Coagulants & Anticoagulants Medicinal Chemistry II

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COAGULANTS & ANTICOAGULANTS
Shree WaranaVibhagShikshan Mandal's
Tatyasaheb Kore College of Pharmacy, Warananagar
Created By
Miss. A. B. Patil
M. Pharm (Pharmaceutical Chemistry)
Assistant Professor

Coagulants & Anticoagulants
Coagulants- Coagulants are the agents which promote the haemostasis
(the process of stopping bleeding or arrest the blood loss) and coagulation
process (is the process where blood transforms from a liquid to a gel-like
state, preventing excessive bleeding) and are indicated for hemorrhagic
(The release of blood from a broken blood vessel, either inside or outside
the body) states.

 It involves two main pathways, the
intrinsic and extrinsic, which converge
into a common pathway.
 Intrinsic Pathway: Activated by
internal damage to the blood vessel
wall, involving factors like Factor XII,
XI, IX, and VIII.
 Extrinsic Pathway: Activated by
external trauma that exposes blood to
tissue factor, a protein found outside the
bloodstream, involving Factor VII.

List of coagulation factors

Coagulants
Drugs
a)Vit K
 K1 (from plants: fat-soluble): Phytonadione (Phylloquinone)
 K3
• (synthetic: Fat-soluble):
Menadione, Acetomenadione/Acetomenaphthone
• Water-soluble: Menadione sod. bisulfite, Menadione sod. Diphosphate
b)Miscellaneous: Fibrinogen (human), Antihaemophilic factor,
Desmopressin, Adrenochrome monosemicarbazone, Rutin, and
Ethamsylate

Coagulants
Vitamin K
 It is a fat-soluble dietary principle required for the synthesis of
clotting factors.
 Dam (1929) produced bleeding disorder in chicken by feeding
deficient diet. This was later found to be due to decreased
concentration of prothrombin in blood and then it could be cured
by a fat soluble fraction of hog liver.
 This factor was called Koagulations vitamin (Vit K) and Soon it’s
structure was worked out.
 A similar vitamin was isolated in 1939 from alfalfa grass and
labeled vit K1, while then from sardine (sea fish) meal was labeled
K2.
 Synthetic compounds have been produced and labeled K3.

Coagulants
Vitamin K
Chemistry and source:
 Vit K has a basic naphthoquinone structure, with or without a side chain (R) at
position C3.
 The side chain in K1 is phytyl (is a 15-carbon isoprenoid alcohol),
 K2, prenyl (a 5-carbon isoprenoid unit),
 While in K3, there is no side chain.

Coagulants
Menadione (Vit K3):
 Menadione is a natural organic
compound.
 It is an analog of 1,4-
naphthoquinone with a methyl
group in the 2-position.
 It is sometimes called vitamin K3.
 Use is allowed as a nutritional
supplement in animal feed because of
its vitamin K activity.
2-methyl naphthalene-1,4-dione

Coagulants
Acetomenadione:
 Acetomenadione is a coagulant.
 It's a synthetic form of vitamin K,
which is essential for blood clotting.
 Specifically, it's a prodrug of
menadione (vitamin K3), and the
active form, menadione, plays a
crucial role in the body's coagulation
process by assisting in the synthesis
of clotting factors.
2-Methyl-1,4-naphthalenediol
Diacetate

Coagulants
MOA of Vitamin K
 Vitamin K is a cofactor of gamma-carboxylase.
 Gamma carboxylase attaches carboxylic acid functional groups
to glutamate, allowing precursors of factors II, VII, IX, and X to
bind calcium ions.
 Binding of calcium ions converts these clotting factors to their
active form, which are then secreted from hepatocytes into the
blood, restoring normal clotting function.

Coagulants
Vitamin K
Dietary sources are: green leafy vegetables, such as cabbage,
spinach; and liver, cheese, etc.
Daily requirement: It is uncertain, because a variable amount of
menaquinone produced by colonic bacteria becomes available.
However, the total requirement of an adult has been estimated to be
50-100 ug/day.
Deficiency : of vit K occurs due to liver disease, obstructive
jaundice, malabsorption, long-term antimicrobial therapy which
alters intestinal flora.

Coagulants
Use of Vitamin K
Use The only use of vit K is in prophylaxis and treatment of bleeding due to
deficiency of clotting factors in the following situations:
 Dietary deficiency is very rare in adults. However, when it occurs 5-10
mg/day oral or parenteral vit K rapidly corrects the defects.
 Prolonged antimicrobial therapy: treat in the same way as dietary
deficiency of vit K.
 Obstructive jaundice or malabsorption syndromes vit K 10 mg i.m./ day,
or orally along with bile salts.
 Liver disease (cirrhosis, viral hepatitis)
 Overdose of oral anticoagulants: This is the most important indication of vit
K. Phytonadione (K1) is the preparation of choice, because it acts most
rapidly; dose depends on the severity of hypoprothrombinaemia (measured
INR) and bleeding.

Anticoagulants
Anticoagulants: The drugs, which inhibit the coagulation
process and prolong the coagulation time.
They are generally used to prevention and/or treatment of
thrombosis, atherosclerosis, embolism, myocardial ischemia,
etc.

Anticoagulants
1. Used in vivo
A. Parenteral anticoagulants-
Heparin, Low molecular weight heparin.
Heparinoids- Heparan sulfate, Danaparoid, Lepirudin, Ancrod.
B. Oral anticoagulants
(i) Coumarin derivatives: Bishydroxycoumarin (dicumarol), Warfarin ,
Acenocoumarol (Nicoumalone), Ethylbiscoumacetate
(ii) Indandione derivative: Phenindione, Anisindione, Diphenadione
2. Used in vitro
A. Organic acid- Heparin : 150 U to prevent clotting of 100 ml blood.
B. Organic acid salt:
Sodium citrate: 1 .65 g for 350 ml of blood; used to keep blood in the fluid state
for transfusion;
Sodium oxalate: 10 mg for 1 ml blood
Sodium edetate: 2 mg for 1 ml blood

Anticoagulants
Warfarin MOA:
 Warfarin and its congeners act as anticoagulant,
only in vivo, not in vitro.
 This is so because they act indirectly by
interfering with the synthesis of vit K dependent
clotting factors in liver.
 They apparently behave as competitive
antagonists of vit K and reduce the plasma levels
of functional clotting factors in a dose-dependent
manner. fact, they interfere with regeneration of
the active hydroquinone form of vit K which
carries out the final step of carboxylation
glutamate residues of prothrombin and factor VII,
IX and X.
 This carboxylation is essential for the ability of
the clotting factors to bind calcium to get bound
to phospholipid surfaces, necessary for
coagulation sequence to proceed.
4-hydroxy-3-(3-oxo-1-phenyl butyl)-2H-
chromen-2-one

Anticoagulants
SAR of Warfarin:
1. Coumarin Ring (Core Structure):
• Warfarin is a derivative of 4-hydroxycoumarin.
• The coumarin ring is crucial for its anticoagulant activity.
• The 4-hydroxy group is essential for warfarin's interaction with
Vitamin k epoxide resuctase, making it critical for its
anticoagulant properties.
2. Chirality:
• Warfarin exists as a racemic mixture of two enantiomers.
• R-warfarin and S-warfarin. S-warfarin is 3-5 times more potent
than R-warfarin in inhibiting Vitamin k epoxide resuctase.

Anticoagulants
SAR of Warfarin:
3. Substitution at Position 3:
• The substitution at the 3-position of the coumarin ring with a phenyl
group linked to a carbonyl group is key to the interaction with Vitamin
k epoxide resuctase.
4. Hydrophobic Interactions:
• The phenyl ring at position 3 increases hydrophobic interactions, which
may enhance binding to plasma proteins and Vitamin k epoxide
resuctase.
5. Substitution of Functional Groups:
• Alterations of the phenyl ring, such as hydroxylation, can reduce the
anticoagulant activity.

Anticoagulants
Synthesis of Warfarin:
 The (–) (S) isomer of warfarin is more potent (5-8 times) than (+) (R) enantiomer
 Commercially Racemic mixture is available for use
Uses:
 They are generally used to prevention and/or treatment of thrombosis,
atherosclerosis, embolism, myocardial ischemia,
 Warfarin is a synthetic anticoagulant used in patients undergoing orthopaedic
surgery.

Anticoagulants
Anisindione MOA;
 Its therapeutic action by
reducing the prothrombin
activity of the blood.
 By inhibiting the vitamin K–
mediated gamma-
carboxylation of precursor
proteins, the formation of
active procoagulation factors
II, VII, IX, and X.
2-(p-methoxy phenyl) indan 1,3-dione
Uses: Used as anticoagulant to prevention and/or treatment of
thrombosis, atherosclerosis, embolism, myocardial ischemia

ANTIPLATELET DRUGS
 These are drugs which interfere with platelet function and are
useful in the prophylaxis of thromboembolic disorders
(conditions where blood clots (thrombi) form in blood vessels,
and these clots can then break loose and travel to other parts of
the body, blocking blood flow)
 Thrombus: A blood clot that forms inside a blood vessel.
 Embolus: A thrombus that has broken loose and is traveling
through the bloodstream.
 Thromboembolism: The process of a thrombus forming and then
becoming an embolus.

ANTIPLATELET DRUGS
Clopidogrel MOA;
 Clopidogrel is activated via a 2 steps
reaction to an active thiol-containing
metabolite.
 This active form is a platelet
inhibitor that irreversibly binds to
P2Y12 ADP receptors on platelets.
 This binding prevents ADP binding
to P2Y12 receptors, activation of the
glycoprotein GPIIb/IIIa complex,
and platelet aggregation
Methyl (2S)-2-(2-chlorophenyl)-2-
(6,7-dihydro-4H-thieno[3,2-c]
pyridin-5-yl) acetate

ANTIPLATELET DRUGS
Clopidogrel:
Uses:
 It is used as an antiplatelet drug to reduce the risk of heart disease
and stroke.
 It is used along with anticoagulants for the prevention of
thrombosis, and other MI disease.

Coagulants & Anticoagulants Medicinal Chemistry II

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