Antidotes in De..

Thiamine (vitamin B1) is a water-soluble vitamin found in organ meats, yeast, eggs, and green leafy vegetables that is essential in the creation and utilization of cellular energy. While there is no toxicity associated with thiamine excess, thiamine deficiency is responsible for "wet" beriberi (congestive heart failure) and "dry" beriberi (Wernicke encephalopathy and the Wernicke-Korsakoff syndrome). Patients at risk include those with poor oral intake (human immunodeficiency virus [HIV], chemotherapy, fad diets, hyperemesis gravidarum) and those with impaired absorption (alcoholism). Typical signs of Wernicke encephalopathy include ataxia, altered mental status, and ophthalmoplegia. Although administration of 100 mg of parenteral thiamine hydrochloride will protect against thiamine deficiency for more than 1 week, patients with clinical deficiencies may require larger doses.

As a coenzyme in the pyruvate dehydrogenase complex, thiamine diphosphate, the active form of thiamine, accelerates the conversion of pyruvate to acetylcoenzyme A (acetyl-CoA). This reaction occurs at the C2 atom of thiamine, which is located between the nitrogen and sulfur atoms on the thiazolium ring.25 In the protein-rich environment of the enzyme complex, this C2 atom is deprotonated to form a carbanion that rapidly attaches to the carbonyl group of pyruvate, thereby stabilizing it for decarboxylation.32 In a series of subsequent reactions, the hydroxyethyl group that remains bound to thiamine diphosphate is transferred to lipoamide, where an acetyl group is later broken off and attached to coenzyme A (CoA). This overall process links anaerobic glycolysis to the Krebs cycle, where subsequent aerobic metabolism produces the equivalent of 36 mol of adenosine triphosphate (ATP) from each mole of glucose (Fig. A25–1). When pyruvate cannot be converted to acetyl-CoA because of thiamine deficiency, for example, only 2 mol of ATP can be generated by anaerobic metabolism from each mole of glucose. Thiamine is also required as a cofactor for α-ketoglutarate dehydrogenase, a second enzyme in the Krebs cycle, and for transketolase, an enzyme in the pentose phosphate pathway, in which nicotinamide adenine dinucleotide phosphate (NADPH) is formed for subsequent use in reductive biosynthesis. In addition, thiamine is important in maintaining normal neuronal conduction.67,84

###### Figure A25–1.

Thiamine links anaerobic glycolysis to the Krebs cycle. Anaerobic glycolysis only yields 2 mol of ATP as each mole of glucose is metabolized to 2 mol of pyruvate. To obtain the 36 additional ATP equivalents that can be derived as the Krebs cycle converts pyruvate to CO2 and H2O, pyruvate must first be combined with CoA to form acetyl-CoA and CO2. This process is dependent on the thiamine-requiring enzyme system known as pyruvate dehydrogenase complex.

Naturally occurring thiamine is a base composed of a substituted pyrimidine ring and a substituted thiazole ring connected by a methylene bridge. This connection between the two rings is weak, and the molecule is unstable in an ...

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