therefore sample systemic osmolality directly. Robertson's foundational work defined the osmotic threshold for AVP release at approximately 280 to 285 mOsm/kg in healthy adults, with plasma AVP rising steeply and linearly above this threshold.1 A rise of as little as 1 to 2 percent in plasma osmolality is sufficient to trigger AVP secretion, and maximal antidiuresis is achieved at plasma AVP concentrations of approximately 5 pg/mL. Below the threshold, AVP is virtually undetectable and urine is maximally dilute; above it, the kidney concentrates urine in proportion to AVP levels, a relationship that Bichet documented at the molecular level through V2 receptor studies.2
Hemodynamic stimuli constitute a second regulatory axis that operates through baroreceptor afferents rather than osmosensory neurons. Low-pressure volume receptors in the left atrium and high-pressure baroreceptors in the carotid sinus and aortic arch relay signals via the vagus and glossopharyngeal nerves to the nucleus tractus solitarius, which projects to the hypothalamic nuclei governing AVP release. This baroreceptor pathway has a higher threshold than the osmotic pathway: a reduction in blood volume or pressure of approximately 8 to 10 percent is required before it begins to augment AVP secretion, but once engaged it overrides osmotic inhibition and can drive AVP to concentrations 10- to 100-fold above those needed for maximum antidiuresis. This supra-physiological AVP release explains why patients with advanced heart failure, cirrhosis, or hypovolemia retain free water despite low or normal plasma osmolality, a pathological state that underpins dilutional hyponatremia and that vaptans are specifically designed to reverse.3
Several pharmacological agents stimulate AVP release through non-osmotic, non-hemodynamic mechanisms and are clinically significant causes of SIADH. These include carbamazepine (direct stimulation of AVP secretion), cyclophosphamide (potentiates tubular AVP action), SSRIs (serotonin-mediated release), and tricyclic antidepressants. Nausea is one of the most potent non-osmotic stimuli known; even a single emetic episode can drive plasma AVP to levels causing measurable antidiuresis, which partly explains postoperative hyponatremia in the setting of nausea without volume depletion. The recognition of non-osmotic AVP release is clinically critical because these patients may not manifest expected signs of either dehydration or volume overload, yet they retain free water in a pattern indistinguishable from classic SIADH.3
Copeptin, released in equimolar amounts with AVP from the posterior pituitary, has emerged as a practical surrogate for AVP measurement in clinical endocrinology. Unlike AVP, which is highly labile and requires special collection conditions, copeptin is stable at room temperature and measurable by standard immunoassay. Plasma copeptin levels are used to differentiate the polyuria-polydipsia syndrome (central diabetes insipidus vs. nephrogenic diabetes insipidus vs. primary polydipsia) without requiring the traditional water deprivation test in some protocols. Although copeptin assays are not yet universally available, their integration into clinical practice is expanding and will increasingly inform dosing decisions for desmopressin, discussed in Section 5.2
AVP mediates its biological effects through three pharmacologically distinct receptor subtypes designated V1a, V1b (also known as V3), and V2. The V1a and V2 subtypes are the primary targets of both endogenous AVP and therapeutic agents; understanding their differential coupling mechanisms is essential for predicting the effects of vaptans (selective V2 antagonists), desmopressin (selective V2 agonist), and terlipressin (predominant V1a agonist) in clinical contexts.2
The V1a receptor is expressed principally on vascular smooth muscle cells, hepatocytes, uterine myometrium, and platelets. It couples through the Gq/11 family of G proteins to activate phospholipase C-beta, which cleaves phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers calcium release from the endoplasmic reticulum, and DAG activates protein kinase C (PKC). The resultant rise in intracellular calcium drives smooth muscle contraction, producing vasoconstriction predominantly in splanchnic, coronary, and skin vascular beds. This vasopressor action of V1a receptor activation is the pharmacological basis for vasopressin use in septic shock and vasodilatory hypotension (at doses of 0.03 to 0.04 units per minute intravenously), where it serves as a catecholamine-sparing vasopressor. V1a stimulation on platelets augments platelet aggregation, which partly contributes to the hemostatic effects seen with vasopressin-class agents, though desmopressin achieves hemostasis through a distinct endothelial V2-mediated mechanism described below.2
The V2 receptor is expressed almost exclusively on the principal cells of the renal collecting duct. Unlike V1a, it couples to the Gs family of G proteins, activating adenylyl cyclase to generate cyclic adenosine monophosphate (cAMP). Elevated intracellular cAMP activates protein kinase A (PKA), which phosphorylates two distinct targets with clinical consequences. First, PKA phosphorylates aquaporin-2 (AQP2) water channel subunits stored in cytoplasmic vesicles, driving their fusion with the apical (luminal) membrane of the principal cell. This exocytic insertion of AQP2 channels dramatically increases apical water permeability, allowing osmotic water reabsorption from the tubular lumen into the hypertonic medullary interstitium; basolateral water exit occurs constitutively through AQP3 and AQP4 channels. The net result is urinary concentration and free water retention, which corrects hyperosmolality and restores circulating volume.2
The second consequence of PKA activation via V2 is stimulation of von Willebrand factor (vWF) and factor VIII release from Weibel-Palade bodies stored in vascular endothelial cells. This effect is exploited therapeutically by desmopressin (DDAVP), a synthetic V2-selective analog, which transiently raises plasma vWF and factor VIII levels by two- to fivefold within 30 to 60 minutes of administration, providing a short-duration hemostatic boost without requiring blood product infusion. This mechanism explains desmopressin's utility in type 1 von Willebrand disease and mild hemophilia A, and forms the basis for its pre-procedural and perioperative hemostatic applications.8
| Receptor | Distribution | G Protein | Second Messenger | Physiological Effect |
|---|---|---|---|---|
| V1a | Vascular smooth muscle, liver, platelets, uterus | Gq/11 | IP3/DAG → Ca²⁺/PKC | Vasoconstriction, platelet aggregation, glycogenolysis |
| V1b (V3) | Anterior pituitary corticotrophs | Gq/11 | IP3/Ca²⁺ | ACTH release (synergism with CRH); stress response |
| V2 | Renal collecting duct principal cells, endothelium | Gs | cAMP → PKA | AQP2 insertion → antidiuresis; vWF/FVIII release from endothelium |
Beyond the acute trafficking of pre-formed AQP2 vesicles to the apical membrane, sustained V2 receptor activation also upregulates AQP2 gene transcription through a cAMP-response element on the AQP2 promoter, increasing the total cellular AQP2 protein pool over hours to days. This long-term adaptation explains why chronic SIADH or chronic AVP (arginine vasopressin) excess produces a stable state of inappropriate water retention rather than a transient one, and why correction of SIADH requires not only removal of the AVP stimulus (or receptor blockade with a vaptan) but also time for AQP2 protein downregulation to occur at the transcriptional level. Conversely, in states of prolonged water deprivation or chronic central diabetes insipidus treated with desmopressin, AQP2 upregulation contributes to the therapeutic efficacy of ongoing DDAVP dosing.29
Loss-of-function mutations in the V2 receptor gene (AVPR2, located on the X chromosome) are the most common cause of congenital nephrogenic diabetes insipidus (NDI), accounting for approximately 90 percent of X-linked cases. Over 200 distinct AVPR2 mutations have been catalogued; the majority impair receptor trafficking to the plasma membrane or diminish Gs coupling efficiency, rather than eliminating ligand binding per se. Because the V2 receptor is X-linked, affected males manifest the full NDI phenotype (massive polyuria, hypernatremia, failure to respond to exogenous AVP or desmopressin) while carrier females are typically asymptomatic or have mild impairment. Autosomal recessive NDI, accounting for the remaining 10 percent of congenital cases, results from mutations in the AQP2 gene itself. Neither form responds to desmopressin, which is a critical prescribing distinction: desmopressin is indicated exclusively in central DI, not in nephrogenic DI, where V2-dependent signaling is constitutively impaired.2
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is defined by the autonomous, non-osmotically regulated release of AVP (or AVP-like peptide activity) that produces euvolemic hypotonic hyponatremia. SIADH is the most common cause of hyponatremia in hospitalized patients, and its diagnosis requires systematic exclusion of volume depletion, hypothyroidism, adrenal insufficiency, and diuretic-induced hyponatremia before attributing urinary sodium wasting and water retention to inappropriate AVP activity.3
The diagnostic criteria for SIADH, as codified by Ellison and Berl and further refined in the 2013 Verbalis consensus panel, require the simultaneous presence of the following: plasma osmolality below 275 mOsm/kg; urine osmolality above 100 mOsm/kg (and typically above plasma osmolality); clinical euvolemia (no orthostatic hypotension, normal skin turgor, no edema, no ascites); urine sodium concentration above 40 mEq/L on a normal sodium intake; and absence of adrenal, thyroid, or renal insufficiency.310 The urine sodium threshold is a particularly important discriminator: in true hypovolemia, the kidney avidly retains sodium (urine Na below 20 mEq/L), whereas in SIADH the sodium conservation mechanism is intact and the kidney continues to excrete sodium in the face of hyponatremia because volume receptors do not sense a deficit. This pattern of euvolemic hyponatremia with high urine sodium and inappropriately concentrated urine is the hallmark biochemical signature of SIADH.
The etiology of SIADH spans four broad categories. Central nervous system disorders, including meningitis, encephalitis, stroke, subarachnoid hemorrhage, and head trauma, produce SIADH through dysregulated hypothalamic AVP output. Pulmonary diseases, particularly pneumonia, tuberculosis, lung abscess, and mechanical ventilation with positive end-expiratory pressure, stimulate AVP release through hypoxia-mediated and vagal-afferent mechanisms. Malignancies produce ectopic AVP or AVP-like peptides, with small cell lung carcinoma accounting for the majority of ectopic SIADH cases; ectopic production should always be suspected when SIADH lacks an obvious alternative cause in a smoker or patient with constitutional symptoms. Finally, drugs represent a major and often underappreciated category: selective serotonin reuptake inhibitors (SSRIs), carbamazepine, cyclophosphamide, vincristine, non-steroidal anti-inflammatory drugs (NSAIDs), and chlorpropamide all promote SIADH through distinct mechanisms.3
The Verbalis consensus classification stratifies hyponatremia by both the plasma sodium concentration and the rate of development, which together determine the urgency and target rate of correction. Mild hyponatremia is defined as plasma sodium 130 to 135 mEq/L, moderate as 125 to 129 mEq/L, and profound (or severe) as below 125 mEq/L. Acute hyponatremia, developing within 48 hours, poses the greatest risk of cerebral edema and herniation because the brain's adaptive volume-regulatory mechanisms have not had time to export intracellular osmoles. Chronic hyponatremia, developing over more than 48 hours, is associated with lower risk of acute cerebral edema but carries substantial risk of osmotic demyelination syndrome (ODS) if corrected too rapidly. The safe correction rate target established by consensus is 4 to 8 mEq/L per 24 hours in chronic hyponatremia, with an absolute ceiling of 10 to 12 mEq/L per 24 hours and no more than 18 mEq/L per 48 hours, regardless of the clinical trajectory.10
Clinicians must classify hyponatremia by volume status before initiating treatment, since the approach differs across the three categories in ways that are not interchangeable. Hypovolemic hyponatremia (dehydration, gastrointestinal losses, diuretics) is treated with isotonic saline to restore volume, which removes the hemodynamic AVP stimulus and allows the kidney to dilute urine spontaneously; vaptans are contraindicated here because they may worsen volume depletion. Euvolemic hyponatremia (SIADH, hypothyroidism, glucocorticoid deficiency) is the primary indication for vaptan therapy when conservative management (fluid restriction, salt tablets) fails; however, underlying causes must be treated in parallel. Hypervolemic hyponatremia (heart failure, cirrhosis, nephrotic syndrome) features both total body sodium excess and excessive free water retention driven by high-volume-mediated AVP release; vaptans correct the water retention component without aggravating sodium balance, and tolvaptan was studied in this population in the EVEREST trial.5
The vaptans are a class of non-peptide, orally or parenterally bioavailable vasopressin receptor antagonists that produce electrolyte-free water excretion (aquaresis) by blocking the V2 receptor on renal collecting duct cells. By preventing AVP-induced AQP2 insertion, they allow the dilute tubular filtrate to remain unabsorbed, generating a hypotonic diuresis that raises plasma sodium without the sodium loss that accompanies conventional diuretics. Their development transformed the pharmacological management of euvolemic and hypervolemic hyponatremia, providing the first agents specifically targeting the underlying pathophysiology of inappropriate water retention rather than simply restricting intake.4
Tolvaptan (Samsca for hyponatremia; Jinarc/Jynarque for autosomal dominant polycystic kidney disease, ADPKD) is a selective oral V2 receptor antagonist and the most extensively studied vaptan in randomized controlled trials. It is a highly lipophilic molecule with oral bioavailability of approximately 56 percent, a peak plasma concentration reached within 2 to 4 hours of dosing, a terminal half-life of 5 to 12 hours, and predominantly fecal elimination via CYP3A4 hepatic metabolism. The dose for hyponatremia begins at 15 mg once daily, with titration to 30 or 60 mg based on serum sodium response assessed after 24 hours. The drug is absolutely contraindicated in patients with an urgent need for rapid sodium correction (acute symptomatic hyponatremia requiring hypertonic saline), in those who are volume-depleted, or in patients who cannot perceive or respond to thirst, because unchecked aquaresis in a patient who cannot drink to replace losses may cause severe hypernatremia.4
The SALT-1 and SALT-2 trials (Study of Ascending Levels of Tolvaptan in Hyponatremia) randomized 448 patients with euvolemic or hypervolemic hyponatremia (plasma sodium below 135 mEq/L) to tolvaptan 15 to 60 mg daily or placebo for 30 days, with follow-up for 7 days after discontinuation. The primary outcome was the mean daily area under the curve for serum sodium concentration through days 4 and 30. Tolvaptan produced a statistically and clinically significant increase in serum sodium at both time points compared with placebo, with the treatment difference averaging approximately 3.7 mEq/L at day 4 and 3.6 mEq/L at day 30. Serum sodium returned to pre-treatment levels within 7 days of discontinuation in the tolvaptan arm, confirming that tolvaptan provides sustained but not permanent correction and that addressing the underlying cause of SIADH remains essential.4
The EVEREST trial (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) randomized 4,133 patients hospitalized for acute decompensated heart failure to tolvaptan 30 mg daily or placebo for a median of 9.9 months. Tolvaptan significantly improved dyspnea and body weight during the first week of hospitalization and reduced urine output compared with placebo in the short term. However, the primary dual endpoint of all-cause mortality and cardiovascular death or hospitalization was not met, with no difference in long-term outcomes between groups. EVEREST therefore established that tolvaptan improves acute symptoms in decompensated heart failure without conferring survival benefit, and current heart failure guidelines do not recommend vaptans as mortality-reducing agents. Their role in heart failure is therefore restricted to short-term correction of symptomatic or severe hypervolemic hyponatremia in hospitalized patients.5
Conivaptan (Vaprisol) is the only FDA-approved non-selective vaptan, antagonizing both V1a and V2 receptors and available only as an intravenous formulation for in-hospital use. Its dual receptor profile means that V1a blockade prevents the vasoconstrictive action of AVP on splanchnic and systemic vascular beds, potentially causing hypotension, while V2 blockade produces aquaresis. The drug is administered as an IV loading dose of 20 mg over 30 minutes followed by a continuous infusion of 20 mg over 24 hours, with the option to titrate to 40 mg per 24 hours if the serum sodium response is inadequate. Maximum treatment duration is 4 days, reflecting its inpatient-only indication and the hypotension risk from V1a antagonism. Because conivaptan is a potent CYP3A4 inhibitor as well as a CYP3A4 substrate, it has significant drug interaction potential; co-administration with other CYP3A4 substrates with narrow therapeutic windows requires particular caution. Conivaptan is approved for euvolemic and hypervolemic hyponatremia in hospitalized patients, and the Zeltser et al. Conivaptan Study Group trial established its safety and efficacy profile at the doses now in clinical use.6
Satavaptan is a selective oral V2 antagonist that was studied in cirrhosis-associated ascites and hyponatremia but did not receive FDA approval following trial results showing no benefit over placebo on the primary clinical endpoint and concern regarding survival outcomes in the satavaptan-treated arms. Its development history illustrates the important lesson that correction of hyponatremia as a surrogate endpoint does not automatically translate into clinical benefit, particularly in patients with advanced liver disease where the hyponatremia reflects systemic hemodynamic decompensation rather than a simple water balance disorder. The pathophysiological complexity of cirrhotic hyponatremia has prompted the consensus recommendation to use vaptans with considerable caution or to avoid them entirely in patients with liver disease, even for tolvaptan (though tolvaptan's hepatotoxicity risk in its ADPKD indication is discussed separately below).7
| Agent | Receptor Selectivity | Route | Key Trials | Current Indication | Key Warnings |
|---|---|---|---|---|---|
| Tolvaptan | V2 selective | Oral | SALT-1/2, EVEREST | Euvolemic/hypervolemic hyponatremia (≤30 days in-hospital); ADPKD (Jynarque) | Hepatotoxicity (ADPKD dose); ODS risk if overcorrection; thirst impairment CI |
| Conivaptan | V1a + V2 | IV only | Zeltser et al. 2007 | Euvolemic/hypervolemic hyponatremia (inpatient; max 4 days) | Hypotension (V1a block); strong CYP3A4 inhibitor; IV only |
| Satavaptan | V2 selective | Oral | Phase III cirrhosis trials | Not FDA approved; no current clinical role | No survival benefit; possible harm in cirrhosis |
All vaptans must be initiated in a monitored inpatient setting because the rate and magnitude of aquaresis are variable and patient-dependent, and the risk of overcorrection (exceeding 12 mEq/L per 24 hours) is clinically significant. Serum sodium should be checked at 6, 12, and 24 hours after the first dose and at least twice daily thereafter. Fluid restriction should generally not be co-administered with vaptans, as this combination may produce excessively rapid sodium correction. If sodium rises more than 8 mEq/L in the first 8 hours, the vaptan should be withheld and the patient offered free water or, if severe, administered 5 percent dextrose in water intravenously to slow the rate of rise. Patient education must include instruction to drink freely in response to thirst during vaptan therapy; patients who cannot perceive thirst or who cannot access free water must not receive vaptans, as this represents an absolute contraindication.710
Desmopressin (1-desamino-8-D-arginine vasopressin; DDAVP) is a synthetic analog of AVP engineered to eliminate vasopressor activity while preserving and enhancing antidiuretic and hemostatic actions. The two structural modifications responsible for this selectivity are deamination of cysteine at position 1, which prolongs half-life by eliminating aminopeptidase cleavage, and substitution of D-arginine for L-arginine at position 8, which abolishes V1a binding affinity. The resulting molecule is a selective V2 agonist with approximately tenfold greater antidiuretic potency than native AVP and no meaningful V1a-mediated vasopressor activity at therapeutic doses, making it safe for repeated outpatient use without the cardiovascular monitoring requirements of vasopressin itself.8
Central diabetes insipidus (central DI) arises from inadequate AVP secretion due to destruction or dysfunction of hypothalamic magnocellular neurons or the posterior pituitary. Common causes include pituitary surgery, craniopharyngioma, traumatic brain injury, granulomatous disease (sarcoidosis, Langerhans cell histiocytosis), and autoimmune hypophysitis. The clinical presentation is polyuria (typically 3 to 20 liters per day), polydipsia, dilute urine (osmolality below 200 mOsm/kg), and hypernatremia if fluid intake cannot keep pace with losses. Desmopressin is the treatment of choice for central DI, administered as intranasal spray (10 to 40 mcg once or twice daily), oral tablet (0.1 to 0.4 mg two to three times daily), or subcutaneous injection (1 to 4 mcg once or twice daily). The intranasal route offers rapid onset but variable absorption, particularly with nasal congestion or mucosal disease; the oral formulation is more reliably absorbed in most outpatient settings despite its lower bioavailability of approximately 5 percent relative to the nasal route.9
An important prescribing consideration in central DI is the avoidance of severe hyponatremia from desmopressin over-administration. Patients with intact thirst who are allowed to drink ad libitum while on fixed-dose desmopressin can develop dilutional hyponatremia, particularly if they overconsume water. The standard clinical guidance is to allow a brief period of breakthrough polyuria between desmopressin doses (by timing the next dose when urine output begins to increase again) rather than dosing on an inflexible fixed schedule. In the pediatric population, nocturnal desmopressin for primary nocturnal enuresis carries a specific risk of hyponatremia if the child drinks excessively before bedtime; families must be counseled to limit fluid intake in the 1 to 2 hours preceding the bedtime dose. Desmopressin is ineffective in nephrogenic DI because the V2 receptor signaling pathway that it activates is constitutively impaired; this distinction is pharmacologically absolute and must guide the diagnostic workup preceding treatment initiation.9
Desmopressin's hemostatic mechanism rests on its ability to trigger rapid exocytic release of vWF (von Willebrand factor) multimers and factor VIII from endothelial Weibel-Palade bodies via V2-mediated cAMP (cyclic AMP)/PKA (protein kinase A) signaling. A single weight-based intravenous dose of 0.3 mcg/kg (infused over 15 to 30 minutes) produces a two- to fivefold rise in plasma vWF antigen, vWF ristocetin cofactor activity, and factor VIII coagulant activity within 30 to 60 minutes, with peak hemostatic effect lasting approximately 4 to 8 hours. This response is adequate to cover minor surgical procedures, dental extractions, and minor trauma in patients with type 1 vWD (the most common form, characterized by quantitatively reduced but qualitatively normal vWF) and mild hemophilia A (baseline factor VIII 5 to 40 percent of normal).8
Patients with type 2B vWD should not receive desmopressin, as the release of abnormal high-molecular-weight vWF multimers can trigger platelet aggregation and thrombocytopenia. Type 3 vWD, characterized by near-total absence of vWF, does not respond meaningfully to desmopressin and requires vWF concentrate. Moderate-to-severe hemophilia A (baseline factor VIII below 5 percent) likewise requires factor VIII concentrate because desmopressin cannot raise factor VIII sufficiently to achieve hemostatic levels for major procedures. A test dose of desmopressin should be administered before a planned procedure in any patient being considered for this indication, with measurement of factor VIII and vWF levels at baseline and 60 minutes post-infusion, to confirm an adequate response and to guide dosing strategy. Tachyphylaxis develops after repeated doses (typically after 2 to 3 consecutive daily doses) due to depletion of releasable Weibel-Palade body stores, and factor VIII levels decline progressively with each subsequent dose even if the interval is adequate; for this reason, desmopressin is suitable for short-duration hemostatic coverage and not for sustained perioperative support requiring more than 2 to 3 days of activity.8
Beyond central DI and hemostasis, desmopressin is approved for primary nocturnal enuresis in children aged 6 years and older and is used off-label in nocturia in adults, where it reduces nocturnal urine volume and the number of nocturnal voids. The intranasal formulation for nocturnal enuresis was voluntarily withdrawn from this indication in the United States due to hyponatremia-associated seizures; oral desmopressin is currently the preferred formulation for enuresis. In adults with nocturia secondary to nocturnal polyuria, particularly elderly patients, the lowest effective dose should be used and serum sodium monitored at baseline, 1 month, and 3 months after initiation, given the higher background risk of hyponatremia in this population from reduced renal concentrating ability and blunted thirst sensation. The principal adverse effects of desmopressin across all indications are dose-dependent hyponatremia, headache, nausea, facial flushing (from trace V1a activity at high doses), and, at the site of nasal administration, rhinitis and epistaxis. Systemic hypertension is not expected at therapeutic doses given the absence of meaningful V1a vasopressor activity, distinguishing desmopressin from native vasopressin and terlipressin in this respect.89
Robertson GL. Vasopressin in osmotic regulation in man. Annu Rev Med. 1974;25:315–322. doi:10.1146/annurev.me.25.020174.001531
Bichet DG. Vasopressin receptor mutations causing nephrogenic diabetes insipidus. Semin Nephrol. 2008;28(3):245–251. doi:10.1016/j.semnephrol.2008.03.005
Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064–2072. doi:10.1056/NEJMcp066837
Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099–2112. doi:10.1056/NEJMoa065181
Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297(12):1319–1331. doi:10.1001/jama.297.12.1319
Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N; Conivaptan Study Group. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007;27(5):447–457. doi:10.1159/000106456
Rozen-Zvi B, Yahav D, Gheorghiade M, Korzets A, Leibovici L, Gafter U. Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis. Am J Kidney Dis. 2010;56(2):325–337. doi:10.1053/j.ajkd.2010.01.013
Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood. 1997;90(7):2515–2521. doi:10.1182/blood.V90.7.2515
Fenske W, Allolio B. Clinical review: current state and future perspectives in the diagnosis of diabetes insipidus: a clinical review. J Clin Endocrinol Metab. 2012;97(10):3426–3437. doi:10.1210/jc.2012-1981
Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1–S42. doi:10.1016/j.amjmed.2013.07.006