Phar 722 Pharmacy Practice III

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Phar 722Pharmacy Practice III

• Vitamins-
• Thiamin (B1)
• Spring 2006

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Thiamin (B1) 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

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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.

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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).

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Hydroscopic Sol 1 gm/ml Uses parenterally
oral liquids.
Non-hygroscopic Sol 1 gm/ml Uses dry oral
dosage forms.
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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.

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Cofactor Role-1

• Oxidative decarboxylations of a-ketoacids.
• The cofactor form of thiamin is required for all
  oxidative decarboxylations of a-ketoacids.
• The most significant of these
• Pyruvate to acetyl CoA
• a-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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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DRIs-1

• Thiamin requirement parallel carbohydrate intake.
• AI
• Infants 0.2 - 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
• Pregnancy 1.2 mg/day
• Lactation 1.2 mg/day

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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
• Pregnancy 1.4 mg/day
• Lactation 1.5 mg/day
• UL
• None reported

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Food Sources

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