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Summary
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).
240
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
241
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
::r
~
..=.
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
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
'0
.3 100
g
90
~ ~~
g 60
8
50
.~
u
40
30
Cl.
10'
'e<J)n
2 20
:
.'
"."
o :"'*W.':,' 00,','
"
"
'
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),
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
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).
246
247
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).
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
Acknowledgement
Supported by the Deutsche Forschungsgemeinschaft.
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