ANTICOAGULANTS,

FIBRINOLYTICS &
ANTIPLATELET AGENTS
Lt Col. JACKSON YAMVWA
 INTRODUCTION
• Little intravascular coagulation of blood occurs in normal
physiological conditions.

• Hemostasis involves the interplay of three procoagulant phases

(vascular, platelet, and coagulation) that promote blood clotting to
prevent blood loss.

• The fibrinolytic system prevents propagation of clotting beyond the

site of vascular injury and is involved in clot dissolution, or lysis.
 HEMOSTATIC MECHANISMS
• Endothelial cells maintain a nonthrombogenic lining in blood vessels.

• This results from several phenomena, including:

1. The maintenance of a transmural negative electrical charge, which is

important in preventing adhesion of circulating platelets

2. The release of plasminogen activators, which activate the fibrinolytic

pathway

3. The activation of protein C, which degrades coagulation factors, a process

involving thrombin and its endothelial cofactor (thrombomodulin).
 HEMOSTATIC MECHANISMS

5. The production of heparinlike proteoglycans, which inhibit coagulation.

6. The release of prostacyclin (PGI2), a potent inhibitor of platelet

aggregation.
 HEMOSTATIC MECHANISMS

• In normal individuals, injury severe enough to cause hemorrhage initiates

coagulation.

• Vasoconstriction, combined with increased tissue pressure caused by

extravasated blood, results in a reduction, or stasis, of blood flow.

• Stasis favors the restriction of thrombus formation to the site of injury.

• The extravasation of blood exposes platelets and the plasma clotting factors
to subendothelial collagen and endothelial basement membranes, which result
in activation of the clotting sequence.
 HEMOSTATIC MECHANISMS
• Several substances that participate in coagulation are released or become
exposed to blood at the site of injury.
• These include:

i. Adenosine diphosphate (ADP), a potent stimulus to platelet aggregation

ii. Tissue factor, a membrane glycoprotein cofactor of factor VII

iii. Thromboxane (TXA2)

iv. Seretonin (5-HT)

v. von Willebrand Factor
 PLATELET AGGREGATION
• Platelet aggregation is the most important defense mechanism
against leakage of blood from the circulation.
• Ordinarily, unstimulated platelets do not adhere to the endothelial
cell surface.
• Following disruption of the endothelial lining and exposure of
blood to the subendothelial vessel wall, platelets come into contact
with and adhere within seconds to factor VIII:vWF polymers and
fibronectin.
 PLATELET ACTIVATION
• The platelets change shape and then undergo a complex secretory process termed
the release reaction.

• This results in the release of ADP from platelet granules and activation of platelet
phospholipase A2.

• Phospholipase A2, cyclooxygenase, and thromboxane synthetase sequentially

convert arachidonic acid into cyclic endoperoxides and thromboxane A2 (TxA2).

• In contrast to endothelial cells, platelets lack PGI2 synthetase.

GPIIb/IIIa Expression & Fibrinogen Binding
• Upon platelet activation with mediators of aggregation (ADP, 5-HT, TxA2,

epinephrine, thrombin, collagen, platelet activating factor), the integrin platelet

receptor for plasma fibrinogen, glycoprotein IIb/IIIa (GPIIb/IIIa), is expressed.

• Activation of platelets results in a conformational change in the αIIbβIII integrin

(IIb/IIIa) receptor, enabling it to bind fibrinogen, which cross-links adjacent

platelets, resulting in aggregation and formation of a platelet plug.

GPIIb/IIIa Expression & Fibrinogen Binding
 GPIIb/IIIa Expression & Fibrinogen Binding
• Fibrinogen, forming a bridge between platelets, and the binding of fibrinogen
and VonWillebrand’s factor to activated platelets via GPIIb/IIIa are key
events in platelet–platelet interactions and play a major role in thrombus
formation.

• Aggregation of circulating platelets to those already adherent amplifies the

release reaction.
 COAGULATION SYSTEMS
• Two interrelated processes, the intrinsic and extrinsic coagulation
systems , converge on a common pathway that leads to the
activation of factor X.
• The formation of thrombin (factor IIa), and the conversion by
thrombin of the soluble plasma protein fibrinogen into insoluble
fibrin.
• The extrinsic pathway appears to be important for initiating fibrin
formation, while the intrinsic pathway is involved in fibrin growth
and maintenance.
• Both systems constitute the coagulation cascade.
 COAGULATION CASCADE
• Blood coagulates due to the transformation of soluble fibrinogen into insoluble
fibrin by the enzyme thrombin.
• Several circulating proteins interact in a cascading series of limited proteolytic
reactions.
• At each step, a clotting factor zymogen undergoes limited proteolysis and
becomes an active protease (eg, factor VII is converted to factor VIIa).
• Each protease factor activates the next clotting factor in the sequence,
culminating in the formation of thrombin (factor IIa).
• Several of these factors are targets for drug therapy.
COAGULATION CASCADE
 INITIATION OF CLOTTING:
THE TISSUE FACTOR-VIIa COMPLEX
• The main initiator of blood coagulation in vivo is the tissue factor (TF)–factor
VIIa pathway.
• Tissue factor is a transmembrane protein ubiquitously expressed outside the
vasculature but not normally expressed in an active form within vessels.
• The exposure of TF on damaged endothelium or to blood that has
extravasated into tissue binds TF to factor VIIa.
• This complex, in turn, activates factors X and IX.
• Factor Xa along with factor Va forms the prothrombinase complex on
activated cell surfaces, which catalyzes the conversion of prothrombin (factor
II) to thrombin (factor IIa).
• This is regulated by tissue factor pathway inhibitor (TFPI).
 THROMBIN
• Thrombin has a central role in hemostasis and has many functions.

• In clotting, thrombin proteolytically cleaves small peptides from fibrinogen,

allowing fibrinogen to polymerize and form a fibrin clot.

• Thrombin also activates many upstream clotting factors, leading to more

thrombin generation, and activates factor XIII, a transaminase that cross-links
the fibrin polymer and stabilizes the clot.
 THROMBIN

• Thrombin is a potent platelet activator and mitogen.

• Thrombin also exerts anticoagulant effects by activating the protein C

pathway, which attenuates the clotting response.

 ANTITHROMBIN (AT), PROTEIN C & PROTEIN S
• Antithrombin (AT) is an endogenous anticoagulant and a member of the
serine protease inhibitor (serpin) family.
• It inactivates the serine proteases IIa, IXa, Xa, XIa, and XIIa.
• The endogenous anticoagulants protein C and protein S attenuate the blood
clotting cascade by proteolysis of the two cofactors Va and VIIIa.
• Defects in natural anticoagulants result in an increased risk of venous
thrombosis.
• The most common defect in the natural anticoagulant system is a mutation in
factor V (factor V Leiden), which results in resistance to inactivation by the
protein C /protein S mechanism.
 FIBRINOLYSIS
• Fibrinolysis refers to the process of • Plasmin remodels the thrombus and
fibrin digestion by the fibrin specific limits its extension by proteolytic
protease, plasmin. digestion of fibrin.

• In response to injury, endothelial cells • Both plasminogen and plasmin have

synthesize and release tissue specialized protein domains (kringles)
plasminogen activator (t-PA), which that bind to exposed lysines on the
converts plasminogen to plasmin. fibrin clot and impart clot specificity to
the fibrinolytic process.
 FIBRINOLYSIS
• It should be noted that this clot
specificity is only observed at
physiologic levels of t-PA.
• At the pharmacologic levels of t-PA
used in thrombolytic therapy, clot
specificity is lost and a systemic
lytic state is created, with attendant
increase in bleeding risk.
• As in the coagulation cascade, there
are negative regulators of
fibrinolysis.
• Endothelial cells synthesize and
release plasminogen activator
inhibitor (PAI) which inhibits t-PA.
• In addition α2 antiplasmin circulates
in the blood at high concentrations
and under physiologic conditions will
rapidly inactivate any plasmin that is
not clot-bound.
• However, this regulatory system is
overwhelmed by therapeutic doses of
plasminogen activators
 FIBRINOLYSIS
• Regulation of the fibrinolytic system • Conversely, decreased fibrinolysis

is useful in therapeutics. protects clots from lysis and reduces the

bleeding of hemostatic failure.
• Increased fibrinolysis is effective
• Aminocaproic acid is a clinically useful
therapy for thrombotic disease.
inhibitor of fibrinolysis.
• Tissue plasminogen activator,
• Heparin and the oral anticoagulant drugs
urokinase, and streptokinase all
do not affect the fibrinolytic mechanism.
activate the fibrinolytic system
DISSEMINATED INTRAVASCULAR COAGULOPATHY (DIC)

• If the coagulation and fibrinolytic systems

are pathologically activated, the
hemostatic system may get out of control,
leading to generalized intravascular
clotting and bleeding.
• This process is called disseminated
intravascular coagulation (DIC).
• It may follow massive tissue injury,
advanced cancers, obstetric emergencies
such as abruptio placentae or retained
products of conception, or bacterial sepsis.
 BASIC PHARMACOLOGY OF
THE ANTICOAGULANT DRUGS

• Anticoagulants inhibit the formation of

fibrin clots.
• The major types of anticoagulants are
available:
1. Heparin and related products (Parenteral)
2. Direct thrombin Inhibitors
(Oral/parenteral)
3. Direct Factor Xa inhibitors (parenteral or
oral)
4. Orally active coumarin derivatives (eg,
warfarin).
 INDIRECT THROMBIN INHIBITORS
HEPARIN AND RELATED DRUGS
• WHAT IS HEPARIN?
• Heparin is a large sulfated glycosaminoglycan (mucopolysaccharide) polymer
obtained from animal sources.
• It is not a single substance but a family of sulfated glycosaminoglycans.
• It is present together with histamine in the granules of mast cells.
• Commercial preparations are extracted from beef lung or hog intestine.
• Because preparations differ in potency, they are assayed against an agreed
international standard.
 HEPARIN CHEMISTRY

• Heparin is a polysaccharide polymer composed of two alternating sugar units,

N-acetyl-d-glucosamine and uronic acid (either d-glucuronic or l-iduronic),
linked by a, 1 → 4 bonds.
• These chains are called glycosaminoglycans and typically are composed of
200 to 300 monosaccharide units.
• Each batch contains molecules of varying size, with an average molecular
weight of 15,000–20,000.
• Heparin is a strongly acidic molecule because of its high content of anionic
sulfate and carboxylic groups.
• Heparin can be neutralized by basic molecules (eg, protamine).
 HEPARIN CHEMISTRY

• The small polymer section shown illustrates the repeating disaccharide units
typical of heparin.
• The sequence shows the critical pentassacharide portion required for binding
to antithrombin.
• In addition to those shown, other saccharides occur.
• Before the molecule is capable of binding to antithrombin, the proteoglycan
must undergo a series of structural modifications.
 BIOLOGICAL ACTIVITY OF HEPARIN
• Doses are specified in units of biological activity rather than mass.

• 1 USP unit is defined as the quantity of heparin that prevents 1 ml of citrated

sheep plasma from clotting for 1 hour after calcium addition.

• 150 USP Units = 1 mg.

• Heparin exerts its biological activity by interacting and activating

antithrombin III.
 TYPES OF HEPARINS
1. Unfractionated Heparin (UFH)

2. Low-molecular-weight heparin (LMWH)

• Enoxaparin
• Dalteparin
• Tinzaparin

3.Synthetic pentasaccharide fondaparinux

MECHANISM OF ACTION OF HEPRIN

• Heparin inhibits coagulation, both in vivo

and in vitro by activating antithrombin III.
• ATIII inhibits thrombin and other serine
proteases by binding to the active serine site.
• Heparin modifies this interaction by binding,
via a unique pentasaccharide sequence, to
ATIII, changing its conformation and
accelarating its rate of action.
• Thrombin is considerably more sensitive to the inhibitory effect of the

heparin-antithrombin III complex than is factor Xa

• To inhibit the thrombin, it is necessary for heparin to bind to both thrombin

and antithrombin III.

• To inhibit factor X, it is necessary for heparin to bind only to antithrombin III.

• LMWH increase the action of ATIII on factor Xa but not its action on thrombin.

• This is because LMWH are too short to bind to both enzyme and inhibitor.
 MECHANISM OF ACTION OF HEPARINS

To increase the inactivation AT III

IIa
of IIa by AT III, hepain needs
to interact with both AT III
and IIa. HEPARIN

Xa IIa
AT III
AT III

HEPARIN
LMWH

To speed up the effect of heparin on Xa, heparin needs to act on LMWH increase the action of AT III on Xa but
cannot increase the action of AT III on thrombin
AT III only. because they cannot bind to both simultaneously.
 IN VITRO CLOTTING TEST
• Whole blood normally clots in 4 - 8 min when placed in a glass tube.
• Under these conditions, contact of blood with glass activates factor XII,
thereby initiating coagulation via the intrinsic pathway.
• Clotting is prevented if a chelating agent such as EDTA or citrate is added to
bind Ca2+.
• Recalcified plasma normally clots in 2 - 4 min.
• The clotting time after recalcification is shortened to 26 - 33 sec by the
addition of negatively charged phospholipids and particulate substances such
as kaolin (aluminium silicate) or celite (diatomaceous earth) which activate
factor XII.
• The measurement of clotting time by this method is known as activated
partial thromboplastin time (aPTT).
 IN VITRO CLOTTING TEST
• Alternatively, in vitro clotting time can be measured by the addition of

thromboplastin to recalcified plasma.

• Thromboplastin is a mixture of Tissue-Factor (TF) and phospholipids.

• Blood clots in 12 - 14 sec after addition of thromboplastin and calcium.

• Measurement of in vitro clotting time by this method is known as

prothrombin time (PT).

 MONITORING OF HEPARIN EFFECT
• Close monitoring of aPTT is necessary in patients receiving UFH.
• Levels of UFH may also be determined by protamine titration (therapeutic
levels 0.2 - 0.4 units) or anti-Xa units (therapeutic levels 0.3 - 0.7 unit/ml)
• Weight-based dosing of LMWH results in predictable pharmacokinetics and
plasma levels in patients with normal renal function.
• Therefore, LMWH levels are not measured generally except in the setting of
renal insufficiency, obesity, and pregnancy.
• LMWH levels can be determined by anti-Xa units.
 ADMINISTRATION AND PHARMACOKINETICS
ASPECTS OF UNFRACTIONATED HEPARINS
• ABSORPTION
• Heparin is not absorbed from the gut because its charge and large size.
• It is therefore given IV or SC (I.M inj cause hematomas).
• ONSET OF ACTION
• Heparin acts immediately following IV administration, but the onset is
delayed by up to 60 minutes when given SC.
• The t1/2 is approx. 40 - 90 min.
• In urgent situations it is usual to start treatment with a bolus IV dose, followed
by constant infusion.
 LOW MOLECULAR WEIGHT HEPARINS

• Enoxaparin • Ardeparin

• Dalteparin • Nadroparin

• Tinzaparin • Reviparin
 LOW MOLECULAR WEIGHT HEPARINS
• LMWH are administered SC.
• They have a longer elimination half-life than UFH.
• The effects are more predictable than and dosing is less frequent (once or
twice daily).
• LMWH do not prolong aPTT therefore routine monitoring is not required.
• They are eliminated renally, thus UFH is preferred in renal failure.
• In general, they are safe and effective as UFH and more convenient to use.
• Patients can be taught to inject themselves at home and there’s no need for
blood tests and dose adjustment.
 HEPARIN TOXICITY
• Haemorrhage
• The major adverse effect of heparin is haemorrhage.
• This risk can be decreased by careful patient selection, dosage control,
and close monitoring.
• Elderly patients and patients with renal failure are more prone to
haemorrhage.
• Hypersensitivity reactions
• Heparin is obtained from animal sources (beef and porcine). It should
therefore be used cautiously in patients with allergy.
• Osteoporosis
• Long-term heparin therapy is associated with with osteoporosis and
spontaneous fractures.
 HEPARIN TOXICITY
• Hypoaldosteronism (with consequent hyperkalemia)

• Heparin-Induced Thrombocytopenia (HIT)

• HIT is a systemic hypercoagulable state that occurs in 1 - 4 % of
individuals treated with UFH for a minimum of 7 days.
• Surgical patients are at greater risk.
• Morbidity and mortality is related to thrombotic events.
• All patients receiving heparin should be subjected to routine testing of
platelet count
 CONTRAINDICATIONS
• Heparin is contraindicated in
1. Patients with HIT
2. Hypersensitivity to the drug
3. Active bleeding
4. Haemophilia
5. Significant thrombocytopenia
6. Purpura
7. Severe hypertension
8. Infective endocarditis
9. Active tuberculosis
10. Ulcerative lesions of the GIT
11. Visceral carcinoma
12. Advanced hepatic or renal disease
13. Recent surgery of the brain, spinal cord or eye
14. Patients undergoing lumber puncture or regional
anesthetic block.
15. Use in pregnancy should be considered only when
clearly indicated
 CLINICAL USE OF HEPARINS
1. Venous thrombosis and Pulmonary embolism
• Heparin is used to initiate treatment of venous thrombosis and
pulmonary embolism because of its rapid onset of action.
• An oral anticoagulant is usually started together with heparin,and
heparin is continued for 4 - 5 days to allow the oral anticoagulant to
achieve its full therapeutic effect.
• Patients who experience recurrent thromboembolism despite adequate
oral anticoagulation may benefit from long-term heparin administration.
 CLINICAL USE OF HEPARINS
2. Unstable Angina or Acute Myocardial Infarction

3. Heparin is used in the initial management of unstable angina or acute

myocardial infarction.

4. Coronary angioplasty or stent placement

5. During surgery requiring cardiopulmonary bypass

6. Disseminated Intravascular Coagulation (DIC)

 ADMINISTRATION AND MONITORING
• Full-dosage heparin therapy is usually
administered by continous IV infusion.
• Treatment of VTE is initiated with
bolus injection of 5000 units, followed
by 1200 to 1600 units per hour
delivered by infusion pump.
• Therapy is monitored routinely aPTT.
• High doses of heparin are required to
prevent coagulation during
cardiopulmonary bypass.
• SC administration can be used to manage
patients in whom Warfarin is C/I. e.g
pregnancy.
• Low-dose heparin is used prophylactically
to prevent DVT and Thromboembolism in
susceptible patients.
 REVERSAL OF HEPARIN ACTION
• Excessive anticoagulant action if heparin is treated by discontinuation of the
drug.
• If bleeding occurs, administration of a specific antagonist such as protamine
sulfate is indicated.
• Protamine is a highly basic peptide that combines with heparin as ion-pair to
form a stable complex devoid of anticoagulant activity.
• For every 100 units of heparin remaining in the patient, 1mg of protamine
sulfate is given IV.
• Neutralisation of LMWH by protamine is incomplete.
 SYNTHETIC HEPARIN DERIVATIVES
• Foudaparinux
• This is a synthetic pentasaccharide based on the structure of AT III binding
region of heparin.
• It mediates inhibition of factor Xa by AT III but does not cause thrombin
inhibition due to its shorter polymer length.
• Foudaparinux is administered by SC injection, reaches peak plasma levels in 2
hours, and excreted in the urine with a t1/2 of 17 - 21 hours.
• It should not be used in patients with renal failure.
• Does not require frequent monitoring.
• Approved for thromboprophylaxis in patients undergoing knee surgery.
• Approved for therapy of pulmonary embolism and DVT
SYNTHETIC HEPARIN DERIVATIVES
 HEPARIN RESISTANCE
• The dose of heparin required to produce a therapeutic aPTT varies due to:

• Differences in the concentration of heparin-binding proteins plasma such as histidine-rich

glycoprotein, vitronectin, and platelet factor 4.

• These proteins competitively inhibit binding of heparin to AT III.

• Occassionally, a patients aPTT will not be prolonged unless very high doses of heparin are
administered.

• Other patients may require larger doses of heparin due to increased clearance of heparin as
may occur with massive pulmonary embolism.

• Heparin resistance may also occur in patients with AT III deficiency.

 DIRECT THROMBIN INHIBITORS (DTIs)
• DTIs exert their anticoagulant effect by directly binding to the active site of
thrombin, thereby inhibiting thrombin’s downstream effects.
• This is in contrast to indirect thrombin inhibitors such as heparin and LMWH,
which act through antithrombin.
• Examples of DTIs
1. Hirudin
2. Lepuridin
3. Bivalirudin
4. Argotroban
5. Melagatran
 LEPIRUDIN
• Lepuridin is a recombinant derivative of hirudin.

• It is a 65 amino acid polypeptide that binds tightly to both the catalytic site and the
extended substrate recognition site (exosite I) of thrombin.

• It is approved for the treatment of patients with heparin-induced thrombocytopenia.

• It is administered I.V at a dose adjusted to maintain the aPTT at 1.5 to 2.5 times the
normal laboratory values.

• The drug is excreted by the kidneys and has a t1/2 of 1.3 hrs.

• It should be administered with caution in patients with renal failure.

 BIVALIRUDIN
• Bivalirudin is a synthetic, 20 amino acid polypetide that directly inhibits
thrombin by a mechanism similar to lepuridin.

• It is administered I.V and is used as an alternative to heparin in patients

undergoing coronary angioplasty.

• The t1/2 of bivalirudin in patients with normal renal function is 25 min.

• Dosage reductions are recommended for patients with moderate or severe

renal failure.
 ARGATROBAN
• Argatroban is a synthetic compound based on the structure of L-arginine.
• It binds reversibly to the catalytic site of thrombin.
• It is administered I.V and has an immediate onset of action.
• Its t1/2 is 40 - 50 min.
• Argatroban is metabolised by CYP450 enzymes in the liver and is excreted in
bile.
• Dose reduction is required in patients with liver insufficiency.
• It is indicated as an alternative to lepirudin for prophylaxis or treatment of
HIT.
 DIBIGATRAN ETEXILATE
• Potent and reversible Oral Direct Thrombin Inhibitor
• Inhibiting both clot bound and free thrombin
• Predictable and consistent PK profile-Rapid onset/offset of action (Peak plasma levels
within 2 hours)
• Anticoagulation monitoring—Not required
• Half-life 12–17 hours (twice-daily dosing)
• Low drug–drug interactions (not metabolised by CYP450 enzymes)
• However, P glycoprotein inhibitors Amiodarone, verapamil and quinidine may increase its
plasma level
• No food–drug interactions reported
• Dosing independent of meals or dietary restrictions
• 65% bioavailability, ~80% renal excretion
DIRECT FACTOR Xa INHIBITORS
 DIRECT FACTOR Xa INHIBITORS

• Rivaroxaban • OTHERS:-

• Apixaban 1. Betrixaban

• Edoxaban 2. YM150

3. TAK442
 RIVAROXABAN
• Direct factor Xa inhibitor.
• Bioavailability:- 80-100%.
• Administration- Oral.
• Pharmacokinetics:-
• Maximum effect-2hours.
• Half life is 5-9 hours.
• 1/3rd Metabolized in Liver and gets excreted in feces.
• 1/3rd is cleared as unchanged drug in Urine
 RIVAROXABAN
• Dosage:- • Precautions:-
• 20mg daily. • Should be taken with food to
• 15mg Twice Daily for initial 21 days. (Acute achieve maximum absorption.
venous thrombosis). • Avoid in pregnancy and lactating
• 10mg Daily for post surgical women.
thromboprophylaxis. • Avoid in renal and liver failure
• Renal dosage:- patients.
• 30-50ml CCL-15 mg Twice Daily. • Bleeding manifestations should be
• 15-30ml CCL- 10mg Twice Daily. monitored frequently in case of
• <15ml- contraindicated.
patients who are already in
antiplatelets
 RIVAROXABAN

• Contraindications:-
• Indications:-
• Renal & liver failure.
1. Non-Valvular Atrial Fibrillation. • Already in ketoconazole and
ritonavir drugs.
2. Deep Vein Thrombosis. • Rifampicin and Phenytoin can reduce
plasma concentrations of drug.
3. Pulmonary Embolism.
• Antidote- none
 APIXABAN
• Direct factor Xa inhibitor.

• Bioavailability:- 50%.

• Administration- Oral.

• Pharmacokinetics:-

• Maximum effect 3- 4 hours.

• Half life is 9-14 hours.

• Metabolized in Liver and gets excreted in feces, urine and biliary system.
 APIXABAN
• DOSAGE:-
• 5mg Twice Daily.
• 2.5mg Twice Daily, If:
• Age >80 years.
• Weight less than 60 kgs.
• Serum Creatinine >1.5mg/dl
• PRECAUTIONS:-
• Should be taken with food to achieve maximum absorption.
• Avoid in pregnancy and lactating women.
• No dosage adjustment needed in patients with mild renal and hepatic failure.
• Avoid in moderate to severe liver failure patients.
 APIXABAN
• Indications:-
1. Non-Valvular Atrial Fibrillation.
2. Deep Vein Thrombosis.
3. Pulmonary Embolism.

• Adverse effects:-
• Bleeding manifestations.

• Antidote
• None.
 EDOXABAN
• Direct factor Xa inhibitor.
• Bioavailability:- 62%.
• Administration- Oral.
• Pharmacokinetics:-
• Maximum effect 1-2hours.
• Half life is 10 hours.
• Metabolized in Liver and gets excreted in mild renal and hepatic failure.
feces, urine and biliary system.
• DOSAGE:-
• 60mg Once Daily for Non-Valvular AF.
• 30mg Once Daily, If:
• Age >80 years.
• Weight less than 60 kgs.
• Creatinine Clearance <15ml/min.
• PRECAUTIONS:-
• Should be taken with food to achieve maximum
absorption.
• Avoid in pregnancy and lactating women.
• No dosage adjustment needed in patients with
• Avoid in moderate to severe liver failure
patients.
 EDOXABAN
• Indications:-
• Non-Valvular Atrial Fibrillation.
• Deep Vein Thrombosis.
• Pulmonary Embolism.
• Adverse effects:-
• Bleeding manifestations.
• Antidote-
• None.
WARFARIN & THE
COUMARIN
ANTICOAGULANTS
VITAMIN K CYCLE
• The metabolic interconversion of vitamin K
associated with the synthesis of vit K
dependent clotting factors.
• Vit K1 or K2 is activated by reduction to the

hydroquinone form (KH2).

• Stepwise oxidation to vitamin K epoxide
(KO) is coupled to prothrombin
carboxylation by the enzyme carboxylase.
• The reactivation of vit K epoxide is the
warfarin-sensitive step.
 Warfarin: Mechanism of Action
• Interferes with the cyclic interconversion of vitamin K and its 2,3 epoxide
(vitamin K epoxide),

• Vitamin K is an essential cofactor for post-translational carboxylation of

glutamate residues on the N-terminus regions of vitamin K-dependent
proteins to gamma-carboxy-glutamates.

• Descarboxyprothrombin is converted to prothrombin by carboxylation of

glutamate residues to gamma-carboxyglutamate
 Warfarin: Mechanism of Action
• By inhibiting vitamin K epoxide reductase and vitamin K reductase, warfarin
leads to the accumulation of vitamin K epoxide in the liver and plasma and
the depletion of reduced vitamin K (active form, KH 2)
• Reduced vitamin K is necessary for carboxylation of glutamate residues
• Decrease in KH2 limits the gamma-carboxylation of vitamin K dependent
coagulant proteins -
– Prothrombin (Factor II)
– Factors VII, IX, X
– Protein C and Protein S
• How does gamma-carboxylation affect the vitamin K dependent proteins ?

• gamma-carboxylation gives the proteins the ability to bind CALCIUM

IONS

• in the presence of calcium, the proteins undergo a conformational

change

• this allows them to bind to their respective cofactors on phospholipid

surfaces
 Pharmacokinetics of Warfarin

• Racemic mixture of two optical isomers

• Absorbed rapidly from GI tract
• Maximal plasma concentration in 90 min
• Plasma t1/2 of 36 to 42 hours
• Circulates bound to plasma proteins
• Administered orally
 Warfarin - drug-drug interactions
Prolong prothrombin time
• Stereoselective inhibition of clearance of the S-isomer -
• Phenylbutazone
• Metronidazole
• Sulfinpyrazone
• Trimethoprim-sulfamethoxazole
• Disulfuram
 Warfarin - drug-drug interactions
Prolong prothrombin time
• Change Warfarin Plasma Concentration
– Stereoselective inhibition of clearance of the R-isomer
• Cimetidine
• Omeprazole
– Nonstereoselective inhibition of R and S isomers
• Amiodarone
 Warfarin - drug-drug interactions
Prolong Prothrombin Time
• Do Not Change Warfarin Plasma Concentration
• Inhibits cyclic interconversion of vitamin K
• 2nd and 3rd Generation of cephalosporins
• Other Mechanisms
• Clofibrate
• Inhibits Blood Coagulation
• Heparin
• Increases metabolism of coagulation factors
• Thyroxine
 Warfarin - drug-drug interactions
Prolong Prothrombin Time
Effects on Warfarin Plasma Concentration are Unknown
Evidence is strong:
• Erythromycin
• Anabolic steroids

Evidence is lacking:
• Ketoconazole; Fluconazole; Isoniazid
• Piroxicam; Tamoxifen; Quinidine; Phenytoin
 Warfarin - drug-drug interactions

Inhibit Platelet Function- Do Not Change Warfarin Plasma Concentration

• Aspirin
• Ticlopidine
• Clopidogrel
• Moxalactam
• Carbenicillin and high doses of other penicillins
 Warfarin - drug-drug interactions
Reduce Prothrombin Time
• Change Warfarin Plasma Concentration
• Cholestyramine (reduces absorption of Warfarin)
• Increase metabolic clearance of warfarin
• Barbiturates
• Rifampin
• Griseofulvin
• Carbamazepine
 Therapeutic Range for Oral Anticoagulant Therapy

• Dose adjusted on the basis of laboratory tests

• Most often used is the one-stage prothrombin time

• PT is sensitive to: Factors II, VII, and X

• Makes use of Ca++ plus thromboplastin added to patient’s citrated plasma

- record time to clot
THROMBOPLASTINS DIFFER IN SENSITIVITY TO THE REDUCTION OF VITAMIN K-
DEPENDENT CLOTTING FACTORS
 Warfarin results in altered hepatic synthesis of several vitamin K-dependent
factors
Factor Coagulant Anticoagulant T1/2
Factor II yes no 50hrs
Factor VII yes no 6 hrs
Factor IX yes no 24hrs
Factor X yes no 36hrs
_________________________________
Protein C no yes 8hrs
Protein S no yes 30hrs
Both Factor VII and Protein C have short t1/2. The decrease in Factor VII activity is
countered by the thrombogenic effect of decreased Protein C in the first 24 hours
 Warfarin - Dosing Considerations
• Onset of anticoagulant effect is delayed as existing clotting factors (II, VII,

IX, X, Protein C and Protein S) must be cleared from the circulation.

• Effect occurs within 24 hours as Factor VII (short t1/2 = 6-7 hrs) is reduced

to a critical value.

• Peak activity in about 72 - 96 hours - longer t1/2 of Factors II, IX, X.

 Warfarin - Dosing Considerations
• Protein C has a short t1/2 as does Factor VII

• In the early phase of treatment (24 - 48 hrs) the relative reduction in the
activity of protein C will enhance the prothrombotic action of Factor VII

• Remember, Protein C exerts a negative feed-back on thrombin via Factor

VIII and Factor V.
 Warfarin - Pharmacokinetics
• Only a small amount of the total circulating drug, 1-2% causes the
pharmacologic effect.
• Displacement of warfarin from albumin binding sites augments
the plasma concentration of active drug and can increase the
anticoagulant effect.
• Half life of racemic warfarin ranges from 20 - 60 hours, reflecting
the contribution of its dextro- and levo- isomers.
• d- isomer has longer half-life. l - isomer is 5.5 times more active.
Each isomer is metabolized by different pathways. Levo
metabolites appear in the bile, dextro-metabolites appear in the
urine.
 Warfarin - Clinical Uses
• Oral anticoagulants are effective in the primary and secondary
prevention of venous thrombo-embolism
• Prevention of systemic embolism in patients with prosthetic heart
valves or atrial fibrillation
• Prevention of stroke, recurrent infarction, and death in patients
with acute MI
• INR of 2.0 - 3.0 (moderate-intensity regimen) is satisfactory for
most situations
 Warfarin - Adverse Effects

• Bleeding is the main concern, risk depends on:

– Intensity of the therapy
– Patient’s underlying disorder
– Concomitant use of aspirin or antiplatelet drugs.
– Patient’s age - risk > 65 yrs old, hx of stroke, hx of GI bleeding
– Bleeding with an INR < 3, usually due to some occult cause, GI or renal
lesion
 Warfarin - Adverse Effects
• Most important non-hemorrhagic effect is skin necrosis

• Occurs on 3rd to 8th day of dosing

• Due to excessive thrombosis of venules and capillaries in subcutaneous fat

• May be associated with Protein C deficiency - initiation of warfarin therapy

can induce a rapid decline in protein C because of its short half life (7 hours)
resulting in a parodoxical syndrome of transient hypercoagulation and
microthrombus formation beginning before effective anticoagulation is
achieved.
 Warfarin in pregnancy
• Crosses the placenta
• Produces characteristic embryopathy, CNS abnormalities, fetal bleeding
• Embryopathy consists of:

• nasal hypoplasia
• stippled epiphyses
• agenesis of corpus callosum
• ventral midline dysplasia - optic atrophy
 Management of Warfarin Overdose
Excessive anticoagulant effect of warfarin can be reversed by:
• stopping the drug
• administering large doses of vitamin K1
(5 to 10 mg; may need to repeat dose)
• administering fresh-frozen plasma (10-20 ml/kg) combined with vitamin K 1
• administering factor IX concentrate
• Improvement in hemostasis does not occur for several hours - may require
24 hours.
 Dosing Regimens for Anticoagulation
• Warfarin (Oral Administration)
• Day 1 - 15 mg
• Day 2 - 10 mg
• Day 3 - 10 mg
• Maintenance dose is 5 to 7.5 mg daily, but there is marked
variation among patients
• Prothrombin time changes little in first 24 hours with gradual
prolongation by the third day.
 Warfarin Anticoagulation Failure
• Altered oral bioavailability
• drug/food interaction within the GI tract
• Variations in Vitamin K availabililty
• dietary
• altered GI flora
• Drug/Drug Interactions
• displacement from plasma albumin
• altered hepatic metabolism (cytochrome p450)
• Hereditary Resistance
• Rare disorder characterized by autosomal dominant inheritance.
• Individuals may require up to 75-80 mg of warfarin to achieve a therapeutic
prothrombin time.