Antidotes to cyanide poisoning: present status

Indian Journal of Pharmacology 2000; 32: 94-101
EDUCATIONAL FORUM
ANTIDOTES TO CYANIDE POISONING: PRESENT STATUS
ANTIDOTES TO CYANIDE POISONING: PRESENT STATUS
Division of Pharmacology and Toxicology, Defence Research and Development Establishment,Jhansi Road, Gwalior, 474 002, India.
Cyanide is ubiquitously present in the environment. It is considered as a potent suicidal, homicidal,genocidal and chemical warfare agent. Cyanide toxicity is mediated through inhibition of cellular respiration,but its other complex toxic manifestations are also well documented. There are a number of antidotesavailable for cyanide poisoning (e.g. sodium nitrite, 4-dimethyl aminophenol, sodium thiosulphate, etc.),however, there is still uncertainty about their safety, efficacy and correct indication for use. This reviewprovides a comprehensive account of toxicology of cyanide and the present status of various antidotesemployed clinically or pursued experimentally.
KEY WORDS
INTRODUCTION
impairs the cellular respiration leading to a cascadeof events culminating in cell death. There are a Cyanide is regarded as a notorious poison dating number of antidotes available for cyanide poisoning.
back to antiquity. Hydrogen cyanide (HCN) was first However, their safety, efficacy and correct indication isolated from cherry laurel by Swedish chemist, Karl for use are frequently being debated9. This article
Wilheim Scheele in 1782 and in 1786 he was feared provides a comprehensive account of the toxicology to be the first victim of this rapid poison1,2. Later in
of cyanide and the current status of various antidotes 1795 Fontana investigated its mechanism of action, employed clinically or being pursued experimentally.
followed by Blakes’s attempts to antagonise its toxiceffects. However, molecular basis for the biochemi- ROUTES OF EXPOSURE AND LETHAL DOSE
cal mechanism of cyanide antagonism was first dem-
onstrated in 1933 only3. The ubiquitous existence of
It is not easy to determine what are the lethal doses cyanide in the environment is associated with the of cyanide to man. Human cyanide poisoning is as- toxic gases produced by pyrolysis of plastic or ni- sociated with a mortality rate of 95% 1. Taken orally
trile-based polymer fibres, ingestion of extracts of the fatal dose of HCN to adult is estimated at 50- plants containing cyanogenic glycosides (e.g., cas- 100 mg, and for potassium cyanide (KCN), about 150- sava) or inhalation from industrial or occupational 250 mg10. However, victims ingesting as much as 3
causes (e.g., electroplating). Administration of cer- g of KCN have been saved with immediate therapy9.
tain drugs (e.g., sodium nitroprusside and laetrile) Inhalation of HCN at a concentration of 270 ppm (ap- also release cyanide when metabolised in the body.
proximately 0.3 mg HCN per litre) will be immedi- Cyanide poisoning also results from exposure to ately fatal. Victims having a blood cyanide level of aliphatic nitrile compounds (e.g. acetonitrile) or by 2.5-3.0 µg/ml frequently succumb to respiratory ces- dermal absorption /ingestion of cyanide salts and sation within 20-30 min of exposure or may survive aliphatic nitriles. Its notoriety as a suicidal, homicidal even upto 3 hr 9,10. The morbidity or mortality depends
and genocidal agent is well known2,4-7. Use of HCN
upon the magnitude of poisoning, which varies with as a potent chemical warfare agent is also well the dose and form of cyanide and the route of poi- documented 8. Cyanide is a very rapid poison which
soning 9.
R. BHATTACHARYA
CLINICAL MANIFESTATIONS
carboxylase and 2-keto-4-hydroxy glutarate aldolase
involving formation of a cyanohydrin intermediate6.
The clinical picture of acute cyanide poisoning var- Therefore, cyanide toxicity may not be attributed ies in both time and intensity depending upon the solely to a single biochemical lesion but a complex magnitude of exposure. Various non-specific signs phenomenon. The primary site of action of cyanide and symptoms like headache, dizziness, nausea, is presumed to be the central nervous system (CNS).
vomiting, confusion, coma and incontinence of fae- In acute cyanide poisoning a rapid inhibition of cyto- ces and urine occur10. Physiologically a series of
chrome oxidase results in an energy deficit within events like dyspnoea, incoordination of movement, the target tissue13,14. Additionally a number of other
cardiac irregularities, convulsive seizures, coma and enzymatic processes are inhibited which exacerbate respiratory failure may occur leading to death 4,5,7,10.
the toxicity14,15. This includes antioxidant defence
Pathologically no particular lesions can delineate enzymes (catalase, superoxide dismutase and glu- cyanide toxicity, albeit animal experiments indicate tathione peroxidase). Cyanide is also potent that the lesions are principally in the central nervous stimulator of neurotransmitter release both in the CNS system, predominantly necrosis in the white mat- and peripheral nervous system16. All of these events
ter5,6,10. Probably the most wide-spread pathologic
contribute to the acute toxic syndrome17. Subacute
condition attributed to chronic cyanide poisoning is or chronic cyanide poisoning is characterized by pro- tropic ataxic neuropathy following cassava consump- longed energy deficit, loss of ionic homeostasis and oxidative stress leading to CNS pathology18.
MECHANISM OF TOXICITY
ANTIDOTES
The toxic effect of cyanide is attributed predominantly Cyanide produces a rapid onset of toxicity which must to the production of anoxia following inhibition of cy- have vigorous and immediate treatment to prevent tochrome oxidase, a terminal mitochondrial respira- the toxic syndrome. To obtain better protection, a se- tory chain enzyme. This enzyme contains two heme ries of newer antidotes either alone or in adjunction A and two copper ions. Cyanide has a special affinity with the conventional treatments have been exam- for the heme ion and the reaction of cyanide with the ined3-5,17. Their mechanism of action, efficacy and
multimeric iron enzyme complex is facilitated by first toxicity have been reviewed as part of a joint IPCS penetration of cyanide to protein crevices, with initial (UNEP, ILO, WHO)/CEC project to evaluate antidotes binding of cyanide to the protein followed by binding used in the treatment of cyanide poisoning19. A wide
of cyanide to heme ion. Thereby, a cyanide-heme variety of compounds have been used as cyanide cytochrome oxidase complex is formed which antidotes and they have been classified into four renders the enzyme incapable of utilizing the oxy- major groups based on their mechanism of action: gen4-6,10. The resultant oxygen saturation of the blood
(i) scavengers, (ii) detoxification, (iii) physiological and imparts a cherry red colour, which aids the diagno- (iv) biochemical17.
sis in most instances of cyanide poisoning. Inhibition Scavengers
of cytochrome oxidase results in interruption of elec-tron transport chain and the oxidative phosphoryla- These are compounds that inactivate cyanide by tion. Resultant anaerobic metabolism with severely binding it or by forming methaemoglobin, which in decreased ATP generation and concomitant increase in lactic acid production eventually leads to tissue
hypoxia and metabolic acidosis12-14. The inhibitory
a. Methemoglobin formers: The basic aim of rapid
properties of cyanide may be ascribed to its ability to detoxification of cyanide is prevention or reversal of complex with metals. Besides, iron containing cyto- inhibition of cytochrome oxidase by cyanide. This is chrome oxidase, there are other metallo-enzymes usually accomplished by providing a large pool of containing molybdenum, zinc or copper which are ferric iron in the form of methemoglobin to complex equally sensitive to cyanide. Other mechanism for cyanide. Cyanide preferentially competes with the cyanide inhibition may be attributed to its affinity to Fe+++ of methemoglobin as compared to that of cyto- Schiff base intermediates, e.g. ribulose diphosphate chrome oxidase, and eventually binds with the former ANTIDOTES TO CYANIDE POISONING: PRESENT STATUS
to form cyanmethemoglobin3-5,20. Thereby, the activ-
vascular system25. However, there are differences in
ity of inhibited cytochrome oxidase is restored. The individual susceptibility to DMAP which may result various methemoglobin formers employed as cya- in an undesirable levels of methemoglobinemia even after normal therapeutic doses26. Intramuscular in-
jection of DMAP results in local abscess and fever.
Amyl nitrite: Inhalation of amyl nitrite as a first aid
Its clinical application remains limited on account of measure to cyanide poisoning is known for many its other toxicological implications like nephrotoxic- years3-5,9,19. However, the efficacy of amyl nitrite as
ity27. Co-administration of a reduced dose of rapid
methemoglobin inducer remained disputed on ac- methemoglobin inducer like DMAP and a slow in- count of its inability to generate methemoglobin ducer like SN were also found to be an effective pre- greater than 6% 20,21, while about 15% is required to
treatment against acute cyanide poisoning. This regi- challenge one LD dose of cyanide9. Now the pro-
men by virtue of a protracted optimal level of methe- tective effect of amyl nitrite is attributed to its moglobinemia provided sustained prophylaxis in vasodilatory effect that can reverse the early cya- nide induced vasoconstriction9,19. Artificial ventilation
with amyl nitrite broken into ambu bags has been
Other methemoglobin formers: Hydroxylamine
reported as a life saving therapy in cyanide poi- soned dogs, prior to induction of significant level inducer29-31 that was endowed with an anticonvulsive
of methemoglobinemia22.
property32. In view of cyanide induced convulsions
and the toxicity of DMAP, the efficacy of HA co-
Sodium nitrite: Sodium nitrite (SN) is the most preva-
administration with SN was also examined in rats33.
lent drug of choice for cyanide poisoning 3-5,23. When
Although, this regimen minimised the cyanide in- given intravenously (i.v.) it takes about 12 min to gen- duced convulsions, it was less effective as compared erate approximately 40% of methemoglobin 9. Inspite
to SN+DMAP treatment. In addition to prophylaxis, of this delay in inducing a significant level of methe- co-administration of SN and DMAP or HA were also moglobinemia, a reasonable protection offered by SN effective therapeutically34, but their extrapolation to
can be ascribed to its vasodilatory property19. A se-
humans warranted caution in view of the persistent rious drawback with SN is that i.v. administration may toxicity of these regimens35,36.
be accompanied by serious cardiovascular embar-rassment, particularly in children, for whom an ad- The cardiovascular implications and poor pharma- justed dose is recommended24. Since SN induced
cokinetics of SN led to evaluation of yet another group methemoglobinemia impairs oxygen transport, it can- of methaemoglobin formers viz. aminophenones and not be recommended for fire victims where in most derivatives [ρ-aminopropiophenone (PAPP), ρ- instances HCN exposure is accompanied by carbon aminooctanoylphenone (PAOP), ρ-nitrosopropio- monoxide poisoning. Since carbon monoxide also phenone (PNPP) and ρ-hydroxy aminopropio- impairs oxygen carrying capacity of blood, adminis- phenone (PHAPP)]. Out of all these agents PAPP tration of SN would further aggravate the hypoxic con- was the most effective as prophylaxis37,38. Another
dition. SN is also not advised for individuals with glu- alternative treatment of cyanide poisoning, involving cose-6-phosphate dehydrogenase (G6PD) deficient stroma free methemoglobin solution (SFMS) was pro- red cells because of possibility of serious hemolytic posed by Ten Eyck et al 39.Intravenous administra-
reactions19.
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
methemoglobin formers and directly sequestered of methemoglobin formation by SN prompted the de- cyanide to protect a 4 X LD dose of sodium cya- velopment of rapid methemoglobin formers like nide in rats. Efficacy and safety of this antidote re- aminophenols. 4-dimethylaminophenol (DMAP) is the mains to be determined in larger animals.
treatment of choice for cyanide poisoning in Germany.
A dose of 3.25 mg/kg., i.v. of DMAP was reported to b. Cobalt containing compounds: Cobalt ion which
produce methemoglobin level of 30% within 10 min forms a stable metal complex with cyanide is an ef- and 15% methemoglobinemia was attained within fective therapeutic agent against cyanide poison- one minute without any immediate effect on cardio- ing 3-5,40. Various cobalt containing compounds known
R. BHATTACHARYA
to antagonise cyanide poisoning are discussed nide poisoning. It is considered safe as oral form of α-KG is sold as an over-the counter nutritional sup-
plement (Klaire Laboratories, San Marcos, CA)45.
Dicobalt edetate (Kelocyanor): This agent (300 mg
of dicobalt edetate in glucose solution; i.v.) is the cur-
DETOXIFICATION
rent treatment of choice in France and United King-dom. Serious side effects like vomiting, urticaria, Under this group those agents are listed which anaphylactoid shock, hypotension and ventricular enzymatically detoxify cyanide by converting it to a arrythmias have been reported in patients receiving relatively non-toxic product which is readily eliminated kelocyanor19.
from the body. The reaction can be catalyzed by aug-menting the levels of the enzyme endogenously or Hydroxocobalamin (Vitamin B 12a): This agent is
by supplementing the enzyme exogenously or, by perhaps the most promising cyanide antidote used providing more substrate to the enzyme, which in in human toxicology9. With the exchange of hydroxy
this case are sulfur donors. The major mechanism group of hydroxocobalamin for cyanide, non toxic of removing cyanide from the body is its enzymatic cyanocobalamin (Vitamin B12) is formed. However, conversion by the mitochondrial enzyme rhodanese use of this antidote remained limited on account of (thiosulphate-cyanide sulfur transferase, EC 2.8.1.1) the large dose required to challenge cyanide poison- to thiocyanate. Transulfuration of cyanide is also fa- ing. An injectable solution of hydroxocobalamin (5 g cilitated by β-mercaptopyruvate-cyanide sulfur trans- in water) is now available in France and Germany. In ferase (EC 2.8.1.2)10. The enzymatic conversion of
France a 4g hydroxocobalamin solution in 80 ml of cyanide to thiocyanate requires a source of sulfane sodium thiosulphate (STS) has also been developed.
sulfur (a divalent ionised sulfur bound to another Recorded side effects of hydroxocobalamin includes sulfur atom) which is usually offered by thiosulfates anaphylactoid reactions and acne19,40.
or other biological compounds containing sulfane Other cobalt compounds: Cobaltous chloride,
sulfur, like polythionates, thiosulfonates, persulfides cobaltous acetate, cobalt histidine and sodium co- etc.50. It is presumed that the sulfane sulfur binds
balt nitrite are also reported to antagonise cyanide first to the serum albumin to yield sulfane sulfur al- poisoning. However, none of them has been used bumin complex which eventually reacts with cyanide clinically40.
to form thiocyanate5,50. Exogenously administered
thiosulfate usually in the form of STS would supple-
c. Cyanohydrin formers: Cyanide is a nucleophile
ment this reaction rapidly. STS alone administered known to react with various carbonyl moieties like i.v. may be sufficient in moderate cases of cyanide ketones and aldehydes to yield cyanohydrin deriva- poisoning while severe cases of poisoning may ne- tives3-5. Sodium pyruvate was reported to effectively
cessitate co-administration of other antidotes, pref- challenge acute cyanide poisoning in mice41. Another
erably SN9. STS is contra-indicated in patients with
α-ketocarboxylic acid like α-ketoglutaric acid (α-KG) renal insufficiency as the thiocyanate formed may is currently being pursued widely as a cyanide anti- cause toxicity19. Endogenous augmentation of rho-
dote42-45. Protective effect of α-KG was also observed
danese has not been worked out extensively but ex- against cyanide induced convulsions in mice46. α-
ogenous supplementation has been reported to KG either alone or in combination with SN and/or accelerate the transulfuration of cyanide to thiocy- STS attenuated toxicity in mice exposed to cyanide anate51-54. However, stability and sensitivity of the
through different routes47. Prophylactic or therapeu-
tic ability of α-KG was also shown to be augmented
by oxygen48. Cyanide induced histotoxic hypoxia was
PHYSIOLOGICAL
reversed by α-KG which was found to be more effec-
tive than cobalt edetate and sodium pyruvate49. Al-
Oxygen appears to be a physiological antagonist.
though, clinical trials of this agent as cyanide anti- Oxygen alone at hyperbaric pressure has slight pro- dote has not yet been conducted in humans, based tective effect in cyanide poisoning but it dramatically on the promising results in experimental animals, it potentiates the protective efficacy of SN and/ or STS5.
is presently envisaged as a potential antidote for cya- This protective mechanism is not yet clear because ANTIDOTES TO CYANIDE POISONING: PRESENT STATUS
inhibition of cytochrome oxidase by cyanide does not ers, antipsychotics, nitric oxide generators, other deplete the availability of oxygen, only cellular utili- neuroprotective drugs, antioxidants, plasma expand- sation of oxygen is impaired. It is presumed that in- ers, glycolytic substrates, carbonyl compounds tracellular oxygen tension may be high enough to etc.5,17,61-64. Many of these drugs have not been used
cause non enzymatic oxidation of reduced cyto- clinically in humans but their results in experimental chrome or oxygen may displace cyanide from cyto- animals or in vitro are quite encouraging.
chrome oxidase by mass action55. During transulfura-
GLOBAL ATTITUDE AND THE POPULAR
tion there is accumulation of sulphite (SO3-2) which TREATMENT
inhibits the progress of the reaction. It is proposedthat oxygen accelerates the oxidation of sulphite, A retrospective examination of various cyanide anti- thereby enhancing cyanide detoxification56.
dotes reveals that there is no unanimity of opinionregarding the efficacy of a particular treatment regi- BIOCHEMICAL
men. This is mainly due to different experimentalconditions, test protocols and species of animals The compounds classified as biochemical antidotes employed in evaluating various antidotes. Adoption have largely unexplained mechanism of action and of a particular treatment in a country is dictated by are also regarded as non-specific antidotes. These various factors including the regulatory bodies and compounds are usually not very effective per se but the legislations. There is no global unanimity on this as adjuncts significantly augment the efficacy of con- issue, like SN and STS combination is the drug of ventional antidotes. A few chemicals belonging to this choice for cyanide poisoning in U.S.A. and many other class of antidotes are discussed below.
countries, France and U.K. have adopted kelocyanorwhile Germany is still continuing with DMAP and STS Chlorpromazine: The potent vasodilatory action of
combination. However, SN (10 ml of 3% solution) and nitrites prompted the examination of vasogenic drugs STS (50 ml 25% solution) combination is still the most as cyanide antagonist. Chlorpromazine a neurolep- prevalent treatment in cyanide poisoning. Artificial tic phenothiazine, was found to significantly potentiate ventilation with 100% oxygen via Ambu bag contain- the efficacy of SN and STS combination in cyanide ing the contents of two ampoules of amyl nitrite (0.6 toxicity5. Its protective effect was attributed to its α-
ml) is usually practiced as the first aid therapy. The adrenergic blocking property57. Subsequently, the
use of antidote should be restricted to patients in deep antidotal activity of chlorpromazine was related to its coma with respiratory insufficiency. Supportive ability to sustain cellular calcium homeostasis and therapy of diazepam i.v.(3 x 10 mg) and 4.2% so- maintenance of membrane integrity by preventing dium bicarbonate solution to correct the convulsions peroxidation of membrane lipids1,58.
and metabolic acidosis respectively have also been Other agents: Other α-adrenergic blocking agents
used in human poisoning. To revert excessive meth- like phenoxybenzamine and various autonomic aemoglobinaemia i.v. administration of 30 ml of 1% drugs, vasodilators such as papaverine, organic ni- methylene blue solution is also recommended9.
trates and anti-histaminic compounds have shown
some antidotal efficacy in cyanide poisoning5. Cya-
CONCLUSION
nide induces respiratory cessation mediated through There are diverse approaches to antagonise cyanide inhibitory action of released endorphin. Therefore, toxicity. However, full expression of antidotal potency stereo-specific opiate antagonist (-) naloxone hydro- of a regimen principally lies on clinical presentations chloride was found to protect against cyanide induced and the immediate judgement. With the resurgence lethality in mice59. Role of neuronal calcium in cya-
of interest on cyanide antidotes a more effective pro- nide induced neurotoxicity and beneficial effects of phylactic or therapeutic regimen can be anticipated chlor promazine and calcium channel blocker in near future. Considering the rapidity of cyanide (diltiazem) are also well documented1,58,60. The recent
poisoning, objective of further research is not to re- thrust to develop mechanistic based antidotes against place the established antidotes completely but to cyanide poisoning has identified some new classes augment their efficacy to a significant level or evolve of lead compounds like calcium antagonists, non-hyp- new regimens with enhanced efficacy and safety notic barbiturates, anticonvulsants, adrenergic block- which is acceptable with global consensus.
R. BHATTACHARYA
ACKNOWLEDGEMENT
Isom GE, Way JL. Effect of oxygen on cyanide intoxicationVI. Reactivation of cyanide inhibited glucose catabolism.
The author is grateful to Dr. R.V. Swamy, Director J Pharmacol Exp Ther 1974;189:235-43.
and Dr. R. Vijayaraghavan, Head of the Pharmacol- Solomonson LP. Cyanide as a metabolic inhibitor. In Cya- ogy and Toxicology Division, Defence R & D Estab- nide in biology edited by B. Vennesland, E.E. Conn, C.J.
lishment, Gwalior for their keen interest and critical Knowles, J. Westley & F. Wissing, San Diego, Academic suggestions in preparation of this manuscript.
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Professor P.C. Dandiya. EmeritusProfessor and Advisor. RobertHeilig Library. S.M.S. Medical Col-lege, Jaipur, talks of his days inJaipur. He recalls life in Jaipur in hisearly childhood when the Maharajafound a third wife. He also narrateshis stay in Lucknow. Varanasi,Toront, Libya and New Delhi anddwells on his impressions on thefreedom movement, the SecondWorld War and the Muslim Connec-tion.
He traces the introduction of newdrugs from 1943 and writes abouthis experience with LSD, the drugwhich was largely misused in theSixties and Seventies.
Vallabh Prakashan
SU-221, Pitampura, Delhi-110 034.
Price: Rs. 350/-

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