Drugs affecting coagulation

Clot = Good
Thrombus = Bad
 Classes of Drugs
• Support Coagulation

• Prevent coagulation

• Dissolve clots

• Prevent bleeding and hemorrhage -

Hemostatic

• Overcome clotting deficiencies

(replacement therapies)
 Haemostasis
Arrest of blood loss from damaged blood
vessels
 Blood Clotting

• Vascular Phase

• Platelet Phase

• Coagulation Phase
 Vascular Phase

 Vasoconstriction
 Exposure to tissues activate Tissue
factor and initiate coagulation

Tissue Factor
Platelet Phase
 Coagulation Phase
 Two major pathways
 Intrinsic pathway

 Extrinsic pathway

 Both converge at a common point

 13 soluble factors are involved in clotting

 Normally inactive and sequentially activated

Intrinsic Pathway Extrinsic Pathway
Blood Vessel Injury Tissue Injury

XII XIIa Tissue Factor

XI XIa

IX IXa VIIa VII

X Xa X

Prothrombin Thrombin

Fibrinogen Fribrin monomer

 Vitamin K-Dependent Clotting
Factors
Vitamin K

VII
Synthesis of
IX Functional
Coagulation
X Factors
II
Natural anti- coagulant
 Menadione
Menadione is an organic
compound with the
formula
C6H4(CO)2C2H(CH3). It
is an analog of 1,4-
naphthoquinone with a
methyl group in the 2- 2-Methylnaphthalene-
position. 1,4-dione
Thrombosis

Pathological formation of haemostatic

plug within the vasculature in the
absence of bleeding
 Drugs influencing coagulation
Drugs effect ; Drugs influencing
coagulation

• fibrin formation Anticoagulants

• Platelet function • Antiplatelet drugs

• Fibrinolysis • Thrombolytic drugs

 Anticoagulants
• Antithrombin activators:- Heparin / LMWH
Synthetic pentasaccharide analogues
• Direct thrombin inhibitors :- Recombinant
hirudins, Bivalirudin, Melagatran
• Direct Factor Xa inhibitors :- Apixaban
• Drugs that oppose action of Vitamin K-
Warfarin
 Heparin
• Heterogeneous mixture of branched
glycosaminoglycans
• Potentiates the inhibition of IIa, IXa, Xa, XIa,
XIIa by AT
• Binds to AT through a unique
pentasaccharide sequence leading to a
conformational change
 Anticoagulants
• Antithrombin activators:-
Heparin / LMWH
Synthetic pentasaccharide
analogues
• Direct thrombin inhibitors :-
Recombinant hirudins, Not in
Bivalirudin, Melagatran syllabus
• Direct Factor Xa inhibitors :-
Apixaban
• Drugs that oppose action of
Vitamin K- Warfarin
 Anticoagulants

• Antithrombin activators

• Direct thrombin inhibitors

• Direct Factor Xa inhibitors

• Drugs that oppose action of Vitamin K

Warfarin Mechanism of Action
Reduces the post-translational
carboxylation of glutamate residues of
factors II, VII, IX, X

Vitamin K

Antagonism VII
of Synthesis of
Vitamin K IX Non Functional
Coagulation
X Factors
II

Warfarin
 Intrinsic Pathway Extrinsic Pathway
Blood Vessel Injury Tissue Injury

Tissue Factor
XII XIIa

Thromboplastin
XI XIa

IX IXa VIIa VII

X Xa X

Prothrombin Thrombin

Fibrinogen Fribrin monomer

Vit. K dependent Factors Affected by Oral Anticoagulants

Synthesis of Warferin
 Warfarin
• Anticoagulant effect seen after 2-3 days
• Monitored by international normalized ratio
(INR)
• Well absorbed form GIT
• Highly protein bound
• Metabolised by CYP-450
• Clearance is slow - 36 hrs
• Can cross placenta - do not use during
pregnancies
 Drug interaction- with Warfarin
Category Mechanism Representative Drugs

Drugs that Increase Decrease binding to

Warfarin Activity Albumin NSAID,

Inhibit hepatic metaboli; Cimetidine, antifungals

Decrease synthesis of Antibiotics (oral)

Clotting Factors
 Drug interaction with Warfarin cont:

Drugs that promote Inhibition of platelets NSAID, Aspirin

bleeding
Inhibition of clotting heparin
Factors

Induction of metabolizing Barbiturates

Enzymes Griseofulvin
Drugs that decrease
Warfarin activity Promote clotting factor Vitamin K
Synthesis

Reduced absorption cholestyramine

colestipol
 Drugs influencing coagulation

• Anticoagulants

• Antiplatelet drugs

• Thrombolytic drugs
 Antiplatelet drugs
• COX inhibitors:- Aspirin
• Adenosine diphosphate P2Y12 receptor
antagonists (thienopyridines):- Clopidogrel**,
Prasugrel, Ticagrelor
• Phosphodiesterase inhibitors :-Dipyridamole
• Glycoprotein IIb/IIIa receptor antagonists :-
Abciximab, Eptifibatide
 Clopidogrel
Clopidogrel, is an anti-platelet
medication used to reduce the
risk of heart disease
and stroke in those at high
risk. It is also used together
with aspirin in heart
attacks and following the IUPAC-
placement of a coronary artery (+)-(S)-methyl 2-(2-
stent . chlorophenyl)-2-(6,
7-dihydrothieno[3,2
Clopidogrel is in -c]pyridin-5(4H)-yl)a
the thienopyridine -class of cetate
anti-platelets
Common side effects include headache,
nausea, easy bruising, itching, and
heartburn. More severe side effects
include bleeding and thrombotic
thrombocytopenic purpura.

Clopidogrel is used to prevent heart attack

and stroke in people who are at high risk of
these events, including those with a history of
myocardial infarction and other forms of acute
coronary syndrome, stroke, and those
with peripheral artery disease.
 Pharmacokinetic data
• Bioavailability >50%
• Protein binding 94–98%
• Metabolism liver
• Onset of action 2 hours
• Elimination half-life 7–8 hours (inactive
metabolite)
• Duration of action 5 days
• Excretion 50% kidney &
46% biliary
 Drugs influencing coagulation

• Anticoagulants

• Antiplatelet drugs

• Thrombolytic drugs
 Fibrinolysis

• Exogenously administered drugs

–Streptokinase

–Urokinase

–Tissue plasminogen activator (tPA)

 Intrinsic Pathway Extrinsic Pathway
Blood Vessel Injury Tissue Injury

Tissue Factor
XII XIIa

Thromboplastin
XI XIa

IX IXa VIIa VII

X Xa X

Prothrombin Thrombin
Factors affected
By Heparin Fibrinogen Fribrin monomer

Vit. K dependent Factors Fibrin polymer

Affected by Oral Anticoagulants XIII