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Phar 722 Pharmacy Practice III

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Title: Phar 722 Pharmacy Practice III


1
Phar 722Pharmacy Practice III
  • Vitamins-
  • Thiamin (B1)
  • Spring 2006

2
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

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.

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8
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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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.

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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.

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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
  • 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

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
  • Pregnancy 1.4 mg/day
  • Lactation 1.5 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.)
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