1. Phar 722 Pharmacy Practice III Vitamins- Thiamin (B 1 ) Spring 2006

2. Thiamin (B 1 ) Study Guide The applicable study guide items in the Vitamin Introduction History Structures including commercial forms of the vitamin Conversion to the cofactor form Function and cofactor including the specific types of reactions Commercial forms of the vitamin

3. History After 26 years of constant research, the vitamin preventative of the disease beri-beri has been isolated, its chemical constitution determined and the vitamin itself synthesized at a cost far lower than that of recovering it from bran. –--Scientific American, February 1938; reprinted in 258, 12 (Feb. 1988) Beriberi is based on a Chinese term. Sailors in the Japanese navy experienced thiamin deficiencies when fed rice in which the polishings had been removed to prevent mold growth. This is somewhat analogous to removing the germ from wheat in order to prolong the shelf life of flour containing foods.

4. Chemistry Thiamin consists of a pyrimidine joined to a thiazole ring by a methylene bridge. The thiazole nitrogen is a quaternary with a permanent positive charge. –There are two commercial salts. Thiamin hydrochloride is, in reality thiamin chloride hydrochloride. It is a double salt consisting of an amine hydrochloride on the pyrimidine amine and a chloride on the thiazole quaternary nitrogen. –The double salt is very water soluble (1 gm/1ml) and, unfortunately, very hygroscopic. Thiamin nitrate is correctly named in that the nitrate anion is found on the quaternary nitrogen, and the pyrimidine amine is not protonated. –The mononitrate is non-hygroscopic and still has good water solubility (1 gm/35 ml).

5. Hydroscopic; Sol: 1 gm/ml Uses: parenterally & oral liquids. Non-hygroscopic’ Sol: 1 gm/ml Uses: dry oral dosage forms.

6. Thiamin Uptake and Metabolism An active transport system provides efficient uptake of the vitamin into the intestinal mucosa cell. A thiamin kinase in the intestinal mucosa cell transfers a pyrophosphate from the ATP to the propyl alcohol at position 5 of the thiazole ring forming thiamin pyrophosphate. –The latter product is the cofactor form of the vitamin. –There is some evidence that this phosphorylation is the rate limiting step and controls the absorption of the vitamin. –The cofactor is then transported to the necessary tissues.

8. Cofactor Role-1 Oxidative decarboxylations of α- ketoacids. –The cofactor form of thiamin is required for all oxidative decarboxylations of α-ketoacids. The most significant of these –Pyruvate to acetyl CoA –α-Ketoglutarate to succinyl CoA –Methioninie and the three nonpolar amino acids, valine, leucine, and isoleucine, also have an oxidative decarboxylation as part of their degradative metabolism.

10. Cofactor Role-2 Transketolase Reaction –Catalyzed transfer of two carbon fragments in the pentose phosphate pathway. The thiamin RDA is based on the amount of carbohydrate in the diet.

12. Possible Non-cofactor Role Based on animal studies, there is evidence that thiamine pyrophosphate (TPP) may be required for proper function of the ion channels in nerve conduction. –This may explain some of the neurological symptoms seen with thiamin deficiencies.

13. Thiamin Deficiency-1 Beriberi. –Wet beriberi Edema resulting from a diseased heart –Dry beriberi Peripheral neurological symptoms. –Cerebral beriberi (Wernicke-Korsakoff Syndrome) –The wet and dry conditions are reversible upon administration of thiamin supplements. Reversibility of cerebral beriberi is dependent on the degree of brain damage. –Thiamin deficient individuals can experience a variety of symptoms.

17. Thiamine Deficiency-2 Thiamin deficiencies are seen in chronic alcoholism. It is thought that chronic ingestion of alcoholic beverages somehow inhibit thiamin uptake by the mucosal cell or possibly interfere with conversion to the cofactor form. It has been routine for many emergency rooms to include thiamin when administering an IV to an unconscious patient caused by improper drug use. It is assumed that these patients also suffer from chronic alcoholism and are experiencing Wernicke-Korsakoff Syndrome (cerebral beriberi), a form of thiamin deficiency.

18. Thiamin Deficiency-3 In November 2003, a German manufacturer of a soy-based infant food formula sold a product lacking thiamin in Israel. –There were six cases of severe neurological conditions including two infant deaths. –The company made the following mistakes in formulating this new product (4 executives were dismissed): The analysis data for the new soy-based formula was wrongly interpreted with the result that thiamin was not added. The final product only contained 10 percent of the amount stated on the label. (It was mislabeled!) Although sent to an outside laboratory for testing, the fact that the analysis came back with the vitamin content missing was ignored. When it finally was discovered that the vitamin analysis was missing, there was no follow-up inquiry.

19. Hypervitaminosis Thiamin The vitamin is considered very safe. Possibly the rate limiting phosphorylation step in the intestinal mucosa reduces the risk of toxicity. Estimated toxic dose: 300 mg –There is no UL.

20. Dosage Forms Most of the commercial forms of the vitamin are synthetic. Thiamin Hydrochloride –Very water soluble (1 gm/1 ml) –Very hygroscopic - making it difficult to use in dry formulations. –Commonly used in liquid preparations including parenterals. Thiamin Mononitrate –Solubility: 1 gm/35 ml –Non-hygroscopic - making it the salt of choice for dry dosage forms.

21. DRIs-1 Thiamin requirement parallel carbohydrate intake. AI –Infants0.2 - 0.3 mg/day EAR –Children (1 - 13 years)0.4 - 0.7 mg/day –Males (14 - 18 years)1.0 mg/day –Females (14 - 18 years)0.9 mg/day –Men (19 - 50+ years)1.0 mg/day –Women (19 - 50+ years)0.9 mg/day –Pregnancy1.2 mg/day –Lactation1.2 mg/day

22. DRIs-2 RDA –Children (1 - 13 years)0.5 - 0.9 mg/day –Males (14 - 18 years)1.2 mg/day –Females (14 - 18 years)1.0 mg/day –Men (19 - 50+ years)1.2 mg/day –Women (19 - 50+ years)1.1 mg/day –Pregnancy1.4 mg/day –Lactation1.5 mg/day UL –None reported

23. Food Sources Beans Nuts Fruits Cereal grain germs Spinach Meat (Animals have to obtain thiamin from plants or eating other animals.)