Under normal circumstances, the iron moiety within deoxyhemoglobin exists in the ferrous (Fe2+) form. Iron in this oxidation state avidly interacts with compounds seeking electrons, such as oxygen, and in the process is oxidized to the ferric (Fe 3+) state. On exposure to a nonoxygen oxidizing agent, iron donates an electron and transforms oxidation states from Fe2+ to Fe3+. The ferric iron that remains is unreactive, and the hemoglobin that contains the ferric iron is termed methemoglobin. Methemoglobin, therefore, is unable to bind oxygen. Under normal circumstances, a small amount of methemoglobin exists in the blood (<1 percent). An elevated level of methemoglobin defines methemoglobinemia, although this is somewhat of a misnomer as the hemoglobin is contained within the erythrocyte and not free within the blood. The accumulation of methemoglobin is normally limited by enzymatic reduction of the ferric iron back to the ferrous form as rapidly as it forms. The enzyme NADH-methemoglobin reductase (also referred to as nAdH cytochrome-b5 reductase) is primarily responsible for this reduction, in which NADH (reduced nicotine adenine dinucleotide) donates its electrons to cytochrome- b5, which subsequently reduces methemoglobin to hemoglobin.2 In this process, NAD+ (oxidized
NAD) is regenerated (Fig, 18,3,-1). This pathway is responsible for reducing nearly 95 percent of the methemoglobin. A second enzymatic pathway utilizes NADPH and
NADPH-methemoglobin reductase to effect methemoglobin reduction analogous to the NADH-linked enzyme system. This enzyme is of limited importance normally (<5 percent total reduction) due to the lack of a suitable molecule to shuttle electrons in a manner similar to cytochrome- b5. However, this enzyme is crucial for the antidotal effect of methylene blue, which performs this function when administered exogenously ( Fig 183,-1). To a very limited extent, nonenzymatic reduction systems, such as vitamin C and glutathione, may participate in the reduction of methemoglobin to hemoglobin. This limited effect of glutathione explains why patients with glucose-6-phosphate dehydrogenase deficiency, who are deficient in reduced glutathione, are not at increased risk of developing methemoglobinemia.
The primary clinical effect of methemoglobin is to reduce the oxygen content of the blood. Because the hemoglobin-bound oxygen accounts for the vast majority of an individual's oxygen-carrying capacity, as the methemoglobin level rises, oxygen delivery to the tissues fall. However, patients with methemoglobinemia are more symptomatic than patients who suffer from a simple anemia that produces an equivalent reduction in their oxygen-carrying capacity. This is due to a leftward shift in the oxyhemoglobin dissociation curve, the consequence of which is a reduced release of oxygen from the erythrocyte to the tissue at a given partial pressure of oxygen (Fig 1,8,3:2.).
FIG. 183-2. The oxyhemoglobin dissociation curve describes the change in oxygen binding to hemoglobin as the dissolved oxygen (pO 2) varies. The oxyhemoglobin dissociation curve of blood with a 50 percent reduction in erythrocytes (anemia) follows a curve similar to that of nonanemic blood, although the oxygen content is lower to start; i.e., unbinding of half of the oxygen occurs at the same pO 2. The oxygen dissociation curve of blood with 50 percent methemoglobin is shifted to the left so that it is less willing to give up its oxygen despite a similar reduction in oxygen binding sites as the anemic blood.
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Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.