Sodium Nitroprusside

Sodium nitroprusside (SNP) is a potent vasodilator that first gained FDA approval for the treatment of severe hypertension in 1974. First discovered in 1849 by Playfair, its applications in human medicine can be traced back to the early 1920s, with the first safety and efficacy data published in 1955. After an initial delay in gaining FDA approval due to difficulty in development of a chemically stable formulation, SNP gained widespread use as a fast-acting antihypertensive agent and has been used clinically for hypertensive crises, heart failure, cardiac/vascular surgery, pediatric surgery, and a variety of other acute applications. While sodium nitroprusside potential adverse effects and toxicity have led to its replacement by newer agents in some practices, it remains a useful tool in certain difficult clinical situations that require a potent, fast-acting, titratable vasodilator.[1][2]

Sodium nitroprusside has the following FDA-approved indications:[3][4][5][6][7]

• Acute hypertensive crises
• Acute decompensated heart failure
• Induction of perioperative hypotension (to reduce blood loss)

 Off-label uses for nitroprusside include:

• Hypertension in the setting of acute ischemic stroke [8]
• Afterload reduction in acute mitral regurgitation 
• Increase cardiac output in cardiogenic shock and high SVR  
• Acute preload reduction in select patients with valvular aortic stenosis [9]

Emerging applications:

• Prevention and treatment of the "no-reflow" phenomenon in the percutaneous coronary intervention [10]
• Symptomatic treatment of schizophrenia [11]

A water-soluble sodium salt, sodium nitroprusside is comprised of ferrous iron complexed with nitric oxide (NO) and five cyanide ions. Acting as a prodrug, SNP reacts with sulfhydryl groups on erythrocytes (as well as albumin and other proteins) to produce nitric oxide (NO). Upon binding to vascular smooth muscle, NO triggers intracellular cGMP-mediated activation of protein kinase G and subsequent inactivation of myosin light chains, resulting in relaxation of vascular smooth muscle. The result of this signaling cascade is peripheral vasodilation of both arteries and veins (with slightly more selectivity for veins). 

From a hemodynamic perspective, the net result is a decrease in systemic vascular resistance (afterload), ventricular filling pressures, and systemic blood pressure with an increase in cardiac output. Onset is rapid (within 2 minutes), and the duration of its hypotensive effect is roughly 10 minutes; these properties make nitroprusside useful in situations requiring an immediate reduction in preload or afterload. In contrast to nitroglycerin, nitroprusside causes a more balanced vasodilatory effect between arteries and veins.[12][13]

Nitroprusside is administered only as an IV infusion diluted in D5W (it is not suitable for direct injection). It must be protected from light at all times.[14]

Typical infusion rates range from 0.5 to 4 mcg/kg/minute which are then titrated to desired effect. Typical infusion concentrations for adults are 200 mcg/mL or 400 mcg/mL. 

The maximum infusion rate is approximately 10 mcg/kg/minute, not to be sustained for more than 10 minutes at a time. If sufficient blood pressure control has not been achieved at that point, alternative agents should be considered (e.g., clevidipine).

The half-life elimination of sodium nitroprusside in circulation is roughly 2 minutes. Once metabolized into thiocyanate, half-life elimination occurs in approximately three days; renal dysfunction can easily double or triple this figure.

SNP is ultimately excreted from the body via urine as thiocyanate. 

Adverse effects include the following:

• Cardiovascular:
  • Bradycardia
  • Tachycardia
  • Flushing
  • Palpitations
  • Severe hypotension
  • Electrocardiographic changes
  • Substernal chest pain
  • Shortness of breath
• Central Nervous System:
  • Headache
  • Dizziness
  • Increased intracranial pressure
  • Apprehension
  • Restlessness
• Dermatologic: 
  • Diaphoresis
  • Skin rash
  • Local skin irritation with erythematous streaking
• Endocrine/Metabolic:
  • Hypothyroidism
• Gastrointestinal:
  • Abdominal pain
  • Nausea
  • Vomiting/retching
• Hematologic/Oncologic:
  • Decreased platelet aggregation
  • Methemoglobinemia
• Musculoskeletal:
  • Muscle twitching 

Nitroprusside is Contraindicated in the Following Situations

• Treatment of compensatory hypertension, such as that seen with arteriovenous malformations or aortic coarctation
• SNP should not be used for inducing controlled perioperative hypotension in patients with known inadequate cerebral perfusion
• Acute heart failure with low systemic vascular resistance (e.g., septic shock)
• Leber's hereditary optic atrophy*
• Tobacco amblyopia*
• Vitamin B12 deficiency (or associated disease states)
• SNP must not be used simultaneously with phosphodiesterase inhibitors such as sildenafil, tadalafil, or Vardenafil (due to synergistic cGMP-mediated mechanism of action)
• Known hypersensitivity to nitroprusside or any component of the formulation 

*These patients are deficient in rhodanese. (rhodanese, also known as rhodanase, thiosulfate cyanide transsulfurase, thiosulfate sulfurtransferase, and thiosulfate thiotransferase, is a mitochondrial enzyme that detoxifies cyanide by converting it to thiocyanate).

Precautions

• Before use for controlled perioperative hypotension, correct any underlying hypovolemia and/or anemia (if possible) 
• Use extreme caution in the setting of acute myocardial infarction in consideration of SNP's potent hemodynamic effects and potential for inducing coronary steal
• In the setting of hepatic impairment, use extreme caution; monitor closely for cyanide toxicity 
• In the setting of renal dysfunction, use the lowest possible dose and monitor closely for thiocyanate toxicity

Additional Considerations

Pregnancy Category C

• Although there is only limited information regarding the use of SNP in pregnancy, there have been animal studies that demonstrate its ability to cross the placental barrier, causing a dose-dependent increase in fetal cyanide levels. 

Breastfeeding Considerations

• While it is unclear if SNP is present in breast milk, the potential for serious adverse reactions in the infant warrant either discontinuation of breastfeeding or discontinuation of SNP depending on the clinical scenario.