Friday, October 15, 2004

Specific antidotal therapy

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; 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.

Scavengers
Methemoglobin formers
Amyl nitrite
Sodium nitrite
4-Dimethylaminophenol
other methemoglobin formers
Cobalt containing compounds
Dicobalt edetate (Kelocyanor)
Hydroxocobalamin (Vitamin B12 a)
Other cobalt compounds
Cyanohydrin formers
Detoxification
Physiological
Biochemical
Chlorpromazine
Other agents

Scavengers
These are compounds that inactive cyanide by binding it or by forming methaemoglobinemia, which in turn sequesters cyanide.

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 cytochrome oxidase, and eventually blinds with the former to form cyanmethemoglobin. Methemoglobin removes cyanide from extracellular fluid space and, by doing so, displaces cyanide from the intracellular fluid. Thereby, the activity of inhibited cytochrome oxidase is restored.
Methemoglobin formation, both sodium and amyl nitrite cause significant vasodilatation, which warrants careful monitoring. Marked vasodilatation with orthostatic hypotension, dizziness, and headache, in addition to the unpredictable levels of methemoglobin formed, limit the utility of amyl nitrite in an upright casualty. Therefore, if casualty is conscious and able to stand, he should not receive any nitrite. These factor, together with other concerns, have caused amyl nitrite to be removed from the cyanide antidote kit in the U.S Army formulary for field units.
Some data indicate that nitrites exert their action by mechanism other than methemoglobin formation. It has been suggested that the protective effect is due to the vasodilating effect of nitrite. Several α-adrenergic antagonists (eg.chlorpromazine, promethazine, promazine, and phenoxybenzamine) that cause vasodilatation also antagonize cyanide toxicity. Further information is needed to determine the mechanism or mechanisms by which chlorpromazine and phenoxybenzamine reverse cyanide intoxication.
Amyl nitrite
Inhalation of amyl nitrite as a first aid measure to cyanide poisoning is known for many years. However, the efficacy of amyl nitrite as methemoglobin inducer remained disputed on account of its inability to generate methemoglobin greater than 6 %, while about 15 % is required to challenge one LD50 dose of cyanide. Now the protective effect of amyl nitrite is attributed to its vasodilatory effect than can reserve the the early cyanide induced vasoconstriction. Artificial ventilation with amyl nitrite broken into ambu bags has been reported as a life saving therapy in cyanide poisoned dogs, prior to introduction of significant level of methemoglobulinemia.

Sodium nitrite
Sodium nitrite (SN) is the most prevalent drug of choice for cyanide poisoning. When given intravenously (i.v.) it takes about 12 minutes to generate approximately 40 % of methemoglobin. In spite of this delay in inducing a significant level of methemoglobulinemmia, a reasonable protection offered by SN can be ascribe to its vasodilatory property. A serious problem with SN is that i.v. administration may be accompanied by serious cardiovascular difficulties, particularly in children, for whom an adjusted dose is recommended. Since SN induced methemoglobulinemia impairs oxygen transport, it can not recommended for fire victims where in most instances HCN exposure is accompanied by carbon monoxide poisoning. Since carbon monoxide also impairs oxygen carrying capacity of blood, administration of SN would further aggravate the hypoxic condition. Alternative therapy in this situation consists of administering oxygen, thiosulfate, and other standard supportive measures. SN is also not advised for individual with glucose-6-phosphatasse dehydrogenase (G6PD) deficient red cells because of possibility of serious hemolytic reactions.
Sodium nitrite is available in 10-mL ampules containing 300 mg mg for intravenous administration. The solution of sodium nitrite (30 mg/mL) should be given to an adult intravenously over 5 to 15 minutes, with careful monitoring of blood pressure. A single dose is sufficient to rise the methemoglobin level to 20 % in an adult, and a second dose, up to half as large as the initial one, can be given. Methemoglobin levels should be monitored if possible and kept bellow 35% to 40%, the range that is associated with oxygen-carrying deficits caused by methemoglobin itself. Because most automated clinical analyzers do not detect cyanmethemoglobin, the residual normal hemoglobin capable of oxygen transport can be overestimated by measuring total hemoglobin only.
In children, sodium nitrate can cause lethal methemoglobin levels if the dose is too high. The recommended dose for children is 0.33 mL of the 10% solution per kilogram of body weight.

4-Dimethylaminophenol
The relatively slow rate of methemoglobin formation by SN prompted the development of rapid methemoglobin formers like amoniphenols. 4-dimethylaminophenol (DMAP) is the treatment of choice for cyanide poisoning in Germany. A dose of 3.25 mg/kg.,i.v. of DMAP was reported to produce methemoglobin level of 30% within 10 min and 15% methemoglobinemia was attained within one minute without any immediate effect on cardiovascular system. However, there are differences in individual susceptibility to DMAP which may result in an undesirable levels of methemoglobulinemia even after normal therapeutic doses. Intramuscular injection of DMAP results in local abscess and fever. Its clinical application remains limited on account of its other toxicological implication like nephrotoxicity. Co-administrator of a reduced dose of rapid methemoglobin inducer like DMAP and a slow inducer like SN were also found to be an effective pretreatment against acute cyanide poisoning.

Other methemoglobin formers :
Hydroxylamine (HA) was yet another rapid methemoglobin inducer that was endowed with an anticonvulsive property. In view of cyanide induced convulsions and the toxicity of DMAP, the efficacy of HA co-administration with SN was so examined in rats. Although, this regiment minimized the cyanide induced convulsions, it was less effective as compared to SN+DMAP treatment. In addition to prophylaxis, co-administration of SN and DMAP or HA were also effective therapeutically, but their extrapolation to humans needed caution in view of the persistent toxicity of these regimens.
Another group of methemoglobin formers namely aminophenones and derivates PAPP (p-aminopropiophenone), PAOP (p-aminooctanoylphenone), PNPP (p-nitrosopropiophenone) and PHAPP ( p-hydroxy aminopropiophenon ), out of all these agents PPAP was the most effective as prophylaxis. Another alternative treatment of cyanide poisoning, involve stroma free methemoglobin solution (SFMS) was proposed by Ten Eyck et al . intravenous administration this solution did not impair the oxygen carrying capacity of blood as caused by most other methemoglobin formers and directly sequestered cyanide to protect a 4 X LD50 dose of sodium cyanide in rats.

Cobalt containing compounds
Cobalt ion which forms a stable metal complex with cyanide is as effective therapeutic agent against cyanide poisoning.
Dicobalt edentate (Kelocyanor)
Cobalt salts have been shown to be an effective means for binding cyanide in vitro and in vivo. Kelocyanor, the cobalt salt of ethylene diamine tetra acetic acid (EDTA), which is commercially available in Europe but not in the United States, is administrated intravenously. In comparison studies against nitrite and thiosulphate , the cobalt chelate was thought to be superior; however, in other studies the nitrite-thiosulfate combination was found to be superior.
This agent (300 mg of dicobolt edentate in glucose solution;i.v.) is the current treatment of choice in France and United Kingdom. The drawback of cobalt compounds is their rather severe toxicity. Cardiac effect such as angina pectoris and ventricular arrythmias, edema around the eyes, vomiting, and death have been observed. A clinical caveat is that severe toxicity from cobalt can be seen even after initial recovery from acute cyanide poisoning.

Hydroxocobalamin (Vitamin B12 a) :
This agent is perhaps the most promising cyanide antidote used in human toxicology. With the exchange of hydroxyl group of hydroxycobalamin for cyanide, non toxic cyanocobalamin (Vitamin B12) is formed. However, use of this antidote remained limited on account of the large dose required to challenge cyanide poisoning. An injectable solution of hydroxocobalamin (5 g in water) is now available in France and Germany. In France a 4g hydroxocobalamin solution in 80 ml of sodium thiosulphate (STS) has also developed. Recorded side effects of hydroxocobalamin includes anaphylactoid reactions and acne.

Other cobalt compounds
Cobaltous chloride, cobaltous acetate, cobalt histidine and sodium cobalt nitrite are also reported to antagonize cyanide poisoning. However, none of them has been used clinically.
Cyanohydrin formers
Cyanide is a nucleophile known to react with various carboxyl moieties like ketones and aldehydes to give cyanohydrine derivatives. Sodium pyruvate was reported to effectively challenge acute cyanide poisoning in mice. Another α-ketoglutaric acid (α-KG) is currently being pursued widely as a cyanide antidote. Protective effect of α-KG was also observed against cyanide induced convulsions in mice. Α-KG either alone or in combination with SN and/or STS attenuated toxicity in mice exposed to cyanide through different routes. Prophylactic or therapeutic ability of α-KG was also shown to be augmented by oxygen. Cyanide induced histotoxic hypoxia was reversed by α-KG which was found to be more effective than cobalt edetate and sodium pyruvate. Although, clinical trials of this agent as cyanide antidote has not yet been conducted in humans, based on the promising results in experimental animals, it is presently envisaged as a potential antidote for cyanide poisoning. It is considered safe as oral form of α-KG is sold as an over-the counter nutritional supplement (Klaire Laboratories, San Marcos, CA)

Detoxification
Under this group those agents are listed which enzymatically detoxify cyanide by converting it to a relatively non-toxic product which is readily eliminated from the body. The reaction can be catalyzed by augmenting the levels of the enzyme exogenously or by supplementing the enzyme exogenously or, by providing more substrate to the enzyme, which in this case are sulfur donors. The major mechanism of removing cyanide from the body is its enzymatic conversion by the mitochondrial enzyme rhodanase (thiosulphate-cyanide sulphur transferase,) to thiocyanate. Transulfuration of cyanide is also facilitated by β-mercaptopyruvate-cyanide sulfur transferase. The enzymatic conversion of cyanide to thiocyanate requires a source of sulfane sulfur (a divalent ionized sulfur bound to another sulfur atom) which is usually offered by thiosulfates or other biological compounds containing sulfane sulfur, like polythionates, thiosulfonates, persulfides etc.
It is presumed that the sulfane sulfur binds first to the serum albumin to yield sulfane sulfur albumin complex which eventually reacts with cyanide to form thiocyanate. Exogenously administrated thiosulfate usually in the form of STS would supplement this reaction rapidly. STS alone administrated i.v. may be sufficient in moderate cases of cyanide poisoning while severe cases of poisoning may necessitate co-administration of other antidotes, preferably SN. STS is contra-indicated in patients with renal insufficiency as the thiocyanate formed may cause toxicity. Endogenous augmentation of rhodanase has not been worked out extensively but exogenous supplementation has been reported to accelerate the transulfuration of cyanide to thiocyanate. However, stability and sensitivity of the enzyme remains to be addressed.

Physiological
Oxygen appears to be a physiological antagonist. Oxygen alone at hyperbaric pressure has slight protective effect in cyanide poisoning but it dramatically potentiates mechanism is not yet clear because inhibition of cytochrome oxidase by cyanide does not deplete the availability of oxygen, only cellular utilization of oxygen is impaired. It is presumed that intracellular oxygen tension may be high enough to cause non enzymatic oxidation of reduced cytochrome or oxygen may displace cyanide from cytochrome oxidase by mass action. During transulfuration there is accumulation of sulphite (SO3-2) which inhibits the progress of the reaction. It is proposed that oxygen accelerates the oxidation of sulfite, thereby enhancing cyanide detoxification.

Biochemical
The compounds classified as biochemical antidotes have largely unexplained mechanism of action and are also regarded as non-specific antidotes. These compounds are usually not very effective per se but as adjuncts significantly augment the efficacy of conventional antidotes. A few chemicals belonging to this class of antidotes :

Chlorpromazine
The potent vasodilatory action of nitrites prompted the examination of vasogenic drugs as cyanide antagonist. Chlorpromazine a neuroleptic phenothiazine, was found to significantly potential the efficacy of SN and STS combination in cyanide toxicity. Its protective effect was attributed to its α-adrenergic blocking property. Subsequently, the antidotal activity of chlorpromazine was related to its ability to sustain cellular calcium hemostasis and maintenance of membrane integrity by preventing peroxidation of membrane lipids.

Other agents
Other α-adrenergic blocking agents like phenoxybenzamine and various autonomic drugs, vasodilators such as papaverine, organic nitrates and anti-histaminic compounds have shown some antidotal efficacy in cyanide poisoning. Cyanide induces respiratory cessation mediated through inhibitory action of released endorphin. Therefore, stereo-specific opiate antagonist cyanide induced lethally in mice. Role of neuronal calcium in cyanide induced neurotoxicity and beneficial effects of chlorpromazine and calcium channel blocker (diltiazem) are also well documented. The recent thrust to develop mechanistic based antidotes against cyanide poisoning has identified some new classes of lead compounds like calcium antagonist, non-hypnotic barbiturates, anticonvulsants, adrenergic blockers, antipsychotics, nitric oxide generators, other neuroprotective drugs, antioxidant, plasma expanders, glycolytic substrate, carbonyl compounds etc. Many of these drugs have not been used clinically but their results in experimental animals or in vitro are quite encouraging.

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