1. Phar 722 Pharmacy Practice III Vitamins- Vitamin K Family Spring 2006

2. 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

3. 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.

4. Chemistry There are two series for this vitamin. –Vitamin K 1 Series Mostly obtained from green plants It is not active and must be converted to the active K 2 series. –Vitamin K 2 series Produced by bacteria (including our intestinal flora) and found in putrefied foods. In one form, it is the active vitamin. –See next slide.

5. Commercial form Active Form Conversion occurs in the liver. The intestinal bacteria produce a family of K 2 forms that are converted to K 2 (n=4). In certain conditions menadione is administered in place of Vitamin K.

6. Vitamin K Uptake and Metabolism The vitamin is obtained from two sources. –The K 1 series is obtained from our diet –The K 2 is from the intestinal flora. –The conversions to the K 2(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.

7. Role in Complexing Calcium

8. 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 γ- carboxyglutamate. Part of the clotting process requires the complexation of Ca++ by γ-carboxyglutamic acid. –The reason that its role was not discovered sooner is that the extra carboxyl group is lost as CO 2 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.)

10. 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:

11. 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.

15. 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.

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

17. 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.

18. 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 “Pharmacist’s 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.

19. 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.

20. DRIs and Sources AI –Infants2 - 2.5 μg/day –Children (1 - 8 years)30 - 55 μg/day –Boys and Girls (9 - 18 years)60 - 75 μg/day –Men120 μg/day –Women90 μg/day –Pregnancy75 - 90 μg/day –Lactation75 - 90 μg/day Sources –Food: green leafy vegetables Broccoli, Brussels sprouts, cabbage, spinach, canola oil, soybean oil –Intestinal bacterial