An Expert Monograph on Vasopressin (Arginine Vasopressin)

Executive Summary

Vasopressin, also known as arginine vasopressin (AVP) or antidiuretic hormone (ADH), is a nonapeptide that functions as both an essential endogenous hormone and a critical care medication.[1] In its physiological role, it is integral to maintaining body fluid homeostasis, osmotic balance, and blood pressure regulation.[2] As a pharmaceutical agent, identified by DrugBank ID DB00067 and CAS Number 11000-17-2, its primary application is in emergency medicine to manage profound hypotension.[1]

The pharmacological activity of vasopressin is mediated through its non-selective agonist action on a family of G-protein-coupled receptors: V1a, V1b, and V2.[1] Activation of V1a receptors on vascular smooth muscle produces potent vasoconstriction, the basis for its pressor effect. Concurrently, activation of V2 receptors in the renal collecting ducts promotes water reabsorption, its classic antidiuretic effect.[2] This dual, non-selective action creates an inherent clinical tension, as the desired hemodynamic support from V1a agonism is inextricably linked to the risk of fluid overload and hyponatremia from V2 agonism, necessitating vigilant patient monitoring.[3]

The primary indication for which vasopressin is approved by the U.S. Food and Drug Administration (FDA) is to increase blood pressure in adults with vasodilatory shock (e.g., septic or post-cardiotomy shock) who remain hypotensive despite adequate fluid resuscitation and catecholamine therapy.[6] Its use in this context is often as a catecholamine-sparing agent, leveraging a non-adrenergic pathway to restore vascular tone.[8] A crucial aspect of its clinical use is the profound difference in dosing between indications. Low-dose continuous infusions (e.g., 0.01-0.04 units/minute) are used for shock, whereas high-dose infusions (e.g., 0.2-0.8 units/minute), an order of magnitude greater, are employed for the off-label management of gastrointestinal hemorrhage.[8] This dosing dichotomy represents a significant potential for medication error.

The safety profile of vasopressin is a direct reflection of its pharmacology. The most severe adverse effects stem from excessive vasoconstriction, leading to peripheral, mesenteric, or coronary ischemia, and from excessive antidiuresis, leading to water intoxication and severe hyponatremia.[3] Its regulatory history in the United States is unique; after decades on the market as an unapproved drug, it gained formal FDA approval in 2014 through the Unapproved Drugs Initiative (UDI). This event led to a period of market exclusivity and significant price increases, highlighting the complex interplay between regulation, pharmaceutical strategy, and healthcare economics.[12]

Historical Development and Chemical Profile

The journey of vasopressin from a mysterious physiological activity to a well-characterized synthetic hormone is a story of key scientific breakthroughs spanning over a century. This history provides the essential context for understanding its modern clinical and research applications.

The Journey from Pituitary Extract to Synthetic Hormone

The scientific narrative of vasopressin began in 1895 with the seminal observation by George Oliver and Edward Albert Schäfer that extracts from the posterior pituitary gland possessed a powerful pressor (blood pressure-raising) effect in mammals.[13] This discovery opened a new field of endocrinological research. Nearly two decades later, in 1913, this crude extract found its first therapeutic application. F. Farini in Italy and, independently, von den Velden in Germany, demonstrated that injections of pituitary extract could control the debilitating polyuria (excessive urination) of diabetes insipidus.[14] This marked one of the earliest successful uses of hormone replacement therapy and established a direct link between the pituitary gland and water homeostasis.[15]

For the next several decades, research focused on isolating the active principles from these extracts. A pivotal moment occurred between 1951 and 1953 when the American biochemist Vincent du Vigneaud and his research team accomplished the monumental task of isolating, determining the amino acid sequence of, and, ultimately, chemically synthesizing vasopressin and the related hormone oxytocin.[1] This work, which earned du Vigneaud the Nobel Prize in Chemistry in 1955, was transformative. It provided pure, synthetic hormones for study, moving beyond crude extracts and enabling precise investigation into their structure-activity relationships.[13]

With pure vasopressin available, the final piece of the puzzle was to understand how it exerted its diverse effects. In 1979, based on pharmacological studies, Michell and his collaborators proposed the existence of at least two distinct receptor types to explain the hormone's separate pressor and antidiuretic actions.[13] They termed the receptor mediating calcium-dependent effects (like vasoconstriction) "V1" and the one mediating cAMP-dependent effects (like antidiuresis) "V2".[13] This hypothesis was confirmed and refined over the following years with the molecular cloning of the receptor subtypes. The V1a receptor was cloned in 1992, followed by the V1b (or V3) and V2 receptors in the early 1990s.[13] This final step provided a complete molecular framework for vasopressin's action and paved the way for the rational design of selective analogues, such as desmopressin.

Chemical Identity and Physicochemical Properties

Vasopressin is classified as a small molecule peptide hormone.[1] Structurally, it is a nonapeptide, meaning it is composed of nine amino acids. Its sequence is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2. A defining feature is its cyclic structure, formed by a disulfide bridge linking the cysteine residues at positions 1 and 6, which creates a six-amino-acid ring with a three-amino-acid C-terminal tail.[4] This structure is remarkably similar to that of oxytocin, another posterior pituitary hormone, differing only in the amino acids at positions 3 (phenylalanine in vasopressin vs. isoleucine in oxytocin) and 8 (arginine in vasopressin vs. leucine in oxytocin).[1]

In its pharmaceutical form, vasopressin is typically supplied as a sterile, white, lyophilized powder that is hygroscopic (tends to absorb moisture from the air) and soluble in water.[4] It is known by several synonyms, the most common being Arginine Vasopressin (AVP), which specifies the arginine at position 8 and distinguishes it from lysine vasopressin found in pigs, and Antidiuretic Hormone (ADH), which describes its primary physiological function.[19]

Table 2.1: Chemical and Physical Identifiers of Vasopressin
Identifier	Value / Code
DrugBank Accession Number	DB00067 1
CAS Number	11000-17-2 4
Molecular Formula	C46​H65​N15​O12​S2​ 4
Molecular Weight	1084.24 g/mol 4
IUPAC Name	(S)-N-((S)-1-((2-amino-2-oxoethyl)amino)-5-guanidino-1-oxopentan-2-yl)-1-((4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-13-benzyl-16-(4-hydroxybenzyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosane-4-carbonyl)pyrrolidine-2-carboxamide 19
InChI Key	KBZOIRJILGZLEJ-LGYYRGKSSA-N 19
Canonical SMILES	O=C(C@@HCSSCC(N2CCC2)=O)NCC4=CC=C(O)C=C4

Pharmacology: Receptor-Mediated Mechanisms of Action

The diverse and potent physiological effects of vasopressin are entirely mediated by its interaction with a family of specific cell surface receptors. As a non-selective agonist, vasopressin binds to and activates three distinct subtypes of G-protein-coupled receptors (GPCRs): the V1a, V1b (also known as V3), and V2 receptors. The unique tissue distribution and downstream signaling pathways of these receptors account for the hormone's dual roles in hemodynamics and fluid balance, as well as its influence on the endocrine system and neurological function.

The Vasopressin Receptor Family: An Overview

The vasopressin receptor system is a classic example of how a single signaling molecule can elicit markedly different responses in different tissues. The V1a and V1b receptors are coupled to the Gq/11 family of G-proteins, initiating a signaling cascade that results in increased intracellular calcium. In contrast, the V2 receptor is coupled to the Gs protein, which stimulates the production of the second messenger cyclic AMP (cAMP). This fundamental divergence in signaling pathways is the basis for vasopressin's distinct vasoconstrictor and antidiuretic properties.

The V1a Receptor Pathway: Vasoconstriction and Hemostasis

The V1a receptor is the primary mediator of vasopressin's hemodynamic effects.

• Location: V1a receptors are densely expressed on the surface of vascular smooth muscle cells throughout the arterial system, which is the principal site of their pressor action. They are also found on platelets, where they influence hemostasis; in the liver, where they affect metabolic processes; and in the kidney's medullary interstitial cells.
• Signaling Cascade: The binding of vasopressin to a V1a receptor initiates a well-defined intracellular signaling pathway. The receptor activates its associated Gq/11 protein, which in turn stimulates the enzyme phospholipase C (PLC). PLC acts on a membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2​), cleaving it into two second messengers: inositol 1,4,5-trisphosphate (IP3​) and diacylglycerol (DAG). IP3​ diffuses through the cytoplasm and binds to receptors on the sarcoplasmic reticulum, triggering a rapid release of stored calcium (Ca2+) into the cytosol. The combination of elevated intracellular Ca2+ and DAG activates Protein Kinase C (PKC). This cascade ultimately leads to the phosphorylation of myosin light chains, causing contraction of the vascular smooth muscle cell.
• Physiological Outcomes: The primary consequence of V1a receptor activation is vasoconstriction. In a clinical context, this translates to an increase in systemic vascular resistance (SVR), which elevates mean arterial pressure, the therapeutic goal in vasodilatory shock. The vasoconstriction is particularly intense in the splanchnic (mesenteric) circulation, an effect that is harnessed to reduce blood flow and pressure in the portal system to control esophageal variceal bleeding. However, this same potent effect is responsible for the major adverse effect of mesenteric ischemia. Additionally, V1a activation on platelets promotes their aggregation, a mechanism that may contribute to hemostasis in the setting of hemorrhagic shock.

The V2 Receptor Pathway: Antidiuresis and Aquaporin-2 Regulation

The V2 receptor is exclusively responsible for vasopressin's antidiuretic action, a cornerstone of bodily fluid regulation.

• Location: V2 receptors are specifically located on the basolateral (blood-facing) membrane of the principal cells that line the final segments of the nephron: the late distal tubule and the entire collecting duct system of the kidney.
• Signaling Cascade: Upon binding vasopressin, the V2 receptor undergoes a conformational change that activates its coupled stimulatory G-protein (Gs). The activated Gs protein then stimulates the membrane-bound enzyme adenylyl cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to the second messenger cyclic adenosine monophosphate (cAMP). The accumulation of intracellular cAMP leads to the activation of Protein Kinase A (PKA).
• Physiological Outcomes: PKA activation orchestrates both short-term and long-term changes to increase water reabsorption.
• Short-Term (Water Permeability): The most immediate effect is the PKA-mediated phosphorylation of intracellular vesicles that contain a pre-formed water channel protein called aquaporin-2 (AQP2). This phosphorylation event acts as a signal, promoting the rapid translocation of these vesicles to the apical (urine-facing) membrane of the principal cell and their fusion with it. The insertion of AQP2 channels into the apical membrane renders it highly permeable to water. Water then moves passively out of the tubular fluid, down the osmotic gradient created by the salty renal medulla, and back into the bloodstream. This process conserves water and produces a smaller volume of concentrated urine.
• Long-Term (Gene Expression): Over a longer timescale, the cAMP-PKA pathway also activates transcription factors (like CREB) that enter the nucleus and increase the genetic transcription of the AQP2 gene itself. This leads to the synthesis of more AQP2 protein, ensuring a sustained capacity for water reabsorption as long as vasopressin is present.

The V1b (V3) Receptor Pathway: Endocrine and Neuromodulatory Roles

The V1b receptor, also known as the V3 receptor, plays a more specialized role, primarily in the endocrine system.

• Location: V1b receptors are most prominently expressed in the corticotroph cells of the anterior pituitary gland. They are also found in the pancreas and in various regions of the brain.
• Signaling Cascade: Like the V1a receptor, the V1b receptor couples to the Gq/11-PLC pathway, leading to an increase in intracellular calcium.
• Physiological Outcomes: The main function of the V1b receptor is to modulate the body's stress response. In the anterior pituitary, vasopressin acts synergistically with corticotropin-releasing hormone (CRH) to stimulate the release of adrenocorticotropic hormone (ACTH). ACTH then travels to the adrenal glands to stimulate cortisol production. Vasopressin is therefore a key potentiator of the hypothalamic-pituitary-adrenal (HPA) axis. In the pancreas, V1b receptors are implicated in the regulation of insulin and glucagon secretion, linking vasopressin to metabolic control.

Pharmacodynamic Nuances: Opposing and Systemic Effects

The net effect of vasopressin in the body is more complex than a simple summation of its receptor actions. The drug's name, "vasopressin," and its primary use as a pressor agent can be misleading, as it possesses counter-regulatory and systemic effects that modulate its primary actions. Evidence suggests that vasopressin can induce vasodilation in certain vascular beds, an effect possibly mediated through cross-activation of oxytocin receptors on endothelial cells, leading to the release of the vasodilator nitric oxide (NO). This may serve as a local feedback mechanism to prevent excessive vasoconstriction in sensitive tissues. Furthermore, vasopressin administration often leads to a decrease in heart rate and cardiac output. This is thought to be a result of both a baroreflex-mediated response to the increase in blood pressure and a direct effect on the heart, possibly involving the release of atrial natriuretic peptide (ANP). These cardiodepressive effects are a critical consideration, particularly in patients with compromised cardiac function, and they illustrate that the drug's hemodynamic profile is a complex balance of opposing forces rather than uniform vasoconstriction.

Table 3.1: Vasopressin Receptor Subtypes: Location, Signaling, and Physiological Effects
Receptor Subtype	Primary Locations	G-Protein Coupling	Second Messenger(s)	Key Physiological Effect(s)
V1a	Vascular smooth muscle, platelets, liver, kidney (medullary interstitial cells)	Gq​/G11​	IP3​, DAG, Ca2+	Vasoconstriction (increased SVR), platelet aggregation, glycogenolysis
V1b (V3)	Anterior pituitary (corticotrophs), pancreas, brain	Gq​/G11​	IP3​, DAG, Ca2+	ACTH release (potentiation of stress response), modulation of insulin/glucagon secretion
V2	Kidney (collecting duct principal cells)	Gs​	cAMP	Antidiuresis via AQP2 translocation and synthesis, increased water reabsorption

Pharmacokinetics: A Profile of a Short-Acting Peptide

The pharmacokinetic profile of vasopressin—its absorption, distribution, metabolism, and excretion (ADME)—is defined by its peptide nature and rapid clearance. These characteristics fundamentally dictate its clinical administration, particularly in critical care settings, and explain its predictable and rapidly reversible effects.

Administration, Absorption, and Distribution

Vasopressin is not orally bioavailable because, as a peptide, it is readily degraded by proteases like trypsin in the gastrointestinal tract. Consequently, it must be administered parenterally. For its primary indication of vasodilatory shock, the only effective method for maintaining stable plasma concentrations and a sustained pressor effect is continuous intravenous (IV) infusion. Following initiation of a continuous IV infusion, steady-state plasma concentrations are typically achieved within 30 minutes. For other indications, such as diabetes insipidus, it can be administered via intramuscular (IM) or subcutaneous (SC) injection, though these routes are less common in modern practice.

Once in the bloodstream, vasopressin is widely distributed throughout the extracellular fluid. It has a relatively small volume of distribution of approximately 140 mL/kg. A key feature is that it does not appear to bind to plasma proteins, meaning the entire circulating concentration is free and pharmacologically active. The onset of action when given intravenously is immediate, but its duration is brief, lasting only 30 to 60 minutes after the infusion is stopped.

Metabolism and Elimination

The defining pharmacokinetic characteristic of vasopressin is its extremely short plasma half-life. Estimates range from 10 to 24 minutes, with an apparent half-life of less than or equal to 10 minutes at the infusion rates used clinically for shock. This rapid clearance is the direct reason why continuous infusion is necessary for sustained therapeutic effect. This short half-life also functions as a critical safety feature; in the event of adverse effects such as severe ischemia or hyponatremia, discontinuing the infusion leads to a rapid decline in plasma levels and a quick cessation of the drug's pharmacological activity.

Elimination occurs primarily through rapid metabolism in the liver and kidneys. The peptide is cleaved at multiple sites by various enzymes, including serine proteases, carboxypeptidases, and disulfide oxidoreductases. These cleavage events occur at sites essential for the hormone's biological activity, rendering the resulting metabolites inactive. Only a very small fraction of the administered dose, approximately 6%, is excreted unchanged in the urine, underscoring the predominance of metabolic clearance.

Pharmacokinetic Variability in Special Populations

The most significant and clinically relevant alteration in vasopressin pharmacokinetics occurs during pregnancy. The placenta produces an enzyme called vasopressinase (a cysteine aminopeptidase) that spills over into the maternal circulation and efficiently degrades vasopressin. The activity of this enzyme increases progressively throughout gestation. As a result, the clearance of both endogenous and exogenous vasopressin increases dramatically, by approximately 4-fold in the third trimester and up to 5-fold at term. This necessitates that pregnant patients may require significantly higher doses of vasopressin to achieve a therapeutic effect. This effect is transient, as vasopressinase levels fall rapidly after delivery, and vasopressin clearance returns to its pre-conception baseline within two weeks.

Clinical Applications and Dosing Regimens

The clinical use of vasopressin is centered on leveraging its potent vasoconstrictor and antidiuretic properties in specific, often critical, medical conditions. A clear understanding of its indications, the rationale for its use, and the crucial, indication-specific dosing regimens is paramount for safe and effective therapy. There is a fundamental difference between its FDA-approved indication and its well-established off-label uses, which is reflected in dosing paradigms that can differ by an order of magnitude.

Primary Indication: Vasodilatory Shock

The sole indication for which vasopressin (as Vasostrict®) is formally approved by the U.S. FDA is to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite adequate fluid resuscitation and treatment with catecholamines. This includes shock secondary to sepsis (septic shock) or following cardiac surgery (post-cardiotomy shock).

The therapeutic rationale is twofold. First, prolonged states of shock are associated with a "relative vasopressin deficiency," where endogenous levels of the hormone are inappropriately low for the degree of hypotension. Low-dose vasopressin infusion serves as a form of hormone replacement to correct this deficiency. Second, it provides a powerful vasoconstrictive mechanism that is independent of the adrenergic system. By acting on V1a receptors, it can restore vascular tone when blood vessels have become refractory to the effects of catecholamines like norepinephrine. This often results in a "catecholamine-sparing" effect, allowing for the dose of norepinephrine to be reduced, potentially mitigating some of the adverse effects of high-dose catecholamine therapy.

The dosing for vasodilatory shock is a low-dose, continuous IV infusion regimen:

• Septic Shock: The recommended starting dose is 0.01 units/minute. The infusion can be titrated upwards by 0.005 units/minute at 10- to 15-minute intervals to achieve the target mean arterial pressure (typically >65 mmHg). The usual therapeutic range is 0.01 to 0.04 units/minute. Doses higher than 0.07 units/minute are associated with increased adverse events and are generally not recommended.
• Post-Cardiotomy Shock: The recommended starting dose is higher, at 0.03 units/minute. It can be titrated as needed, with a maximum recommended dose of 0.1 units/minute.

Established Off-Label Uses

Despite having only one FDA-approved indication, vasopressin has several long-standing off-label uses that are well-established in medical practice and supported by clinical literature.

1. Central Diabetes Insipidus (CDI)

Historically, this was the primary use for vasopressin. In CDI, the hypothalamus fails to produce or the posterior pituitary fails to release adequate amounts of ADH. Vasopressin administration serves as direct hormone replacement therapy to restore the kidney's ability to concentrate urine, thereby controlling the severe polyuria and polydipsia that characterize the condition. While the long-acting, V2-selective synthetic analogue desmopressin is now the agent of choice for chronic management, vasopressin may still be used in acute settings or for diagnosis.

Dosing for CDI is typically via intermittent injection:

• Adults: 5 to 10 units administered IM or SC two to three times per day as needed.
• Children: 2.5 to 10 units administered IM or SC three to four times per day.
• A continuous IV infusion can also be utilized, typically starting at 0.0005 units/kg/hour (0.5 milliunits/kg/hour) and titrated based on urine output and serum sodium.

2. Gastrointestinal and Variceal Hemorrhage

Vasopressin is used as a potent vasoconstrictor to manage life-threatening bleeding from esophageal varices or other sources of diffuse gastrointestinal hemorrhage. The therapeutic goal is to induce intense vasoconstriction of the splanchnic arterioles, which dramatically reduces blood flow into the portal venous system. This decrease in portal pressure can help to control the hemorrhage.

The dosing for this indication represents a completely different pharmacological paradigm from its use in shock. It is a high-dose regimen intended to produce a supra-physiological effect:

• Dosing: Initiate a continuous IV infusion at a rate of 0.2 to 0.4 units/minute. This can be titrated upwards as needed to control bleeding, to a maximum dose of 0.8 or 0.9 units/minute.
• Adjunctive Therapy: Because these high doses of vasopressin cause significant systemic and coronary vasoconstriction, it is a common practice to co-administer a continuous IV infusion of nitroglycerin (e.g., 40-400 mcg/min). The nitroglycerin helps to counteract these dangerous ischemic side effects while preserving the desired splanchnic vasoconstriction.

Emerging and Investigational Uses

Research continues to explore new applications for vasopressin's unique physiological effects.

• Hemorrhagic Shock in Trauma: In massive trauma, endogenous vasopressin stores are rapidly depleted. Clinical trials have investigated the early use of vasopressin in these patients. The rationale is that it may help restore vascular tone, reduce the need for blood product transfusions, and potentially improve hemostasis through its V1a-mediated effects on platelet aggregation.
• Massive Pulmonary Embolism: In cases of massive pulmonary embolism with obstructive shock, vasopressin is being explored for its potential to selectively increase systemic vascular resistance (supporting blood pressure) while simultaneously promoting pulmonary vasodilation, which could unload the failing right ventricle.

Table 5.1: Dosing Regimens for Vasopressin by Clinical Indication
Clinical Indication	Status	Rationale	Initial Dose	Titration / Dose Range	Key Clinical Pearls
Vasodilatory Shock (Septic)	FDA-Approved	Hormone replacement for relative deficiency; non-catecholamine pressor	0.01 units/min IV	Titrate by 0.005 units/min q10-15 min; Max: 0.07 units/min	Low-dose regimen. Used as an adjunct to catecholamines.
Vasodilatory Shock (Post-Cardiotomy)	FDA-Approved	Restore vascular tone after cardiopulmonary bypass	0.03 units/min IV	Titrate as needed; Max: 0.1 units/min	Low-dose regimen. Higher starting dose than septic shock.
Gastrointestinal Hemorrhage	Off-Label	Intense splanchnic vasoconstriction to reduce portal pressure	0.2-0.4 units/min IV	Titrate to max of 0.8-0.9 units/min	High-dose regimen. Concurrent nitroglycerin infusion is often used to mitigate ischemia.
Central Diabetes Insipidus	Off-Label	ADH replacement to promote renal water reabsorption	5-10 units IM/SC	Administered 2-3 times daily as needed	Intermittent dosing. Desmopressin is preferred for chronic therapy.

Safety Profile and Risk Management

The safety profile of vasopressin is a direct and predictable consequence of its potent, non-selective pharmacology. The adverse effects, contraindications, and necessary monitoring are all intrinsically linked to its powerful actions on the V1a and V2 receptors. Effective risk management, therefore, depends on a thorough understanding of its mechanism of action and proactive monitoring for its expected physiological consequences.

Adverse Drug Reactions

The most common and serious adverse reactions are extensions of vasopressin's therapeutic effects.

• Mechanism-Based Effects:
• Ischemia (V1a-mediated): This is the most feared complication and is directly related to the V1a receptor-mediated vasoconstriction. The risk is dose-dependent and is highest with the high-dose regimens used for gastrointestinal bleeding. Ischemia can manifest in multiple critical vascular beds, including:
• Coronary Ischemia: Presenting as angina or acute myocardial infarction.
• Mesenteric Ischemia: Leading to bowel ischemia and infarction.
• Peripheral Ischemia: Affecting the extremities (especially digits) and skin, which can progress to gangrene and necrosis.
• Cardiovascular Effects: Beyond ischemia, vasopressin can cause a decrease in cardiac output and reflex bradycardia due to the rise in blood pressure. Tachyarrhythmias and right heart failure have also been reported.
• Fluid & Electrolyte Imbalances (V2-mediated): The potent antidiuretic effect mediated by the V2 receptor can lead to excessive water retention. This can result in dilutional hyponatremia and water intoxication, a serious condition that can manifest with symptoms of lethargy, headache, and confusion, and can progress to seizures and coma if not promptly addressed.
• Reversible Diabetes Insipidus: Paradoxically, upon cessation of vasopressin therapy, some patients may experience a rebound phenomenon of reversible diabetes insipidus. This is characterized by the sudden onset of polyuria with dilute urine and rising serum sodium (hypernatremia), requiring careful monitoring and potential fluid and electrolyte correction.
• Other Common Effects: More common, less severe side effects include abdominal cramps, nausea, vomiting, diarrhea, pallor (especially circumoral), sweating, and a pounding sensation in the head.

Contraindications and High-Risk Populations

• Absolute Contraindication: The only absolute contraindication is a known allergy or hypersensitivity to 8-L-arginine vasopressin. The 10 mL multiple-dose vial, which contains the preservative chlorobutanol, is also contraindicated in patients with a known allergy to chlorobutanol.
• Use with Extreme Caution: Vasopressin should be used with extreme caution in patients with underlying conditions that could be exacerbated by its physiological effects. This includes individuals with pre-existing coronary artery disease, peripheral vascular disease, or heart failure, as they are at a much higher risk for severe ischemic complications. Caution is also warranted in patients with asthma, epilepsy, or migraine headaches, as the drug may worsen these conditions.

Warnings, Precautions, and Monitoring

Given its high-risk nature, strict precautions and vigilant monitoring are essential during vasopressin therapy.

• Extravasation Risk: Vasopressin is a potent vesicant. If it leaks out of a peripheral vein (extravasation), it can cause severe local vasoconstriction, leading to tissue ischemia and necrosis. For this reason, it must be administered through a central venous line whenever possible, especially for high-dose or prolonged infusions. If a peripheral IV must be used, the site must be monitored hourly for any signs of infiltration (e.g., pain, swelling, blanching). The alpha-adrenergic blocker phentolamine should be readily available as an antidote for local infiltration to counteract the vasoconstriction.
• Essential Monitoring:
• Hemodynamics: Continuous monitoring of blood pressure, ideally with an intra-arterial catheter, is mandatory. Heart rate and continuous ECG monitoring are also required to detect bradycardia or arrhythmias.
• Fluid and Electrolytes: Frequent monitoring of serum electrolytes, particularly sodium, is critical to detect hyponatremia. Strict monitoring of fluid balance (intake and output) and urine output is essential to manage the antidiuretic effect and to detect the onset of reversible diabetes insipidus upon drug cessation.
• Perfusion: Regular assessment for signs of end-organ ischemia is crucial. This includes monitoring skin color and temperature in the extremities, assessing mental status, and monitoring for abdominal pain or distension.

Management of Overdose

An overdose of vasopressin will present as an exaggeration of its pharmacological effects: severe, widespread vasoconstriction (peripheral, mesenteric, coronary), life-threatening arrhythmias, and profound hyponatremia. Management is guided by the drug's very short half-life. The immediate and most important intervention is to stop or significantly decrease the infusion rate. The effects of vasopressin will resolve rapidly, typically within minutes. Further treatment is supportive and symptomatic, addressing the consequences of ischemia and correcting any electrolyte abnormalities.

Significant Drug Interactions

Several drug classes can interact with vasopressin, either potentiating or diminishing its effects.

Table 6.1: Clinically Significant Drug Interactions with Vasopressin
Interacting Drug/Class	Mechanism of Interaction	Clinical Effect	Management Recommendation
Catecholamines (e.g., norepinephrine, dopamine)	Additive pharmacodynamic effect	Additive pressor response	Expected and often therapeutic. Monitor hemodynamics closely.
Ganglionic Blocking Agents	Increased sensitivity to pressor effect	Increased pressor response	Use with caution; may require lower vasopressin dose.
Drugs Causing SIADH (e.g., TCAs, carbamazepine, clofibrate)	Potentiate antidiuretic action	Increased risk of water retention and hyponatremia	Monitor serum sodium and fluid balance more frequently.
Drugs Causing Diabetes Insipidus (e.g., lithium, demeclocycline)	Decrease antidiuretic action	Reduced antidiuretic effect; may require higher vasopressin dose for DI	Monitor urine output and serum sodium; titrate vasopressin dose accordingly.
Indomethacin	Unknown; may inhibit prostaglandin synthesis	Prolongs the hemodynamic effects (pressor and cardiac output) of vasopressin	Be aware that effects may persist longer after dose changes or cessation.
Alcohol	Inhibits endogenous ADH release	May decrease the antidiuretic effect of vasopressin	Avoid concurrent use.

Comparative Analysis: Vasopressin versus Desmopressin (DDAVP)

Comparing vasopressin with its most important synthetic analogue, desmopressin (DDAVP), provides a classic illustration of rational drug design in medicinal chemistry. By making subtle modifications to the parent hormone, scientists were able to create a new molecule with a dramatically different pharmacological profile, isolating a desired therapeutic effect while minimizing unwanted side effects. This head-to-head comparison clarifies their distinct and largely non-overlapping roles in modern medicine.

Structural and Pharmacokinetic Distinctions

The differences between the two drugs begin at the molecular level. Desmopressin is created from the vasopressin template through two key structural modifications:

1. Deamination of 1-cysteine: The amine group on the first amino acid (cysteine) is removed.
2. Substitution at position 8: The naturally occurring L-arginine is replaced with its stereoisomer, D-arginine.

These seemingly minor changes have profound pharmacokinetic consequences. They make the desmopressin molecule significantly more resistant to degradation by peptidases (vasopressinases) in the body. As a result, desmopressin has a much longer plasma half-life of approximately 2 to 4 hours, compared to the very short half-life of less than 30 minutes for vasopressin. This extended duration of action makes desmopressin suitable for intermittent dosing (e.g., once or twice daily) for chronic conditions, whereas vasopressin requires continuous infusion for sustained effects.

Divergent Receptor Selectivity and Pharmacodynamic Profiles

The most critical difference between vasopressin and desmopressin lies in their receptor selectivity. This divergence is the direct result of the structural modifications and is the foundation of their distinct clinical uses.

• Vasopressin is a non-selective agonist, binding with high affinity to and potently activating V1a, V1b, and V2 receptors. This results in a pharmacodynamic profile characterized by both powerful vasoconstriction (V1a-mediated) and potent antidiuresis (V2-mediated).
• Desmopressin is a highly selective V2 receptor agonist. It retains and even enhances the affinity for the V2 receptor but has markedly diminished activity at the V1a receptor.

This selectivity translates into a completely different profile of effects. Desmopressin exerts strong, prolonged antidiuretic effects with very little to no pressor (vasoconstrictive) activity. The development of desmopressin was a triumph of medicinal chemistry, successfully separating the desired antidiuretic properties of vasopressin from the often-undesirable pressor effects for the treatment of conditions like diabetes insipidus.

Contrasting Clinical Applications and Side Effects

The differences in pharmacology and pharmacokinetics lead to clinical applications that are almost mutually exclusive.

• Clinical Roles:
• Vasopressin is used almost exclusively for its V1a-mediated pressor effects in the management of vasodilatory shock and gastrointestinal bleeding. Its V2 effects are typically considered a side effect in these settings.
• Desmopressin is used for its V2-mediated antidiuretic effects in the treatment of central diabetes insipidus and nocturnal enuresis (bed-wetting). It also has a unique indication in the management of certain bleeding disorders (mild hemophilia A and von Willebrand disease type I). This effect is not due to V1a vasoconstriction but rather a V2-mediated release of von Willebrand factor and Factor VIII from endothelial storage sites.
• Side Effect Profiles: The adverse effect profiles of the two drugs directly reflect their receptor selectivity.
• The dominant side effects of vasopressin are related to excessive V1a activation: ischemia (coronary, mesenteric, peripheral) and arrhythmias. While hyponatremia can occur, it is often the ischemic complications that are most feared.
• The side effects of desmopressin are almost entirely related to excessive V2 activation: water retention, fluid overload, and hyponatremia. Ischemic complications are not a feature of desmopressin therapy.

Table 7.1: Comparative Profile of Vasopressin vs. Desmopressin
Feature	Vasopressin (AVP)	Desmopressin (DDAVP)
Structure	Natural nonapeptide with L-arginine at position 8	Synthetic analogue; deaminated at position 1, D-arginine at position 8
Receptor Selectivity	Non-selective agonist for V1a, V1b, and V2 receptors	Highly selective agonist for V2 receptors; minimal V1a activity
Primary Pharmacodynamic Effect	Potent vasoconstriction and antidiuresis	Potent and prolonged antidiuresis; negligible vasoconstriction
Plasma Half-Life	< 30 minutes	~2-4 hours
Primary Clinical Uses	Vasodilatory shock, gastrointestinal bleeding	Central diabetes insipidus, nocturnal enuresis, bleeding disorders (vWD, Hemophilia A)
Dominant Adverse Effects	Ischemia (coronary, mesenteric, digital), arrhythmias, decreased cardiac output	Water intoxication, hyponatremia, fluid overload

Evidence from Clinical Trials and Future Directions

The clinical evidence base for vasopressin, particularly in its primary role in shock, has been shaped by several landmark trials. While these studies have established its place in therapy, they have also left key questions unanswered, fueling a vibrant and ongoing area of clinical research. Concurrently, basic and translational science is uncovering novel roles for this ancient hormone, suggesting a renaissance in its therapeutic potential beyond hemodynamics.

Review of Landmark Trials in Septic Shock

The modern use of vasopressin in septic shock is largely informed by two major randomized controlled trials (RCTs).

• VASST (Vasopressin and Septic Shock Trial): Published in 2008, VASST was a large, multicenter RCT that randomized 778 patients with septic shock to receive either norepinephrine plus a placebo or norepinephrine plus a low-dose vasopressin infusion (0.01-0.03 units/minute). The primary outcome, 28-day mortality, was not significantly different between the two groups (39.3% in the norepinephrine group vs. 35.4% in the vasopressin group). The trial confirmed that vasopressin has a significant norepinephrine-sparing effect, allowing for lower doses of catecholamines. A key pre-specified subgroup analysis suggested a potential mortality benefit for vasopressin in patients with less severe shock (requiring <15 mcg/min of norepinephrine at baseline), although this finding was hypothesis-generating.
• VANISH (Vasopressin versus Norepinephrine as Initial Therapy in Septic Shock): Published in 2016, the VANISH trial sought to determine if early vasopressin use could prevent the progression of acute kidney injury in septic shock. This trial randomized 409 patients to receive either vasopressin (titrated up to 0.06 units/minute) or norepinephrine as their initial vasopressor, with the other agent added if needed. The primary outcome, the number of kidney-failure-free days at day 28, was not significantly different between the groups. However, a key secondary outcome revealed that patients in the vasopressin group had significantly lower rates of requiring renal replacement therapy (dialysis) compared to the norepinephrine group.

Collectively, these trials established vasopressin as a legitimate, safe adjunct to norepinephrine in septic shock, but they did not demonstrate a definitive survival benefit. Instead, they generated crucial new hypotheses regarding its potential benefit in specific patient subgroups (less severe shock) and its possible renal-protective effects, setting the stage for the next wave of research.

Analysis of Ongoing and Recent Clinical Research

The ambiguity left by VASST and VANISH has led to a dynamic and unsettled period in critical care research, with a central focus on the timing and sequence of vasopressor initiation.

• The "Early Vasopressin" Question: A key debate is whether vasopressin should be added earlier in the course of shock, rather than being reserved for refractory cases. The hypothesis is that earlier initiation might prevent the full depletion of endogenous stores and mitigate the harmful effects of high-dose catecholamines. Several large-scale RCTs are currently underway to address this question directly.
• The NoVa trial (NCT06464510) is a phase 3 trial randomizing 2,800 patients to either an early vasopressin strategy or a standard norepinephrine-first strategy with vasopressin reserved for rescue.
• Another trial (NCT06265259) is investigating vasopressin as the first-line vasopressor compared to norepinephrine.
• The RENOVA trial (NCT05506319) investigated the weaning strategy, comparing the initial reduction of norepinephrine versus vasopressin, finding no difference in the incidence of hypotension.
• Pragmatic Trials: Recognizing the complexities of real-world practice, researchers are also employing pragmatic trial designs. The VASSPR trial (NCT06217562) is a large, cluster-randomized, crossover trial comparing two different thresholds for initiating vasopressin (a lower threshold of 0.1 mcg/kg/min norepinephrine equivalent vs. a higher threshold of 0.4 mcg/kg/min). This design will provide valuable evidence on common clinical strategies in a real-world setting.

Emerging Frontiers: Beyond Pressure and Plumbing

While its role in critical care continues to be refined, the most exciting recent developments for vasopressin have come from research into its functions outside the cardiovascular and renal systems. This work suggests a renaissance for the molecule, revealing unexpected complexity and novel therapeutic possibilities.

• Metabolic Regulation: There is accumulating evidence that vasopressin is a key regulator of metabolism. Research has shown that vasopressin, acting through its V1a and V1b receptors in the liver and pancreas, plays a role in glucose and lipid metabolism, including processes like gluconeogenesis and glycogenolysis. Dysregulation of the vasopressin system has been linked in human and animal studies to hyperglycemia, insulin resistance, metabolic syndrome, and the progression of diabetic kidney disease. This opens up the possibility of targeting vasopressin receptors for the treatment of metabolic disorders.
• Neuropsychiatric Applications: Perhaps the most groundbreaking recent finding is in the field of neuroscience. Vasopressin has long been known to function as a neuropeptide involved in regulating social behaviors in mammals. A landmark randomized, placebo-controlled pilot trial published in 2019 demonstrated that a 4-week course of intranasal vasopressin significantly improved social responsiveness and reduced anxiety in children with autism spectrum disorder (ASD). This finding, which was well-tolerated, has opened an entirely new and promising therapeutic avenue for a core deficit of autism for which no effective medications currently exist.

Regulatory History and Market Landscape

The regulatory and commercial history of vasopressin in the United States is a unique and often controversial case study that illuminates the complex intersection of pharmaceutical law, market strategy, and healthcare economics. The journey of vasopressin from a long-marketed, inexpensive generic to a high-priced, patent-protected brand name product was driven by a specific FDA initiative and has had significant financial implications for the healthcare system.

The Unapproved Drugs Initiative and the Path to Approval

For most of its history, vasopressin was marketed in the U.S. without formal FDA approval. It was considered a "pre-1938" or "grandfathered" drug, one of many that were on the market before the Food, Drug, and Cosmetic Act of 1938 gave the FDA authority to review drugs for safety. In 2006, the FDA launched the Unapproved Drugs Initiative (UDI), an effort to bring these legacy drugs into the modern regulatory framework by requiring them to undergo a formal review for safety and effectiveness.

In 2012, JHP Pharmaceuticals (which was later acquired by Par Pharmaceutical) took advantage of this initiative. They submitted a New Drug Application (NDA 204-485) for their vasopressin product, which they would eventually name Vasostrict. The application was submitted under the 505(b)(2) pathway, a regulatory route that allows a company to rely on published literature and the FDA's previous findings of safety and efficacy for a listed drug, rather than conducting new, large-scale clinical trials. The application was based on a review of existing literature demonstrating vasopressin's use in vasodilatory shock. On April 17, 2014, the FDA approved Vasostrict, making it the first and only FDA-approved vasopressin product for increasing blood pressure in adults with vasodilatory shock.

Market Exclusivity, Patent Strategy, and Pricing Dynamics

The FDA approval of Vasostrict had immediate and profound market consequences. As part of the UDI, the FDA ordered other manufacturers of unapproved vasopressin to cease production, effectively granting Par Pharmaceutical a monopoly on the market. This regulatory action was leveraged into a commercial strategy that saw the price of vasopressin skyrocket. Between 2010 and 2020, the price of the drug increased by more than 5,400%.

Par Pharmaceutical aggressively defended this newfound monopoly through several tactics:

• Building a "Patent Thicket": Despite vasopressin being a century-old molecule, the company obtained numerous new patents related to its specific formulation and methods of use. As of 2022, it had listed 14 patents with the FDA, with the last set to expire in 2035. This strategy made it more difficult and legally risky for generic manufacturers to enter the market.
• Blocking Competition: The company actively fought efforts by compounding pharmacies to produce alternative, less expensive versions of vasopressin. When the FDA initially proposed allowing compounding due to clinical need, Par Pharmaceutical sued the agency, leading the FDA to reverse its decision. This move protected Par's market exclusivity.
• Citizen Petitions: The company also filed at least one citizen petition with the FDA, a regulatory tool that can be used to raise concerns about a pending generic application, a tactic that can delay generic approval.

The Advent of Generic Competition

Par Pharmaceutical's period of market exclusivity lasted for over seven years. It finally came to an end in late 2021 after a federal court ruled that a proposed generic version from Eagle Pharmaceuticals did not infringe on Par's patents. The FDA approved Eagle's generic vasopressin in December 2021, and a second generic competitor launched in early 2022. This introduction of competition marked the end of a controversial chapter in vasopressin's history, one that serves as a powerful example of how regulatory pathways can be used to generate significant commercial returns on long-established medicines.

Conclusion and Expert Synthesis

Vasopressin is a molecule of remarkable duality. It is simultaneously an ancient, highly conserved peptide hormone essential for life and a modern, high-acuity medication central to the practice of critical care. This comprehensive analysis reveals a drug defined by its non-selective pharmacology, its unique regulatory history, and its expanding therapeutic horizons.

The established place of vasopressin in therapy is secure but nuanced. Its role as a non-catecholamine, catecholamine-sparing agent in adults with vasodilatory shock refractory to initial therapy is its primary, evidence-supported, and FDA-approved indication. In this setting, it corrects a state of relative hormone deficiency and offers an alternative pathway to restore vascular tone. Its off-label use in controlling variceal hemorrhage, while historically important, represents a high-risk, high-reward intervention that leverages a supra-physiological vasoconstrictive effect. The paramount importance of adhering to strict, indication-specific dosing regimens—recognizing the order-of-magnitude difference between shock and bleeding doses—cannot be overstated. Safe administration is contingent upon this knowledge, as well as on vigilant monitoring for the predictable, mechanism-based adverse effects of ischemia and hyponatremia.

The clinical science surrounding vasopressin is far from settled; rather, it is in a period of dynamic evolution. The landmark trials in septic shock did not provide a definitive mortality benefit but instead generated critical new hypotheses about renal protection and the optimal timing of initiation. The flurry of ongoing, large-scale clinical trials investigating "early vasopressin" strategies is a testament to the fact that the ideal use and sequencing of vasopressors remains one of the most pressing and active questions in contemporary critical care. The results of these trials are poised to further refine or potentially redefine vasopressin's role in the resuscitation of the critically ill.

Perhaps most compelling is the renaissance of vasopressin in fields far removed from the intensive care unit. Emerging research into its integral role in metabolic regulation has implicated the vasopressin system in the pathophysiology of diabetes and metabolic syndrome, suggesting entirely new therapeutic targets. Furthermore, the groundbreaking discovery of its ability to improve core social deficits in children with autism heralds a potential paradigm shift, harnessing its neuromodulatory functions to address a major unmet medical need.

In conclusion, vasopressin, a hormone whose pressor effects were first observed over 125 years ago, remains a subject of intense scientific study and profound clinical importance. Its journey—from a crude pituitary extract to a synthetic peptide, from an unapproved legacy drug to a focus of medico-economic controversy, and from a simple pressor to a complex neuromodulator—illustrates the perpetual evolution of pharmacology. Future research must continue to optimize its use in established critical care indications while rigorously exploring the exciting and novel therapeutic potential that this ancient molecule continues to reveal.

Works cited

1. Vasopressin: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed August 8, 2025, https://go.drugbank.com/drugs/DB00067
2. Physiology, Vasopressin - StatPearls - NCBI Bookshelf, accessed August 8, 2025, https://www.ncbi.nlm.nih.gov/books/NBK526069/
3. Vasopressin: Blood Pressure Uses, Warnings, Side Effects, Dosage, accessed August 8, 2025, https://www.medicinenet.com/vasopressin/article.htm
4. Vasopressin, 98+% - Fisher Scientific, accessed August 8, 2025, https://www.fishersci.ca/shop/products/vasopressin-98-thermo-scientific/p-7042063
5. Vasopressin (Antidiuretic Hormone) - Cardiovascular Physiology Concepts, accessed August 8, 2025, https://cvphysiology.com/blood-pressure/bp016
6. Vasopressin: Package Insert / Prescribing Information - Drugs.com, accessed August 8, 2025, https://www.drugs.com/pro/vasopressin.html
7. This label may not be the latest approved by FDA. For current ..., accessed August 8, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/204485Orig1s020lbl.pdf
8. What are the clinical scenarios and dosing recommendations for vasopressin (antidiuretic hormone) use? - Dr.Oracle, accessed August 8, 2025, https://www.droracle.ai/articles/205461/vasopressin
9. Vasopressin and its analogues in shock states: a review - PMC - PubMed Central, accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6975768/
10. 2Lyndsay Ryan, PharmD, PGY1 1Ekaterina Shapiro, DO, PGY-2; 1Jennifer Nef - Oklahoma State University Center for Health Sciences, accessed August 8, 2025, https://medicine.okstate.edu/gme/quality-symposium/posters-2021/poster-24-vasopressin.pdf
11. Vasopressin: a review of clinical indications - PMC, accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12015599/
12. The Vexing Voyage of Vasopressin: The Consequences of Granting ..., accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9353103/
13. Vasopressin and oxytocin receptors | Introduction | BPS/IUPHAR ..., accessed August 8, 2025, https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=66
14. The Biology of Vasopressin - PMC - PubMed Central, accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7832310/
15. Diabetes Insipidus: Celebrating a Century of Vasopressin Therapy ..., accessed August 8, 2025, https://academic.oup.com/endo/article/155/12/4605/2422825
16. Vasopressin and Its Analogues: From Natural Hormones to ..., accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8955888/
17. V2 vasopressin receptor mutations and fluid homeostasis ..., accessed August 8, 2025, https://academic.oup.com/cardiovascres/article/51/3/409/367029
18. Vasopressin | 11000-17-2 - ChemicalBook, accessed August 8, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8410252.htm
19. Vasopressin | CAS#11000-17-2 - MedKoo Biosciences, accessed August 8, 2025, https://www.medkoo.com/products/16349
20. Vasopressin | CAS 11000-17-2 | SCBT - Santa Cruz Biotechnology, accessed August 8, 2025, https://www.scbt.com/p/vasopressin-11000-17-2
21. Vasopressin - Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Hepatic Dose | Drug Index | Pediatric Oncall, accessed August 8, 2025, https://www.pediatriconcall.com/drugs/vasopressin/1038
22. Vasopressin - Wikipedia, accessed August 8, 2025, https://en.wikipedia.org/wiki/Vasopressin
23. Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2 receptor-mediated effects - Oxford Academic, accessed August 8, 2025, https://academic.oup.com/cardiovascres/article/51/3/372/366579
24. Vasopressin Regulation: A Comprehensive Guide, accessed August 8, 2025, https://www.numberanalytics.com/blog/ultimate-guide-vasopressin-regulation
25. go.drugbank.com, accessed August 8, 2025, https://go.drugbank.com/drugs/DB00067#:~:text=Vasopressin%20binding%20to%20V2,trafficking%20to%20the%20cell%20surface.
26. Critical Care Corner - :: Clinical and Experimental Emergency Medicine, accessed August 8, 2025, https://www.ceemjournal.org/m/journal/view.php?doi=10.15441/ceem.24.351
27. Arginine Vasopressin Receptors - YouTube, accessed August 8, 2025, https://www.youtube.com/watch?v=ccRkl_fwG0k
28. V2 vasopressin receptor mutations: future personalized therapy based on individual molecular biology - Frontiers, accessed August 8, 2025, https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1173601/full
29. Characterization of a functional V1B vasopressin receptor in the male rat kidney: evidence for cross talk between V1B and V2 receptor signaling pathways - American Journal of Physiology, accessed August 8, 2025, https://journals.physiology.org/doi/abs/10.1152/ajprenal.00081.2021
30. Rethinking Vasopressin: New Insights into Vasopressin Signaling ..., accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10476687/
31. 204485Orig1s000 | FDA - accessdata.fda.gov, accessed August 8, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204485Orig1s000PharmR.pdf
32. Vasopressin (injection route) - Side effects & dosage - Mayo Clinic, accessed August 8, 2025, https://www.mayoclinic.org/drugs-supplements/vasopressin-injection-route/description/drg-20066681
33. Vasopressin | - Truman State University, accessed August 8, 2025, https://shadwige.sites.truman.edu/cardiac-medications/vaughan-williams-classification-of-antidysrhythmic-drugs/vasopressin/
34. Study Details | Efficacy of the Use of Vasopressin as a Primary ..., accessed August 8, 2025, https://clinicaltrials.gov/study/NCT06265259
35. VASOSTRICT® (vasopressin injection) for intravenous use - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 8, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204485Orig1s013lbl.pdf
36. Vasostrict, ADH (vasopressin) dosing, indications, interactions ..., accessed August 8, 2025, https://reference.medscape.com/drug/vasostrict-adh-vasopressin-342073
37. Argipressin (Vasopressin) 2021, accessed August 8, 2025, https://www.anmfonline.org/wp-content/uploads/2021/06/argipressin-vasopressin-15042021-2.0.pdf
38. Title: Octreotide Shortage: Vasopressin for Variceal Bleeding, accessed August 8, 2025, https://em.umaryland.edu/educational_pearls/3852/
39. Traumatic Shock Completed Phase 2 Trials for Vasopressin (DB00067) | DrugBank Online, accessed August 8, 2025, https://go.drugbank.com/indications/DBCOND0057246/clinical_trials/DB00067?phase=2&status=completed
40. Desmopressin: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed August 8, 2025, https://go.drugbank.com/drugs/DB00035
41. NeuroEMCrit - The Many Aliases and Uses of ADH by Casey Albin, accessed August 8, 2025, https://emcrit.org/emcrit/uses-adh/
42. Vasopressin and Its Analogues: From Natural Hormones to Multitasking Peptides - MDPI, accessed August 8, 2025, https://www.mdpi.com/1422-0067/23/6/3068
43. Desmopressin vs Vasopressin Comparison - Drugs.com, accessed August 8, 2025, https://www.drugs.com/compare/desmopressin-vs-vasopressin
44. Potential clinical applications of current and future oral forms of desmopressin (Review), accessed August 8, 2025, https://www.spandidos-publications.com/10.3892/etm.2024.12592
45. Vasopressin - brand name list from Drugs.com, accessed August 8, 2025, https://www.drugs.com/ingredient/vasopressin.html
46. my.clevelandclinic.org, accessed August 8, 2025, https://my.clevelandclinic.org/health/drugs/19345-desmopressin-tablets#:~:text=Desmopressin%20is%20a%20synthetic%20form,this%20medication%20is%20DDAVP%C2%AE.
47. VASST - The Bottom Line, accessed August 8, 2025, https://www.thebottomline.org.uk/summaries/icm/vasst/
48. Norepinephrine and Vasopressin for Rescue Versus Early Vasopressin for Vasopressor Dependent Sepsis (NoVa) - ClinicalTrials.gov, accessed August 8, 2025, https://clinicaltrials.gov/study/NCT06464510
49. Reduction of norepinephrine versus vasopressin in the stabilization phase of septic shock: RENOVA clinical trial - PubMed, accessed August 8, 2025, https://pubmed.ncbi.nlm.nih.gov/39890531/
50. Study Details | Vasopressin for Septic Shock Pragmatic Trial ..., accessed August 8, 2025, https://clinicaltrials.gov/study/NCT06217562
51. A randomized placebo-controlled pilot trial shows that intranasal ..., accessed August 8, 2025, https://pubmed.ncbi.nlm.nih.gov/31043522/
52. 204485Orig1s000 - accessdata.fda.gov, accessed August 8, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204485Orig1s000OtherR.pdf
53. Generic Vasostrict Availability - Drugs.com, accessed August 8, 2025, https://www.drugs.com/availability/generic-vasostrict.html