VITAMIN K, [MEDICINAL CHEMISTRY] BY P.RAVISANKAR,STRUCTURES OF VITAMIN K1 AND K2, CHEMISTRY, RECOMMENDED DIETARY INTAKE, SOURCES OF VITAMIN K, BLOOD COAGULATION, ROLE OF VITAMIN K, FUNCTIONS, MECHANISM OF ACTION, VITAMIN K DEFICIENCY, DURG INTERACTIONS, SUMMARY. BY P. RAVISANKAR, VIGNAN PHARMACY COLLEGE, VADLAMUDI, GUNTUR, A.P, INDIA.

1. Prof. Ravisankar
Vignan Pharmacy college
Valdlamudi
Guntur Dist.
Andhra Pradesh
India.
banuman35@gmail.com
00919059994000
Vitamin K and Blood KoagulationCoagulation

2. Vitamin K is a fat-soluble vitamin that plays an important role in blood clotting.
Vitamin K is known as the clotting vitamin .
Vitamin K (K from "Koagulations-Vitamin" (clotting of blood)in German.
They are 2-methyl-1,4-naphthoquinone derivatives.
Vitamin K is Vitamin K" has also been used as a slang term for
ketamine, an unrelated anaesthetic.
Vitamin K is not a single chemical substance but rather a family of
chemically related substances that go by the general name of "vitamin K.".
Vitamin K exists in both natural and synthetic forms. The natural forms of
vitamin K include K1(phylloquinone and vitamin K2 (menaquinone from the
purified fish meal, while synthetic froms are vitamin K3(menadione) and
K4(menadiol sodium diphosphate)
All types of vitamin K fall into a large chemical category of substances
called naphthoquinones. Within this naphthoquinone category, there are
two basic types of vitamin K.
Vitamin K1 is also called phylloquinones, is made by plants. The second
basic type, called menaquinones, is made by bacteria in the large intestine.
(The only exception to this rule involves a special group of bacteria, called
cyanobacteria, which make phylloquinones instead of menaquinones.

3. WHAT IS IT?
RECOMMENDED DAILY INTAKE
DIETARY SOURCES
Vitamin K is also known as anti-hemorrhagic
factor, for its role in the coagulation of blood
Vitamin K

4. Fat-soluble vitamin:
K1 (Phylloquinone) K2 (Menaquinone)
Synthesized by:
• Vegetable and plants.
Synthesized by:
• Bacterial flora of the gut
• Minor source

5. 1
2
3
4
56
7
8
9
10
Basic quinoid nucleus
Phytyl
3-methyl 2-butenyl (prenyl)
(2-methyl-3-phytyl-1,4 napha
quinone)Vitamin K1
(2-methyl-1,4 napthaquinone)
(3,7,11,15,-tetramethyl-2-hexadecenyl)
Quinoid nucleus: 2-methyl-1,4 naphthaquinone.
side chain :(prenyl)n
class name :prenyl menaquinone-n, abbrevated as :MK-n
class name=
n = 10 vitamin k2 (50 is this is no. of “C” atoms
n = 7 vitamin k2 (35)
n= 6 (no. of isoprene units)vitamin k2 (30)
(4W)

6. Menaquinoe-6- indicates vitamin K2(30)
menaquinone-7 indicates vitamink2 (35)
6 and 7 implies number of isoprene units
while 30 and 35 indicate the number of carbon
atoms.
trival names of k2
prenyl menaquinone-n
n=10 vitamin k2 (50)
n=7vitamin (35)
n=6 vitamin k2 (30)

7. What are current public health recommendations for vitamin K?
Adequate Intake (AI) for Vitamin K
Life Stage Age
Males
(mcg/day)
Females
(mcg/day)
Infants 0-6 months 2.0 2.0
Infants 7-12 months 2.5 2.5
Children 1-3 years 30 30
Children 4-8 years 55 55
Children 9-13 years 60 60
Adolescents 14-18 years 75 75
Adults
19 years and
older
120 90
Pregnancy
18 years and
younger
- 75
Pregnancy
19 years and
older
- 90
Breast-
feeding
18 years and
younger
- 75
Breast-feeding
19 years and
older
- 90
http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/
Recommended Daily Intake

8. spinach
cabbage,
cauliflower,
broccoli

9. Cooking does not remove significant
amounts of vitamin K from these foods,
but freezing does

10. Sources of Vitamin K
People usually do not suffer from a deficiency of
vitamin K as it is widely found in our daily diet. It is
abundantly found in green vegetables like spinach,
broccoli,, and cabbage. Cauliflower, yogurt, soya
bean, wheat, oat and tomatoes also contain vitamin
K.
Vitamin K can also be obtained from the
consumption of nuts like cashew nuts, chestnuts
and pine nuts.
Fruits such as avocado and kiwi fruit are a
significant source of this vitamin.
Vitamin K can be found in meat, eggs, cow's milk
and pig's liver. However, vegetables are a richer
source of vitamin K than animals. In addition to all
these natural sources, vitamin K supplements are
also available.

11. FUNCTIONS
COAGULATION CASCADE
MECHANISM
Blood Coagulation

12. Role of vitamin K:
Vitamin K plays a crucial role when it comes to metabolism of
the bones as well as blood clotting. The low serum concentration
of vitamin K has been affiliated with lower bone mineral density,
which essentially leads to an increased risk in hip fractures.
 Vitamin supplements may also have the ability to improve bone mass in
those women that are postmenopausal. Vitamin K prohibits the calcification
of the arteries, as well as other soft tissue throughout the body – this is an
adverse side effect of aging. Vitamin K may also play some kind of role in the
regulation of the body’s blood sugar levels as the pancreas (maker of insulin)
has the second highest concentration of vitamin K found within the body.
Blood clotting – The primary function belonging to vitamin K is
to regulate the routine clotting of blood – this is an automatic
process which begins whenever a blood vessel tears. Vitamin K
plays a role in this by helping the body transport calcium to
areas in need.

13. Role of Vitamin K
Bone health
Role of vitamin K
. Bone health – Supplements including vitamin K as an
ingredient may have the ability to improve bone health as
well as reduce the risk of bone fractures. This is
particularly accurate in women that are postmenopausal
and have a risk for osteoporosis. It’s typically seen that if
an individual has higher levels of vitamin K within their
system, they’ll have a greater bone density. Alternatively,
those that have osteoporosis have low levels of vitamin K.
Liver disease – Usage of vitamin K is able to reduce your
chances of bleeding in the liver, which includes a myriad
of other conditions like jaundice, malabsorption. Vitamin K
has also been used to help treat those that experience
heavy menstrual bleeding.
Vitamin K may also be prescribed to your newborn as
they are at an elevated risk for bleeding in the brain due
to the trauma experienced going through the birth canal
during deliv
Vascular health
Vitamin K also decreases calcification in the arteries by
absorbing the hardened calcium to lessen your risk of heart
disease.

14. Functions
Hemostasis
Designed to maintain blood within injured vessels by three
sequential events:
1. Vasoconstriction
2. Platelet plug formation
3. Coagulation
Coagulation
Fibrin meshwork forms a blood clot, which provides
structural support to the temporary plug formed by platelets
Without fibrin, the initial plug would soon fall apart
Fibrin proteins are the end products of coagulation cascade

15. Coagulation Cascade
 Clotting factors are generally serine
proteases
 Activated form of one clotting
factor catalyzes the activation of the
next
 Occurs on the platelet or tissue
phospholipids, which only becomes
available in injuries
 Activation is amplified at each
stage, resulting in an increased
production of fibrin
 Fibrin clot is formed by the
interplay of the intrinsic, extrinsic,
and final common pathways
http://www.frca.co.uk/images/clotting_cascade.gif

16. Mechanism – Intrinsic Pathway
Begins with activation of
factor XII by surface
contact with a vessel
removed of endothelium
Factor XIII enzymatically
cross-links fibrin
Factor XIII
Activates
Activates
Activates
Activates
Activates
Fischbach, P. David. Coagulation The Essentials

17. Mechanism – Extrinsic Pathway
Alternate method to
activate factor X
Triggered by trauma,
which activates factor VII
Tissue phospholipids
provide surface for
clotting factor binding
and activation
Factor XIII
Activates
Activates
Activates
Fischbach, P. David. Coagulation The Essentials

18. ROLE IN THE MECHANISM
EFFECTS OF DEFICIENCY ON THE MECHANISM
The Role of Vitamin K in
Blood Coagulation

19. Role in the Mechanism
In blood clotting, vitamin K is
needed as a cofactor to
activate clotting factors:
•Clotting factor II
(prothrombin)
•Clotting factor VII
(proconvertin)
•Clotting factor IX
(thromboplastin)
•Clotting factor X
(Stuart factor)
http://www.frca.co.uk/images/clotting_cascade.gif

20. Role in the Mechanism
1. Post-translational modification of glutamate
residues in clotting factors
Carboxylation to γ-carboxyglutamate by
vitamin K-dependent enzyme system
http://www.ch.ic.ac.uk/local/projects/bhonoah/gla.gif

21. Role in the Mechanism
2. γ-carboxyglutamate can
better bind to Ca2+
3. Binding of Ca2+
allows
anchoring of clotting
factor to phospholipid
membranes of blood
platelets -> activation
4. Activated clotting factor
catalyzes activation of the
next clotting factor in the
coagulation cascade
http://www.ch.ic.ac.uk/local/projects/bhonoah/binding.gif
http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi?
book=stryer&part=A1378&blobname=ch10f43.jpg

22. Effects of Deficiency on the Mechanism
Vitamin K limits the
carboxylation reaction
Without vitamin K, lack
of carboxylation results in
inactive clotting factors
Harrison’s Principles of Internal Medicine Online
Two enzymes affect ALL vitamin
K dependent proteins:
1.γ-glutamylcarboxylase (GGCX)
2.Vitamin K epoxide reductase
complex 1 (VKOR-1)

23. SYMPTOMS AND DIAGNOSIS
CAUSES AND RISK FACTORS
MEDICATIONS AND SUPPLEMENTS
CASE STUDY
Vitamin K Deficiency
and Pharmacy

24. The following are some signs(symptoms) of Vitamin-
K deficiency:
• easy or excessive bleeding
• easy or excessive bruising
• nosebleeds
• bleeding gums
• blood in the urine and stool
• extremely heavy menstrual bleeding
• liver damage or disease
• low bone density
• arterial calcification
• malabsorption in the digestive tract

25. Diagnosis
Diagnosis can be confirmed by using blood tests to check
for increased prothrombin time (PT) or International
Normalized Ratio (INR)
http://img.medscape.com/fullsize/migrated/423/474/pharm423474.fig1.jpg

26. Causes and Risk Factors
Infants have higher risk of vitamin K deficiency, especially in
infants that don’t use infant formula
o Low vitamin K levels in breast milk
o Poor transport of vitamin K through placenta
o Low fat stores of vitamin K
o Sterile intestines
o Liver immaturity
Consequently, all newborns receive a vitamin K injection
right after delivery for prevention

27. Causes and Risk Factors
Risk of dietary vitamin K deficiency is rare in adults unless
other risk factors exist in addition to chronic malnutrition
Any disease or surgery that causes malabsorption
o Obstructed biliary tracts
o Chronic small-intestine diseases like Crohn’s disease
o Surgery like small intestine resection
o Cystic fibrosis
o Persistent diarrhea

28.  DEFICIENCY CAUSED BY
 In Babies:
 low levels in human breast milk
 poor transfer across placenta
 sterile intestine with no bacteria
 In Adults:
 as a consequence of sprue
 Celiac's Disease
 destruction of intestinal bacteria by antibiotics
 lack of bile salts
 liver conditions, such as viral hepatitis
 surgical removal of intestines
 prolonged ingestion of liquid paraffin
 DEFICIENCY LEADS TO
 inability of blood to coagulate
 SYMPTOMS OF TOXICITY
 none reported

29. Vitamin K shots are routinely administered to newborn babies in U.S.
hospitals, birth centers and by some home birth midwives because 1.8
out of every 100,000 babies who do not receive vitamin K injections
suffer permanent injury or death due to uncontrolled bleeding in the
brain (hemorrhagic disease of the newborn) that may be the result of
having extremely low levels of vitamin K in their systems
Vitamin K is produced by bacteria, including the
flora found in our gut. However, a newborn’s
gastrointestinal tract is typically sterile for a few days
after birth. The body's production of Vitamin K and,
therefore, clotting factors, begins by the fourth day of
life, giving babies their ability to clot blood. This is
why newborns are typically given Vitamin K
injections shortly after birth in hospitals and some
birth centers

30. Deficiency of vitamin K is quite rare, as it is widely
distributed in many sources of food and also because
it is produced by the intestinal bacteria. Its
absorption depends on bile salts and therefore, any
disease of the liver which can impair bile secretion is
more likely to cause a deficiency of this vitamin.
Infants, are at a higher risk of suffering from a
deficiency of this vitamin, as human milk is not a
very rich source of vitamin K. People suffering from
intestinal diseases, like the inflammatory bowel
disease, may experience a deficiency of vitamin K, as
the disease can impair intestinal functions. Certain
medications such as antibiotics may also be an
important factor leading to a vitamin K deficiency

31. vitamin K deficiency is rare – almost everyone gets more than enough from their own bacteria
and from their food.
Sometime newborn babies don’t have enough vitamin K because they don’t yet have any
bacteria to make it in their intestine.
To make up for them, most newborns are given an injection of a tiny amount of vitamin K soon
after birth.
When adults get vitamin K deficiency, it’s generally because they eat very few green vegetables
or because they have been taking oral antibiotics for a long time.
The antibiotics kill off the intestine bacteria that make vitamin K. Sometimes vitamin K deficiency
is caused by liver disease or a problem digesting fat.
The major symptom of vitamin K deficiency is that blood clot very slow, so it will bleed for along
time even from minor injuries.
Vitamin K deficiency causes bug black and blue marks from very slight bruises or even for no
reason, nosebleeds, blood in your urine and intestinal bleeding.
Vitamin K

32. Causes and Risk Factors
Those taking certain medications are also at risk
 Drugs can reduce Vitamin K levels if they affect liver function
or kill intestinal bacteria that synthesize menaquinones
 Long-term use of broad-spectrum antibiotics
 High doses of salicylates like aspirin
 Anticonvulsants
 Some sulfa drugs
 Quinine/quinidine
 Cholestyramine

33. Medications and Supplements
Toxicity:
No known excess vitamin K toxicity effects in adults
In newborns, there is a risk of hemolysis and jaundice

34. Medications and Supplements
Drug Interactions:
Orlistat and mineral oil can decrease absorption of
orally-administered Vitamin K
Vitamin K can reduce the effects of oral anticoagulants
like warfarin
 Vitamin K can thus increase risk of clotting in those patients
 Avoid taking a lot of vitamin K in supplements or food
 Use to reverse effects of warfarin before surgery or after overdose

35. FUNCTION
aids in reducing excessive menstrual flow
aids the absorption of calcium in bone
essential for normal liver functioning
essential for synthesis of four proteins that act in
coagulation
important in maintaining vitality and longevity
necessary for formation of prothrombin which is
required for effective blood clotting
involved in electron transport mechanism and
oxdative phosphorylation

36. INCREASED INTAKES NEEDED
after prolonged paraffin ingestion
for those with biliary obstructions
for those with liver disease
if taking antibiotics for long duration
if you have a malabsorption disease
in newborn babies
in overdose of anticoagulant drugs, such as Warfarin,
Dicoumarol, which neutralize the effect of Vitamin K

37. Vitamin K used for:-
anticoagulant drug overdose
reduces excessive menstral flow
essential for blood clotting/haemorrhage and
bleeding
hemorrhagic disease in newborn babies
inhibiting some cancer tumors
overcoming inability to absorb vitamins
overcoming effects of antibiotics on intestinal
bacteria
protection against osteoporosis

38. DESTROYED BY
acids
alkalis
commercial processing
light and ultra-violet irradiation
oxidizing agents
SYMPTOMS OF DEFICIENCY
excessive bleeding and hemorrhage
In babies:
bleeding from the stomach, intestines, umbilical cord site
DEFICIENCY CAUSED BY
In Babies:
low levels in human breast milk
poor transfer across placenta
sterile intestine with no bacteria
In Adults:
as a consequence of sprue
Celiac's Disease
destruction of intestinal bacteria by antibiotics
lack of bile salts
liver conditions, such as viral hepatitis
surgical removal of intestines
prolonged ingestion of liquid paraffin
DEFICIENCY LEADS TO
inability of blood to coagulate
SYMPTOMS OF TOXICITY
none reported

39. Summary
 Vitamin K is a fat-soluble vitamin that is found in green leafy vegetables
and is involved in blood coagulation
 Two natural subtypes: K1 (phylloquinone) and K2 (menaquinone)
 A coagulation cascade produces fibrin to clot blood
 Vitamin K is involved in the activation of clotting factors
 Vitamin K is a cofactor in the carboxylation of glutamate residues in
clotting factors, leading to Ca2+
binding and clotting factor activation
 Vitamin K deficiency can cause hemorrhage symptoms
 Vitamin K deficiency is rare in adults, but is a risk in newborns
 Oral anticoagulants inhibit the effects of vitamin K and vice versa