Mechanism Of Action
Sodium nitroprusside interacts with oxyhemoglobin to
produce methemoglobin, cyanide, and nitric oxide (NO). NO then reacts with
guanylate cyclase in vascular smooth muscle to produce cGMP that reduces
intracellular calcium concentrations resulting in 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
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.
Infused sodium nitroprusside is rapidly distributed to a
volume that is approximately coextensive with the extracellular space. The drug
is cleared 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 (CNÂ¯).
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
- 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. CNÂ¯ levels in packed
erythrocytes are typically less than 1 μmol/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. Relatively large quantities of sodium
nitroprusside, however, are required to produce significant methemoglobinemia.
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). 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
Thiocyanate (SCNÂ¯) is 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. In Renal failure, the half-life
can be doubled or tripled.
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 steady-state 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.
Animal Toxicology And/Or Pharmacology
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
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 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.
Progressive tachyphylaxis to the hypotensive effects of
sodium nitroprusside has been reported in several trials and numerous case
reports. The mechanism of tachyphylaxis to sodium nitroprusside remains
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 prepubertal, 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 30minute 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
Table 2: 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
||-11 ± 16
||-17 ± 13
||-20 ± 16
||-17 ± 19
|Mean ± SD (95% CI)