Indian Journal of Pharmacology 2000; 32: 94-101 EDUCATIONAL FORUM

ANTIDOTES TO CYANIDE POISONING: PRESENT STATUS

ANTIDOTES TO CYANIDE POISONING: PRESENT STATUS

R. BHATTACHARYA

Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi
Road, Gwalior, 474 002, India.

Manuscript Received: 13.10.99 Accepted: 2.2.2000

SUMMARY
environment. It is considered as a potent suicidal, homicidal, genocidal and
y is mediated through inhibition of cellular respiration, but its other complex
umented. There are a number of antidotes available for cyanide poisoning
phenol, sodium thiosulphate, ​etc​.), however, there is still uncertainty about
tion for use. This review provides a comprehensive account of toxicology of
s antidotes employed clinically or pursued experimentally.
KEY WORDS
acetonitrile) or by dermal absorption /ingestion of cyanide
salts and aliphatic nitriles. Its notoriety as a suicidal,
homicidal and genocidal agent is well known​2,4-7​. Use of
HCN as a potent chemical warfare agent is also well
documented 8​​ . Cyanide is a very rapid poison which
impairs the cellular respiration leading to a cascade of
events culminating in cell death. There are a number of
antidotes available for cyanide poisoning. However, their
safety, efficacy and correct indication for use are
frequently being debated​9​. This article provides a
comprehensive account of the toxicology of cyanide and
the current status of various antidotes employed clinically
or being pursued experimentally.

INTRODUCTION
ROUTES OF EXPOSURE AND LETHAL DOSE
Cyanide is regarded as a notorious poison dating back to
It is not easy to determine what are the lethal doses of
antiquity. Hydrogen cyanide (HCN) was first isolated from
cyanide to man. Human cyanide poisoning is as- sociated
cherry laurel by Swedish chemist, Karl Wilheim Scheele
with a mortality rate of 95% 1​​ . Taken orally the fatal dose
in 1782 and in 1786 he was feared to be the first victim of
of HCN to adult is estimated at 50- 100 mg, and for
this rapid poison​1,2​. Later in 1795 Fontana investigated its
potassium cyanide (KCN), about 150- 250 mg​10​. However,
mechanism of action, followed by Blakes’s attempts to
victims ingesting as much as 3 g of KCN have been saved
antagonise its toxic effects. However, molecular basis for
with immediate therapy​9​. Inhalation of HCN at a
the biochemi- cal mechanism of cyanide antagonism was
concentration of 270 ppm (ap- proximately 0.3 mg HCN
first dem- onstrated in 1933 only​3​. The ubiquitous
per litre) will be immedi- ately fatal. Victims having a
existence of cyanide in the environment is associated with
blood cyanide level of 2.5-3.0 μg/ml frequently succumb
the toxic gases produced by pyrolysis of plastic or ni-
to respiratory ces- sation within 20-30 min of exposure or
trile-based polymer fibres, ingestion of extracts of plants
​ . The morbidity or mortality
may survive even upto 3 hr 9,10​
containing cyanogenic glycosides (​e.g., ​cas- sava) or
depends upon the magnitude of poisoning, which varies
inhalation from industrial or occupational causes (​e.g.,
with the dose and form of cyanide and the route of poi-
electroplating). Administration of cer- tain drugs (​e.g., soning 9​​ .
sodium nitroprusside and laetrile) also release cyanide
when metabolised in the body. Cyanide poisoning also
results from exposure to aliphatic nitrile compounds (​e.g. R. 95

CLINICAL MANIFESTATIONS
The clinical picture of acute cyanide poisoning var- ies in
both time and intensity depending upon the magnitude of
exposure. Various non-specific signs and symptoms like
headache, dizziness, nausea, vomiting, confusion, coma
and incontinence of fae- ces and urine occur​10​.
Physiologically a series of events like dyspnoea,
incoordination of movement, cardiac irregularities,
convulsive seizures, coma and respiratory failure may
​
occur leading to death 4,5,7,10​ . Pathologically no particular
lesions can delineate cyanide toxicity, albeit animal
experiments indicate that the lesions are principally in the
central nervous system, predominantly necrosis in the
white mat- ter​5,6,10​. Probably the most wide-spread
pathologic condition attributed to chronic cyanide
poisoning is tropic ataxic neuropathy following cassava
consump- tion​11​.
MECHANISM OF TOXICITY
The toxic effect of cyanide is attributed predominantly to
the production of anoxia following inhibition of cy-
tochrome oxidase, a terminal mitochondrial respira- tory
chain enzyme. This enzyme contains two heme A and two
copper ions. Cyanide has a special affinity for the heme
ion and the reaction of cyanide with the multimeric iron
enzyme complex is facilitated by first penetration of
cyanide to protein crevices, with initial binding of cyanide
to the protein followed by binding of cyanide to heme ion.
Thereby, a cyanide-heme cytochrome oxidase complex is
formed which renders the enzyme incapable of utilizing
the oxy- gen​4-6,10​. The resultant oxygen saturation of the
blood imparts a cherry red colour, which aids the diagno-
sis in most instances of cyanide poisoning. Inhibition of
cytochrome oxidase results in interruption of elec- tron
transport chain and the oxidative phosphoryla- tion.
Resultant anaerobic metabolism with severely decreased
ATP generation and concomitant increase in lactic acid
production eventually leads to tissue hypoxia and
metabolic acidosis​12-14​. The inhibitory properties of cyanide
may be ascribed to its ability to complex with metals.
Besides, iron containing cyto- chrome oxidase, there are
other metallo-enzymes containing molybdenum, zinc or
copper which are equally sensitive to cyanide. Other
mechanism for cyanide inhibition may be attributed to its
affinity to Schiff base intermediates, ​e.g. ​ribulose
diphosphate
carboxylase and 2-keto-4-hydroxy glutarate aldolase
involving formation of a cyanohydrin intermediate​6​.
Therefore, cyanide toxicity may not be attributed solely to
a single biochemical lesion but a complex phenomenon.
The primary site of action of cyanide is presumed to be the
central nervous system (CNS). In acute cyanide poisoning
a rapid inhibition of cyto- chrome oxidase results in an
energy deficit within the target tissue​13,14​. Additionally a
number of other enzymatic processes are inhibited which
exacerbate the toxicity​14,15​. This includes antioxidant
defence enzymes (catalase, superoxide dismutase and glu-
tathione peroxidase). Cyanide is also potent stimulator of
neurotransmitter release both in the CNS and peripheral
nervous system​16​. All of these events contribute to the
acute toxic syndrome​17​. Subacute or chronic cyanide
poisoning is characterized by pro- longed energy deficit,
loss of ionic homeostasis and oxidative stress leading to
CNS pathology​18​.
ANTIDOTES
Cyanide produces a rapid onset of toxicity which must
have vigorous and immediate treatment to prevent the
toxic syndrome. To obtain better protection, a se- ries of
newer antidotes either alone or in adjunction with the
conventional treatments have been exam- ined​3-5,17​. Their
mechanism of action, efficacy and toxicity have been
reviewed as part of a joint IPCS (UNEP, ILO, WHO)/CEC
project to evaluate antidotes used in the treatment of
cyanide poisoning​19​. A wide variety of compounds have
been used as cyanide antidotes and they have been
classified into four major groups based on their
mechanism of action: (i) scavengers, (ii) detoxification,
(iii) physiological and (iv) biochemical​17​.
Scavengers
These are compounds that inactivate cyanide by binding it
or by forming methaemoglobin, which in turn sequesters
cyanide.
a. Methemoglobin formers: ​The basic aim of rapid
detoxification of cyanide is prevention or reversal of
inhibition of cytochrome oxidase by cyanide. This is
usually accomplished by providing a large pool of ferric
iron in the form of methemoglobin to complex cyanide.
Cyanide preferentially competes with the Fe​+++ ​of
methemoglobin as compared to that of cyto- chrome
oxidase, and eventually binds with the former velopment of rapid methemoglobin formers like
aminophenols. 4-dimethylaminophenol (DMAP) is the
treatment of choice for cyanide poisoning in Germany. A
ANTIDOTES TO CYANIDE POISONING: PRESENT STATUS dose of 3.25 mg/kg., ​i.v. ​of DMAP was reported to
96
produce methemoglobin level of 30% within 10 min and
15% methemoglobinemia was attained within one minute
to form cyanmethemoglobin​3-5,20​. Thereby, the activ- ity of without any immediate effect on cardio-
inhibited cytochrome oxidase is restored. The various vascular system​25​. However, there are differences in
methemoglobin formers employed as cya- nide antidotes individual susceptibility to DMAP which may result in an
are discussed below. undesirable levels of methemoglobinemia even after
normal therapeutic doses​26​. Intramuscular in- jection of
Amyl nitrite: ​Inhalation of amyl nitrite as a first aid DMAP results in local abscess and fever. Its clinical
measure to cyanide poisoning is known for many application remains limited on account of its other
years​3-5,9,19​. However, the efficacy of amyl nitrite astoxicological implications like nephrotoxic- ity​27​.
methemoglobin inducer remained disputed on ac- count of Co-administration of a reduced dose of rapid
its inability to generate methemoglobin greater than 6% methemoglobin inducer like DMAP and a slow in- ducer
20,21​
, while about 15% is required to challenge tective effect like SN were also found to be an effective pre- treatment
one LDof 50 ​ ​amyl dose nitrite of cyanideis 9​​ . Now the pro- against acute cyanide poisoning. This regi- men by virtue
attributed to its vasodilatory effect that can reverse the of a protracted optimal level of methe- moglobinemia
early cya- nide induced vasoconstriction​9,19​. Artificial provided sustained prophylaxis in rats​28​.
ventilation with amyl nitrite broken into ambu bags has
been reported as a life saving therapy in cyanide poi- soned Other methemoglobin formers: ​Hydroxylamine (HA)
29-31 ​
dogs, prior to induction of significant level of was yet another rapid methemoglobin inducer​ that was
methemoglobinemia​22​. endowed with an anticonvulsive property​ . In view of
32​

cyanide induced convulsions and the toxicity of DMAP,

Sodium nitrite: ​Sodium nitrite (SN) is the most preva- the efficacy of HA co- administration with SN was also
lent drug of choice for cyanide poisoning 3-5,23​ ​ . When given examined in rats​33​. Although, this regimen minimised the
intravenously (​i.v.​) it takes about 12 min to gen- erate cyanide in- duced convulsions, it was less effective as
approximately 40% of methemoglobin 9​​ . Inspite of this compared to SN+DMAP treatment. In addition to
delay in inducing a significant level of methe- prophylaxis, co-administration of SN and DMAP or HA
moglobinemia, a reasonable protection offered by SN can were also effective therapeutically​34​, but their
be ascribed to its vasodilatory property​19​. A se- rious extrapolation to humans warranted caution in view of the
drawback with SN is that ​i.v. ​administration may be persistent toxicity of these regimens​35,36​.
accompanied by serious cardiovascular embar- rassment,
The cardiovascular implications and poor pharma-
particularly in children, for whom an ad- justed dose is
cokinetics of SN led to evaluation of yet another group of
recommended​24​. Since SN induced methemoglobinemia
methaemoglobin formers ​viz​. aminophenones and
impairs oxygen transport, it can- not be recommended for
fire victims where in most instances HCN exposure is derivatives [ρ-aminopropiophenone (PAPP), ρ-
accompanied by carbon monoxide poisoning. Since carbon aminooctanoylphenone (PAOP), ρ-nitrosopropio- phenone
monoxide also impairs oxygen carrying capacity of blood, (PNPP) and ρ-hydroxy aminopropio- phenone (PHAPP)].
adminis- tration of SN would further aggravate the hypoxic Out of all these agents PAPP was the most effective as
con- dition. SN is also not advised for individuals with glu- prophylaxis​37,38​. Another alternative treatment of cyanide
cose-6-phosphate dehydrogenase (G6PD) deficient red poisoning, involving stroma free methemoglobin solution
cells because of possibility of serious hemolytic (SFMS) was pro- posed by Ten Eyck ​et al 39​ ​ .Intravenous
reactions​19​. administra- tion of this solution did not impair the oxygen
carry- ing capacity of blood as caused by most other
4 - Dimethylaminophenol: ​The relatively slow rate of methemoglobin formers and directly sequestered cyanide
methemoglobin formation by SN prompted the de- nide in rats. to protect Efficacy a 4 and X LDsafety ​90 dose ​
 of this of sodium antidote cya- re- mains to be determined combination with SN and/or STS attenuated toxicity in
in larger animals. mice exposed to cyanide through different routes​47​.
Prophylactic or therapeu- tic ability of α-KG was also
b. Cobalt containing compounds: ​Cobalt ion which shown to be augmented by oxygen​48​. Cyanide induced
forms a stable metal complex with cyanide is an ef- fective histotoxic hypoxia was reversed by α-KG which was
​ . Various
therapeutic agent against cyanide poison- ing 3-5,40​ found to be more effec- tive than cobalt edetate and
cobalt containing compounds known sodium pyruvate​49​. Al- though, clinical trials of this agent
as cyanide anti- dote has not yet been conducted in
97
humans, based on the promising results in experimental
animals, it is presently envisaged as a potential antidote for
cya-
nide poisoning. It is considered safe as oral form of α-KG
to antagonise cyanide poisoning are discussed below.
is sold as an over-the counter nutritional sup- plement
Dicobalt edetate (Kelocyanor): ​This agent (300 mg of (Klaire Laboratories, San Marcos, CA)​45​.
dicobalt edetate in glucose solution; ​i.v.​) is the cur- rent
treatment of choice in France and United King- dom. DETOXIFICATION
Serious side effects like vomiting, urticaria, anaphylactoid
Under this group those agents are listed which
shock, hypotension and ventricular arrythmias have been
enzymatically detoxify cyanide by converting it to a
reported in patients receiving kelocyanor​19​.
relatively non-toxic product which is readily eliminated
Hydroxocobalamin (Vitamin B 12a): ​This agent is from the body. The reaction can be catalyzed by aug-
perhaps the most promising cyanide antidote used in menting the levels of the enzyme endogenously or by
human toxicology​9​. With the exchange of hydroxy group supplementing the enzyme exogenously or, by providing
of hydroxocobalamin for cyanide, non toxic more substrate to the enzyme, which in this case are sulfur
cyanocobalamin (Vitamin B12) is formed. However, use donors. The major mechanism of removing cyanide from
of this antidote remained limited on account of the large the body is its enzymatic conversion by the mitochondrial
dose required to challenge cyanide poison- ing. An enzyme rhodanese (thiosulphate-cyanide sulfur
injectable solution of hydroxocobalamin (5 g in water) is transferase, EC 2.8.1.1) to thiocyanate. Transulfuration of
now available in France and Germany. In France a 4g cyanide is also fa- cilitated by
hydroxocobalamin solution in 80 ml of sodium β-mercaptopyruvate-cyanide sulfur trans- ferase (EC
thiosulphate (STS) has also been developed. Recorded side 2.8.1.2)​ . The enzymatic conversion of cyanide to
10​

effects of hydroxocobalamin includes anaphylactoid thiocyanate requires a source of sulfane sulfur (a divalent
reactions and acne​19,40​. ionised sulfur bound to another sulfur atom) which is
usually offered by thiosulfates or other biological
Other cobalt compounds: ​Cobaltous chloride, cobaltous compounds containing sulfane sulfur, like polythionates,
acetate, cobalt histidine and sodium co- balt nitrite are also thiosulfonates, persulfides etc.​50​. It is presumed that the
reported to antagonise cyanide poisoning. However, none sulfane sulfur binds first to the serum albumin to yield
of them has been used clinically​40​. sulfane sulfur al- bumin complex which eventually reacts
with cyanide to form thiocyanate​5,50​. Exogenously
c. Cyanohydrin formers: ​Cyanide is a nucleophile known
administered thiosulfate usually in the form of STS would
to react with various carbonyl moieties like ketones and
supple- ment this reaction rapidly. STS alone administered
aldehydes to yield cyanohydrin deriva- tives​3-5​. Sodium
i.v. ​may be sufficient in moderate cases of cyanide
pyruvate was reported to effectively challenge acute
poisoning while severe cases of poisoning may ne-
cyanide poisoning in mice​41​. Another α-ketocarboxylic
cessitate co-administration of other antidotes, pref- erably
acid like α-ketoglutaric acid (α-KG) is currently being
SN​9​. STS is contra-indicated in patients with renal
pursued widely as a cyanide anti- dote​42-45​. Protective
insufficiency as the thiocyanate formed may cause
effect of α-KG was also observed against cyanide induced
toxicity​19​. Endogenous augmentation of rho- danese has
convulsions in mice​46​. α- KG either alone or in
not been worked out extensively but ex- ogenous
supplementation has been reported to accelerate the integrity by preventing peroxidation of membrane
transulfuration of cyanide to thiocy- anate​51-54​. However, lipids​1,58​.
stability and sensitivity of the enzyme remains to be
Other agents: ​Other α-adrenergic blocking agents like
addressed.
phenoxybenzamine and various autonomic drugs,
vasodilators such as papaverine, organic ni- trates and
PHYSIOLOGICAL
anti-histaminic compounds have shown some antidotal
Oxygen appears to be a physiological antagonist. Oxygen efficacy in cyanide poisoning​5​. Cya- nide induces
alone at hyperbaric pressure has slight pro- tective effect in respiratory cessation mediated through inhibitory action of
cyanide poisoning but it dramatically potentiates the released endorphin. Therefore, stereo-specific opiate
5​
protective efficacy of SN and/ or STS​ . This protective antagonist (-) naloxone hydro- chloride was found to
mechanism is not yet clear because protect against cyanide induced lethality in mice​59​. Role of
neuronal calcium in cya- nide induced neurotoxicity and
beneficial effects of chlorpromazine and calcium channel
ANTIDOTES TO CYANIDE POISONING: PRESENT STATUS blocker (diltiazem) are also well documented​1,58,60​. The
98 recent thrust to develop mechanistic based antidotes
against cyanide poisoning has identified some new classes
inhibition of cytochrome oxidase by cyanide does not of lead compounds like calcium antagonists, non-hyp-
deplete the availability of oxygen, only cellular utili- notic barbiturates, anticonvulsants, adrenergic block-
sation of oxygen is impaired. It is presumed that in- ers, antipsychotics, nitric oxide generators, other
tracellular oxygen tension may be high enough to cause neuroprotective drugs, antioxidants, plasma expand- ers,
non enzymatic oxidation of reduced cyto- chrome or glycolytic substrates, carbonyl compounds etc.​
5,17,61-64​
.
oxygen may displace cyanide from cyto- chrome oxidase Many of these drugs have not been used clinically in
by mass action​55​. During transulfura- tion there is humans but their results in experimental animals or ​in
accumulation of sulphite (SO3-2) which inhibits the vitro ​are quite encouraging.
progress of the reaction. It is proposed that oxygen
GLOBAL ATTITUDE AND THE POPULAR
accelerates the oxidation of sulphite, thereby enhancing
TREATMENT
cyanide detoxification​56​.
A retrospective examination of various cyanide anti-
BIOCHEMICAL dotes reveals that there is no unanimity of opinion
regarding the efficacy of a particular treatment regi- men.
The compounds classified as biochemical antidotes have
This is mainly due to different experimental conditions,
largely unexplained mechanism of action and are also
test protocols and species of animals employed in
regarded as non-specific antidotes. These compounds are
evaluating various antidotes. Adoption of a particular
usually not very effective ​per se ​but as adjuncts
treatment in a country is dictated by various factors
significantly augment the efficacy of con- ventional including the regulatory bodies and the legislations. There
antidotes. A few chemicals belonging to this class of is no global unanimity on this issue, like SN and STS
antidotes are discussed below. combination is the drug of choice for cyanide poisoning in
Chlorpromazine: ​The potent vasodilatory action of U.S.A. and many other countries, France and U.K. have
adopted kelocyanor while Germany is still continuing with
nitrites prompted the examination of vasogenic drugs as
DMAP and STS combination. However, SN (10 ml of 3%
cyanide antagonist. Chlorpromazine a neurolep- tic
solution) and STS (50 ml 25% solution) combination is
phenothiazine, was found to significantly potentiate the
still the most prevalent treatment in cyanide poisoning.
efficacy of SN and STS combination in cyanide toxicity​5​.
Artificial ventilation with 100% oxygen via Ambu bag
Its protective effect was attributed to its α- adrenergic
contain- ing the contents of two ampoules of amyl nitrite
blocking property​57​. Subsequently, the antidotal activity of
(0.6 ml) is usually practiced as the first aid therapy. The
chlorpromazine was related to its ability to sustain cellular
use of antidote should be restricted to patients in deep
calcium homeostasis and maintenance of membrane
coma with respiratory insufficiency. Supportive therapy of
diazepam ​i.v.​(3 x 10 mg) and 4.2% so- dium bicarbonate
solution to correct the convulsions and metabolic acidosis
respectively have also been used in human poisoning. To
revert excessive meth- aemoglobinaemia ​i.v.
administration of 30 ml of 1% methylene blue solution is
also recommended​9​.
CONCLUSION ​There are diverse approaches to
antagonise cyanide toxicity. However, full expression of
antidotal potency of a regimen principally lies on clinical
presentations and the immediate judgement. With the
resurgence of interest on cyanide antidotes a more
effective pro- phylactic or therapeutic regimen can be
anticipated in near future. Considering the rapidity of
cyanide poisoning, objective of further research is not to
re- place the established antidotes completely but to
augment their efficacy to a significant level or evolve new
regimens with enhanced efficacy and safety which is
acceptable with global consensus.
99
ACKNOWLEDGEMENT
The author is grateful to Dr. R.V. Swamy, Director and
Dr. R. Vijayaraghavan, Head of the Pharmacol- ogy and
Toxicology Division, Defence R & D Estab- lishment,
Gwalior for their keen interest and critical suggestions in
preparation of this manuscript.
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