Anticoagulants

ILOs

Introduction about coagulation cascade

Classify drugs acting as anticoagulants
Elaborate on their mechanism of action, correlating that with methods
of monitoring
Contrast the limitations & benefits of injectable anticoagulants in
clinical settings
Emphasis on the limitations of VKAs & on variables altering
or modifying their response.
 Drugs and coagulation
 Anticoagulants: prevent thrombus formation and extension
by inhibiting clotting factors e.g. heparin, low molecular
weight heparin, coumarins/ warfarin.
 Antiplatelet drugs: reduce risk of clot formation by inhibiting
platelet functions e.g. aspirin and ticlopidine.
 Fibrinolytic agents: dissolve thrombi already formed
e.g. streptokinase.
Coagulation Pathways
All clotting
Initiating factors
factor is are
 Two major pathways
within
outside the blood
the blood
 Intrinsic pathway (tissue factor =
 Extrinsic pathway
thromboplastin)
 Both converge to a common pathway
 13 soluble factors are involved in clotting which

normally circulate in an inactive state and must

be activated to form a fibrin clot
Common pathway & Fibrin clot formation

Thrombin
 Endogenous Inhibitors of Coagulation
 Antithrombin III, is a plasma protein that
inhibits activated thrombin (factor IIa) and Xa,
it is the site of action of heparin
 Prostacyclin ( PGI ), is synthesized by
2
endothelial cells and inhibits platelet
aggregation
 Protein C and Protein S
 ANTICOAGULANTS

Parenteral Oral
Anticoagulants Anticoagulants

Thrombin inhibitors Vitamin K antagonists

Indirect Warfarin
Direct
Indication of anti-coagulants
Anticoagulants are indicated in:
 Myocardial infarction (MI)
Deep venous thrombosis (DVT)
Peripheral arterial emboli, pulmonary embolism (PE) and many
other conditions
Anticoagulants are also used in blood transfusions, and dialysis
procedures
Parenteral Anticoagulants

Indirect Thrombin inhibitors

Heparin and
heparin- related agents
Heparin (Unfractionated Heparin)
 Normally occurs as macromolecule in mast cells with
histamine ( its physiological role is unknown )
 Commercial preparations are extracted from beef lung
or pig intestine (can cause hypersensitivity reaction)
 Heparin stops the expansion of a thrombus and
prevents the formation of new thrombi but it does not
dissolve an existing thrombus
Heparin and related H- agents
 Heparin is an injectable rapidly acting
anticoagulant
 Active in vitro and in vivo
 Low–molecular–weight forms (LMWHs), 1/3 the
size of UFH are used as well and have many
advantages over UFH
Heparin: Mechanism of action
 Indirect Thrombin Inhibitor
 It acts indirectly by increasing the activity of the endogenous
anticoagulant “antithrombin III” (1000 folds) which inhibits
activated clotting factors mainly thrombin (factor IIa) and Xa
 When Heparin binds to antithrombin III, it causes conformational changes
that accelerates its rate of action 1000 fold
 Heparin: Mechanism of action
Heparin
 Heparin binds to both
Antithrombin III antithrombin III and
Thrombin thrombin to form a ternary
complex

Heparin

Antithrombin III Thrombin

 Heparin: Mechanism of action
 Heparin dissociates leaving the thrombin bound to its
inhibitor
 Once dissociated, Heparin is free to bind to another
antithrombin molecule and subsequently inhibits more
thrombin

Heparin Antithrombin III

Thrombin Thrombin
Antithrombin III
 UFH : Pharmacokinetics
 Heparin is not absorbed from the GIT
 It should be administered by IV or SC injection. Not injected
IM as it causes haematomas at injection site
 Once in the blood stream, UFH binds to plasma proteins,
endothelial cells and macrophages
 Heparin does not cross the placenta; therefore it is the drug of
choice as anticoagulat during pregnancy
 Close monitoring of the activated partial thromboplastin time
(aPTT) is necessary in patients receiving UFH.
Heparin: Therapeutic uses
 Due to its rapid onset of action, it is used to initiate
immediate anticoagulation in thromboembolic
disease (PE, DVT, MI) mainly as induction for oral
vitamin K antagonists (VKAs)
 Prevention of postoperative DVT (in patient
undergoing hip replacement)
 Prevention of coagulation during renal dialysis or
cardiac surgery
Disadvantages of UFH
 The inconvenience of administration by injection
 The need for regular monitoring (aPTT)
 UFH carries a risk of heparin-induced
thrombocytopenia (HIT), a fall in the platelet
count and increased risk of thrombosis due to
binding to platelets
Heparin-induced thrombocytopenia (HIT )

 Generally, if the number of platelets is too low,

excessive bleeding can occur
 If the number of platelets is too high, blood clots
can form thrombosis
 However, There are disorders that reduce the
number of platelets, such as heparin-induced
thrombocytopenia (HIT) that typically cause
thrombosis, or clots, instead of bleeding
 UFH: Adverse effects
 The major adverse effect of heparin is bleeding
 Allergic reactions (chills, fever, urticaria) as heparin is of
animal origin and should be used cautiously in patients
with allergy
 Long-term heparin therapy is associated with osteoporosis
 Heparin-induced thrombocytopenia (HIT )
Heparin: Contraindications
 Bleeding disorders, hemophilia
 Patients with hypersensitivity to
the drug
 Recent surgery of the brain, eye or spinal
cord, threatened abortion
Reversal of Heparin Action
 Discontinuation of the drug
 Heparin is strongly acidic and is neutralized by
i.v. protamine sulfate (a strongly basic
protein)
 It combines with heparin to form a stable
complex devoid of anticoagulant activity
 Low-Molecular-Weight Heparins
 LMWHs are derived from the chemical or enzymatic
degradation of UFH into fragments approximately one-third
the size of heparin.
 Have equal efficacy, without frequent laboratory monitoring
( suitable for outpatient therapy)
 Have a more predictable anticoagulant response
( better bioavailability, longer t 1/2)
 Binding to platelets and osteoblasts is reduced with LMWH
compared with UFH
 Examples of LMWHs:
 Heparin fragments (e.g. enoxaparin, dalteparin)
 Synthetic pentasaccharide (fondaparinux)
 are used increasingly in place of unfractionated heparin
 LMWHs increase the action of antithrombin III on factor Xa
but not its action on thrombin, because the molecules are too
small to bind to both enzyme and inhibitor
 Synthetic Heparin Derivatives
 Fondaparinux is a synthetic compound that
inhibits factor Xa by antithrombin but does not
inhibit thrombin
Advantages:
 Fondaparinux can be given once a day at a fixed
dose without coagulation monitoring
 Less likely than UFH or LMWHs to trigger HIT
 Differences between UFH and LMW Heparins
Drug Heparin LMWH
characteristics (UFH)
IV ½ life 2 hours 4 hours

Bioavailability 20% 90%

after SC injection

Anticoagulant variable Predictable

response
Major adverse Frequent Less frequent
effect bleeding bleeding
HIT, Less
osteoporosis
Specific Protamine -Incomplete-
antagonist sulphate

Setting for Hospital Hospital and

therapy OPC

Laboratory Needed Not needed

monitoring aPTT
 Advantages of LMWHs over UFH
 The theoretical pharmacologic advantages of LMWH over UFH arise
from the preferential binding ratio to factor Xa over thrombin
 The convenience of once- or twice- daily subcutaneous injections
without regular coagulation monitoring due to:
 More predictable response
 Long plasma half-life and improved bioavailability
 Less plasma protein binding
 Less platelet activation and lower risk of re-thrombosis and
thrombocytopenia
Direct thrombin inhibitors (DTIs)
 DTIs exert their anticoagulant effect by direct
binding to thrombin
 This direct effect is rapid and potent
 DTIs are not associated with the development
of thrombocytopenia
 Direct thrombin inhibitors (DTIs)
 The first DTI to be developed was hirudin, which was
isolated from the saliva of the leech (‫علقة‬
( )
 Lepirudin is a polypeptide that binds directly to the active site
of thrombin
 Recombinant hirudin “Lepirudin” is used as IV anticoagulant
in patients with HIT
 Oral Anticoagulants
“Vitamin K antagonists”
 Vitamin K (Fat soluble vitamin)
 Source of vitamin K Green vegetables
Synthesized by intestinal flora
 Required for synthesis Factors II, VII, IX ,X
Protein C and S (endogenous
anticoagulants)
 Causes of deficiency Malnutrition
Malabsorption
Antibiotic therapy
 Vitamin K-Dependent Clotting Factors

Vitamin K
II Synthesis of
VII functional
IX coagulation
factors
X

Protein C and
Protein S
 Warfarin: Mechanism of action
Inactive clotting Active clotting
factors factors
( II, VII, IX, X )
Vitamin K Epoxide form
Warfarin
Protein C and
protein
Epoxide S
reductase
Warfarin inhibits the synthesis of biologically active forms of
vitamin K-dependent clotting factors II, VII, IX and X
 Mechanism of Action of Warfarin

 Inhibits synthesis of Vitamin K-dependent

coagulation factors II, VII, IX, & X as well as
anticoagulant proteins C & S
 3-4 days until effect is seen ??
 Does not have any effect on already-synthesized
coagulation factors; therefore, the therapeutic
effects are not seen until these factors are depleted
 Coumarins: Warfarin
 Act only in vivo
 Bioavailability 100%
 98% bound to plasma proteins (albumin)
 Monitoring anticoagulant effect of warfarin by
measuring PT, which is expressed as an
International Normalized Ratio (INR)
 Coumarins: Warfarin
 Their effect takes several days (3-4 ) to develop
because of the time taken for degradation of circulating
functional clotting factors
 Therefore the onset of action starts when these factors
have been eliminated
 Warfarin has a slow offset of action due to the time
required for synthesis of new, functional coagulation
factors
Disadvantages of Warfarin therapy
 Variable, unpredictable effect necessitating regular INR
monitoring and dose adjustment
 Narrow therapeutic window leading to increased risk of
severe bleeding
 Slow onset and offset of action
 Numerous interactions with foods containing vitamin K
and drugs
Drug interactions with oral anticoagulants
1. Inhibition of Vit. K synthesis by intestinal flora; oral antibiotics
2. Inhibition of Vit K absorption; liquid paraffin
3. Decrease in drug metabolism by microsomal enzyme inhibitors;
chloramphenicol, & cimetidine
4. Displacment of the drug from protein binding sites;
phenylbutazone & salicylates
5. Co-administration of drugs that increase bleeding tendency by;
inhibiting platelet function; NSAIDs
heparin

1. Inhibition of drug absorption from GIT; cholystyramine, colestipol

2. Increase in synthesis of clotting factors; Vit K, oral contraceptives
3. Increase in drug metabolism by microsomal enzyme inducers; Carbamazepine;
barbiturates, rifampicin
ticoagulants : Teratogenicity
Warfarin is contraindicated during pregnancy as it can
cross the placental barrier and cause abortion,
hemorrhagic disorder in the fetus and birth defects
Bleeding due to Warfarin

 Stop the drug

 IV injection of vitamin K
 Fresh frozen blood
Thank
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