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Sodium nitroprusside
Sodium nitroprusside
Sodium nitroprusside
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Sodium nitroprusside
Molecular structure of this compound (top), and a picture of a sample (bottom).
Clinical data
Trade namesNipride, Nitropress, others
Other namesSNP
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: C
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100% (intravenous)
MetabolismBy haemoglobin being converted to cyanmethaemoglobin and cyanide ions
Onset of actionnearly immediate[3]
Elimination half-life<2 minutes (3 days for thiocyanate metabolite)
Duration of action1 to 10 minutes[3]
Excretionkidney (100%; as thiocyanate)[4]
Identifiers
  • Sodium pentacyanidonitrosylferrate(III)
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.119.126 Edit this at Wikidata
Chemical and physical data
FormulaC5FeN6Na2O
Molar mass261.921 g·mol−1
3D model (JSmol)
Density1.72 g/cm3
Solubility in water100 mg/mL (20 °C)
  • [Na+].[Na+].O=N[Fe--](C#N)(C#N)(C#N)(C#N)C#N
  • InChI=1S/5CN.Fe.NO.2Na/c5*1-2;;1-2;;/q;;;;;2*-1;2*+1
  • Key:FPWUWQVZUNFZQM-UHFFFAOYSA-N

Sodium nitroprusside (SNP), sold under the brand name Nitropress among others, is a medication used to lower blood pressure.[3] This may be done if the blood pressure is very high and resulting in symptoms, in certain types of heart failure, and during surgery to decrease bleeding.[3] It is used by continuous injection into a vein.[3] Onset is nearly immediate and effects last for up to ten minutes.[3]

Common side effects include low blood pressure and cyanide toxicity.[3] Other serious side effects include methemoglobinemia.[3] It is not generally recommended during pregnancy due to concerns of side effects.[5] High doses are not recommended for more than ten minutes.[6] It works by increasing nitric oxide levels in the blood, which increases cGMP levels in cells, and causes dilation of blood vessels.[7][3]

Sodium nitroprusside was discovered as early as 1850 and found to be useful in medicine in 1928.[7][8] It is on the World Health Organization's List of Essential Medicines.[9][10] Sodium nitroprusside is light sensitive, so it needs to be shielded from light to prevent degradation.[11] It is available as a generic medication.[12]

Medical uses

[edit]

Sodium nitroprusside is intravenously infused in cases of acute hypertensive crises.[13][14] Its effects are usually seen within a few minutes.[4]

Nitric oxide reduces both total peripheral resistance and venous return, thus decreasing both preload and afterload. So, it can be used in severe congestive heart failure where this combination of effects can act to increase cardiac output. In situations where cardiac output is normal, the effect is to reduce blood pressure.[13][15] It is sometimes also used to induce hypotension (to reduce bleeding) for surgical procedures (for which it is also FDA, TGA, and MHRA labelled).[13][14][16]

The medication is extremely beneficial for use in medical patients because the effects of the medication will directly stop the second that it stops being infused. This is due to the metabolism of the drug, and the rapid inactivation to thiocyanate once conversion of the drug stops.

This compound has also been used as a treatment for aortic valve stenosis,[17] oesophageal varices,[18] myocardial infarction,[19] pulmonary hypertension,[20][21][22] respiratory distress syndrome in the newborn,[23][24] shock,[24] and ergot toxicity.[25]

Contraindications

[edit]

Sodium nitroprusside should not be used for compensatory hypertension (e.g. due to an arteriovenous stent or coarctation of the aorta).[15] It should not be used in patients with inadequate cerebral circulation or in patients who are near death. It should not be used in patients with vitamin B12 deficiency, anaemia, severe renal disease, or hypovolaemia.[15] Patients with conditions associated with a higher cyanide/thiocyanate ratio (e.g. congenital (Leber's) optic atrophy, tobacco amblyopia) should only be treated with sodium nitroprusside with great caution.[15] Its use in patients with acute congestive heart failure associated with reduced peripheral resistance is also not recommended.[15] Its use in hepatically impaired individuals is also not recommended, as is its use in cases of pre-existing hypothyroidism.[13]

Its use in pregnant women is advised against, although the available evidence suggests it may be safe, provided maternal pH and cyanide levels are closely monitored.[15][26] Some evidence suggests sodium nitroprusside use in critically ill children may be safe, even without monitoring of cyanide level.[27]

Adverse effects

[edit]

Adverse effects by incidence and severity[13][15][28]

Common

Unknown frequency

  • Nausea
  • Retching
  • Anxiety
  • Chest discomfort
  • Paraesthesial warmth
  • Abdominal pain
  • Orthostatic hypotension
  • ECG changes
  • Skin irritation
  • Flushing
  • Injection site erythema
  • Injection site streaking

Serious

Overdose

[edit]

Due to its cyanogenic nature, overdose may be particularly dangerous. Treatment of sodium nitroprusside overdose includes the following:[15][29]

  • Discontinuing sodium nitroprusside administration
  • Buffering the cyanide by using sodium nitrite to convert haemoglobin to methaemoglobin as much as the patient can safely tolerate
  • Infusing sodium thiosulfate to convert the cyanide to thiocyanate.

Haemodialysis is ineffective for removing cyanide from the body but it can be used to remove most of the thiocyanate produced from the above procedure.[15]

Toxicology

[edit]

The cyanide can be detoxified by reaction with a sulfur-donor such as thiosulfate, catalysed by the enzyme rhodanese.[30] In the absence of sufficient thiosulfate, cyanide ions can quickly reach toxic levels.[30] Hydroxocobalamin can be administered to reduce the risk of thiocyanate toxicity induced by nitroprusside.[31]

Species LD50 (mg/kg) for oral administration[32] LD50 (mg/kg) for IV administration[15] LD50 (mg/kg) for skin administration[32]
Mouse 43 8.4 ?
Rat 300 11.2 >2000
Rabbit ? 2.8 ?
Dog ? 5 ?

Interactions

[edit]

The only known drug interactions are pharmacodynamic in nature, that is it is possible for other antihypertensive drugs to reduce the threshold for dangerous hypotensive effects to be seen.[15]

Mechanism of action

[edit]

As a result of its breakdown to nitric oxide (NO), sodium nitroprusside has potent vasodilating effects on arterioles and venules (arterial more than venous), whereas other nitrates exhibit more selectivity for veins (e.g., nitroglycerin).[13][15][28][33]

Sodium nitroprusside breaks down in circulation to release nitric oxide (NO).[7] It does this by binding to oxyhaemoglobin to release cyanide, methaemoglobin and nitric oxide.[7] NO activates guanylate cyclase in vascular smooth muscle and increases intracellular production of cGMP. cGMP activates protein kinase G which activates phosphatases which inactivate myosin light chains.[34] Myosin light chains are involved in smooth muscle contraction. The result is vascular smooth muscle relaxation, which allow vessels to dilate.[34] This mechanism is similar to that of phosphodiesterase 5 (PDE5) inhibitors such as sildenafil (Viagra) and tadalafil (Cialis), which elevate cGMP concentration by inhibiting its degradation by PDE5.[35]

A role for NO in various common psychiatric disorders including schizophrenia,[36][37][38][39] bipolar disorder[40][41][42] and major depressive disorder[43][44][45] has been proposed and supported by several clinical findings. These findings may also implicate the potential of drugs that alter NO signalling such as SNP in their treatment.[38][44] Such a role is also supported by the findings of the recent SNP clinical trial.[46]

Structure and properties

[edit]
Structure of sodium nitroprusside in the solid state, obtained by neutron diffraction
Space filling model of sodium nitroprusside

Nitroprusside is an inorganic compound with the chemical formula Na2[Fe(CN)5NO], usually encountered as the dihydrate, Na2[Fe(CN)5NO]·2H2O.[47] This red-colored sodium salt dissolves in water or ethanol to give solutions containing the free complex dianion [Fe(CN)5NO]2−.

Nitroprusside is a complex anion that features an octahedral iron(II) centre surrounded by five tightly bound cyanide ligands and one linear nitric oxide ligand (Fe-N-O angle = 176.2°[48]). The anion possesses idealized C4vsymmetry.

Due to the linear Fe-N-O angle, the relatively short N-O distance of 113 pm[48] and the relatively high stretching frequency of 1947 cm−1, the complex is formulated as containing an NO+ ligand.[49] Consequently, iron is assigned an oxidation state of +2. The iron center has a diamagnetic low-spin d6 electron configuration, although a paramagnetic long-lived metastable state has been observed by EPR spectroscopy.[50]

The chemical reactions of sodium nitroprusside are mainly associated with the NO ligand.[51] For example, addition of S2− ion to [Fe(CN)5(NO)]2− produces the violet colour [Fe(CN)5(NOS)]4− ion, which is the basis for a sensitive test for S2− ions. An analogous reaction also exists with OH− ions, giving [Fe(CN)5(NO2)]4−.[49] Roussin's red salt (K2[Fe2S2(NO)4]) and Roussin's black salt (NaFe4S3(NO)7) are related iron nitrosyl complexes. The former was first prepared by treating nitroprusside with sulfur.[52]

Preparation

[edit]

Sodium nitroprusside can be synthesized by digesting a solution of potassium ferrocyanide in water with nitric acid, followed by neutralization with sodium carbonate:[53]

K4[Fe(CN)6] + 6 HNO3 → H2[Fe(CN)5(NO)] + CO2 + NH4NO3 + 4 KNO3
H2[Fe(CN)5NO] + Na2CO3 → Na2[Fe(CN)5(NO)] + CO2 + H2O

Alternatively, the nitrosyl ligand can be introduced using nitrite:[49]

[Fe(CN)6]4− + H2O + NO−2 → [Fe(CN)5(NO)]2− + CN− + 2 HO−

History

[edit]

Sodium nitroprusside is primarily used as a vasodilator. It was first used in human medicine in 1928.[7] By 1955, data on its safety during short-term use in people with severe hypertension had become available.[7] Despite this, due to difficulties in its chemical preparation, it was not finally approved by the US FDA until 1974 for the treatment of severe hypertension.[7] By 1993, its popularity had grown such that total sales in the US had totalled US$2 million.[7]

Other uses

[edit]
Sodium nitroprusside spectrum is used to calibrate Mössbauer spectrometers

Sodium nitroprusside is often used as a reference compound for the calibration of Mössbauer spectrometers.[54] Sodium nitroprusside crystals are also of interest for optical storage. For this application, sodium nitroprusside can be reversibly promoted to a metastable excited state by blue-green light, and de-excited by heat or red light.[55]

In physiology research, sodium nitroprusside is frequently used to test endothelium-independent vasodilation. Iontophoresis, for example, allows local administration of the drug, preventing the systemic effects listed above but still inducing local microvascular vasodilation. Sodium nitroprusside is also used in microbiology, where it has been linked with the dispersal of Pseudomonas aeruginosa biofilms by acting as a nitric oxide donor.[56][57]

Analytical reagent

[edit]

Sodium nitroprusside is also used as an analytical reagent under the name sodium nitroferricyanide for the detection of methyl ketones, amines, and thiols. It is also used as a catalyst in the quantitative determination of ammonia in water samples via the phenate method.[58]

Ketones

[edit]

The nitroprusside reaction is used for the identification of ketones in urine testing.[59] Sodium nitroprusside was found to give a reaction with acetone or creatine under basic conditions in 1882. Rothera refined this method by the use of ammonia in place of sodium or potassium hydroxide. The reaction was now specific for methyl ketones. Addition of ammonium salts (e.g. ammonium sulfate) improved the sensitivity of the test, too.[60]

In this test, known as Rothera's test, methyl ketones (CH3C(=O)-) under alkaline conditions give bright red coloration (see also iodoform test). Rothera's test was initially applied to detecting ketonuria (a symptom of diabetes) in urine samples. This reaction is now exploited in the form of urine test strips (e.g. "Ketostix").[61]

Thiols and cysteine

[edit]

The nitroprusside reaction is a chemical test used to detect the presence of thiol groups of cysteine in proteins. Proteins with the free thiol group give a red colour when added to a solution of sodium nitroprusside in aqueous ammonia. Some proteins test positive when denatured, indicating that thiol groups are liberated.[62][63][64]

Sodium nitroprusside is used in a separate urinalysis test known as the cyanide nitroprusside test or Brand's test. In this test, sodium cyanide is added first to urine and let stand for about 10 minutes. In this time, disulfide bonds will be broken by the released cyanide. The destruction of disulfide bonds liberates cysteine from cystine as well as homocysteine from homocystine. Next, sodium nitroprusside is added to the solution and it reacts with the newly freed sulfhydryl groups. The test will turn a red/purple colour if the test is positive, indicating significant amounts of amino acids were in the urine (aminoaciduria). Cysteine, cystine, homocysteine, and homocystine all react when present in the urine when this test is performed. This test can indicate inborn errors of amino acid transporters such as cystinuria, which results from pathology in the transport of dibasic amino acids.[65]

Amines

[edit]

Sodium nitroprusside is also used to detect amines, including those in illicit drugs. This compound is thus used as a stain to indicate amines in thin layer chromatography.[66] Sodium nitroprusside is similarly used as a presumptive test for the presence of alkaloids (amine-containing natural products) common in illicit substances.[67] The test, called Simon's test, is performed by adding 1 volume of a solution of sodium nitroprusside and acetaldehyde in deionized water to a suspected drug, followed by the addition of 2 volumes of an aqueous sodium carbonate solution. The test turns blue for some secondary amines. The most common secondary amines encountered in forensic chemistry include 3,4-methylenedioxymethamphetamine (MDMA, the main component in ecstasy) and phenethylamines such as methamphetamine. Sodium nitroprusside is also useful in the identification the mercaptans (thiol groups) in the nitroprusside reaction.

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Sodium nitroprusside

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from Grokipedia
Sodium nitroprusside is an inorganic with the Na₂[Fe(CN)₅NO], consisting of the nitroprusside anion [Fe(CN)₅NO]²⁻ and two sodium cations. It appears as a dark red to reddish-brown crystalline powder or solid, with a molecular weight of 261.92 g/mol for the form and 297.95 g/mol for the common dihydrate Na₂[Fe(CN)₅NO]·2H₂O. First synthesized in , it is highly soluble in water and decomposes upon heating, releasing and ions. As a potent vasodilator, sodium nitroprusside acts by releasing (NO), which activates in vascular cells, increasing (cGMP) levels and leading to relaxation of both arterial and venous . This results in rapid reduction of through balanced , making it suitable for intravenous administration in acute settings. Approved by the FDA in 1974, it is primarily indicated for the treatment of hypertensive crises, controlled during to reduce surgical bleeding, and when other agents are unsuitable. Despite its efficacy, sodium nitroprusside carries significant risks due to its metabolism into and , which can accumulate and cause with prolonged or high-dose use, particularly in patients with renal impairment. Common adverse effects include , , , and muscle twitching, while severe complications may involve , , or (which can be fatal) with cumulative doses exceeding approximately 3-7 mg/kg, particularly with prolonged . Its short of approximately 2 minutes necessitates continuous and close hemodynamic monitoring, often with co-administration of to mitigate buildup. Beyond , it has historical uses as a for detecting sulfhydryl groups and in .

Structure and properties

Molecular structure

Sodium nitroprusside has the Na₂[Fe(CN)₅NO], typically encountered as the dihydrate Na₂[Fe(CN)₅NO]·2H₂O. The [Fe(CN)₅NO]²⁻ anion consists of a central iron atom octahedrally coordinated by five (CN⁻) ligands in the equatorial plane and one axial nitrosyl (NO) ligand, resulting in approximate C_{4v} for the complex . The formal of iron is +2, with the nitrosyl considered as NO⁺; however, structures involving Fe(III) and NO⁻ (or even NO⁰) contribute to the electronic description of the complex. In the solid state, the dihydrate crystallizes in the orthorhombic Pnnm, with lattice parameters a ≈ 6.17 , b ≈ 11.84 , and c ≈ 15.43 . The molecular structure is confirmed through vibrational spectroscopy, particularly , which reveals characteristic stretching frequencies for the ligands: multiple CN stretches at approximately 2161, 2158, and 2144 cm⁻¹, and the NO stretch at around 1947 cm⁻¹.

Physical properties

Sodium nitroprusside is typically obtained as a reddish-brown or ruby-red crystalline solid. The compound is odorless in its solid form, though aqueous solutions may develop a characteristic smell from minor decomposition products. Its molecular formula is Na₂[Fe(CN)₅NO]·2H₂O, corresponding to a molecular weight of 297.95 g/mol. The density of sodium nitroprusside dihydrate is approximately 1.72 g/cm³ at 20°C. The dihydrate loses its upon heating above approximately 100 °C, while the compound decomposes without melting above 300 °C. Sodium nitroprusside exhibits high in water, dissolving up to approximately 40 g per 100 mL at 20°C to form a clear solution, with slow decomposition occurring in the process. It is slightly soluble in (about 1.1 g per 100 mL at 25°C) and insoluble in non-polar solvents such as hydrocarbons.

Stability and reactivity

Sodium nitroprusside exhibits significant sensitivity, undergoing rapid photodecomposition in aqueous solutions upon exposure to white or blue light, which leads to the release of (NO) and ions (CN⁻). This degradation process is wavelength-dependent, with minimal effect from , and occurs at similar rates in , saline, or glucose solutions under daylight or UV illumination. The compound's stability is also influenced by pH and ; it remains relatively stable in acidic conditions but decomposes more readily in alkaline media, with NO release being most pronounced at 5.0 and decreasing toward 7.2. At , freshly prepared solutions are stable for up to 24 hours when protected from , though exposure accelerates breakdown, resulting in color changes indicative of . Autoclaving in neutral or alkaline solutions can cause spectral shifts and pH alterations, but addition of stabilizers like improves thermal stability. Decomposition of sodium nitroprusside yields (NO), ions (CN⁻), ferricyanide, and ferrocyanide as primary products, with the process often producing a blue haze or odor in acidic, light-exposed solutions. These products arise from the breakdown of the [Fe(CN)₅NO]²⁻ complex, particularly under photolytic or hydrolytic conditions. Sodium nitroprusside reacts with thiols and reducing agents to form colored complexes, a property exploited in for detecting sulfhydryl groups in compounds like , where a violet or red-purple color develops. This reactivity involves coordination to the iron center, facilitating NO release and complex formation suitable for spectrophotometric assays. Due to its and tendency for moisture-induced degradation, sodium nitroprusside must be stored as a dry powder in airtight containers, protected from light, often in vials or original packaging, at under desiccated conditions to maintain stability for at least one year.

Preparation

Laboratory synthesis

Sodium nitroprusside is commonly synthesized in the by digesting a solution of in with , followed by neutralization and . The process involves oxidation and substitution to replace one with a nitrosyl group. The simplified reaction is: \ceNa4[Fe(CN)6]+HNO3−>Na2[Fe(CN)5NO]+byproducts\ce{Na4[Fe(CN)6] + HNO3 -> Na2[Fe(CN)5NO] + byproducts} This generates byproducts such as , , , and , requiring careful handling under a . A typical procedure, adapted from early methods, begins with dissolving (e.g., 60 g of the potassium salt analog) in and adding diluted concentrated (specific gravity 1.42). The mixture is evaporated on a bath until the reaction completes, indicated by no color with ferrous sulfate test. The solution is cooled, nitrates are crystallized and filtered off, and the filtrate is neutralized with . The solution is then evaporated to half volume, cooled slowly to precipitate ruby-red crystals of sodium nitroprusside dihydrate, which are collected by filtration. Purification is achieved by recrystallization from hot : the crude product is dissolved in minimal boiling water, filtered hot, and the filtrate slowly cooled to yield pure crystals, washed with cold water, and dried in vacuo. Laboratory yields are typically around 25-30% based on , with purity >98% after recrystallization, confirmed by deep red color and . An alternative laboratory route involves preparing the pentacyanoaquoferrate(II) complex, Na3[Fe(CN)5H2O], from or iron salts and , followed by reaction with gas to incorporate the nitrosyl . This method is useful for isotopic studies but requires NO gas handling and yields 50-70%. Purification follows recrystallization from water.

Commercial production

Commercial production of sodium nitroprusside relies on a modified synthesis process derived from methods, scaled up for pharmaceutical-grade to ensure high purity and safety. The primary industrial approach involves reacting with concentrated at controlled temperatures (65-75°C) to form an intermediate nitroprusside, followed by reaction with to yield copper nitroprusside, and final conversion to sodium nitroprusside using with pH adjustment to 5-7 via glacial acetic acid, culminating in purification through , , and to isolate red crystals. This batch process achieves a total yield exceeding 83% and purity of at least 99.6%, meeting pharmacopoeial standards for bulk drug substances. Production occurs in kilogram-scale batches to supply pharmaceutical demands, with example processes starting from 1000 g of , scalable for broader industrial output. Environmental considerations are paramount due to the cyanide-containing precursors, necessitating rigorous protocols, including neutralization of effluents and efforts to minimize hazardous byproducts through process optimizations and principles.

Medical uses

Indications

Sodium nitroprusside is primarily indicated for the immediate reduction of in adult and pediatric patients experiencing acute hypertensive crises, where rapid control is essential to prevent organ damage. The drug received FDA approval in 1974 for this indication, based on its established role in swiftly lowering through balanced arterial and venous . Clinical trials, including comparative studies against other antihypertensives like urapidil, have demonstrated its efficacy in achieving target reductions, with rapid onset suitable for settings. Secondary approved uses include the induction and maintenance of controlled during surgical procedures in adults and children to reduce intraoperative , particularly in and other high-risk operations. It is also indicated for acute with concomitant , where it decreases preload and to improve and alleviate pulmonary congestion. A landmark multicenter trial showed that sodium nitroprusside markedly enhances left ventricular function in decompensated patients with severe systolic dysfunction and severe , leading to significant hemodynamic improvements. Off-label applications include management of , especially type B, to control and limit dissection propagation, often in combination with beta-blockers. It is also employed for perioperative in to stabilize and minimize vascular stress. In pediatric populations, including neonates and infants, it is used for hypertensive crises, with administration tailored to age-specific physiological needs for safe modulation. Its use in pediatric hypertensive crises is supported by clinical experience and studies establishing efficacy similar to adults, though close monitoring is required.

Administration and dosing

Sodium nitroprusside is administered exclusively via intravenous infusion and is not suitable for oral, intramuscular, or subcutaneous use. It is available as a sterile solution in vials, typically containing 50 mg of sodium nitroprusside in 2 mL or 5 mL, or as ready-to-use formulations such as 10 mg/50 mL (0.2 mg/mL), 20 mg/100 mL (0.2 mg/mL), or 50 mg/100 mL (0.5 mg/mL) in 0.9% sodium chloride. For preparation, the concentrated solution must be diluted prior to infusion in 5% dextrose injection or isotonic saline to concentrations of 50–400 mcg/mL, using an infusion pump for precise control; ready-to-use formulations require no further dilution but must be inspected for particulates or discoloration. All preparations must be protected from light by wrapping in aluminum foil or an opaque cover, as exposure leads to decomposition, and diluted solutions should be used within 24 hours. In adults, dosing typically begins at an initial rate of 0.3 mcg/kg/min, titrated upward in increments every few minutes based on blood pressure response, with a usual effective range of 0.5–4 mcg/kg/min and a maximum of 10 mcg/kg/min not exceeding 10 minutes to minimize toxicity risks. For patients with renal impairment (e.g., eGFR <30 mL/min/1.73 m²), the rate should be limited to less than 3 mcg/kg/min, and in anuric patients, to 1 mcg/kg/min. Pediatric dosing follows similar guidelines to adults, starting at 0.3 mcg/kg/min or less and titrating to effect, with a maximum of 10 mcg/kg/min for short durations; however, conservative ranges of 0.25–5 mcg/kg/min are often employed, particularly for prolonged infusions, due to heightened risk of cyanide accumulation. Close monitoring is essential in children to prevent toxicity. Administration requires continuous monitoring of arterial blood pressure in a controlled setting, such as an intensive care unit, using an intra-arterial catheter; infusion should not be initiated without such capabilities, and the drug must be discontinued gradually to avoid rebound hypertension.

Pharmacology

Mechanism of action

Sodium nitroprusside functions as a nitric oxide (NO) donor, releasing NO specifically upon reduction within vascular smooth muscle cells. This process involves the nitroprusside ion undergoing enzymatic or non-enzymatic reduction by physiological reductants, such as sulfhydryl groups, leading to NO liberation. A simplified representation of the NO release reaction is: [\ceFe(CN)5NO]2−+reductant→[\ceFe(CN)5H2O]2−+\ceNO[\ce{Fe(CN)_5NO}]^{2-} + \text{reductant} \to [\ce{Fe(CN)_5H_2O}]^{2-} + \ce{NO} The released NO diffuses into adjacent vascular smooth muscle cells, where it binds to the heme moiety of soluble guanylate cyclase, activating the enzyme. This activation stimulates the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), thereby elevating intracellular cGMP concentrations. Increased cGMP levels activate cGMP-dependent protein kinase (PKG), which phosphorylates and activates myosin light chain phosphatase, leading to dephosphorylation of myosin light chain. PKG also inhibits myosin light chain kinase activity. This cascade results in decreased intracellular calcium sensitivity and smooth muscle relaxation. The vasodilatory effects of sodium nitroprusside occur directly on both arterial and venous smooth muscle, leading to balanced dilation that reduces both preload (via venodilation) and afterload (via arteriolar dilation). It exhibits a preferential action on arteriolar resistance vessels, which potently lowers systemic vascular resistance and blood pressure.

Pharmacokinetics

Sodium nitroprusside is administered exclusively via intravenous infusion and is not absorbed through gastrointestinal or other routes, resulting in an immediate onset of action within seconds of infusion initiation. Following infusion, sodium nitroprusside rapidly distributes throughout the extracellular fluid, with a volume of distribution approximately 0.25 L/kg, and it crosses the placental barrier in pregnant individuals. The compound undergoes non-enzymatic metabolism in the blood and tissues, primarily reacting with sulfhydryl groups on hemoglobin, erythrocytes, and plasma proteins to release nitric oxide and cyanide ions; the cyanide is subsequently detoxified by the enzyme rhodanese (thiosulfate sulfurtransferase) to form thiocyanate using thiosulfate as a sulfur donor. The plasma half-life of the parent compound is approximately 2 minutes due to its rapid decomposition, while the half-life of the thiocyanate metabolite ranges from 2 to 3 days in individuals with normal renal function. Thiocyanate is primarily excreted unchanged in the urine via renal clearance, necessitating monitoring of thiocyanate levels and potential dose adjustments in patients with renal impairment to prevent accumulation. Prolonged infusion of sodium nitroprusside, particularly at rates exceeding 2 mcg/kg/min for more than 48 hours, can lead to cyanide accumulation due to saturation of detoxification pathways, increasing the risk of toxicity.

Adverse effects

Common adverse effects

Sodium nitroprusside, as a potent vasodilator, commonly causes cardiovascular adverse effects during therapeutic infusion. The most frequent is hypotension, often resulting from an overshoot beyond the intended blood pressure reduction, which requires close monitoring to prevent complications. Reflex tachycardia frequently accompanies this hypotension as a compensatory mechanism to maintain cardiac output. Flushing and palpitations are also reported in patients receiving the drug. Gastrointestinal side effects, including nausea, vomiting, and abdominal pain, can occur, particularly with rapid changes in blood pressure during infusion initiation or adjustment. These symptoms are typically transient and resolve with dose modification. Neurological effects such as headache, dizziness, and muscle twitching are observed, often linked to the drug's impact on cerebral blood flow and systemic hemodynamics. Apprehension and restlessness may also arise in some cases. Dermatological reactions include sweating (diaphoresis) and irritation at the infusion site, sometimes presenting as erythematous streaking along the vein. These local effects are generally mild and related to the intravenous administration route. Management of these common adverse effects involves careful dose titration, starting at low infusion rates (e.g., 0.3–0.5 mcg/kg/min) and adjusting based on continuous arterial blood pressure monitoring. Supportive measures, such as slowing or temporarily halting the infusion for hypotension or related symptoms, and positioning the patient in the Trendelenburg position if needed, help mitigate risks. Intensive hemodynamic monitoring is essential throughout therapy.

Contraindications and interactions

Sodium nitroprusside is contraindicated in patients with hypersensitivity to the drug or any of its components. It is also absolutely contraindicated in compensatory hypertension, such as that associated with arteriovenous shunts or coarctation of the aorta, as well as in acute heart failure with reduced peripheral vascular resistance, including conditions like endotoxic sepsis. Furthermore, it is contraindicated in individuals with Leber's hereditary optic atrophy or tobacco amblyopia, conditions characterized by defective rhodanese activity that impairs cyanide detoxification. Concomitant use with phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) or soluble guanylate cyclase stimulators (e.g., riociguat) is also contraindicated due to risk of profound hypotension. Relative contraindications include renal or hepatic impairment, where the drug's metabolism to cyanide and thiocyanate may accumulate, necessitating careful monitoring. Hypothyroidism warrants caution, as thiocyanate ions can inhibit thyroidal uptake of iodine and exacerbate the condition. Drug interactions with sodium nitroprusside primarily involve additive effects leading to excessive hypotension when combined with other vasodilators, such as nitroglycerin. A key disease interaction exists with Leber's hereditary optic atrophy, where sodium nitroprusside's cyanide metabolite can worsen optic nerve damage due to underlying rhodanese deficiency. Precautions include avoiding use during pregnancy (FDA Pregnancy Category C), as the drug crosses the placenta and may elevate fetal cyanide levels, with benefits weighed against risks only in life-threatening situations. In all cases, awareness of cyanide metabolism pathways is critical, as impaired detoxification heightens toxicity risks across these contraindications and interactions.

Overdose and toxicity

Overdose of sodium nitroprusside primarily manifests as severe hypotension, which can lead to inadequate perfusion of vital organs, metabolic acidosis, and tachyphylaxis (diminished hypotensive response due to accumulating metabolites). Cyanide poisoning from nitroprusside metabolism presents with symptoms including coma, seizures, lactic acidosis, bradycardia, and confusion. Methemoglobinemia may also occur, particularly after total doses exceeding 10 mg/kg, impairing oxygen delivery and presenting with cyanosis or chocolate-brown blood; levels >10% are clinically significant. In cases of chronic or prolonged infusion, particularly in patients with renal impairment, thiocyanate toxicity may develop, leading to fatigue, confusion, and hypothyroidism due to inhibition of iodine uptake by the thyroid gland. Early symptoms of thiocyanate toxicity may appear at serum levels around 35-100 mcg/mL (3.5-10 mg/dL), with severe toxicity at >100 mcg/mL (10 mg/dL). Diagnosis of overdose involves clinical assessment and laboratory confirmation. Severe and are evaluated via arterial blood gas analysis, revealing elevated lactate and anion gap . Plasma levels exceeding 1 mcg/mL (1 mg/L) indicate significant toxicity and are associated with , while whole-blood levels above 0.5 mg/L are elevated. levels should be checked if suspected, with >10-30% warranting treatment. toxicity is confirmed by serum levels greater than 10 mg/dL (100 mcg/mL), with early symptoms appearing at lower thresholds around 35 mcg/mL. Treatment requires immediate discontinuation of the infusion to halt further metabolite accumulation. For cyanide toxicity, administer (to convert to ) or (which binds to form , excreted renally); supportive measures include oxygen and hemodynamic stabilization. For , (1-2 mg/kg IV) is the if levels >30%. toxicity is managed supportively, with recommended for severe cases or renal failure to enhance elimination. For prolonged infusions (>2 mcg/kg/min or >48 hours), co-administration of (typically at a 10:1 ratio to nitroprusside) is recommended to mitigate accumulation. The estimated from rapid intravenous bolus is approximately 2-3 mg/kg in humans, based on animal LD50 values (e.g., 2.8 mg/kg in rabbits) and clinical reports of fatal overdoses.

Other uses

Analytical applications

Sodium nitroprusside serves as a versatile in qualitative chemical analysis, particularly for detecting carbonyl compounds, sulfur-containing groups, and amines through characteristic color developments in alkaline media. A freshly prepared 5% of sodium nitroprusside is commonly employed due to its instability in light and air, with color formation typically occurring within seconds to minutes, offering sensitivity in the range of 1-5 mg/dL for targeted analytes. In the detection of ketones, sodium nitroprusside is integral to Rothera's test, where methyl ketones such as acetone and react in ammoniacal conditions to form a purple-colored complex. The procedure involves saturating a sample (e.g., 5 mL of solution) with , adding a crystal or 0.75 g of sodium nitroprusside, and overlaying with concentrated ammonium hydroxide; a pink-to-purple ring at the interface indicates the presence of ketones at concentrations above 10-20 mg/dL for acetone. This test is specific for methyl ketones and does not react with aldehydes, providing a qualitative distinction in organic analysis. For thiols and , the nitroprusside test exploits the reaction of free sulfhydryl (-SH) groups to produce a violet or red-colored thio-nitroprusside complex. The standard procedure entails adding 0.5 mL of 2-5% sodium nitroprusside solution to 2 mL of the sample, followed by 0.5 mL of concentrated ; a red color develops immediately or upon brief heating if -SH groups are present at levels as low as 0.1-1 μmol. This method is widely used as an indicator for free sulfhydryl residues in proteins, where the reagent selectively binds to accessible cysteine residues without interfering with disulfide bonds. Sodium nitroprusside also facilitates the detection of primary amines under conditions, yielding a -colored complex attributable to the formation of an imine-like intermediate. In the procedure, a sample is treated with 5% sodium nitroprusside solution and (e.g., NaOH), resulting in a hue for aliphatic and aromatic primary amines at levels; secondary amines may produce a similar but less intense color in modified tests. This application extends to qualitative screening in organic synthesis and forensic analysis. Additionally, sodium nitroprusside is employed in qualitative tests for , where ions (S²⁻) react to form a violet sodium thio-nitroprusside complex. The test involves adding a few drops of dilute (0.1-1%) freshly prepared sodium nitroprusside solution to an acidified sample; immediate violet coloration confirms at concentrations above 0.01 M, distinguishing them from other species like sulfites, which yield a transient pale red. This reagent's reactivity underscores its utility in environmental and industrial sample analysis for compounds.

Research and emerging applications

Sodium nitroprusside serves as a (NO) donor in various cell studies, where it is employed to induce and nitrosative stress in vascular and endothelial cells. For instance, exposure to sodium nitroprusside at concentrations around 10⁻⁴ M promotes NO-mediated relaxation in arterioles by inhibiting β₂-adrenergic receptor internalization and enhancing low-dose potency, while also generating that mimic oxidative conditions. These applications leverage its controlled NO release to probe signaling pathways, such as G activation in cells. In psychiatric research, low-dose intravenous infusions of sodium nitroprusside have been investigated as an adjunctive therapy for , targeting NO modulation to alleviate symptoms. Randomized controlled trials, including double-blind studies up to 2025, administered doses of 0.5 μg/kg/min over 4 hours, showing reductions in Ndel1 oligopeptidase activity and improvements in (PANSS) and Brief Psychiatric Rating Scale (BPRS) scores in some patients. A 2023 meta-analysis of six trials indicated no overall significant symptom relief compared to , though individual studies and subsequent 2024-2025 reviews suggest potential benefits in positive symptoms via NO-mediated . These efforts represent phase II-level explorations, with ongoing assessments of biomarkers like Ndel1 for treatment response. In , sodium nitroprusside is applied exogenously to investigate NO signaling in responses, particularly and tolerance. Treatments at micromolar concentrations (e.g., 100–300 μM) enhance antioxidant enzyme activity, reduce accumulation, and modulate nitrosative pathways in crops like and , improving and water retention under stress. It acts as a priming agent, preconditioning to better withstand environmental challenges by upregulating genes involved in NO-mediated defense, as seen in 2025 studies on salt-stressed tomato seedlings and salinity-tolerant fig transplants. This research highlights NO's role in integrating hormonal signals, such as , for stress adaptation. Emerging applications in include sodium nitroprusside's role in photochromic compounds and catalytic precursors. As a photochromic material, it undergoes light-induced of the upon (350–580 nm), forming metastable states reversible at low temperatures, which enables applications in and optical switching devices; 2024 studies further elucidated the electronic structure of these isomers. In catalysis, it serves as a precursor for nitroprussides, facilitating photocatalytic reactions and exhibiting photoswitchable ionic conduction or magnetic properties in hybrid materials. Despite these investigational uses, research on sodium nitroprusside remains predominantly preclinical, with human applications constrained by risks including accumulation and . Clinical trials, such as those for , report good tolerability at low doses but highlight the need for monitoring to avoid adverse effects, limiting broader translation to therapeutic or industrial scales.

History

Discovery and early preparation

Sodium nitroprusside, also known as sodium nitroferricyanide, was first prepared in 1849 by the chemist Lyon Playfair during his investigations into the action of on (yellow prusside of potassium). Playfair's work revealed that digesting a solution of with produced a new class of compounds termed nitroprussides, characterized by the incorporation of a nitrosyl group into the structure. This synthesis involved the oxidation and rearrangement of the ferrocyanide ion, yielding the deep red crystalline sodium salt after neutralization and isolation. Early observations highlighted the compound's distinctive reactivity, particularly its tendency to produce vivid color changes in reactions with various substances. For instance, solutions of sodium nitroprusside reacted with alkaline sulfides to form a or coloration, a phenomenon first noted by chemists like Gmelin and Mercer in related experiments and confirmed in Playfair's memoir. These color shifts were attributed to the formation of transient complexes involving the nitrosyl and ligands, making the salt a promising candidate for qualitative analysis. By the 1870s, sodium nitroprusside had gained recognition as an analytical reagent due to its sensitivity in detecting sulfur-containing compounds. In the late 19th and early 20th centuries, it was further employed in qualitative tests for sulfhydryl groups, producing a characteristic violet hue with thiols such as , as developed by Mörner in 1899, which facilitated its adoption in early chemical assays for organic functional groups. This utility stemmed from the compound's ability to undergo reactions that amplified subtle differences in reactant structures through observable spectral changes.

Development as a pharmaceutical

Early interest in sodium nitroprusside (SNP) as a therapeutic agent emerged in the , following reports of its hypotensive effects in . The compound's vasodilatory properties were first noted in experimental settings, leading to its inaugural clinical use reported by Johnson in 1929 for blood pressure management. Widespread adoption was limited by toxicity concerns until the mid-20th century. Clinical introduction of SNP occurred in the 1950s in , where it was employed for treating severe . Pivotal studies in 1955 established its safety and efficacy for intravenous administration in hypertensive crises, marking a shift from experimental to therapeutic use. In the United States, regulatory hurdles delayed approval until 1974, when the FDA authorized it under the brand name Nitropress for acute hypertensive emergencies. Key milestones in the included clinical trials demonstrating SNP's utility in inducing controlled during to minimize blood loss. Reports from that decade, such as those by Neill and Nixon in 1965, highlighted its rapid onset and reversibility in operative settings like hip arthroplasty. The 1970s brought recognition of associated risks, with case reports from 1970 onward documenting toxicity from prolonged or high-dose infusions, prompting guidelines for monitoring and co-administration of antidotes like . SNP became available as a generic in the 1980s following patent expiration of the original formulation, broadening access beyond branded products. It was included on the World Health Organization's Model List of for hypertensive treatment, affirming its role in global critical care. As of 2025, SNP remains a standard vasodilator for acute and perioperative control, though alternatives like have gained traction due to shorter half-lives and reduced risks.

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