For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
NISIDE (Sodium Nitroprusside) is a short-acting hypotensive drug. Chemically, Sodium Nitroprusside is Disodium pentacyanonitrosylferrate(2-) dihydrate. The molecular formula is Na2[Fe(CN)5NO]· 2H2O and molecular weight is 297.95.
STRUCTURAL FORMULA :
Its structural formula is :
NISIDE is a reddish brown colour powder filled in 5 ml amber tubular glass vial
Each vial contains :
Sterile Sodium Nitroprusside USP 50 mg
The principal pharmacological action of sodium nitroprusside is relaxation of vascular smooth muscle and consequent dilation of peripheral arteries and veins. Other smooth muscle (eg. 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). Dilation 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.
I.V. infusion of sodium nitroprusside produces an almost immediate reduction in blood pressure. Blood pressure begins to rise immediately when the infusion is slowed or stopped and returns to pretreatment levels within 1 - 10 minutes.
Distribution of nitroprusside in the body as well as passage across the placenta into milk, or across the blood-brain barrier has not been studied.
Sodium nitroprusside is rapidly metabolised, probably by interaction with sulphhydryl groups in the erythrocytes and tissues. Cyanogen (cyanide radical) is produced which is converted to thiocyanate in the liver by the enzyme rhodanase. A thiocyanate oxidase present
in the erythrocytes may oxidise small quantities of thiocyanate back to cyanogen. Toxic symptoms begin to appear at plasma thiocyanate concentrations of 50 - 100 mcg/ml; fatalities have been reported at concentrations of 200 mcg/ml. Sodium nitroprusside is excreted entirely as metabolites, principally thiocyanate. In animals, sodium nitroprusside metabolites are excreted mainly in urine, exhaled air, and probably in faeces. The elimination half-life of thiocyanate is 2.7 - 7 days when renal function is normal but is longer in patients with impaired renal function or hyponatraemia.
Sodium nitroprusside is indicated for :
1. Immediate reduction of blood pressure in patients with hypertensive crises. Concomitant oral antihypertensive medication should be started while the hypertensive emergency is being brought under control with sodium nitroprusside.
2. Producing controlled hypotension during anaesthesia in order to reduce bleeding in surgical procedures where surgeon and anaesthetist deem it appropriate.
3. Short term therapy of cardiac failure, to enhance cardiac output and lower myocardial oxygen requirements. Patients should be commenced on oral therapy as soon as possible.
Sodium nitroprusside is to be administered only by intravenous infusion.
NOT FOR DIRECT INJECTION.
Reconstitution can only be carried out using Glucose Intravenous Infusion. A concentrated solution of sodium nitroprusside may be prepared by dissolving 50 mg of the drug in 2 - 3 ml of Glucose Intravenous Infusion. The concentrated solution should be further diluted to 250, 500, or 1000 ml in Glucose Intravenous Infusion to provide solutions containing 200, 100 or 50 mcg/ml respectively. Nitroprusside solutions should be protected from light by promptly wrapping the containers in aluminium foil or other opaque material. Administration should be carried out at all times under close supervision. No other drug should be added to the infusion fluid for simultaneous administration with sodium nitroprusside and in hypotensive patients receiving concomitant antihypertensive medication, smaller doses of sodium nitroprusside might be required. It is recommended that the blood pressure should not be allowed to drop rapidly and that systolic pressure should not be lowered below 60 mm Hg. This can be achieved by increasing the dose slowly which should also prevent any physiological compensatory reactions resulting from the release of catecholamines and renins into the blood, which would lead to tachycardia.
The rate of administration should be adjusted to maintain the desired hypotensive effect, as determined by continuous blood pressure monitoring. In order to avoid excessive levels of cyanide and thiocyanate and lessen the possibility of a precipitous drop in blood pressure, infusion rates greater than 10 mcg/kg/min should not be used. If, at this rate, an adequate reduction of blood pressure is not obtained within 10 minutes, the administration of sodium nitroprusside should be stopped. The intravenous infusion should not be stopped suddenly as this might lead to an excessive rebound rise in blood pressure, but rather over a period of 15 - 30 minutes. In hypertensive emergencies sodium nitroprusside infusion may be continued until an alternative oral therapy can be safely introduced.
Intravenous infusion of sodium nitroprusside may be continued for several days but care must be taken to ensure that the blood cyanide concentration does not exceed 100 mcg/100 ml and that the serum cyanide concentration does not exceed 8 mcg/100 ml. If infusion is carried out for a period in excess of three days then the blood thiocyanate concentration should be checked and not exceed 100 mcg/ml.
Dosage in Adults :
In hypertensive crisis :
Dosage varies considerably between patients, hence the need for individual titration. In adults not receiving other hypotensive agents, the average dosage of sodium nitroprusside is 3 mcg/kg/min.The initial dose is normally within the range of 0.5 - 1.5 mcg/kg/min, but can then be adjusted in a stepwise fashion, e.g. in increments of 0.5 mcg/kg/min every 5 minutes, to fall between 0.5 - 8 mcg/kg/min. To maintain the blood pressure at 30 to 40 % lower than the pretreatment diastolic blood pressure levels an average of 200 mcg/min (range of 20 to 400 mcg/min) is usually sufficient. In hypertensive patients receiving concomitant antihypertensive medication, smaller doses might be required.
In heart failure :
The initial dose should be between 10 - 15 mcg/min increased every 5 - 10 minutes in increments of 10 - 15 mcg/min as necessary to the normal range of 10 - 200 mcg/min to obtain the desired response. In some patients the additive effects of a vasodilator and a potent inotropic agent may be used to advantage. If a vasodilator is used haemodynamic monitoring should be used to guide its administration. If during treatment signs of hypotension, hypoperfusion or any other adverse effects are observed the infusion rate should be reduced or administration stopped. The infusion may be continued until an alternative oral therapy can be safely introduced. The infusion therapy should not normally exceed 3 days.
In controlled hypotension during general anaesthesia :
For the induction of hypotension during anaesthesia a maximum dose of 1.5 mcg/kg/min is recommended. The intrinsic hypotensive effect of many anaesthetic agents must be remembered and all normal procedures for hypotensive techniques should be carried out.
Dosage in elderly patients :
Commence therapy with low doses since geriatric patients appear to be more sensitive to the hypotensive effects of the drug. Therefore, the drug should be administered with caution in this age group.
Dosage in children :
Dosage recommendations have not been established.
The contents of a vial of 50 mg Sodium Nitroprusside for Injection USP should be dissolved in 2 ml to 3 ml of Glucose I.V. Infusion 5 %. No other diluent should be used. Depending on the desired concentration, all of the prepared stock solution should be diluted in 500 ml to 1000 ml of Glucose I.V. Infusion B.P. 5 %.
Sodium nitroprusside tends to deteriorate in the presence of light. The solution should therefore be promptly wrapped in aluminium foil or other opaque material to protect from light. Both the stock solution and the infusion solution should be freshly prepared and any unused portion discarded. The freshly prepared solution for infusion has a very faint brownish tinge. Sodium nitroprusside in aqueous solution yields the nitroprusside ion which reacts with even minute quantities of a wide variety of organic and inorganic substances to form usually highly coloured reaction products (blue, green or dark red). Discoloured solutions or solutions in which particulate matter is visible should not be used. Once prepared, the solution should not be kept or used for longer than 24 hours, while protected from light. It is not necessary to cover the drip chamber or the tubing. The I.V. infusion of sodium nitroprusside should not be infused through ordinary I.V. apparatus regulated only by gravity. Only an infusion pump, micro-drip regulator, or any similar device that allows precise measurement of the flow rate should be used. Care should be taken to avoid extravasation.
1. Treatment of compensatory hypertension, e.g. arteriovenous shunt or coarctation of the aorta.
2. Inadequate cerebral circulation.
3. Cyanide and thiocyanate are metabolites of nitroprusside and may interfere with the metabolism of cyanocobalamin. Nitroprusside is therefore contraindicated in patients suffering from severe vitamin B12 deficiency, hepatic failure and Leber’s optic atrophy.
4. As a nitric oxide donor, sodium nitroprusside is contraindicated in patients taking phosphodiesterase inhibitors (e.g. sildenafil, tadalafil, vardenafil).
WARNINGS AND PRECAUTIONS :
SODIUM NITROPRUSSIDE IS ONLY TO BE USED AS AN INFUSION WITH STERILE 5 % GLUCOSE IN WATER. IT SHOULD NOT BE ADMINISTERED BY DIRECT INJECTION.
The principal hazards of sodium nitroprusside administration are excessive hypotension and excessive accumulation of cyanide.
Excessive Hypotension :
Sodium nitroprusside can cause precipitous decreases in blood pressure. In patients not properly monitored, these decreases can lead to irreversible ischaemic injuries or death. Sodium nitroprusside should be used only when available equipment and personnel allow blood pressure to be continuously monitored. 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 haemodynamic 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 maximise 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 Poisoning :
Except when used briefly or at low (less than 2 mcg/kg/min) infusion rates, sodium nitroprusside gives rise to important quantities of cyanide ion, which can reach toxic, potentially lethal levels. The usual dose rate is 0.5 - 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. Methaemoglobin 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 nitroprussideinduced 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 hyperoxaemia 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. Although acid-base balance and venous oxygen concentration should be monitored and may indicate cyanide toxicity, these laboratory tests provide imperfect guidance.
Pregnancy : Category C
There are no adequate or well controlled studies of sodium nitroprusside in either laboratory animals or pregnant women. It is not known whether sodium nitroprusside can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Sodium nitroprusside should be given to a pregnant woman only if clearly needed. There have been no reports on its use in the hypertension of preclampsia. Sodium nitroprusside is used in high risk situations and there may be additional hazards associated with the drug. It crosses the placenta. Short term use for control of hypertensive crises may be safe provided the maternal pH and cyanide levels are monitored.
Nursing mothers :
It is not known whether sodium nitroprusside or its metabolites are excreted into breast milk, nor whether they have a harmful effect on the newborn. Therefore, the drug is not recommended for nursing mothers, unless the expected benefits outweigh any potential risk.
INTERACTIONS AND INCOMPATIBILITIES :
The hypotensive effect of sodium nitroprusside is increased when used concomitantly with most other circulatory depressants including :
• antihypertensives (e.g. ACE inhibitors, calcium channel blockers, beta-blockers)
• general anaesthetics (e.g. halothane, enflurane)
An increase in blood pressure during sodium nitroprusside therapy occurs with pressor agents (e.g. adrenaline) which stimulate the myocardium.
Prior treatment with medications that increase blood pressure may antagonise the hypotensive effect of nitroprusside (e.g.carbenoxolone, corticosteroids, non-steroidal anti-inflammatory drugs, oestrogens).
SIDE EFFECTS :
The most important adverse reactions to sodium nitroprusside are the avoidable ones of excessive hypotension and cyanide toxicity. The adverse reactions described in this section develop less rapidly and, as it happens, less commonly.
Sodium nitroprusside infusions can cause sequestration of haemoglobin as methaemoglobin. The back-conversion process is normally rapid, and clinically significant methaemoglobinaemia (>10 %) is seen only rarely in patients receiving sodium nitroprusside. Even patients congenitally incapable of back-converting methaemoglobin should demonstrate 10 % methaemoglobinaemia only after they have received about 10 mg/kg of sodium nitroprusside, and a patient receiving sodium nitroprusside at the maximum recommended rate (10 mcg/kg/min) would take over 16 hours to reach this total accumulated dose. Methaemoglobin levels can be measured by most clinical laboratories. The diagnosis should be suspected in patients who have received >10 mg/kg of sodium nitroprusside and who exhibit
signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methaemoglobinaemic blood is described as chocolate brown, without colour change on exposure to air.
Since thiocyanate inhibits both uptake and binding of iodine, symptoms of hypothyroidism may occur.
Decreased platelet aggregation.
Raised intracranial pressure.
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.
PHARMACEUTICAL PRECAUTIONS :
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstituted solutions and prepared infusions of sodium nitroprusside should be protected from light by covering with aluminium foil or other opaque material.
Sodium nitroprusside solutions are only stable for 24 hours and the drug must be used within 24 hours of reconstitution. The solution should be protected from light by wrapping in aluminium foil or other opaque material.
Store below 25°C (77°F), protected from light and moisture.
Do not refrigerate.
SHELF LIFE :
24 months from the date of manufacture.
NISIDE is supplied as 50 mg of Sterile Sodium Nitroprusside USP in 5 ml amber glass vial.
Single vial pack.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.