Clinical Pharmacokinetics 9: 239-251 (1984)

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Clinical Pharmacokinetics of Nitroprusside, Cyanide,

Thiosulphate and Thiocyanate
V. Schulz
University Medical Clinic, Cologne

Summary

Sodium nitroprusside decomposes within a few minutes after intravenous infusion to

form metabolites which are pharmacologically inactive but toxicologically important. Free
cyanide, which represents 44% w/w of the sodium nitroprusside molar mass, is formed
and must be detoxified in the body into thiocyanate using thiosulphate as substrate.
Nitroprusside penetrates cell membranes slowly. At therapeutic dose levels its distribution is probably mainly extracellular. Contact with the suljhydryi groups in the cell
walls, however, immediately initiates breakdown of the molecule. Sodium nitroprusside
taken orally is not absorbed from the gastrointestinal tract to any appreciable extent.
Cyanides in the body form prussic acid, which can rapidly penetrate mucous and cell
membranes. In the blood, about 99% of the prussic acid binds to the methaemoglobin of
erythrocytes. At normal physiological levels, however, the total body methaemoglobin of
an adult human can only bind about JOmg of prussic acid; this is a small fraction of the
amounts usually in/used therapeutically as sodium nitroprujside.
The endogenous detoxification ofprussic acid exhibits zero-order kinetics. The limiting
factor is a sulphur donor, principally thiosulphate, which is available in the body in only
limited amounts. The rate of spontaneous detoxification of prussic acid in humans is only
about J I1g/kg/min, corresponding to a sodium nitroprusside in/usion of about 2 I1g/kg/
min. This dose limit set by the prussic acid toxicity of sodium nitroprusside can, however,
be increased considerably by simultaneous infusion ofthiosulphate. A lack ofthiosulphate
can be detected early by a rise of the prussic acid concentration in the erythrocytes.
Thiosulphate taken orally is not absorbed by the body. After intravenous in/usion, its
serum half-life is about 15 minutes. Most of the thiosulphate is oxidised to sulphate or is
incorporated into endogenous sulphur compounds; a small proportion is excreted through
the kidneys.
Thiocyanate taken orally is completely absorbed by the body. In healthy persons its
volume of distribution is approximately 0.25 L/kg and the serum half-life about 3 days;
elimination is mainly renal. Thiocyanate toxicity does not represent a serious therapeutic
problem with intravenous infusion of sodium nitroprusside.

Sodium nitroprusside has been used as an antihypertensive agent by intravenous infusion since
the mid-1950s (Page et aI., 1955). Since 1979 it has
been classified by the World Health Organization
as an 'essential drug' (WHO Expert Committee,
1979).

Sodium nitroprusside is an inorganic complex compound with the empirical formula

Na2[Fe(CN)sNO]2H20. The CN- radical represents 44% by weight of the molecule. This cyanide
is completely released in the bloodstream (Ivankovich et aI., 1978; Kreye, 1980), producing non-

240

Clinical Pharmacokinetics of Nitroprusside

ionised prussic acid (pK = 9.3) which is responsible for the acute toxicity of sodium nitroprusside.
This toxicity is proven not only by numerous animal experiments, but also by reported cases of sodium nitroprusside poisoning in humans (Davies et
al.. 1975; Greiss et al., 1976; Hill, 1942; Humphrey
and Nash. 1978; Jack, 1974; Lazarus-Barlow and
Norman, 1941; MacRae and Owen, 1974; Mellino
and Phillips, 1980; Merrifield and Blundell, 1974;
Montoliu et al., 1979; Peleg et aL, 1979; Posner et
aI., 1977; Schulz and Roth, 1982).
The endogenous detoxification of prussic acid
in the body occurs by means of the mitochondrial
enzyme rhodanese (thiosulphate: cyanide sulphur
transferase, EC 2.8.1.1). Prussic acid is converted
by thiosulphate into thiocyanate, which is less toxic
by a factor of around 100. This enzyme is p),esent
in the body in large excess relative to its substrates.
This gives a reaction with zero-order kinetics, the
limiting factor normally being the thiosulphate,
which is present in only limited amounts (Baumeister et aL, 1975; Himwich and Saunders, 1948;
Lang, 1933; Mintel and Westley, 1966; Saunders
and Himwich, 1950). Consequently, the margin of
safety for sodium nitroprusside could be decisively
increased hy simultaneous intravenous infusion of
sodium thiosulphate (Pasch et aL, 1983; Schulz et
aI., 1982). The metabolite resulting from the primary detoxification of prussic acid, thiocyanate, produces intoxication only occasionally, e.g. where
sodium nitroprusside is infused for several days
(Schulz et al., 1979b).
For safe therapeutic use of sodium nitroprusside. the pharmacokinetics of nitroprusside, prussic acid, thiosulphate and thiocyanate are all equally
important. and are reviewed here in this context.

1. Pharmacokinetics of Nitroprusside
1.1 Analytical Methods
Two methods have been reported for quantitative determination of nitroprusside in blood or
plasma: Habel and Raithelhuber (1976) used 14C_
nitroprusside; and Rodkey and Collison (1977) determined the prussic acid concentration photometrically before and after incubation of samples

with cysteine. [The cysteine causes CN- to be

quantitatively released from nitroprusside.] Both
these authors were able to detect nitroprusside for
only short periods in the plasma of rats and baboons when extremely high doses, in relation to
the animals' bodyweight, were infused. At doses
which would correspond to those used therapeutically in man, the only evidence for the presence
of sodium nitroprusside in animal blood was the
intensity and duration of the antihypertensive action (Habel and Raithelhuber, 1976).
1.2 Absorption
Page et al. (1955) administered oral doses of
sodium nitroprusside to 16 hypertensive patients
for periods ranging from 6 weeks to 2 years. When
doses of 30 to 60mg were taken 4 times a day, in
no case was there any immediate lowering of blood
pressure. Relatively small effects were apparent only
after several weeks; however, the magnitude of the
blood pressure-lowering effect corresponded to the
demonstrated thiocyanate concentrations in serum.
It may be concluded from these data that no appreciable amounts of unchanged sodium nitroprusside are absorbed from the gastrointestinal
tract, but that prussic acid, released from it as the
preliminary stage towards forming thiocyanate, is
probably absorbed. Suicides aftp,r oral ingestion of
sodium nitroprusside showed the same clinical
course as for prussic acid poisoning (Hill, 1942; Lazarus-Barlow and Norman, 1941; Peleg et al., 1979).
1.3 Distribution
Smith and Kruszyna (1974) found that the
breakdown of nitroprusside, which is accelerated
considerably by contact with sulfhydryl groups of
haemoglobin (Hill, 1942), occurred up to 10 times
more rapidly with erythrocyte haemolysate than
with intact erythrocytes. This was interpreted as an
indication of the low permeability of nitroprusside
through the erythrocyte membrane.
Three to 5 minutes after intravenous infusion
of 14C-nitroprusside to rats, the radioactivity in the
blood was almost exclusively in the serum portion.

Clinical Pharmacokinetics of Nitroprusside

The radioactivity in the serum was then higher by

a factor of 10 to 20 than in the animals' organ tissues (Hbbel and Raithelhuber, 1976).
Rodkey and Collison (1977) demonstrated by
chemical methods (see section 1.1) that the nitroprusside in blood is almost wholly in the plasma,
with scarcely any at all present in blood cells. These
results suggest that nitroprusside, at least at therapeutic concentrations, is a mainly extracellular and
intravascular ion. Its distribution volume in the
body is approximately the same as the extracellular
space (Kreye and Reske, 1982).
1.4 Breakdown of Nitroprusside
In Vitro and In Vivo
The stability of sodium nitroprusside in aqueous
solution has been reviewed by Van Loenen and
Hofs-Kemper (1979), and its breakdown in vivo has
been reviewed by Ivankovich et al. (1978) and
Kreye (1980).
Aqueous solutions of sodium nitroprusside can
be stored, under exclusion of light, for long periods
without loss of efficacy (Schulz et aI., 1982; Van
Loenen and Hofs-Kemper, 1979). Homogenates of
animal tissue added to sodium nitroprusside solutions caused rapid, non-enzymatic breakdown
(Hill, 1942). The breakdown of sodium nitroprusside in aqueous solution was also found to be accelerated by adding sulfhydryl compounds such as
cysteine (Page et a!., 1955; Rodkey and Collison,
1977), glutathione or ascorbic acid (Nakamura et
a!., 1977).
Smith and Kruszyna (1974) suggested that in the
blood, an electron is transferred from haemoglobin
to the nitroprusside molecule, resulting in the formation of an unstable nitroprusside radical which
then immediately dissociates into its ionic components. The breakdown of nitroprusside after incubation with erythrocytes in vitro is, however,
many times slower [Smith and Kruszyna (1974)
found that approximately 10% of the applied dose
decomposed after I hour] than after intravenous
infusion in vivo. Habel et a!. (1976), for example,
found a biological half-life of about 2 minutes for
nitroprusside at 'therapeutic' concentrations in rats,

241

which is in agreement with the short duration of

efficacy of the drug when used clinically as an antihypertensive agent. Against this, uncritical adoption of the breakdown time in vitro as being
applicable to in vivo conditions has recently contributed to a serious error of judgement regarding
the acute toxicity of sodium nitroprusside (Bisset
et a!., 1981; Smith et a!., 1982).
After intravenous infusion, the breakdown of
nitroprusside probably occurs mainly in the bloodstream and in the extracellular space (Kreye and
Reske, 1982). The breakdown of the molecule is
probably initiated by a reduction reaction. It is
thought that contact between nitroprusside and
membrane bound sulfhydryl groups of the vascular
wall, and to a lesser extent also between nitroprusside and blood cells, has a triggering function
(Ivankovich et aI., 1978; Kreye, 1980). The fact that
the effects of nitroprusside after intravenous infusion are very rapidly reversible would then be
attributable to an equally short lifetime for the
complex molecule in the circulation.

2. Pharmacokinetics of Cyanide and

Prussic Acid
2.1 Analytical Methods
Quantitative determinations are reliably made
only by first separating the prussic acid from the
blood. Direct measurement in blood using selective electrodes (Bisset et aI., 1981; Blaedel et aI.,
1971) has not to date provided adequate accuracy
or sensitivity (Kistner et aI., 1979).
Prussic acid is isolated by microdistillation or
by distilling it over in a stream of gas (Aldridge,
1944; Asmus and Garschagen, 1953; Bruce et aI.,
1955; Epstein, 1947; Gettler and Bain, 1938; Ohkawa et aI., 1972; Rodkey and Collison, 1977), or
by microdiffusion (Feldstein and Klendshoj, 1954;
Pettigrew and Fell, 1973). In both methods the
blood specimen is acidified, and the escaping prussic acid is quantitatively absorbed in an alkaline
solution. The cyanide thus isolated is usually then
converted, using chloramine T, into cyanogen
chloride which, using pyridine and pyrazolones
(Epstein, 1947) or barbiturates (Asmus and Gar-

Clinical Pharmacokinetics of Nitroprusside

242

schagen, 1953), forms polymethine dyes whose extinction is measured photometrically. The lower
detection limit in blood of prussic acid by this
method is around 1 ~mol/L. Compared with this
conventional method of isolating cyanide and
measuring it as a dye, neither fluorometry (Morgan
and Way, 1980; Takanashi and Tamura, 1970) nor
the abovementioned electric potential method show
any practical advantages (Kistner et aI., 1979).
Practical difficulties are caused by the volatility
of prussic acid from blood specimens. Our experience shows that for this reason, the analysis is
best performed on erythrocyte sediment from the
specimen (see section 2.3). By adding small quantities of methaemoglobin promoters, the erythrocyte samples can be stored for several days, though
the concentration in this case falls at a rate of 5 to
10% per day. Measurement of the 'freely diffusible'
prussic acid in blood plasma can be theoretically
justified (Kreye, 1980; Vesey et aI., 1976), but in
practice can only be performed relatively inaccurately because of the extremely low concentration
and the high volatility.

20

fl\
\
\

18

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~

..=.

16
14

. 12

8
'0
'2

8
6

g
II>
en

0..

!\
\

10

1/\

1\

'{:r' ~ I--..

"'- ~

l---

10 20 30

Time (minutes)

60

90

Fig. 1. Prussic acid concentrations in the erythrocytes after oral

intake of potassium cyanide 3mg (0-0), 6mg (A-A) or
12mg (e-e) [after Schulz et aI., 1983].

2.2 Absorption
Liquid prussic acid diffuses not only through
mucous membranes but also through the skin.
Gaseous prussic acid can also be absorbed by inhalation (Anderson et aI., 1978).
Sodium or potassium cyanides in the acidic gastric juices release prussic acid, which is immediately absorbed through the mucous membrane of
the stomach. On taking alkaline cyanides orally with
suicidal intent, subjects become unconscious within
a few minutes (Daunderer et aI., 1974; Hillman et
aI., 1974; Naughton, 1974). On taking 3 to 12mg
of potassium cyanide in a self-administered experiment (Schulz et aI., 1983), the maximum concentrations of prussic acid in the blood were reached
after 10 to 20 minutes (fig. 1). However, the release
and absorption of prussic acid from sodium nitroprusside in the stomach and intestine appear to occur at a much slower rate (Page et ai., 1955).
2.3 Distribution and Blood Concentrations
A complete analysis of the body distribution in
3 poisoned human cadavers showed about 50% of
the absorbed prussic acid to be in the blood, about
25% in muscles, and the remaining 25% in all the
other organs together, predominantly in the liver
and the brain (Gettler and Bain, 1938). Similar patterns of distribution of prussic acid in the body can
be inferred from data in poisoned humans (Ansell
and Lewis, 1970) and animals (H6bel and Raithelhuber, 1976; Michenfelder, 1977; Simpson et al.,
1979) reported by other authors.
Of the prussic acid in the blood, 98 to 99% is
contained in the erythrocytes. Vesey et al. (1976),
for example, found a mean of only 1.5 0.6% of
prussic acid in the plasma portion of the blood in
26 patients given sodium nitroprusside for deliberate hypotension. Simultaneous measurements
showed that the prussic acid concentration in
plasma was approximately proportional to that in
the erythrocytes, though the plasma concentrations
were often at the lower limit of detectability (Vesey
et al., 1976).
In erythrocytes, prussic acid is bound to met-

243

Clinical Pharmacokinetics of Nitroprusside

haemoglobin. Theoretically, Ig of methaemoglobin

can bind approximately 60 ~mol of prussic acid
(Friedberg, 1968; Kiese and Weger, 1969). Accordingly, 1L of natural erythrocytes should be able to
bind approximately 50 to 200 ~mol of prussic acid
at normal physiological methaemoglobin levels
(0.25 to 1%). The prussic acid probably only enters
the tissues to a toxicologically significant extent at
higher concentrations, and this can be further delayed by the formation of additional methaemoglobin (Chen et aI., 1934; Kiese and Weger,
1969). The relative volume of distribution for
prussic acid is therefore variable, and depends both
on its total concentration in the body and on the
methaemoglobin content of the blood. The relative
volume of distribution has been estimated as approximately 0.075 L/kg (Schulz et aI., 1982).
In 25 healthy subjects the prussic acid concentration in an erythrocyte concentrate was less than
1 ~mol/L (Schulz et aI., 1983). Whether therapeutically administered or in cases of poisoning, prussic acid concentrations of less than 150 ~mol/L
usually cause no recognisable symptoms; at 150 to
250 ,umol/L, headaches, palpitations and hyperventilation occur; at 250 to 350 /-Lmol/L, metabolic
acidosis and coma are produced; and in fatal poisoning cases, concentrations of 300 to 3000 ~mol/
L have been measured (Aitken et aI., 1977; Ansell
and Lewis, 1970; Davies et aI., 1975; Graham et
aI., 1977; Hillman et aI., 1974; Posner et aI., 1977;
Schulz et aI., 1979, 1982, 1983; Vesey et aI., 1976).
2.4 Elimination and Detoxification
Prussic acid is exhaled in unchanged form in
small amounts with the respiratory air (Friedberg
and Schwarzkopf, 1969), but most is detoxified in
the body by conversion into thiocyanate with the
aid of the enzyme rhodanese. Rhodanese can be
detected in the mitochondria of almost all tissues
in the body, and in total is present in large amounts
(Himwich and Saunders, 1948; Lang, 1933; Mintel
and Westley, 1966; Saunders and Himwich, 1950).
This enzyme is functional even in the newborn
(Schulz and Roth, 1982). Suspected enzyme defects
of rhodanese apparently do not result in a serious

reduction in the capacity to detoxify prussic acid

(Wilson, 1965).
The enzymatic detoxification of prussic acid exhibits zero-order kinetics. The limiting factor is the
low concentration of the sulphur-containing substrates in the body; these consist primarily of thiosulphate, but also include cystine and cysteine
(Himwich and Saunders, 1948; Saunders and Himwich, 1950).
The rate of spontaneous detoxification of prussic acid in humans is around I /-Lg/kg bodyweight
per minute (Schulz et aI., 1982) which is considerably slower than in small rodent animals (Schubert and Brill, 1968) or dogs (Lawrence, 1947). Extrapolating the results from animal experiments to
man (Hbbel et aI., 1976) has therefore led to false
assumptions regarding the prussic acid toxicity of
sodium nitroprusside. With therapeutic use of sodium nitroprusside, several groups of authors have
since demonstrated that dose levels of more than
2 /-Lg/kg/min cause prussic acid to accumulate in
the body (Aitken et aI., 1977; Bogusz et aI., 1979;
Lawson et aI., 1982; Schulz et aI., 1982). This rise

'0

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8

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40
30

Cl.

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'e<J)n
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:
.'
"."

o :"'*W.':,' 00,','

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50100 200 300 400 500 600 700 800 9001000

Dosage (ILg/min)

Fig. 2. Maximum prussic acid concentrations in the erythrocytes during therapy with sodium nitroprusside as a function of
the mean dosage (e
sodium nitroprusside 'monoinfusion';
o = sodium nitroprusside + thiosulphate 'mixed infusiOn'),
Treatment was for deliberate hypotension in 50 patients, for
hypertenSive criSis in 17 patients, and for dissecting aortic aneurysm in 3 patients (after Schulz et aI., 1982),

Clinical Pharmacokinetics of Nitroprusside

in the prussic acid concentration did not occur,

however, even at higher dose levels of sodium nitroprusside, if an excess of sodium thiosulphate was
infused simultaneously (Pasch et al., 1983; Schulz
et aI., 1982; fig. 2).

3. Pharmacokinetics of Thiosulphate
Thiosulphate, like thiocyanate, is a normal
physiological constituent of serum. Thiosulphate
has acquired pharmacological importance as an
antidote in cases of prussic acid and mustard gas
(dichlorodiethyl sulphide) poisoning, for which it
has been administered intravenously at doses of up
to I g/kg bodyweight (Eichler, 1950). Basic investigations of the effects of thiosulphale as an antidote to prussic acid poisoning were published as
long ago as the end oflast century (Lang, 1895).
3.1 Analytical Methods
Measurement of the thiosulphate concentration
in plasma is based on reduction by iodine (Dixon,
1962; Gast et aI., 1952). This method is nonspecific, and can be distorted by other reducing substances, e.g. many drugs. Pharrnacokinetic measurements with thiosulphate are therefore only
reliable provided the non-relevant initial concentrations in the serum are adequately taken into account, and provided the period studied does not
exceed a few hours on each occasion.
Recently, an assay for thiosulphate has been described based on its use in photography. This
method was reported to be more specific for thiosulphate and simpler to perform (lvankovich et aI.,
1983).
3.2 Absorption and Distribution
Thiosulphate taken orally is not absorbed by the
body but breaks down in the acidic gastric juices
to form sulphite and sulphur (Eichler, 1950).
Like sulphate and thiocyanate, thiosulphate is
an extracellular anion. Its volume of distribution
is assumed to be identical to the extracellular space
(Gilman et aI., 1946).

244

3.3 Elimination
After bolus injections, the serum half-life of
thiosulphate in man is around 15 to 20 minutes
(Ivankovich et aI., 1983; Schulz et at, 1982). Depending on dosage, around 20 to 50% of exogenous
thiosulphate is eliminated unchanged via the kidneys (Eichler, 1950; Gilman et al., 1946; Ivankovich et aI., 1983).
In animals, thiosulphate is largely oxidised in
the body to sulphate. This is the case for all of the
'inner' S atoms of the thiosulphate molecule, but
the 'outer'S atoms may initially be incorporated
in endogenous sulphur compounds - in the detoxification of prussic acid this is the rhodanite sulphur (Eichler, 1950; Skarzynski et at, 1959;
Szczepkowski et aI., 1961).
3.4 Toxicity of Thiosulphate as an
Infusion with Sodium Nitroprusside
Since rhodanese is present in large amounts in
the body (Himwich and Saunders, 1948), cyanide
detoxification can be accelerated considerably by
infusing thiosulphate concurrently with the sodium
nitroprusside. The optimum molar cyanide/thiosulphate ratio for the rhodanese reaction in vitro is
about I : 3 (Saunders and Himwich, 1950). Using
a mixed infusion of sodium nitroprusside with
thiosulphate (Schulz et ai., 1982), the thiosulphate
and the sulphate produced from it are present in
about 3 times molar excess over the thiocyanate
also produced in the body. The renal clearance of
thiosulphate and sulphate is, however, at least 10
times higher, and their toxicity at least 10 times
lower than for thiocyanate (Chakmakjian and Bethune, 1966; Gilman et ai., 1946; Lang, 1895; Schulz
et al., 1978, 1979b). Therefore, during therapy with
a mixture of sodium nitroprusside and thiosulphate as recommended elsewhere (Schulz et ai.,
1982), the toxicity of thiosulphate itself does not
need to be monitored during therapy, since the
thiocyanate will causp, toxic effects considerably
sooner.
In patients with severe hypertensive crisis we
have infused in individual cases up to Ig of sodium

Clinical Pharmacokinetics of Nitroprusside

nitroprusside and 109 of sodium thiosulphate per

day. Such extreme doses mean an intake of up to
100 mmol of Na+. The effects of such intake on
the patient's electrolyte balance and fluid balance
must be taken into account in order to avoid
hypernatraemia.

4. Pharmacokinetics of Thiocyanate
From 1925 to 1945, potassium thiocyanate was
the most important drug for treating arterial hypertension (Kaplan, 1982). Its margin of safety in this
application was low. Clinical toxicity in relation to
measured serum concentrations in antihypertensive therapy has been reviewed by Domzalski et
al. (1953), and a comprehensive account of the biochemistry of the thiocyanates has been given by
Newman (1975). Specific pharmacokinetic investigations with potassium thiocyanate on both
healthy subjects and patients with renal insufficiency have been carried out by Schulz et al.
( 1979b).
4.1 Analytical Methods
The principle for measuring thiocyanate concentrations is the same as for prussic acid (see section 2.1), but in the case of thiocyanate it is not
necessary to first separate it from the serum. The
reaction with chloramine T is much slower than
for prussic acid, and for this reason ferric chloride
must be added as a catalyst (Asmus and Garschagen, 1953; Boxer and Rickards, 1952; Bruce et
aI., 1955). The older measurement methods, by
which ferric rhodanite is formed (Ginsburg and
Benotti, 1939), are less specific, and are no longer
used today. The detection limit for thiocyanate is
the same, mole for mole, as for prussic acid. The
physiological level of thiocyanate in the blood is,
however, greater by a factor of 100 to 200 than that
of prussic acid.
4.2 Absorption, Distribution and Elimination
After oral administration of 900 to 3000mg of
potassium thiocyanate, the percentage absorbed

245

(measured by recovery in urine) by 7 healthy subjects was almost 100%. The mean relative volume
of distribution in healthy subjects was of 0.25 L/
kg compared with 0.36 L/kg in patients with renal
insufficiency (Schulz et al., 1979b).
The mean elimination half-life of thiocyanate
was measured as 2.7 days in healthy subjects and
9 days for renally insufficient patients. Elimination
was almost wholly through the kidneys. The elimination constants were inversely proportional to the
renal creatinine clearances (Schulz et al., I 979b).

5. Implications for Clinical Use of

Sodium Nitroprusside
Despite its toxicity, sodium nitroprusside is currently classified as an 'essential drug' (WHO Expert Committee, 1979). The rapidity and prompt
reversibility of its action in lowering blood pressure are hitherto unique with respect to comparable preparations. In hypertensive crisis, sodium
nitroprusside remains the therapy of choice when
other vasodilators such as hydralazine or diazoxide
are ineffective (AMA Committee on Hypertension,
1974). In cases of cardiac failure it expands the arterial and venous vessels and thereby simultaneously reduces the preload and afterload of the heart
(Miletich and Ivankovich, 1978). For deliberate
hypotension in anaesthesiology, its action is almost
always to be relied upon, whereas with glyceryl trinitrate (nitroglycerin) some 15 to 20% of patients
show non-responsiveness (Flaherty et al., 1982;
Pasch et al., 1983).
For these indications, sodium nitroprusside
cannot at present be replaced by less toxic drugs.
Therefore, precautions must be taken to ensure that
the dangers in using it remain under control, for
which not only pharmacokinetic considerations but
also practical clinical considerations must be taken
into account.
Prussic acid can be expected to accumulate in
the body when the rate of sodium nitroprusside
infusion exceeds 2 jlg/kg/min (see section 2.4). In
many patients, however, this upper dosage rate limit
is not sufficient to produce effective lowering of the
blood pressure. Furthermore, the endogenous thio-

Clinical Pharmacokinetics of Nitroprusside

sulphate pool in an adult human is sufficient for

short term detoxification of around SOmg of sodium nitroprusside (Ivankovich et al., 1983), and
this total dose, likewise, often has to be exceeded
- especially in patients in internal medicine.
Nevertheless, cases of prussic acid poisoning with
sodium nitroprusside therapy are seldom reported
in the literature. This could be for several reasons.
Firstly, the gradual build-up of prussic acid in
the body does not at that stage represent an immediate risk of intoxication. Furthermore, the upper dosage rate limit (2 }.tg/kg/min) is only exceeded for short periods in many cases, so that while
prussic acid does temporarily accumulate in the
body, it does not reach toxic concentrations (see
section 2.3). This is particularly true of deliberate
hypotension in anaesthesia. Such patients usually
do not require any additional thiosulphate. Doubts
must arise, however, in individual cases in anaesthesia where much higher dosages are needed; in
these cases severe or fatal intoxication has occasionally occurred (Schulz et al., 1982).
For patients in internal medicine the risks are
substantially higher. When treating hypertensive
emergency cases, it is almost always necessary to
exceed the abovementioned upper dosage limits.
Furthermore, these patients often arrive at the hospital at night or over the weekend, when less experienced personnel are on duty, and in this type
of situation, in particular, a recommendation, for
example, to only infuse additional thiosulphate if
certain side effects of the sodium nitroprusside are
observed under monitoring would be totally inadequate. Changes in blood gases, such as metabolic acidosis or increased venous oxygen tension,
arise relatively suddenly in prussic acid intoxication, and when they do arise, are an indication that
the intoxication is already critical (see section 2.3).
It is not possible to ensure therapeutic safety of
sodium nitroprusside by relying on the observation
of such parameters. The clinical symptoms of prussic acid intoxication can also be so similar to those
of, for example, hypertensive encephalopathy that
the less experienced physician will not be able to
differentiate between them. It is evident that when
fatal complications occur in such cases, the as-

246

sumption of death from natural causes will always

be made. This could also be the reason why many
cases of fatal intoxication under sodium nitroprusside therapy have been reported in anaesthesia
(where they were to be least expected) but very
rarely in internal medicine, where it must be suspected that they have more often occurred.
5.1 'Mixed Infusion' Technique: Rationale
and Application
The difficulty of defining clear and unmistakable dosage limits for sodium nitroprusside in
practical clinical use have led us to develop a new
method of application in the form of a 'mixed infusion' of sodium nitroprusside and thiosulphate.
This 'mixed infusion' technique reiains the
pharmacological benefits of sodium nitroprusside
but removes the possibility of prussic acid toxicity
(Pasch et aL, 1983; Schulz et aI., 1982). After thorough clinical tests in several hundred patients, we
have recommended that the present formulation of
sodium nitroprusside be replaced by a 'kit' containing: I ampoule of 50mg Iyophilised sodium nitroprusside, 1 bottle of SOml I % sodium thiosulphate solution, 1 light-opaque SOml syringe, and a
iight-opaque infusion tube. The thiosulphate and
the sodium nitroprusside are mixed together just
before use and are drawn up as a mixed solution
into the syringe. Infusion is then performed with
the normal commercial 'Perfusor' apparatus. Such
kitsl will be available on the German market at
the end of 1984.
This innovation simplifies the making-up of the
solution and also removes the acute problems of
dosage level and toxicity. There is, however, some
resistance to this concept. Some of the arguments
which have been put forward against use of ' mixed
infusions' are of a pharmacokinetic nature and
should be discussed here. It has been claimed that:
I. The stability of sodium nitroprusside in the
mixed solution cannot be guaranteed
2. The accumulation of prussic acid in the
I

Manufacturcd by Pharma Schwartz. Monheim. West Gcrman).

Clinical Pharmacokinetics of Nitroprusside

247

blood, which has been repeatedly reported, is solely

due to the analytical methods used (Bisset et a!.,
1981)
3. The raised prussic acid concentration in the
erythrocytes has no toxicological relevance (Vesey
et a!., 1976)
4. The subacute toxicity of the thiocyanate remains, despite the mixed infusion.
Regarding the first of these points, the rapid decomposition of sodium nitroprusside in aqueous
solution is based on a photochemical reaction; the
rate of this decomposition also depends on the
concentration, since it increases with increasing dilution. Under exclusion of light, however, aqueous
solutions of sodium nitroprusside are stable under
storage for a period of weeks or months (Van Loenen and Hofs-Kemper, 1979), and the abovementioned 'mixed infusion' kit ensures reliable exclusion of light. Also, the concentration of sodium
nitroprusside in the kit is higher by a factor of 5
to 10 than in usual applications. Clinical tests have
shown no difference in the antihypertensive efficacy of the combination as compared with an in-

fusion of sodium nitroprusside alone (Schulz et a!.,

1982).
Regarding the second point, the work of Bisset
et a!. (1981) has already been refuted elsewhere
(Smith et a/., 1982). The experiments were only
performed in vitro and in the evaluation of the results no account was taken of the fact that the
breakdown of sodiun nitroprusside in vivo is substantially faster than in vitro (see section 1.4). The
quantitative conversion of sodiun nitroprusside
cyanide into thiocyanate (Bbdigheimer et a!., 1979;
Japp et a!., 1978; Nourok et aI., 1964; Schulz et a!.,
1978) itself presupposes that the sodium nitroprusside is first fully broken down in vivo.
With regard to point 3, in erythrocytes, only the
methaemoglobin forms a fixed compound with
prussic acid (Kiese and Weger, 1969). The normal
physiological content of around 0.5% of methaemoglobin in the blood could thus, for example,
bind 100 tlmol of prussic acid per litre of erythrocytes (see also section 2.3). On this basis, the total
erythrocyte volume of an adult human would be
able to bind around 8mg of prussic acic, which cor-

4000+-----------------------------------------------------3500
10 ltg/kg/min
1
~

(5

,g

3000

2500

'ug"

*'"
u

2000+-------------~~------------------------------------
5 /lg/kg/min
1500

~ 1000+---~~----~~~~-----------------------------------

2.5 /lg/kg/min

~ 5001~~~~~~~~~====~==~==~==~====:===~~~~~o
11
12
1.25 /lg/kg/min

3
4
2
Treatment duration (dayS)

10

Fig. 3. Prospective accumulation of thiocyanate with monoinfusion or mixed infUSion of sodium nitroprusside 1.25 to 10 /lg/kg/min
in patients with normal renal function. Normal physiological thiocyanate level, 50-250 /lmol/l; at 1000 /lmol/l, slight symptoms
possible; at 2000 "moltl, more serious symptoms; at 4000 "moltl, life-threatening intoxication (after Schulz et aI., 1979b).

Clinical Pharmacokinetics of Nitroprusside

248

5000
4500

;Z

4000

3500

15

,Q

3000

c:

2500

2000

Q)
<.)

<.)

*'"
c

2.5 ~gfkgfmin

1500

>- 1000

<.)

:r.
f-

1 .25 ~gfkgfmin

500
0

4
2
3
Treatment duration (days)

10

11

12

Fig. 4. Prospective accumulation of thiocyanate in anuric patients. Details as for figure 3.

responds to a cyanide content of approximately

18mg of sodiun nitroprusside. Total doses of several thousand milligrammes of sodium nitroprusside are, however, used from time to time in cases
in internal medicine. Thus the methaemoglobin
content of the erythrocytes is for quantitative reasons scarcely capable of removing the toxin from
the body. The decisive factor is rather the metabolic elimination of prussic acid. This is normally
adequate to keep the concentration in the erythrocytes below I /lmol/L (section 2.3). Any marked
rise, however, indicates disequilibrium between the
rate of supply and the rate of detoxification.
By contrast, prussic acid levels 100 times greater
than normal have been dissipated within a few
hours after the injection of thiosulphate (Schulz et
aI., 1979a, 1982, 1983). It can therefore be concluded that the prussic acid bound in the erythrocytes can rapidly diffuse into other cells provided
there is an adequate concentration gradient, since
erythrocytes contain no rhodanese and the enzymatic detoxification takes place only in the mitochondria of the organs (Himwich and Saunders,
1948; Lang, 1933). It is thus highly probable that
prussic acid is able to exchange very rapidly be-

tween the erythrocytes and the sites of toxicity in

the body: a rise in the erythrocyte prussic acid concentration is therefore an early recognisable indicator that intoxication is arising.
Regarding the fourth point, the toxicity of thiocyanate is about 100 times less than that of prussic
acid. However, since it is eliminated slowly from
the body (see section 4.2), thiocyanate can still give
rise to serious intoxication if sodium nitroprusside
is infused for long periods. We have reported 1 such
case some years ago (Schulz et aI., 1978). Furthermore, the antithyroid action of thiocyanate must
be considered (Nourok et aI., 1964). The lowering
of blood pressure by thiocyanate is not likely to be
of significance in the patients under consideration
here:.
Thiocyanate does not in principle present any
therapeutic problem where sodium nitroprusside is
infused for short periods, e.g. for deliberate hypotension. When sodium nitroprusside is infused for
several days at medium dosages (2 to 5 Ilg/kg/min),
however, toxic levels of thiocyanate in serum can
be expected after about 7 to 14 days' infusion for
patients with normal renal function, or about 3 to
6 days for patients with severely restricted renal

Clinical Pharmacokinetics of Nitroprusside

function. The corresponding symptoms (see

Domzalski et aI., 1953) develop slowly, and can be
calculated beforehand on the basis of sets of standard curves (figs 3 and 4). If intoxication is suspected, haemodialysis of a few hours is sufficient
to eliminate most of the thiocyanate from the body.

Acknowledgement
Supported by the Deutsche Forschungsgemeinschaft.

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Author's address: Dr V. Schulz, University Medical Clinic,

Joseph-Stelzmann-Strasse 9, 5000 K61n (West Germany).