Norepinephrine (DB00368): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Norepinephrine, also known as noradrenaline, is an endogenous catecholamine that functions as a primary neurotransmitter of the sympathetic nervous system and as a hormone released by the adrenal medulla. In its therapeutic form, norepinephrine is a potent sympathomimetic medication, indispensable in critical care medicine for the management of life-threatening hypotension. It is identified by DrugBank ID DB00368 and CAS Number 51-41-2.[1]

Pharmacologically, norepinephrine exerts its effects through potent agonism at alpha-1 (α1​) and beta-1 (β1​) adrenergic receptors, with minimal activity at beta-2 (β2​) receptors.[2] Its primary mechanism of action involves intense peripheral vasoconstriction mediated by

α1​ receptors, leading to a significant increase in systemic vascular resistance (SVR) and, consequently, mean arterial pressure (MAP). Concurrently, its β1​ receptor activity provides positive inotropic effects, enhancing myocardial contractility.[1] This dual action makes it uniquely effective in treating vasodilatory shock states.

The clinical application of norepinephrine is firmly established, with the Surviving Sepsis Campaign guidelines recommending it as the first-line vasopressor for septic shock unresponsive to fluid resuscitation.[2] Evidence from multiple meta-analyses demonstrates its superiority over dopamine in this setting, primarily due to a lower incidence of cardiac arrhythmias and a potential mortality benefit.[1] Its role in other shock states, particularly cardiogenic shock, remains a subject of clinical investigation and debate, as the increase in afterload may elevate myocardial oxygen demand in an already compromised heart.[2]

The safety profile of norepinephrine is a direct extension of its potent pharmacology. The principal risks include severe hypertension, reflex bradycardia, and end-organ ischemia resulting from excessive vasoconstriction.[7] A critical and feared complication is tissue necrosis following intravenous extravasation, which necessitates immediate intervention with the alpha-adrenergic antagonist phentolamine.[9] Significant drug-drug interactions exist, most notably with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), which can lead to severe, prolonged hypertension by inhibiting norepinephrine's metabolic clearance.[2]

Administered exclusively as a continuous intravenous infusion due to its extremely short half-life of approximately 2.4 minutes, norepinephrine allows for precise, minute-to-minute titration of blood pressure.[2] This report provides an exhaustive analysis of norepinephrine, covering its physicochemical properties, dual physiological roles, detailed clinical pharmacology, therapeutic applications, comparative efficacy, and comprehensive safety considerations, intended to serve as a definitive reference for medical and pharmaceutical professionals.

Drug Identification and Physicochemical Properties

A precise understanding of norepinephrine's identity and chemical characteristics is fundamental to its safe and effective use in clinical practice. These properties dictate its formulation, stability, storage requirements, and method of administration.

Nomenclature and Identifiers

Norepinephrine is known by several names and is cataloged across numerous chemical and regulatory databases. This extensive list of identifiers reflects its long history of use and global importance.

• Generic Name: Norepinephrine.[1]
• Common Synonyms: Noradrenaline, L-Noradrenaline, L-Norepinephrine, (-)-Noradrenaline, Levarterenol, L-Arterenol, (-)-Arterenol.[1]
• Systematic (IUPAC) Name: 4-benzene-1,2-diol.[14]
• Brand Names: The most common brand name in the United States is Levophed®.[11] Internationally, it is marketed under a multitude of names including Noradrec, Noralin, Hyponor, Adrenor, and Sinora, among others.[11]
• Regulatory and Database Identifiers:
• DrugBank ID: DB00368.[1]
• CAS Number: 51-41-2.[1]
• FDA UNII: X4W3ENH1CV.[11]
• ATC Code: C01CA03 (Adrenergic and dopaminergic agents).[11]
• EC Number: 200-096-6.[12]
• ChEMBL ID: CHEMBL1437.[14]
• KEGG ID: C00547.[14]

Chemical and Structural Profile

Norepinephrine is a small molecule catecholamine, a class of monoamines characterized by a catechol (benzene ring with two adjacent hydroxyl groups) moiety and an amine side chain.[12]

• Chemical Formula: C8​H11​NO3​.[1]
• Molecular Weight: The average molecular weight is 169.18 g/mol (or 169.1778 Da), with a monoisotopic mass of 169.073893223 Da.[1]
• Structure: Structurally, norepinephrine is nearly identical to epinephrine, differing only by the absence of a methyl group on the terminal nitrogen of the amine side chain. It differs from its precursor, dopamine, by the addition of a hydroxyl group on the beta-carbon of the side chain.[2]
• Stereochemistry: The biologically active form is the R-enantiomer, designated as (R)-(-)-norepinephrine or L-norepinephrine.[1]

Physicochemical Characteristics

The physical and chemical properties of norepinephrine have direct implications for its clinical preparation, stability, and administration.

• Appearance: Off-white to tan crystalline solid.[11]
• Solubility: It is slightly soluble in water and ethanol but soluble in dilute aqueous acids (e.g., hydrochloric acid) and alkali solutions.[11]
• Stability and Storage: The compound is stable but is notably sensitive to air and light, which can cause oxidation and degradation, leading to a loss of potency. It is incompatible with acids, bases, and oxidizing agents. For laboratory purposes, the pure crystalline solid is typically stored at -20°C. Pharmaceutical preparations have specific storage requirements, often at controlled room temperature, protected from light.[11]
• Melting Point: Approximately 220-230°C.[11]
• Acidity (pKa): The pKa is approximately 8.64 at 25°C, reflecting the basicity of the amine group.[11]
• Optical Activity: As a chiral molecule, it exhibits optical activity. The specific rotation, [α]D25​, is reported as -37.3° (c=5 in water with 1 equivalent HCl).[11]

The inherent chemical instability of the norepinephrine molecule, particularly its susceptibility to oxidation due to the catechol and amine groups, directly informs and necessitates specific clinical handling protocols. This sensitivity is the primary reason that clinical guidelines for intravenous (IV) preparation explicitly recommend dilution in dextrose-containing solutions (e.g., 5% Dextrose in Water, D5W).[2] The dextrose acts as an antioxidant, protecting the catecholamine structure from degradation and ensuring that the patient receives the intended therapeutic dose. The use of 0.9% sodium chloride (normal saline) as the sole diluent is not recommended precisely because it lacks this protective effect, which could lead to a significant loss of potency and result in sub-therapeutic dosing and apparent treatment failure.[3]

Table 1: Physicochemical and Identification Properties of Norepinephrine

Property	Value / Description	Source(s)
Generic Name	Norepinephrine	1
Synonyms	Noradrenaline, L-Noradrenaline, Levarterenol	1
Brand Name (US)	Levophed®	11
DrugBank ID	DB00368	1
CAS Number	51-41-2	11
Chemical Formula	C8​H11​NO3​	1
Molecular Weight	169.18 g/mol	11
Appearance	Off-white to tan crystalline solid	11
Solubility	Slightly soluble in water; soluble in dilute acids and alkali	11
Melting Point	220-230°C	11
pKa	8.64 (at 25°C)	11
Storage (Pure Substance)	-20°C; Air & Light Sensitive	11
ATC Code	C01CA03	11
FDA UNII	X4W3ENH1CV	11

Endogenous Role: The Neurotransmitter and Hormone

Norepinephrine possesses a crucial dual identity within the body, functioning as both a neurotransmitter within the nervous system and a hormone in the endocrine system.[21] This distinction is vital for understanding its broad physiological effects and the different ways it is targeted by pharmaceuticals.

Dual Identity and Biosynthesis

As a neurotransmitter, norepinephrine is a chemical messenger that transmits signals between nerve cells (neurons) or from neurons to target cells like muscle or glands.[22] It is synthesized and released from nerve cells located primarily in the brainstem, specifically the locus coeruleus, and from postganglionic neurons of the sympathetic nervous system.[11]

As a hormone, norepinephrine is synthesized in and released from the chromaffin cells of the adrenal medulla, the inner part of the adrenal glands located atop the kidneys.[1] From here, it enters the bloodstream and travels throughout the body to act on distant target tissues.[25]

The biosynthesis pathway begins with the amino acid tyrosine, which is converted to dopamine. Dopamine is then hydroxylated by the enzyme dopamine beta-hydroxylase to form norepinephrine.[2] In the adrenal medulla, a further step can occur where the enzyme phenylethanolamine-N-methyl transferase (PNMT) methylates norepinephrine to form epinephrine (adrenaline).[21]

Physiological Functions

Norepinephrine is a principal mediator of the body's response to stress and plays a key role in maintaining physiological homeostasis.

The "Fight-or-Flight" Response

Norepinephrine is central to the acute stress response, also known as the "fight-or-flight" response, which prepares the body to handle perceived danger.[21] When the sympathetic nervous system is activated, norepinephrine release triggers a cascade of physiological changes:

• Cardiovascular: It increases heart rate and the force of contraction, boosting cardiac output. It also causes widespread constriction of blood vessels, which shunts blood away from non-essential areas (like the skin, causing pallor) and toward skeletal muscles, while simultaneously increasing blood pressure to ensure adequate perfusion of vital organs.[22]
• Respiratory: It contributes to the dilation of bronchioles, allowing for increased air intake.[21]
• Metabolic: It stimulates the liver to break down glycogen (glycogenolysis) and promotes the creation of new glucose (gluconeogenesis), increasing blood sugar levels to provide a rapid source of energy. It also induces the breakdown of fats (lipolysis).[21]
• Ocular: It causes pupils to dilate, allowing more light to enter the eye for enhanced visual acuity.[21]

Central Nervous System and Homeostatic Regulation

Within the central nervous system (CNS), noradrenergic neurons originating from the locus coeruleus project widely throughout the brain, influencing a range of critical functions [11]:

• Arousal and Attention: It increases alertness, arousal, focus, and attention, helping to maintain consciousness and vigilance.[22]
• Mood and Cognition: It plays a significant role in mood regulation, learning, and memory processing. Imbalances in norepinephrine levels are implicated in conditions like depression and attention-deficit/hyperactivity disorder (ADHD).[11]
• Sleep-Wake Cycle: Norepinephrine helps regulate circadian rhythms, with levels naturally rising in the morning to promote wakefulness and decreasing at night to facilitate sleep.[23]

Receptor Pharmacology and Signal Termination

Norepinephrine exerts its effects by binding to and activating adrenergic receptors (adrenoceptors) on the surface of target cells. The main types it interacts with are alpha-1 (α1​), alpha-2 (α2​), and beta-1 (β1​) receptors.[1]

• Alpha-1 Receptors: Coupled to Gq proteins. Activation leads to the formation of inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers the release of intracellular calcium stores, while DAG activates protein kinase C (PKC), collectively producing excitatory cellular effects like smooth muscle contraction.[21]
• Beta-1 Receptors: Coupled to Gs proteins. Activation stimulates adenylyl cyclase, leading to an increase in cyclic adenosine monophosphate (cAMP) levels. cAMP then activates protein kinase A (PKA), which phosphorylates various intracellular proteins, resulting in effects such as increased heart rate and contractility.[3]

The action of norepinephrine in the synapse is terminated primarily by reuptake into the presynaptic neuron via the norepinephrine transporter (NET). Once back inside the neuron, it is either repackaged into vesicles for future release or broken down by the enzyme monoamine oxidase (MAO).[21]

Critical Clarification: Distinguishing from SNRIs and other Psychiatric Medications

The shared name of the molecule creates a significant potential for conceptual confusion between the critical care drug norepinephrine (Levophed) and medications that modulate the endogenous norepinephrine system for psychiatric indications. An expert-level understanding requires a clear delineation between these two vastly different therapeutic approaches.

A common source of this confusion arises with drugs like Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), which include venlafaxine (Effexor®) and duloxetine (Cymbalta®), and Tricyclic Antidepressants (TCAs).[25] These medications are used to treat conditions like major depressive disorder, anxiety disorders, and neuropathic pain.[26] Their mechanism involves

blocking the norepinephrine transporter (NET) in the CNS. This inhibition prevents the reuptake of endogenous norepinephrine from the synapse, thereby increasing its concentration and prolonging its action on postsynaptic receptors.[26] The therapeutic goal is to subtly modulate neurotransmission over weeks to months to achieve an antidepressant or anxiolytic effect.

In stark contrast, the drug norepinephrine (Levophed) is administered as a high-dose, continuous intravenous infusion in a critical care setting.[3] Its purpose is not to modulate CNS neurotransmission but to act as a potent

exogenous agonist on peripheral α1​ and β1​ adrenergic receptors to produce immediate, powerful vasoconstriction and cardiac stimulation.[1] The goal is to rapidly reverse life-threatening hypotension within minutes.

Confusing the side effect profiles of these two classes of drugs can be dangerous. A patient taking an SNRI might experience side effects like nausea, drowsiness, or a discontinuation syndrome upon stopping the drug.[27] A patient receiving an IV norepinephrine infusion faces entirely different risks, such as severe hypertension, cardiac arrhythmias, and ischemic tissue injury.[7] A responsible monograph must therefore proactively identify and dismantle this ambiguity, ensuring that information related to CNS modulators is not misapplied to the acute care vasopressor.

Clinical Pharmacology

The clinical utility of norepinephrine is a direct consequence of its distinct pharmacodynamic and pharmacokinetic properties. Its mechanism of action defines its powerful hemodynamic effects, while its metabolic profile dictates its route and manner of administration.

Pharmacodynamics (Mechanism of Action)

Norepinephrine is a sympathomimetic amine derived from tyrosine that acts as a potent adrenergic agonist.[2] Its pharmacological effects are mediated through its binding to adrenergic receptors on various effector cells.

Receptor Agonism

The defining feature of norepinephrine's pharmacology is its receptor selectivity. It is a powerful agonist at:

• Alpha-1 (α1​) Adrenergic Receptors: Strong stimulation of these receptors, located on vascular smooth muscle, causes intense vasoconstriction of both peripheral resistance arterioles and capacitance veins. This is the primary mechanism by which norepinephrine increases systemic vascular resistance (SVR) and elevates blood pressure.[1]
• Beta-1 (β1​) Adrenergic Receptors: Potent stimulation of these receptors, located predominantly in the heart, results in positive inotropic (increased contractility) and chronotropic (increased heart rate) effects. The inotropic effect contributes to maintaining or increasing cardiac output, while the chronotropic effect is often blunted by a reflex bradycardia in response to the rise in blood pressure.[1]

Norepinephrine has minimal to no significant activity at alpha-2 (α2​) or beta-2 (β2​) receptors.[2] The lack of a methyl group on its nitrogen atom is the key structural difference that confers this receptor profile, distinguishing it from epinephrine, which has potent

β2​ activity.[11] This lack of

β2​ agonism means norepinephrine does not cause the significant vasodilation in skeletal muscle or bronchodilation seen with epinephrine.

Hemodynamic Effects

The integrated hemodynamic response to norepinephrine infusion is a combination of its receptor activities:

• Systemic Vascular Resistance (SVR): Markedly increased due to potent α1​-mediated vasoconstriction.[1]
• Blood Pressure: Both systolic and diastolic blood pressure are significantly elevated, leading to an increase in Mean Arterial Pressure (MAP).[3]
• Cardiac Output (CO): The effect on CO is variable. The positive inotropic effect from β1​ stimulation tends to increase CO. However, this can be counteracted by two factors: the profound increase in afterload (due to high SVR) which the heart must pump against, and the baroreceptor-mediated reflex bradycardia that can occur in response to the sharp rise in blood pressure. Consequently, CO may increase, remain unchanged, or even decrease.[2]
• Coronary Perfusion: Norepinephrine causes dilation of the coronary arteries via its β1​ activity, which can improve blood flow to the myocardium.[1]

Dose-Dependent Effects

The balance of norepinephrine's effects can shift depending on the infusion rate. At lower doses (e.g., <2 mcg/min), the cardiac-stimulant β1​ effects may be more prominent. As the infusion rate increases (e.g., >3 mcg/min), the powerful α1​-mediated vasoconstrictor effects tend to predominate, driving the significant increase in SVR.[2]

Pharmacokinetics (ADME)

The pharmacokinetic profile of norepinephrine is characterized by a rapid onset, short duration of action, and extensive metabolism, which collectively mandate its administration as a continuous intravenous infusion.

• Administration: Norepinephrine is administered exclusively via continuous intravenous (IV) infusion. It has poor oral bioavailability and is absorbed erratically after subcutaneous injection due to rapid metabolism by Catechol-O-methyltransferase (COMT) and Monoamine Oxidase (MAO) in the gut and liver.[1]
• Absorption (Onset of Action): The onset of action is rapid, with hemodynamic effects appearing almost immediately. Steady-state plasma concentrations are typically achieved within 5 minutes of initiating or adjusting a continuous infusion.[2]
• Distribution: The apparent volume of distribution is 8.8 L. Plasma protein binding is relatively low at approximately 25%. Norepinephrine is known to cross the placenta but does not effectively cross the blood-brain barrier, limiting its direct central nervous system effects when administered peripherally.[2]
• Metabolism: Norepinephrine is rapidly and extensively metabolized in the liver, kidneys, and other tissues by two principal enzyme systems: COMT and MAO.[2] These enzymes convert norepinephrine into inactive metabolites, primarily normetanephrine and vanillylmandelic acid (VMA).[2] This rapid degradation is responsible for its short half-life.
• Elimination (Excretion): The inactive metabolites are conjugated (primarily as sulfate and glucuronide conjugates) and excreted in the urine. Only very small amounts of norepinephrine are excreted unchanged.[2]
• Half-Life: The plasma half-life of intravenously administered norepinephrine is extremely short, estimated to be approximately 2.4 minutes.[2]

The pharmacokinetic profile, and particularly the very short half-life, is the primary determinant of norepinephrine's clinical utility and method of administration. This property is both a key advantage and a strict requirement. The advantage lies in its high degree of titratability; clinicians can make minute-to-minute adjustments to the infusion rate to precisely control a patient's blood pressure. If iatrogenic hypertension occurs, the effect can be reversed almost immediately by slowing or stopping the infusion. This contrasts sharply with drugs that have longer half-lives, which can be given as intermittent boluses but offer far less control. The corresponding requirement is that norepinephrine is unsuitable for any route other than continuous IV infusion and necessitates constant, vigilant patient monitoring in a high-acuity setting. This profile defines norepinephrine's role as a highly controllable but high-risk medication reserved for critically ill patients.

Therapeutic Applications: Clinical Efficacy and Investigational Uses

Norepinephrine is a cornerstone therapy in critical care, with well-established FDA-approved indications for managing severe hypotension. Furthermore, ongoing research is continuously exploring its utility in more nuanced clinical scenarios, expanding its application beyond traditional shock management.

FDA-Approved Indications

The U.S. Food and Drug Administration (FDA) has approved norepinephrine for the following indications, which center on the restoration of hemodynamic stability in critically ill patients:

• Acute Hypotensive States: Norepinephrine is indicated for blood pressure control in adult patients with acute, severe hypotensive states.[1] Its potent vasoconstrictor effect makes it highly effective at raising mean arterial pressure when endogenous compensatory mechanisms have failed.
• Vasodilatory Shock (Septic and Neurogenic): Norepinephrine is established as the first-line vasopressor for treating patients in vasodilatory shock states, most notably septic shock.[1] The Surviving Sepsis Campaign guidelines strongly recommend its use over other agents like dopamine, citing evidence of a survival benefit and a lower risk of adverse events, particularly tachyarrhythmias.[1] It is also a primary agent for managing the profound vasodilation seen in neurogenic shock resulting from spinal cord injury.[29]
• Adjunctive Therapy in Cardiac Arrest: It is approved as an adjunct in the management of cardiac arrest, specifically for treating the profound hypotension that may persist after return of spontaneous circulation (ROSC).[1]

Off-Label and Investigational Uses

The predictable and highly titratable nature of norepinephrine has led to its investigation and use in a variety of off-label settings.

• Cardiogenic Shock: While frequently used, the role of norepinephrine in cardiogenic shock is more complex and considered off-label.[2] The primary pathology is pump failure, and while norepinephrine can raise blood pressure to improve coronary perfusion, its potent vasoconstriction increases afterload, which can further strain the failing myocardium and increase oxygen demand. Its use is often weighed against other agents, and a recruiting Phase 4 clinical trial (NCT05168462) is currently investigating whether using lower blood pressure targets can reduce the total norepinephrine dose and improve outcomes in patients with cardiogenic shock from acute myocardial infarction.[30]
• Management of Anesthesia-Induced Hypotension: Norepinephrine is used both prophylactically and therapeutically to counteract the hypotension that frequently occurs after the administration of spinal anesthesia, particularly for cesarean deliveries. Clinical trials have evaluated its efficacy and safety in this setting, often comparing it to phenylephrine.[2]
• Hepatorenal Syndrome (HRS-AKI): In patients with cirrhosis who develop hepatorenal syndrome-acute kidney injury (HRS-AKI), norepinephrine is recognized as a therapeutic option. It is typically used as an alternative to terlipressin (where unavailable) to induce vasoconstriction and improve renal perfusion pressure.[2]

The pattern of ongoing clinical trials reveals a strategic evolution in the use of norepinephrine. Research is moving beyond its core competency of reversing systemic vasodilation and exploring its application in more specialized areas requiring precision hemodynamic control. This trend suggests a shift from using norepinephrine as a blunt instrument for global shock to a finely tuned tool for organ-specific or procedure-specific stabilization.

• Acute Ischemic Stroke: A recruiting Phase 3 trial (NCT06059144, "PROGRESS-PERE") is investigating the use of peripherally administered dilute norepinephrine to induce controlled hypertension. The hypothesis is that raising systemic blood pressure can improve perfusion through collateral vessels to ischemic brain tissue in patients with acute progressive perforating artery stroke, potentially salvaging the penumbra.[32] This represents a novel, targeted application of the drug's pressor effect for a neurological indication.
• Prevention of Peri-Intubation Cardiovascular Collapse: Another recruiting Phase 3 trial (NCT05014581) is studying the use of norepinephrine to prevent cardiovascular collapse during tracheal intubation in critically ill patients. Intubation is a high-risk procedure that can precipitate severe hypotension. This trial explores whether prophylactic vasopressor support can mitigate this transient but dangerous event.[33]
• Severe Abdominal Sepsis: A completed clinical trial (NCT01568853) included norepinephrine as part of the standard of care for hemodynamic support in a study examining complement depletion in patients with severe abdominal sepsis and digestive system fistulas, underscoring its foundational role in this patient population.[34]

This body of research highlights that the future of vasopressor therapy may lie in leveraging norepinephrine's highly controllable nature to achieve specific, localized, or time-limited hemodynamic goals, marking a new frontier in its clinical application.

Comparative Analysis with Other Vasoactive Agents

The selection of a vasopressor in a critically ill patient is a nuanced decision based on the underlying pathophysiology of the shock state, the agent's receptor profile, and its potential side effects. Norepinephrine's position as a first-line agent is best understood through a comparative analysis with other commonly used vasoactive drugs. The ideal vasopressor corrects the primary hemodynamic defect with the fewest detrimental "off-target" effects.

Norepinephrine vs. Dopamine

For decades, dopamine was a primary vasopressor for shock. However, robust evidence has led to a paradigm shift, establishing norepinephrine as the superior first-line agent in septic shock.

• Efficacy and Mortality: A landmark 2010 randomized controlled trial and subsequent meta-analyses have shown that while both drugs can effectively raise MAP, norepinephrine is associated with a lower risk of death in patients with septic shock.[4] One meta-analysis found that norepinephrine use corresponded to an 11% absolute risk reduction in mortality compared to dopamine.[5] In cardiogenic shock, the SOAP II trial's subgroup analysis also found a higher mortality risk with dopamine.[35]
• Adverse Effects: The primary reason for norepinephrine's superiority is its more favorable safety profile. Dopamine has a significantly higher propensity to cause tachyarrhythmias, including atrial fibrillation and ventricular tachycardia. One study found that dopamine nearly doubled the risk of arrhythmic events compared to norepinephrine.[29] This arrhythmogenic potential is particularly detrimental in patients who are already hemodynamically unstable.

Norepinephrine vs. Epinephrine

Epinephrine is a potent catecholamine with a different receptor profile and clinical niche.

• Receptor Profile and Mechanism: Epinephrine is a powerful agonist at α1​, β1​, and β2​ receptors. Its potent β2​ activity leads to significant bronchodilation, an effect norepinephrine lacks.[36] This makes epinephrine the undisputed first-line treatment for anaphylactic shock, where bronchospasm is a life-threatening feature.[36]
• Hemodynamic and Metabolic Effects: Compared to norepinephrine, epinephrine tends to cause a greater increase in heart rate and cardiac output. However, it is also associated with more significant metabolic disturbances, including hyperglycemia and elevated serum lactate levels.[36] This "epinephrine-induced hyperlactatemia" can complicate the clinical picture, as lactate is also a marker of tissue hypoperfusion, making it difficult to interpret.
• Clinical Context: In septic shock, epinephrine is considered a second-line agent, to be added to or substituted for norepinephrine if the target MAP is not achieved.[37] In cardiogenic shock, evidence is more cautious. The increased heart rate and myocardial oxygen consumption associated with epinephrine can be harmful to a failing heart, and some studies suggest a higher incidence of refractory shock with its use compared to norepinephrine.[6]

Norepinephrine vs. Phenylephrine

Phenylephrine is a pure alpha-agonist, which defines its distinct hemodynamic profile and limited clinical role.

• Mechanism and Hemodynamics: As a selective α1​-agonist, phenylephrine causes potent vasoconstriction with virtually no direct effect on the heart (inotropy or chronotropy).[29] The sharp rise in SVR often triggers a significant baroreceptor-mediated reflex bradycardia and a subsequent decrease in cardiac output and stroke volume.[29] In contrast, norepinephrine's intrinsic β1​ activity typically counteracts this reflex, resulting in a stable or slightly increased heart rate and better preservation of cardiac output.[44]
• Clinical Application: Due to its potential to reduce cardiac output, phenylephrine is not recommended as a first-line agent in most forms of shock, especially septic shock.[45] Its clinical niche is reserved for specific scenarios of "hyperdynamic" hypotension where tachycardia is a prominent feature (e.g., hypotensive atrial fibrillation with a rapid ventricular response) or in cases of pure vasodilation without a cardiac component, such as anesthesia-induced hypotension.[43]

Role of Adjunctive Vasopressin

Vasopressin (antidiuretic hormone) has emerged as a key second-line agent in the management of vasodilatory shock.

• Mechanism: Vasopressin causes vasoconstriction via a non-adrenergic pathway, acting on V1a receptors on vascular smooth muscle.[37] Patients in septic shock often have a relative vasopressin deficiency, making them particularly sensitive to its effects.[45]
• Clinical Role: The Surviving Sepsis Campaign guidelines recommend adding vasopressin (at a fixed low dose, typically 0.03 units/min) to norepinephrine in patients with refractory septic shock.[29] This strategy is often described as "norepinephrine-sparing," as the addition of vasopressin frequently allows for a reduction in the norepinephrine dose required to achieve the target MAP. This may mitigate the adverse effects associated with high-dose catecholamine administration, such as tachyarrhythmias and excessive vasoconstriction.[45]

Table 2: Comparative Profile of Key Vasopressors

Agent	Receptor Profile	Primary Hemodynamic Effects (SVR, CO, HR)	Recommended First-Line Indication	Major Limitations / Adverse Effects	Source(s)
Norepinephrine	α1​ > β1​ >> β2​	SVR: ↑↑↑CO: ↔ or ↑HR: ↔ or ↓ (reflex)	Septic Shock, Vasodilatory Shock	Peripheral ischemia, arrhythmias (less than dopamine), increased myocardial oxygen demand	2
Epinephrine	α1​ = β1​ = β2​	SVR: ↑↑CO: ↑↑HR: ↑↑	Anaphylactic Shock	Tachycardia, arrhythmias, hyperglycemia, increased lactate, splanchnic ischemia	36
Dopamine	Dose-dependent:D > β1​ > α1​	SVR: ↑CO: ↑HR: ↑↑	(Largely superseded by Norepinephrine)	Significant tachyarrhythmias, higher mortality in cardiogenic shock vs. norepinephrine	5
Phenylephrine	Pure α1​ agonist	SVR: ↑↑↑CO: ↓HR: ↓↓ (reflex)	Hypotension with Tachycardia	Reflex bradycardia, decreased cardiac output, splanchnic and renal vasoconstriction	29
Vasopressin	V1a, V2	SVR: ↑↑CO: ↔ or ↓HR: ↔ or ↓	Adjunct in Septic Shock	Splanchnic and digital ischemia, hyponatremia; not easily titratable	37

Note: ↑ = increase, ↓ = decrease, ↔ = variable/no change. The number of arrows indicates the relative magnitude of the effect.

Safety Profile, Risks, and Management

The safety profile of norepinephrine is a direct and logical extension of its potent pharmacology. Nearly every major risk—including ischemia, severe hypertension, extravasation necrosis, and critical drug interactions—can be traced back to its powerful α1​ and β1​ adrenergic agonism and its metabolic pathways. A thorough understanding of this mechanism-to-risk relationship is essential for anticipating, preventing, and managing its adverse effects.

Adverse Reactions

The adverse effects of norepinephrine are primarily dose-dependent and result from excessive stimulation of adrenergic receptors.

• Cardiovascular:
• Ischemic Injury: The most significant risk is ischemic injury due to potent vasoconstriction. This can manifest as decreased perfusion to vital organs (e.g., kidneys, gut) or as peripheral ischemia, potentially leading to cold extremities, cyanosis, and, in severe cases, gangrene of the digits or limbs.[1]
• Bradycardia: A common cardiovascular effect is reflex bradycardia, where the baroreceptor reflex slows the heart rate in response to the sharp increase in blood pressure.[7]
• Arrhythmias: While less arrhythmogenic than dopamine or epinephrine, norepinephrine can still induce cardiac arrhythmias, particularly at high doses or in patients with underlying heart disease or electrolyte imbalances.[15]
• Increased Myocardial Oxygen Demand: By increasing afterload (SVR), norepinephrine increases the workload of the heart, which elevates myocardial oxygen consumption. This can be detrimental in patients with coronary artery disease or cardiogenic shock.[2]
• Local Infusion Site Reaction (Extravasation): This is a medical emergency and one of the most feared complications. If the IV catheter dislodges and norepinephrine infuses into the surrounding subcutaneous tissue, its intense local vasoconstrictive action can lead to severe tissue hypoxia, ischemia, and ultimately, sloughing and necrosis of the skin and underlying tissue.[7]
• Central Nervous System: Anxiety, restlessness, and transient headache are common, likely due to the overall state of sympathetic activation and hypertension.[7]
• Respiratory: Respiratory difficulty and, in cases of fluid overload or cardiac dysfunction exacerbated by hypertension, pulmonary edema can occur.[7]

Contraindications and Precautions

While there are few absolute contraindications to the use of a life-saving drug, there are several situations where norepinephrine must be used with extreme caution or is generally contraindicated.

• Absolute Contraindications:
• Hypovolemic Hypotension: Norepinephrine should not be used to treat hypotension caused by a blood volume deficit (e.g., hemorrhage). Administering a potent vasoconstrictor in the absence of adequate intravascular volume can lead to severe visceral and peripheral vasoconstriction, poor systemic blood flow despite a "normal" blood pressure reading, and profound tissue hypoxia.[7] It should only be used as a temporary emergency measure to maintain coronary and cerebral perfusion until blood volume replacement can be completed.[7]
• Concomitant Use with Certain Anesthetics: The use of norepinephrine during anesthesia with certain halogenated agents like halothane and cyclopropane is generally considered contraindicated due to the risk of sensitizing the myocardium and precipitating severe ventricular arrhythmias (tachycardia or fibrillation).[2]
• Warnings and Precautions:
• Mesenteric or Peripheral Vascular Thrombosis: Norepinephrine should be avoided in patients with pre-existing blood clots in mesenteric or peripheral vessels (e.g., in conditions like atherosclerosis, diabetic endarteritis, Buerger's disease), as the drug-induced vasoconstriction can worsen ischemia and extend the area of infarction.[2]
• Sulfite Sensitivity: Many norepinephrine formulations contain sodium metabisulfite as a preservative. This can trigger allergic-type reactions, including anaphylaxis and severe asthmatic episodes, in susceptible individuals. This risk is higher in patients with a history of asthma.[2]
• Profound Hypoxia or Hypercarbia: These conditions can increase myocardial irritability, and the addition of norepinephrine may trigger arrhythmias.[2]
• Geriatric Patients: Elderly patients may have decreased cardiac, renal, or hepatic function and are more likely to have occlusive vascular disease. Dose selection should be cautious, starting at the low end of the range. Infusion into the veins of the leg should be avoided due to the higher risk of thrombosis.[2]

Drug-Drug Interactions

The risk of adverse events is significantly increased when norepinephrine is co-administered with drugs that interfere with its metabolism or potentiate its effects.

Table 3: Clinically Significant Drug-Drug Interactions with Norepinephrine

Mechanism of Interaction	Interacting Drug Class / Agents	Clinical Result and Management	Source(s)
Inhibition of Metabolism (MAO)	Monoamine Oxidase Inhibitors (MAOIs):e.g., phenelzine, tranylcypromine, isocarboxazid, linezolid	Blocks a primary degradation pathway, leading to a massive accumulation of norepinephrine. Results in severe, prolonged hypertension. Use with extreme caution or avoid.	2
Inhibition of Metabolism (COMT)	COMT Inhibitors:e.g., entacapone	Inhibits a key metabolic enzyme, potentially increasing norepinephrine levels and effects. Dose norepinephrine conservatively and monitor for hypertension.	9
Inhibition of Neuronal Reuptake	Tricyclic Antidepressants (TCAs):e.g., amitriptyline, imipramineSerotonin-Norepinephrine Reuptake Inhibitors (SNRIs)	Blocks the norepinephrine transporter (NET), preventing its clearance from the synapse and potentiating its pressor effects. Results in severe, prolonged hypertension. Use with extreme caution.	2
Myocardial Sensitization	Halogenated Anesthetics:e.g., halothane, cyclopropane, sevoflurane, desflurane	Increases cardiac autonomic irritability, sensitizing the myocardium to the arrhythmogenic effects of norepinephrine. Increases risk of ventricular tachycardia or fibrillation. Generally contraindicated or requires continuous cardiac monitoring.	2
Pharmacodynamic Antagonism	Alpha- and Beta-Blockers:e.g., phentolamine, metoprolol	Directly antagonize the effects of norepinephrine at its receptors. Beta-blockers can block the cardiac (β1​) effects, potentially unmasking pure vasoconstriction.	9
Pharmacodynamic Synergy	Other Sympathomimetic Agents	Additive adrenergic effects, increasing the risk of hypertension, tachycardia, and arrhythmias. Requires careful dose titration and monitoring.	1

Overdose and Toxicity Management

Overdose with norepinephrine is a direct exaggeration of its pharmacological effects.

• Signs and Symptoms of Overdose: Overdosage typically manifests as severe hypertension, which can lead to complications like intense headache, photophobia, stabbing retrosternal pain, pale skin, intense sweating, and vomiting. The cardiovascular consequences include a marked increase in peripheral resistance, a decrease in cardiac output, and a profound reflex bradycardia.[2]
• General Management of Overdose: Treatment is to immediately reduce the rate of the infusion or discontinue it temporarily. Due to norepinephrine's very short half-life, its effects will dissipate rapidly once the infusion is stopped. The patient's vital signs should be monitored continuously until they stabilize.[2]
• Management of Extravasation: This is a specific form of localized toxicity that requires immediate and specific intervention to prevent tissue death. The management strategy is a direct countermeasure to the underlying pathophysiology:

1. Stop the infusion immediately and leave the catheter in place initially to attempt aspiration of any residual drug from the tissue.[2]
2. Infiltrate the affected area as soon as possible with a solution of phentolamine, an α1​-adrenergic antagonist. The standard dose is 5 mg to 10 mg of phentolamine diluted in 10 mL to 15 mL of normal saline, administered via a fine hypodermic needle into multiple sites throughout the ischemic, blanched area.[2]
3. Phentolamine works by directly blocking the local α1​ receptors, reversing the intense vasoconstriction, restoring blood flow, and preventing necrosis. Successful treatment is indicated by a return of normal skin color and temperature (hyperemia).[9] This intervention is most effective if performed within 12 hours of the extravasation event.[2]
4. Alternative, less-established treatments include topical application of 2% nitroglycerin paste or infiltration with terbutaline.[9]

Dosage, Administration, and Monitoring

The administration of norepinephrine is a high-risk procedure that demands meticulous attention to formulation, dilution, dosing, and patient monitoring to ensure efficacy while minimizing the risk of severe adverse events.

Formulations and Brand Names

Norepinephrine is commercially available as a sterile, concentrated solution for intravenous infusion, typically as the bitartrate salt.[8]

• Brand Name: The most widely recognized brand name is Levophed®.[15]
• Formulations: It is supplied as a concentrate for injection, commonly in ampules or vials containing 1 mg/mL of norepinephrine base.[54] Premixed, ready-to-use infusion bags are also available in various concentrations, such as 4 mg in 250 mL (16 mcg/mL) or 8 mg in 250 mL (32 mcg/mL) of diluent.[16]

Preparation and Dilution

Proper preparation is critical to ensure drug stability and accurate dosing.

• Dilution is Mandatory: Norepinephrine concentrate must be diluted in a larger volume of a compatible IV fluid before administration.[19]
• Recommended Diluent: The FDA and multiple guidelines recommend diluting norepinephrine in solutions containing 5% Dextrose (e.g., D5W or D5NS). Dextrose provides protection against oxidation, which can lead to a significant loss of drug potency. Administration in 0.9% Sodium Chloride (normal saline) alone is not recommended for this reason.[3] The diluted solution should be visually inspected for particulate matter or discoloration (it should be colorless to slightly yellow) before use.[19]
• Standard Dilutions: A common standard dilution for adults is to add 4 mg of norepinephrine base (one 4 mL ampule) to 250 mL of D5W, yielding a final concentration of 16 mcg/mL.[3] For fluid-restricted patients, higher concentrations (e.g., 8 mg in 250 mL, or up to 32 mcg/mL) may be used.[3] The diluted solution is generally stable for up to 24 hours at room temperature when protected from light.[19]

Dosing Regimens

Dosing is highly individualized and must be titrated to the patient's hemodynamic response. A critical point of clarification is the distinction between norepinephrine base and norepinephrine bitartrate salt. The bitartrate salt, which is the common commercial form, is approximately half as potent as the base (e.g., 2 mg of bitartrate salt contains 1 mg of norepinephrine base).[47] Major clinical guidelines often provide dosing recommendations in terms of the base. Failure to account for this difference can lead to a

two-fold dosing error. Clinicians must confirm which formulation is being referenced by guidelines and which is being prepared for administration to prevent under- or overdosing.

Table 4: Dosing and Administration Summary for Norepinephrine

Indication	Patient Population	Initial Dose	Titration and Maintenance	Max Dose / Notes	Source(s)
Acute Hypotension / Septic Shock	Adults	8-12 mcg/minOR0.05-0.1 mcg/kg/min	Titrate every 2-5 min to achieve target MAP (typically ≥65 mmHg).Maintenance: 2-4 mcg/min.	Refractory shock may require doses up to 3.3 mcg/kg/min or higher.	3
Acute Hypotension / Shock	Pediatrics (Infants, Children)	0.05-0.1 mcg/kg/min	Titrate to desired hemodynamic effect.	Usual max: 1-2 mcg/kg/min.	3
Cardiac Arrest (Post-ROSC)	Adults	0.1-0.5 mcg/kg/min	Titrate to maintain adequate MAP.	Part of ACLS protocol.	20

Administration and Monitoring

Continuous and vigilant monitoring is the standard of care for any patient receiving a norepinephrine infusion.

• Route of Administration: Must be administered via a continuous intravenous infusion using an electronically controlled infusion pump to ensure precise and consistent delivery.[56]
• Intravenous Access:
• Central Venous Catheter (CVC): Infusion through a CVC is strongly preferred. This allows the drug to be delivered into a large central vein, enabling rapid dilution and minimizing the risk of extravasation.[61]
• Peripheral IV: Peripheral administration is sometimes used as a temporary bridge to CVC placement but carries a significant risk of extravasation. If used, a large-gauge catheter (e.g., ≥20G) should be placed in a large vein (e.g., antecubital fossa), avoiding hand, wrist, or leg veins.[7] The infusion site must be checked frequently for any signs of infiltration.
• Patient Monitoring:
• Blood Pressure: Continuous invasive arterial blood pressure monitoring via an arterial line is the gold standard and is strongly recommended for accurate, real-time assessment.[39] If non-invasive monitoring is used, blood pressure should be checked every 2 minutes during initial titration and at least every 5 minutes once the patient is stable.[3]
• Cardiac Monitoring: Continuous electrocardiogram (ECG) monitoring is mandatory to detect arrhythmias and changes in heart rate.[3]
• Perfusion Assessment: Clinicians must monitor for signs of end-organ perfusion, including urine output, mental status, skin temperature, and capillary refill. Worsening perfusion despite a "normal" MAP may indicate excessive vasoconstriction or uncorrected hypovolemia.
• Discontinuation: The infusion should never be stopped abruptly, as this can cause acute rebound hypotension. The dose must be weaned down gradually, allowing the patient's own vascular tone to recover, while closely monitoring blood pressure.[56]

Synthesis and Concluding Remarks

Norepinephrine has undergone a remarkable evolution in clinical practice, transforming from a drug once considered a "last resort" to the evidence-based, first-line vasopressor for the management of septic shock. This shift is rooted in a deeper understanding of its pharmacology—a favorable profile of potent alpha-1 vasoconstriction combined with modest beta-1 cardiac support, which effectively reverses the vasodilation of sepsis with a lower risk of tachyarrhythmias compared to older agents like dopamine.[4] Its extremely short half-life provides a high degree of titratability, allowing for precise hemodynamic control in the volatile environment of the intensive care unit.

Despite its established role, the clinical application of norepinephrine continues to evolve. The most significant area of ongoing debate is its use in cardiogenic shock. Here, the therapeutic benefit of increasing perfusion pressure must be carefully weighed against the potential harm of increasing afterload on a failing heart.[6] Current research is actively exploring strategies, such as targeting lower mean arterial pressures, to optimize this delicate balance.[30] Furthermore, emerging clinical trials are investigating novel applications for norepinephrine, moving beyond systemic shock to targeted procedural support and organ-specific perfusion strategies in conditions like acute stroke, highlighting a future focused on precision medicine.[32]

The primary challenges in norepinephrine therapy remain centered on safety. The risks of end-organ ischemia and extravasation necrosis are direct consequences of its powerful vasoconstrictive mechanism. Safe practice requires strict adherence to administration protocols, including the use of central venous catheters whenever possible and vigilant monitoring. A critical and often underappreciated patient safety issue is the potential for dosing errors arising from the confusion between norepinephrine base and bitartrate salt formulations.[47] The fact that the common commercial salt form is half as potent as the base form referenced in many guidelines creates a significant risk of underdosing. A global effort toward standardized nomenclature and clear labeling on pharmaceutical products is imperative to mitigate this risk.

In conclusion, norepinephrine is a cornerstone of modern critical care, valued for its efficacy and superior safety profile in vasodilatory shock. The future of norepinephrine therapy will likely focus not on finding a replacement, but on refining its use. This includes personalizing treatment by identifying the optimal hemodynamic targets for individual patients and shock states, clarifying the role of adjunctive therapies like vasopressin, and leveraging its unique pharmacokinetic properties for novel, organ-protective applications. Continued education and a commitment to standardized safety practices will ensure that this potent and life-saving medication is used to its greatest therapeutic potential.

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