Phar 722 Pharmacy Practice III

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Phar 722Pharmacy Practice III

• Vitamins-
• Vitamin K Family
• Spring 2006

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Vitamin K Study Guide

• The applicable study guide items in the Vitamin
  Introduction
• History
• Structures of the various forms of the vitamin
  including the commercial form
• Nomenclature used with this vitamin
• Provitamin concept
• Common causes of deficiency
• Role in the blood clotting process
• Drug-vitamin interactions

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History

• 1929
• Using a special fat free diet designed to
  determine whether chickens synthesize
  cholesterol, Dam observed that the animals
  developed a hemorrhagic condition characterized
  by a prolonged clotting time.
• The condition could be cured by an organic factor
  found in fresh cabbage, ether extract of alfalfa,
  putrefied fish meal, cereals, or hog livers.
• It was named Vitamin K for koagulation vitamin.
• 1989
• An Adequate Intake (AI) was established for this
  vitamin for the first time with the recent 1989
  release.
• PROBLEM Some of the vitamin comes from our
  intestinal flora.
• There still is no RDA.

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Chemistry

• There are two series for this vitamin.
• Vitamin K1 Series
• Mostly obtained from green plants
• It is not active and must be converted to the
  active K2 series.
• Vitamin K2 series
• Produced by bacteria (including our intestinal
  flora) and found in putrefied foods.
• In one form, it is the active vitamin.
• See next slide.

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Commercial form
In certain conditions menadione is administered
in place of Vitamin K.
Conversion occurs in the liver. The intestinal
bacteria produce a family of K2 forms that are
converted to K2 (n4).
Active Form
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Vitamin K Uptake and Metabolism

• The vitamin is obtained from two sources.
• The K1 series is obtained from our diet
• The K2 is from the intestinal flora.
• The conversions to the K2(20) product occur in
  the liver and possibly the intestinal flora.
• Little is known regarding its transport or
  storage.
• It is extensively recycled.
• Except for biochemical mechanism of action, it is
  a poorly studied vitamin.

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Role in Complexing Calcium
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Role in Blood Clotting

• The vitamin is required for the production of
  some of the clotting proteins including
  prothrombin, factors VII, IX, and X, and of
  clot-inhibiting proteins C and S by converting 10
  to 12 glutamate residues to ?-carboxyglutamate.
• Part of the clotting process requires the
  complexation of Ca by ?-carboxyglutamic acid.
• The reason that its role was not discovered
  sooner is that the extra carboxyl group is lost
  as CO2 during the amino acid sequencing.
• (The reason that whole blood is citrated is that
  the citric acid chelates the Ca before it can
  be complexed by the prothrombin. Otherwise the
  bag of blood would contain a big clot which would
  be unsuitable for transfusion.)

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Vitamin K Deficiency-1

• Hemorrhage caused by a lack of clotting proteins.
• Rarely is a vitamin K deficiency caused by
  insufficient diet.
• Many references assume that a significant amount
  of the vitamin is obtained from the patient's
  intestinal flora.
• Therefore, a vitamin K more likely is due to a
  medical condition.
• Originally, many vitamin supplements did not
  contain vitamin K. The main causes of a vitamin
  K deficiency tend to be pathological and include

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Vitamin K Deficiency-2

• Obstructive jaundice (rare today)
• Bile acids are required for absorption of vitamin
  K. Blockage of the bile duct means that the
  concentration of bile salts in the intestine will
  be insufficient for adequate mixed micelle
  formation. If surgery is indicated, an injection
  of phytonadione may be given.
• Loss of the intestinal flora producing the
  vitamin, usually from intensive, long term
  antibiotic treatment
• Much of the vitamin K is obtained from these
  bacteria. It is likely that a patient who is
  receiving antibiotic treatment to reduce the
  bacteria count in the intestine is not receiving
  food nor has been eating well due to the
  intestinal illness. If surgery is involved, an
  injection of phytonadione may be indicated.
• Hemorrhagic Disease of the Newborn
• Infants are born with a sterile intestinal tract.
  
• Little vitamin K in maternal milk.
• There is some evidence that vitamin K recycling
  is not fully developed at birth.
• Until the flora are established, the infant will
  have to get along with the vitamin K they
  received from the mother.
• In the past an infant might die from
  hemorrhaging.
• Oregon and most states require that each newborn
  receive an injection of phytonadione.
• Menadione injection should not be given because
  it can cause a hemolytic anemia in the newborn.

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Possible Role in Bone Formation

• Carboxylated glutamate residues are also found in
  proteins (osteocalcin) associated with bone
  formation.
• There is evidence that adequate levels of the
  vitamin are required for proper bone formation.
  Definite proof still is lacking to correlate
  vitamin K status with osteoporosis.
• Studies that look for a correlation between
  incidence or severity of osteoporosis and use of
  the anticoagulant, coumadin (Warfarin), are
  inconclusive.
• The Framingham Study indicates lower incidence of
  hip fracture with higher intake of vitamin K.
• Some calcium supplements that contain vitamin D
  now have Vitamin K.

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What Is Ahead for Vitamins K?

• There have been reports that vitamin K may have
  some cellular role other than formation of
  ?-glutamyl residues in proteins that complex
  calcium.
• Yes, another vitamin receptor that may regulate
  cell division in some way.
• See Linus Pauling monograph.

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Hypervitaminosis K

• While it is possible to overdose with this
  vitamin, the fact that it generally has not been
  available in OTC products, particularly as an
  individual vitamin, little is known about its
  toxicity in humans. Also, there has been no
  mystique that has caused people to take large
  doses.
• Excess intake of the vitamin does not promote
  clot formation.

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Vitamin-Drug Interaction

• Phytonadioine and menadione overcome the
  anticoagulation activity of the coumadin based
  anticoagulants.
• In general oral phytonadione is as effective as
  the parenteral dosage form and may have less
  adverse reactions.
• IM skin lesions and rashes
• IV chest pain, hypotension, anaphylaxis if
  given too rapidly
• Subcu unpredictable and delayed
• Dosing of coumadin must consider vitamin K intake
  including both vitamin preparations and food.
• A Pharmacists Letter monograph reports that
  low doses may help patients on coumadin stabilize
  their INRs.
• The patient on anticoagulant therapy must be
  counseled to be consistent with the use of
  multivitamins in terms of Vitamin K being
  present.
• Prothrombin time must be monitored regularly as
  the Vitamin K content of the diet will change
  with the availability of seasonal foods.

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Dosage Forms

• The vitamin is very unstable in the presence of
  UV light.
• Phytonadione
• Tablets
• Injection
• This is a clear colloidal solution in which a
  surfactant has been used to disperse the oil
  soluble phytonadione. It normally is
  administered subcutaneously or IM. The solution
  must be warmed for IV administration.
• Menadione
• A water soluble form (Synkavite) administered
  orally is the most common. It is indicated for
  obstructive jaundice, other fat malabsorption
  conditions, and as an antidote for coumadin
  overdosing. The latter will produce a
  prothrombin to thrombin (prothrombin time)
  response within 1 - 2 hours.

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DRIs and Sources

• AI
• Infants 2 - 2.5 µg/day
• Children (1 - 8 years) 30 - 55 µg/day
• Boys and Girls (9 - 18 years) 60 - 75 µg/day
• Men 120 µg/day
• Women 90 µg/day
• Pregnancy 75 - 90 µg/day
• Lactation 75 - 90 µg/day
• Sources
• Food green leafy vegetables
• Broccoli, Brussels sprouts, cabbage, spinach,
  canola oil, soybean oil
• Intestinal bacterial