SODIUM NITROPRUSSIDE- sodium nitroprusside injection, solution, concentrate
Slate Run Pharmaceuticals, LLC
Sodium Nitroprusside Injection is not suitable for direct injection. The solution must be further diluted in sterile 5% dextrose injection before infusion.
Sodium Nitroprusside can cause precipitous decreases in blood pressure (see DOSAGE AND ADMINISTRATION). In patients not properly monitored, these decreases can lead to irreversible ischemic injuries or death. Sodium nitroprusside should be used only when available equipment and personnel allow blood pressure to be continuously monitored.
Except when used briefly or at low (< 2 mcg/kg/min) infusion rates, sodium nitroprusside gives rise to important quantities of cyanide ion, which can reach toxic, potentially lethal levels (see WARNINGS). The usual dose rate is 0.5 to 10 mcg/kg/min, but infusion at the maximum dose rate should never last more than 10 minutes. If blood pressure has not been adequately controlled after 10 minutes of infusion at the maximum rate, administration of sodium nitroprusside should be terminated immediately.
Although acid-base balance and venous oxygen concentration should be monitored and may indicate cyanide toxicity, these laboratory tests provide imperfect guidance.
Sodium nitroprusside is disodium pentacyanonitrosylferrate(2-) dihydrate, a hypotensive agent
whose structural formula is
whose molecular formula is Na 2 [Fe(CN) 5 NO] • 2H 2 O, and whose molecular weight is 297.95. Dry sodium nitroprusside is a reddish-brown powder, soluble in water. In an aqueous solution infused intravenously, sodium nitroprusside is a rapid-acting vasodilator, active on both arteries and veins.
Sodium nitroprusside solution is rapidly degraded by trace contaminants, often with resulting color changes. (See DOSAGE AND ADMINISTRATION section.) The solution is also sensitive to certain wavelengths of light, and it must be protected from light in clinical use.
Sodium Nitroprusside Injection is available as:
50 mg Single Dose Vial – Each 2 mL vial contains the equivalent of 50 mg sodium nitroprusside dihydrate in sterile water for injection.
The principal pharmacological action of sodium nitroprusside is relaxation of vascular smooth muscle and 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, but this selectivity is much less marked than that of nitroglycerin. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs.
In association with the decrease in blood pressure, sodium nitroprusside administered intravenously to hypertensive and normotensive patients produces slight increases in heart rate and a variable effect on cardiac output. In hypertensive patients, moderate doses induce renal vasodilatation roughly proportional to the decrease in systemic blood pressure, so there is no appreciable change in renal blood flow or glomerular filtration rate.
In normotensive subjects, acute reduction of mean arterial pressure to 60 to 75 mm Hg by infusion of sodium nitroprusside caused a significant increase in renin activity. In the same study, ten renovascular-hypertensive patients given sodium nitroprusside had significant increases in renin release from the involved kidney at mean arterial pressures of 90 to 137 mm Hg.
The hypotensive effect of sodium nitroprusside is seen within a minute or two after the start of an adequate infusion, and it dissipates almost as rapidly after an infusion is discontinued. The effect is augmented by ganglionic blocking agents and inhaled anesthetics.
Pharmacokinetics and Metabolism: Infused sodium nitroprusside is rapidly distributed to a volume that is approximately coextensive with the extracellular space. The drug is cleared from this volume by intraerythrocytic reaction with hemoglobin (Hgb), and sodium nitroprusside’s resulting circulatory half-life is about 2 minutes.
The products of the nitroprusside/hemoglobin reaction are cyanmethemoglobin (cyanmetHgb) and cyanide ion (CN –). Safe use of sodium nitroprusside injection must be guided by knowledge of the further metabolism of these products.
As shown in the diagram below, the essential features of nitroprusside metabolism are
- one molecule of sodium nitroprusside is metabolized by combination with hemoglobin to produce one molecule of cyanmethemoglobin and four CN – ions;
- methemoglobin, obtained from hemoglobin, can sequester cyanide as cyanmethemoglobin;
- thiosulfate reacts with cyanide to produce thiocyanate;
- thiocyanate is eliminated in the urine;
- cyanide not otherwise removed binds to cytochromes; and
- cyanide is much more toxic than methemoglobin or thiocyanate.
Cyanide ion is normally found in serum; it is derived from dietary substrates and from tobacco smoke.
Cyanide binds avidly (but reversibly) to ferric ion (Fe +++), most body stores of which are found in erythrocyte methemoglobin (metHgb) and in mitochondrial cytochromes. When CN – is infused or generated within the bloodstream, essentially all of it is bound to methemoglobin until intraerythrocytic methemoglobin has been saturated.
When the Fe +++ of cytochromes is bound to cyanide, the cytochromes are unable to participate in oxidative metabolism. In this situation, cells may be able to provide for their energy needs by utilizing anaerobic pathways, but they thereby generate an increasing body burden of lactic acid. Other cells may be unable to utilize these alternative pathways, and they may die hypoxic deaths.
CN – levels in packed erythrocytes are typically less than 1 mcmol/L (less than 25 mcg/L); levels are roughly doubled in heavy smokers.
At healthy steady state, most people have less than 1% of their hemoglobin in the form of methemoglobin. Nitroprusside metabolism can lead to methemoglobin formation (a) through dissociation of cyanmethemoglobin formed in the original reaction of sodium nitroprusside with Hgb and (b) by direct oxidation of Hgb by the released nitroso group. Relatively large quantities of sodium nitroprusside, however, are required to produce significant methemoglobinemia.
At physiologic methemoglobin levels, the CN – binding capacity of packed red cells is a little less than 200 mcmol/L (5 mg/L). Cytochrome toxicity is seen at levels only slightly higher, and death has been reported at levels from 300 to 3000 mcmol/L (8 to 80 mg/L). Put another way, a patient with a normal red-cell mass (35 mL/kg) and normal methemoglobin levels can buffer about 175 mcg/kg of CN – , corresponding to a little less than 500 mcg/kg of infused sodium nitroprusside.
Some cyanide is eliminated from the body as expired hydrogen cyanide, but most is enzymatically converted to thiocyanate (SCN –) by thiosulfate-cyanide sulfur transferase (rhodanase, EC 184.108.40.206), a mitochondrial enzyme. The enzyme is normally present in great excess, so the reaction is rate-limited by the availability of sulfur donors, especially thiosulfate, cystine, and cysteine.
Thiosulfate is a normal constituent of serum, produced from cysteine by way of β-mercaptopyruvate. Physiological levels of thiosulfate are typically about 0.1 mmol/L (11 mg/L), but they are approximately twice this level in pediatric and adult patients who are not eating. Infused thiosulfate is cleared from the body (primarily by the kidneys) with a half-life of about 20 minutes.
When thiosulfate is being supplied only by normal physiologic mechanisms, conversion of CN – to SCN – generally proceeds at about 1 mcg/kg/min. This rate of CN – clearance corresponds to steady-state processing of a sodium nitroprusside infusion of slightly more than 2 mcg/kg/min. CN – begins to accumulate when sodium nitroprusside infusions exceed this rate.
Thiocyanate (SCN –) is also a normal physiological constituent of serum, with normal levels typically in the range of 50 to 250 mcmol/L (3 to 15 mg/L). Clearance of SCN – is primarily renal, with a half-life of about 3 days. In renal failure, the half-life can be doubled or tripled.
Clinical Trials: Baseline-controlled clinical trials have uniformly shown that sodium nitroprusside has a prompt hypotensive effect, at least initially, in all populations. With increasing rates of infusion, sodium nitroprusside has been able to lower blood pressure without an observed limit of effect.
Clinical trials have also shown that the hypotensive effect of sodium nitroprusside is associated with reduced blood loss in a variety of major surgical procedures.
In patients with acute congestive heart failure and increased peripheral vascular resistance, administration of sodium nitroprusside causes reductions in peripheral resistance, increases in cardiac output, and reductions in left ventricular filling pressure.
Many trials have verified the clinical significance of the metabolic pathways described above. In patients receiving unopposed infusions of sodium nitroprusside, cyanide and thiocyanate levels have increased with increasing rates of sodium nitroprusside infusion. Mild to moderate metabolic acidosis has usually accompanied higher cyanide levels, but peak base deficits have lagged behind the peak cyanide levels by an hour or more.
Progressive tachyphylaxis to the hypotensive effects of sodium nitroprusside has been reported in several trials and numerous case reports. This tachyphylaxis has frequently been attributed to concomitant cyanide toxicity, but the only evidence adduced for this assertion has been the observation that in patients treated with sodium nitroprusside and found to be resistant to its hypotensive effects, cyanide levels are often found to be elevated. In the only reported comparisons of cyanide levels in resistant and nonresistant patients, cyanide levels did not correlate with tachyphylaxis. The mechanism of tachyphylaxis to sodium nitroprusside remains unknown.
Pediatric: The effects of sodium nitroprusside to induce hypotension were evaluated in two trials in pediatric patients less than 17 years of age. In both trials, at least 50% of the patients were pre-pubertal, and about 50% of these pre-pubertal patients were less than 2 years of age, including 4 neonates. The primary efficacy variable was the mean arterial pressure (MAP).
There were 203 pediatric patients in a parallel, dose-ranging study (Study 1). During the 30 minute blinded phase, patients were randomized 1:1:1:1 to receive sodium nitroprusside 0.3, 1, 2, or 3 mcg/kg/min. The infusion rate was increased step-wise to the target dose rate (i.e., 1/3 of the full rate for the first 5 minutes, 2/3 of the full rate for the next 5 minutes, and the full dose rate for the last 20 minutes). If the investigator believed that an increase to the next higher dose rate would be unsafe, the infusion remained at the current rate for the remainder of the blinded infusion. Since there was no placebo group, the change from baseline likely overestimates the true magnitude of blood pressure effect. Nevertheless, MAP decreased 11 to 20 mmHg from baseline across the four doses (Table 1).
There were 63 pediatric patients in a long-term infusion trial (Study 2). During an open-label phase (12 to 24 hours), sodium nitroprusside was started at ≤0.3 mcg/kg/min and titrated according to the BP response. Patients were then randomized to placebo or to continuing the same dose of sodium nitroprusside. The average MAP was greater in the control group than in the sodium nitroprusside group for every time point during the blinded withdrawal phase, demonstrating that sodium nitroprusside is effective for at least 12 hours. In both studies, similar effects on MAP were seen in all age groups.
76 ± 11
77 ± 15
74 ± 12
76 ± 12
65 ± 13
60 ± 15
54 ± 12
60 ± 18
-11 ± 16
-17 ± 13
-20 ± 16
-17 ± 19
Mean ± SD (95% Cl)
Sodium nitroprusside is indicated for the immediate reduction of blood pressure of adult and pediatric patients in hypertensive crises. Concomitant longer-acting antihypertensive medication should be administered so that the duration of treatment with sodium nitroprusside can be minimized.
Sodium nitroprusside is also indicated for producing controlled hypotension in order to reduce bleeding during surgery.
Sodium nitroprusside is also indicated for the treatment of acute congestive heart failure.
Sodium nitroprusside should not be used in the treatment of compensatory hypertension, where the primary hemodynamic lesion is aortic coarctation or arteriovenous shunting.
Sodium nitroprusside should not be used to produce hypotension during surgery in patients with known inadequate cerebral circulation, or in moribund patients (A.S.A. Class 5E) coming to emergency surgery.
Patients with congenital (Leber’s) optic atrophy or with tobacco amblyopia have unusually high cyanide/thiocyanate ratios. These rare conditions are probably associated with defective or absent rhodanase, and sodium nitroprusside should be avoided in these patients.
Sodium nitroprusside should not be used for the treatment of acute congestive heart failure associated with reduced peripheral vascular resistance such as high-output heart failure that may be seen in endotoxic sepsis.
(See also the boxed warning at the beginning of this insert.)
Excessive Hypotension: Small transient excesses in the infusion rate of sodium nitroprusside can result in 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; see ADVERSE REACTIONS. Nitroprusside induced hypotension will be self-limited within 1 to 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 Injection, Sodium Nitroprusside Injection is not the cause, and the true cause must be sought.
Cyanide Toxicity: As described in CLINICAL PHARMACOLOGY above, 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, as described under DOSAGE AND ADMINISTRATION, 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 to 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.
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