Cardiac toxicity cyanide

Cyanide s binding to metallic ions is also employed in a reaction with cobalt-containing compounds that yields cyanocobalamin (see Section 2.6). Cobalt compounds generally are not used because of their toxicity however, Co2EDTA (Klimmek et al. 1983) and hydroxocobalamin (Benabid et al. 1987 Mengel et al. 1989 Mushett et al. 1952) have been used as antidotes both in clinical and laboratory trials. Cardiac toxicity from Co2EDTA use under clinical conditions has raised caution in its clinical use, as the cardiac... 

Zoltani, C.K., Baskin, S.I., Platoff, G.E. (2004). ECGs and metabolic networks an in silico exploration of cyanide-caused cardiac toxicity. In Pharmacological Perspectives of Some Toxic Chemicals and their Antidotes (S.J.S. Flora, J.A. Romano, S.I. Baskin, eds), pp. 467-78. Narosa Pub., New Delhi. 

HCN is a systemic poison toxicity is due to inhibition of cytochrome oxidase, which prevents cellular utilization of oxygen. Inhibition of the terminal step of electron transport in cells of the brain results in loss of consciousness, respiratory arrest, and ultimately, death. Stimulation of the chemoreceptors of the carotid and aortic bodies produces a brief period of hyperpnea cardiac irregularities may also occur. The biochemical mechanisms of cyanide action are the same for all mammalian species. HCN is metabolized by the enzyme rhodanese which catalyzes the transfer of sulfur from thiosulfate to cyanide to yield the relatively nontoxic thiocyanate. 

Combined arteriolar and venodilator Releases NO spontaneously activates guanylyl cyclase Marked vasodilation reduces preload and afterload Acute cardiac decompensation hypertensive emergencies (malignant hypertension) IV only duration 1-2 min. Toxicity Excessive hypotension, thiocyanate and cyanide toxicity Interactions Additive with other vasodilators... 

Toxic compounds, which interfere with major pathways in intermediary metabolism, can lead to depletion of energy-rich intermediates. For example, fluoroacetate blocks the tricarboxylic acid cycle, giving rise to cardiac and CNS effects, which may be fatal (see chap. 7). Another example is cyanide (see chap. 7). 

The toxic effect is known as histotoxic hypoxia. Cyanide also directly stimulates chemoreceptors, causing hyperpnea. Lack of ATP will affect all cells, but heart muscle and brain are particularly susceptible. Therefore, cardiac arrythmias and other changes often occur, resulting in circulatory failure and delayed tissue ischemic anoxia. Death is usually due to respiratory arrest resulting from damage to the CNS, as the nerve cells of the respiratory control center are particularly sensitive to hypoxia. The susceptibility of the brain to pathological damage may reflect the lower concentration of cytochrome oxidase in white matter. 

Nitroprusside [nye troe PRUSS ide] is administered intravenously, and causes prompt vasodilation, with reflex tachycardia. It is capable of reducing blood pressure in all patients, regardless of the cause of hypertension. The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. [Note Because nitroprusside also acts on the veins, it can reduce cardiac preload.] Nitroprusside is metabolized rapidly (t1/2 of minutes) and requires continuous infusion to maintain its hypotensive action. Sodium nitroprusside exerts few adverse effects except for those of hypotension caused by overdose. Nitroprusside metabolism results in cyanide ion production, although cyanide toxicity is rare and can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys (Figure 19.14). [Note Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.]... 

Adiponitrile s mechanism of toxicity is similar to cyanide because it can potentially liberate cyanide in the body spontaneously. It forms a stable complex with ferric iron in the cytochrome oxidase enzymes, thereby inhibiting cellular respiration. Cyanide affects primarily the central nervous system (CNS), producing early stimulation followed by depression. It initially stimulates the peripheral chemoreceptors (causing increased respiration) and the carotid bodies (thereby slowing the heart). Early CNS, respiratory, and myocardial depression result in decreased oxygenation of the blood and decreased cardiac output. These effects produce both stagnation and hypoxemic hypoxia in addition to cytotoxic hypoxia from inhibition of mitochondrial cytochrome oxidase. 

Ricinine (76) and A-demethylricinine (77) are produced by Ricinus communis [207]. A pharmacological study of ricinine (76) has been reported [208]. The cyanide group of 76 was found to be essential for toxicity. Ricinine did not inhibit cytochrome oxidase it presumably inhibited other respiratory enzymes. Administration of 76 to dogs (30 mg/kg, i.v.) caused a hypotensive effect and 30% decrease in renal blood flow. Administration of 76 to rabbits (>2.0 mg/ml cannula) led to dose dependent cardiac inhibition and reduced coronary blood flow. Ricinine stimulated the motility of rat uterus and rabbit intestine, and was highly toxic to mice (LD50= 10.0 mg/kg) [208]. 

The drawback of cobalt compounds is their rather severe toxicity. Cardiac effects such as angina pectoris and ventricular arrhythmias, edema around the eyes, vomiting, and death have been observed.71 A clinical caveat is that severe toxicity from cobalt can be seen even after initial recovery from acute cyanide poisoning. 

Cyanide is one of the least toxic of the lethal CWAs. The inhalational LCtso values for AC and CK have been estimated to be 2,500-5,000 and 11,000 mg min/m respectively (Simeonova, 2004). The cyanide ion (CN ) is the toxic moiety, mediated primarily by its great affinity for the heme as moiety of cytochrome c-oxidase in mitochondria, a key component in oxidative respiration. This interaction blocks the last stage in the electron transfer chain, resulting in cellular hypoxia and a shift of aerobic to anaerobic cellular respiration, leading to cellular ATP depletion and lactic acidosis. Therefore, tissues with high metabolic demands, such as neurons and cardiac cells, are key targets for toxicity. At lethal doses, death occurs within 6-8 min (Sidell et al., 1997). 

---