Sodium Nitroprusside

Sodium Nitroprusside is an Antihypertensive agent belonging to Vasodilator class..

Sodium Nitroprusside is approved for the treatment of acute hypertension, to induce controlled hypotension to decrease postoperative bleeding, and to manage the acute heart failure.

Sodium Nitroprusside is rapidly metabolised to cyanide in red blood cells and smooth muscle, leading to release of nitric oxide. Cyanide is further metabolised hepatically to thiocyanate and excreted in the form of urine. Plasma half-life of thiocyanate is about 3 days.

The common side effects associated with Sodium Nitroprusside include Nausea, retching, apprehension, headache, restlessness, muscle twitching, retrosternal discomfort; palpitation, dizziness, abdominal discomfort., etc.

Sodium Nitroprusside is available in the form of dosage forms such as injection solution.

Sodium Nitroprusside is available in USA, India, Russia, Europe.

Sodium Nitroprusside, belonging to Vasodilator, acts as an antihypertensive agent. Sodium Nitroprusside acts directly on the venous and arteriolar smooth muscle causing peripheral vasodilation, thus decreasing peripheral resistance. It is also used to reduce preload and afterload in severe heart failure.

Sodium nitroprusside is a water-soluble salt 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 onset of action of Sodium Nitroprusside is immediate, and its effect may last 3 to 5 minutes after discontinuing the infusion.

The Duration of Action for Sodium Nitroprusside is within 2 minutes.

• Sodium Nitroprusside is available in the form of injection solution.

To be administered by intravenous infusion only after dilution with appropriate diluents. Sodium Nitroprusside should be infused into a large vein whenever possible, preferably with an infusion syringe pump system. Special care should be given to the perfusion rate in order to avoid inadvertent boluses.

Sodium Nitroprusside is approved for the treatment of acute hypertension, to induce controlled hypotension to decrease postoperative bleeding, and to manage the acute heart failure.

Sodium Nitroprusside is approved for use in the following clinical indications:

• Acute hypertensive crises :

Adult: For patients not receiving any antihypertensives, initially 0.3-1.5 mcg/kg/min, adjust gradually according to response. Usual range: 0.5-6 mcg/kg/min. Lower doses should be used in patients receiving antihypertensives. Max rate: 8 mcg/kg/min, discontinue infusion if there is no response after 10 minutes. May continue for a few hours if there is response. Introduce oral antihypertensive as soon as possible.

Elderly: Lower doses may be required.

• Acute decompensated heart failure:

Adult: Initially 10-15 mcg/min, may increase by 10-15 mcg/min every 5-10 min according to response. Usual dose range: 10-200 mcg/min. Max: 280 mcg/min.

• Induction of perioperative hypotension (to reduce blood loss)

Adult: Recommended max dose: 1.5 mcg/kg/min.

• Although not approved there have been certain off label indication documented for Sodium Nitroprusside which includes:
• Hypertension in the setting of acute ischemic stroke
• 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

The dosage and duration of the treatment should be as per the clinical judgment of the treating physician

Sodium Nitroprusside is available in various dosage strength : 50 mg; 25 mg/mL; 50 mg/100 mL-NaCl 0.9%; 10 mg/50 mL-NaCl 0.9%; 20 mg/100 mL-NaCl 0.9%

Sodium Nitroprusside is available in the form of injection solution.

Sodium Nitroprusside is approved for the treatment in Shock; hemodynamic imbalance; hypertension; heart failure. It is also used in treatment of Bradycardia and Solid organ Transplant

Heart Failure: Limit sodium to no more than 2,300 mg a day (eating only 1,500 mg a day is an even more effective goal). Reduce saturated fat to no more than 6% of daily calories and total fat to 27% of daily calories.

The dietary restriction should be individualized as per the patient requirements.

Sodium Nitroprusside is approved for the treatment in Shock; hemodynamic imbalance; hypertension; heart failure. It is also used in treatment of Bradycardia and Solid organ Transplant

Heart Failure: Limit sodium to no more than 2,300 mg a day (eating only 1,500 mg a day is an even more effective goal). Reduce saturated fat to no more than 6% of daily calories and total fat to 27% of daily calories.

The dietary restriction should be individualized as per the patient requirements.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

The principal hazards of sodium nitroprusside administration are excessive hypotension and excessive accumulation of cyanide

• Excessive Hypotension

Small transient excesses in the infusion rate of sodium nitroprusside can result in the excessive hypotension, sometimes to levels so low as to compromise the perfusion of vital organs. These hemodynamic changes may lead to a variety of associated symptoms, Nitroprusside-induced hypotension will be self-limited within 1-10 minutes after discontinuation of the nitroprusside infusion; during these few minutes, it may be helpful to put the patient into a head-down (Trendelenburg) position to maximize venous return. If hypotension persists more than a few minutes after discontinuation of the infusion of sodium nitroprusside. Sodium nitroprusside is not the cause, and the true cause must be sought.

• Cyanide Toxicity

sodium nitroprusside infusions at rates above 2 mcg/kg/min generate cyanide ion (CN¯) faster than the body can normally dispose of it. (When sodium thiosulfate is given, the body's capacity for CN¯ elimination is greatly increased.) Methemoglobin normally present in the body can buffer a certain amount of CN¯, but the capacity of this system is exhausted by the CN¯ produced from about 500 mcg/kg of sodium nitroprusside. This amount of sodium nitroprusside is administered in less than an hour when the drug is administered at 10 mcg/kg/min (the maximum recommended rate). Thereafter, the toxic effects of CN¯ may be rapid, serious, and even lethal.

The true rates of clinically important cyanide toxicity cannot be assessed from spontaneous reports or published data. Most patients reported to have experienced such toxicity have received relatively prolonged infusions, and the only patients whose deaths have been unequivocally attributed to nitroprusside-induced cyanide toxicity have been patients who had received nitroprusside infusions at rates (30-120 mcg/kg/min) much greater than those now recommended. Elevated cyanide levels, metabolic acidosis, and marked clinical deterioration, however, have occasionally been reported in patients who received infusions at recommended rates for only a few hours and even, in one case, for only 35 minutes. In some of these cases, infusion of sodium thiosulfate caused dramatic clinical improvement, supporting the diagnosis of cyanide toxicity.

Cyanide toxicity may manifest itself as venous hyperoxemia with bright red venous blood, as cells become unable to extract the oxygen delivered to them; metabolic (lactic) acidosis; air hunger; confusion; and death. Cyanide toxicity due to causes other than nitroprusside has been associated with angina pectoris and myocardial infarction; ataxia, seizures, and stroke; and other diffuse ischemic damage.

Hypertensive patients, and patients concomitantly receiving other antihypertensive medications, may be more sensitive to the effects of sodium nitroprusside than normal subjects.

PRECAUTIONS

General

Like other vasodilators, sodium nitroprusside can cause increases in intracranial pressure. In patients whose intracranial pressure is already elevated, sodium nitroprusside should be used only with extreme caution.

• Hepatic

Use caution when administering nitroprusside to patients with hepatic insufficiency.

• Use In Anesthesia

When sodium nitroprusside (or any other vasodilator) is used for controlled hypotension during anesthesia, the patient's capacity to compensate for anemia and hypovolemia may be diminished. If possible, pre-existing anemia and hypovolemia should be corrected prior to administration of sodium nitroprusside.

Hypotensive anesthetic techniques may also cause abnormalities of the pulmonary ventilation/perfusion ratio. Patients intolerant of these abnormalities may require a higher fraction of inspired oxygen.

Extreme caution should be exercised in patients who are especially poor surgical risks (A.S.A. Class 4 and 4E).

• Laboratory Tests

The cyanide-level assay is technically difficult, and cyanide levels in body fluids other than packed red blood cells are difficult to interpret. Cyanide toxicity will lead to lactic acidosis and venous hyperoxemia, but these findings may not be present until an hour or more after the cyanide capacity of the body's red-cell mass has been exhausted.

• Carcinogenesis, Mutagenesis, And Impairment of Fertility

Animal studies assessing sodium nitroprusside's carcinogenicity and mutagenicity have not been conducted. Similarly, sodium nitroprusside has not been tested for the effects on fertility.

Consumption of alcohol is not recommended while receiving this medicine as it may increase the risk of adverse effects and lowers the blood pressure.

Use has been associated with decreased prolactin levels in non-nursing women and in those with hyperprolactinemia; this drug may affect milk production during lactation.

Limit excessive Caffeine intake (examples: coffee, teas, colas, chocolate and some herbal supplements) while taking Sodium nitroprusside and avoid medicines containing additional Caffeine whenever possible.

Taking a high amount of Caffeine with Sodium nitroprusside can gain the risk of nausea, nervousness, palpitations, problems with sleep, rapid heartbeat, or other side effects.

The adverse reactions related to molecule Sodium Nitroprusside can be categorized as

• Common Adverse effects:

Nausea, retching, apprehension, headache, restlessness, muscle twitching, retrosternal discomfort

• Less Common adverse effects:

Fast, pounding, or irregular heartbeat or pulse, Lightheadedness, dizziness, or fainting, qhing, Unusual tiredness

• Rare adverse effects:

Cyanosis and hypothyroidism.

The clinically relevant drug interactions of Sodium nitroprusside is briefly summarized here.

• Additive effect when used with other antihypertensives. May prolong the fibrinolytic activity of alteplase.

• Risk of severe hypotension if used with phosphodiesterase inhibitors. May reduce serum digoxin levels.

Pediatric Use

Safety and effectiveness in children have not been established. Nitroprusside has been used in a limited number of pediatric patients, but such use has been inadequate to fully define proper dosage and limitations for use.

Geriatic Use

Clinical studies of Sodium Nitroprusside did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy

Overdosage of nitroprusside can be manifested as excessive hypotension or cyanide toxicity or as thiocyanate toxicity.

The acute intravenous mean lethal doses (LD50) of nitroprusside in rabbits, dogs, mice, and rats are 2.8, 5.0, 8.4, and 11.2 mg/kg, respectively.

Treatment of cyanide toxicity: Cyanide levels can be measured by many laboratories, and blood-gas studies that can detect venous hyperoxemia or acidosis are widely available. Acidosis may not appear until more than an hour after the appearance of dangerous cyanide levels , and laboratory tests should not be awaited. Reasonable suspicion of cyanide toxicity is adequate grounds for initiation of treatment.

Treatment of cyanide toxicity consists of

• Discontinuing the administration of sodium nitroprusside.
• Providing a buffer for cyanide by using sodium nitrite to convert as much hemoglobin into methemoglobin as the patient can safely tolerate; and then
• Infusing sodium thiosulfate in sufficient quantity to convert the cyanide into thiocyanate.

The necessary medications for this treatment are contained in commercially available Cyanide Antidote Kits. Alternatively, discrete stocks of medications can be used.

• Hemodialysis is ineffective in removal of cyanide, but it will eliminate most thiocyanate.
• Cyanide Antidote Kits contain both amyl nitrite and sodium nitrite for induction of methemoglobinemia. The amyl nitrite is supplied in the form of inhalant ampoules, for administration in environments where intravenous administration of sodium nitrite may be delayed. In a patient who already has a patent intravenous line, use of amyl nitrite confers no benefit that is not provided by infusion of sodium nitrite.
• Sodium nitrite is available in a 3% solution, and 4-6 mg/kg (about 0.2 mL/kg) should be injected over 2- 4 minutes. This dose can be expected to convert about 10% of the patient's hemoglobin into methemoglobin; this level of methemoglobinemia is not associated with any important hazard of its own.
• The nitrite infusion may cause transient vasodilatation and hypotension, and this hypotension must, if it occurs, be routinely managed.
• Immediately after infusion of the sodium nitrite, sodium thiosulfate should be infused. This agent is available in 10% and 25% solutions, and the recommended dose is 150-200 mg/kg: a typical adult dose is 50 mL of the 25% solution. Thiosulfate treatment of an acutely cyanide-toxic patient will raise thiocyanate levels, but not to a dangerous degree.
• The nitrite/thiosulfate regimen may be repeated, at half the original doses, after two hours.

Pharmacodynamics:

• Nitroprusside a powerful vasodilator relaxes the vascular smooth muscle and produce consequent dilatation of peripheral arteries and veins. Other smooth muscle (e.g., uterus, duodenum) is not affected. Sodium nitroprusside is more active on veins than on arteries.
• Sodium nitroprusside is further broken down in the circulation to release nitric oxide (NO), which activates guanylate cyclase in the vascular smooth muscle. This leads to increased production of intracellular cGMP, which stimulates calcium ion movement from the cytoplasm to the endoplasmic reticulum, reducing the level of available calcium ions that can bind to calmodulin. This ultimately results in vascular smooth muscle relaxation and vessel dilation.

Pharmacokinetics :

• Metabolism:

Rapidly metabolised to cyanide in red blood cells and smooth muscle, leading to release of nitric oxide.

• Excretion:

Cyanide is further metabolised hepatically to thiocyanate and excreted in the urine. Plasma half-life of thiocyanate is about 3 days.

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2. Hottinger DG, Beebe DS, et.al., Sodium nitroprusside in 2014: A clinical concepts review. Journal of anaesthesiology, clinical pharmacology. 2014 Oct;30(4):462.
3. https://www.mayoclinic.org/drugs-supplements/sodium-nitroprusside-intravenous-route/precautions/drg-20406115?p=1
4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209387s000lbl.pdf