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EC number: 200-240-8
CAS number: 55-63-0
In industrial environments NG may be absorbed by human skin, mucosa, and respiratory tract.
The studies byGrossand others show that the rate of Nitroglycerin absorption trough the skin of rat’s side amounts to 0,85 mg/cm2/hour, which equals to the 1/12 of the limit value, as defined for EGDN.
Distribution and accumulation in organisms
Di Carloand others have found, that the radioactivity levels in rats, after 30 minutes from the intragastric administration of radiocarbon-labeled NG, were respectively 6,4% in blood, 2,9% in urine, and 2,4 % in the air breathed out by them as carbon dioxide.
In rabbits and dogs, after the intravenous administration of NG in rate of 1 mg/kg, it was found that the parent compound’s concentration in blood plasma reaches its maximal level of 10 μg/ml during first 10 to 20 minutes after the administration, and then rapidly decreases. In parenchymatous organs this process is alike. The NG is fixed by plasma proteins in quantities up to 30% of the administrated dose. The concentration in erythrocytes is lower than in the plasma.
The toxicokinetic data show that NG does not accumulate in organisms.
The biotransformation of NG, which consist in progressive splitting of ester bonds, takes place in the presence of reduced glutathion(G-SH).HeppelandHilmoehave found in their experimentsin vitrothat NG enters in reaction with G-SH to form inorganic nitrite (NO2-) and oxidized glutathione. This reaction seems to be catalyzed by an enzyme that is present in the soluble fraction of liver.According to the opinion by the above researchers, since the G-SH does not react spontaneously with inorganic nitrides, therefore it would be a reduction by G-SH before. In this manner electrons that are released when disulfide bonds are generated, may be easily attached by nitrate radicals, the latter finally transforming in NO2-ions.
In biotransformation process of NG 1,2-ethanediol dinitrate, 1,3-ethanediol dinitrate, 1-mononitrate, 2-mononitrate, as well as glycerol and other metabolites are created. The above metabolites are characterized by levels of biological activity that are significantly lower that those of parent compounds. According toNeelemanandKrantz, glycerol dinitrates are about 4 times less efficient in increasing the coronary circulation of blood, and about 8 times less efficient in decreasing arterial systolic pressure, in comparison with NG.
The lack of NG residues in excrements proves that the substance undergoes total metabolic transformation in the organism
The elimination of NG from organism is ensured mainly by kidneys and by the respiratory tract. Only metabolites are expelled from the organism. Although no toxicokinetic data are available now, on the basis of studies byDi Carloand others it has been well ascertained that the elimination of metabolites in urine and air breathed out is rapid and similar as to the quantities. After 4 hours from a single intragastric administration, circa 20% of NG dose were found in urine in form of the above mentioned metabolites, and circa 20% of NG dose were found in the air breathed out in form of carbon dioxide.
Mechanism of the toxic action
The NG belongs to the group of compounds characterized by their spasmolytic action. The relaxing effect by this substance to the smooth muscles of blood vessels is caused by the creation of so-called S-nitrozothiols which are biologically active metabolic intermediaries. These intermediary substances are generated in non enzymatic manner, through the reaction of NO which is released from lipophile compounds of NG type, thiol chains that are free (cysteine, for instance), and those bond in smooth muscles of blood vessels. The S-nitrozothiols enable guanylyl cyclase, and increase the level of intracellular cyclic guanosine monophosphate (cGMP) that has a relaxing effect to the smooth muscles of blood vessels. The mechanism of this process is still unknown.
The spasmolytic effects of NG are manifested by several hemodynamic changes in the circulatory system caused by angiectasia of heart’s coronary vessels, coronary arteries, and bed of veins. These changes include several symptoms, such as increased blood flow in the coronary system, lower arterial systolic pressure, lower pulse pressure (amplitude of systolic-diastolic pressure of the pulse), lower stroke volume, and tachycardia, as a result of a reflex stimulation by the adrenergic system.
Cephalalgia, which is a characteristic sign for the NG toxicity, and similar to histaminic headache, is caused by angiectasia of intracranial blood vessels.
According toNeedlmanandJohnson, the tolerance to NG, which is typical for repeated exposures, is caused by the metabolism. Under multiple exposures active thiol groups of the nitroglycerin receptor may oxidize, and consequently reduce its sensibility for NG. This conclusion seems to be supported by the specificity of NG biotransformation mechanism itself (18), as well as by the lack of such a tolerance if previously 2-thiol chains have been added.
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