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
In normotensive subjects, acute reduction of mean
arterial pressure to 60-75 mm Hg by infusion of sodium nitroprusside caused a
significant increase in renin activity. In the same study, ten
renovascularhypertensive patients given sodium nitroprusside had significant
increases in renin release from the involved kidney at mean arterial pressures
of 90-137 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
The products of the nitroprusside/hemoglobin reaction are
cyanmethemoglobin (cyanmetHgb) and cyanide ion (CNÂ¯). 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 CNÂ¯ 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
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 CNÂ¯ 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.
CNÂ¯ levels in packed erythrocytes are typically less than
1 μmol/L (less than 25 mcg/L); levels are roughly doubled in heavy
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
At physiologic methemoglobin levels, the CNÂ¯ binding
capacity of packed red cells is a little less than 200 μmol/L (5 mg/L).
Cytochrome toxicity is seen at levels only slightly higher, and death has been reported
at levels from 300 to 3000 μmol/L (8–80 mg/L). Put another way, a patient
with a normal redcell mass (35 mL/kg) and normal methemoglobin levels can
buffer about 175 mcg/kg of CNÂ¯, 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 (SCNÂ¯) by
thiosulfate-cyanide sulfur transferase (rhodanase, EC 18.104.22.168), 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
When thiosulfate is being supplied only by normal
physiologic mechanisms, conversion of CNÂ¯ to SCNÂ¯ generally proceeds at about 1
mcg/kg/min. This rate of CNÂ¯ clearance corresponds to steadystate processing of
a sodium nitroprusside infusion of slightly more than 2 mcg/kg/min. CNÂ¯ begins
to accumulate when sodium nitroprusside infusions exceed this rate.
Thiocyanate (SCNÂ¯) is also a normal physiological
constituent of serum, with normal levels typically in the range of 50-250
μmol/L (3-15 mg/L). Clearance of SCNÂ¯ is primarily renal, with a half-life
of about 3 days. In renal failure, the half-life can be doubled or tripled.
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.
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 3μg/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 μg/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
Table 1: Change from Baseline in MAP (mmHg) After 30
Minutes Double-Blind Infusion (Study 1)
(N = 50)
(N = 49)
(N = 53)
(N = 51)
||76 ± 11
||77 ± 15
||74 ± 12
||76 ± 12
||65 ± 13
||60 ± 15
||54 ± 12
||60 ± 18
|Change from Baseline
||-11 ± 16
|-17 ± 13
|-20 ± 16
|-17 ± 19
|Mean ± SD (95% CI)