Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2019 Publisher: Pfizer New Zealand Limited, P O Box 3998, Auckland, New Zealand, 1140, Toll Free Number: 0800 736 363
The principal pharmacological action of sodium nitroprusside is relaxation of vascular smooth muscle and consequent dilation 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). 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.
In normotensive subjects, acute reduction of mean arterial pressure to 60 to 75 mmHg 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 mmHg.
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 anaesthetics.
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 rate 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 non-resistant patients, cyanide levels did not correlate with tachyphylaxis. The mechanism of tachyphylaxis to sodium nitroprusside remains unknown.
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 haemoglobin (Hgb), and sodium nitroprusside’s resulting circulatory half life is about 2 minutes.
The products of the nitroprusside/haemoglobin reaction are cyanmethaemoglobin (cyanmet Hgb) andcyanide ion (CN-). Safe use of sodium nitroprusside injection must be guided by knowledge of the further metabolism of these products. The essential features of nitroprusside metabolism are:
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 methaemoglobin (metHgb) and in mitochondrial cytochromes. When CNis infused or generated within the bloodstream, essentially all of it is bound to methaemoglobin until intraerythrocytic methaemoglobin 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 utilising anaerobic pathways, but they thereby generate an increasing body burden of lactic acid. Other cells may be unable to utilise these alternate pathways, and they may die hypoxic deaths.
CNlevels in packed erythrocytes are typically less than 1 micromol/L (less than 25 microgram/L); levels are roughly doubled in heavy smokers.
At healthy steady state, most people have less than 1% of their haemoglobin in the form of methaemoglobin. Nitroprusside metabolism can lead to methaemoglobin formation (a) through dissociation of cyanmethaemoglobin 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 methaemoglobinaemia.
At physiologic methaemoglobin levels, the CNbinding capacity of packed red cells is a little less than 200 micromol/L (5 milligram/L). Cytochrome toxicity is seen at levels only slightly higher, and death has been reported at levels from 300 to 3000 micromol/L (8 to 80 milligram/L). Put another way, a patient with a normal red cell mass (35 mL/kg) and normal methaemoglobin levels can buffer about 175 microgram/kg of CN-, corresponding to a little less than 500 microgram/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 2.8.1.1), 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 betamercaptopyruvate. Physiological levels of thiosulfate are typically about 0.1 millimol/L (11 milligram/L), but they are approximately twice this level in children and in adults 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 CNto SCNgenerally proceeds at about 1 microgram/kg/min. This rate of CNclearance corresponds to steady state processing of a sodium nitroprusside infusion of slightly more than 2 microgram/kg/min. CNbegins 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 micromol/L (3 to 15 milligram/L). Clearance of SCNis primarily renal, with a half life of about 3 days. In renal failure, the half life can be doubled or tripled.
The mutagenic potential of sodium nitroprusside has not been assessed.
Sodium nitroprusside has not undergone adequate carcinogenicity testing in animals.
Sodium nitroprusside has not been tested for effects on fertility.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
