AzL & YSP

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
29 Mei 2015, HIS KBK FK USU, Medan

The Balance
Bleeding

Clotting

Blood Coagulation Cascade:

Overview
Intrinsic pathway
Blood disturbances and
platelet phospholipids
activate factor XII to
initiate the intrinsic
coagulation pathway,
which
X leads to the
activation of
(factor
X).

Extrinsic pathway

Xll

When a vessel is injured,

TF

Xl
lX

TF
VII

VIIIa

Common pathway
(factor II, or prothrombin) is
converted by factor Xa into factor IIa, or
thrombin.

Va

Factor Xa:

II

Thrombin cleaves
(factor I, or
fibrinogen) to form fibrin (factor Ia), a
key component of clot formation.

(tissue factor, or
thromboplastin) is
released from the
endothelium initiating
the extrinsic coagulation
X
pathway, which leads to
the activation of
(factor X).

I
Fibrin Clot

Occupies a critical
juncture of the
coagulation cascade,
common to both the
intrinsic and extrinsic
pathways
An attractive target for
anticoagulation

Adapted from Ansell J. J Thromb Haemost. 2007;5(suppl1):60-64.

Guyton AC, Hall JE. Hemostasis and blood coagulation. In: Textbook of Medical Physiology. 10th ed. Philadelphia, PA: WB Saunders Co; 2000:419-429.
Moake JL. Hemostasis. In: Porter RS, Kaplan JL, Homeier BP, eds. The Merck Manual Online. http://www.merck.com/mmpe/sec11/ch134/ch134a.html. Accessed March 4,
2008.

Thrombosis
Arterial Thrombosis :
Adherence of platelets to arterial walls
White in color - Often associated with
MI, stroke and ischemia

Venous Thrombosis :
Develops in areas of stagnated blood flow
(deep vein thrombosis),
Red in color- Associated with
Congestive Heart Failure, Cancer,
Surgery.

Secondary
prevention
antiplatelet

myocardial
infarction
white
thrombus

stroke

fibrinolytic
thrombosis
anticoagulant
Primary
prevention

red
thrombus

deep vein
thrombosis
pulmonary
embolism

Clinical Manifestations of
Atherothrombosis
Acute coronary
syndromes
STEMI
NSTEMI
Unstable angina
Stable CAD
Atrial Fibrillation
Angioplasty
Bare metal stent
Drug eluting stent
CABG
Abdominal aortic
aneurysm (AAA)

Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

Stroke
TIA
Intracranial stenosis
Carotid artery stenosis
CEA
Carotid stenting
Renal artery stenosis
Renal artery stenting

Peripheral arterial
disease
Acute limb ischemia
Claudication
Amputation
Endovascular stenting
Peripheral bypass
Abnormal ABI

Principles Management and

Therapy of Thrombosis
Pathogenesis

Therapy

Prothrombotic State Reduced Of Risk Factor

Platelet Adhesion
Platelet Aggregation
Blood Coagulation
Thrombosis

Anti-platelet

AntiThrombotic
Anti-coagulant
Agent
Thrombolytic Agent

Antithrombotic drugs to treat

thrombo-embolism
Drug Class

Prototype

Action

Effect

Anticoagulant
Parenteral

Heparin

Inactivation of
clotting
Factors

Prevent venous
Thrombosis

Anticoagulant
Oral

Warfarin

Decrease
synthesis of
Clotting factors

Prevent venous
Thrombosis

Antiplatelet
drugs

Aspirin

Decrease
platelet
aggregation

Prevent arterial
Thrombosis

Thrombolytic
Drugs

Streptokinase

Fibrinolysis

Breakdown of
thrombin

Currently Available

Antithrombotic Drugs
ANTI-PLATELET
AGENTs

ORAL

PARENTERAL

Aspirin
GPIIb/IIIa
Dipyridamol Antagonists
Ticlopidin
Abciximab
Clopidogrel
Tirofiban
Cilostazol
Eptifibatide
Sulfinpyrazone

ANTICOAGULANTs

THROMBOLYTIC
AGENTs

ORAL

PARENTERAL

PARENTERAL

Coumarin
Warfarrin
Melagatran

Heparin
LMWH
Hirudin
Argatroban
Fondaparinox

Streptokinase
Urokinase
tPA

Anticoagulant Targets
ORAL

PARENTERAL

TTP889

TFPI (tifacogin)

TF/VIIa
X

Warfari
n

IX
VIIIa

Va

Rivaroxaban
Apixaban
Betrixaban

Xa

APC (drotrecogin alfa)

sTM (ART-123)

IXa

AT

II (thrombin)
Dabigatran
Ximelagatra
n

IIa
Fibrinogen

Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7.

Heparin
Idraparinux

Otamixaban
Melagatran

Fibrin

APC
AT
sTM
TF
TFPI

activated protein C
antithrombin
soluble thrombomodulin
tissue factor
tissue factor pathway

Anticoagulant
A substance that prevents coagulation;
that is which stop blood from clotting
Reduce blood clotting
This prevents:
Deep vein thrombosis
Pulmonary embolism
Myocardial infarction
Stroke

Current Anticoagulants
Classes

Examples

Vitamin K Antagonist
Unfractionated Heparin
(UFH)

Warfarin
Heparin

Low Molecular Weight

Heparin (LMWH)

Enoxaparin

Direct Thrombin Inhibitors

Bivalirudin,
Dabigatran,

Factor Xa Inhibitors

Apixaban,
Rivaroxaban

Unfractionated Heparin (UFH)

5,000-30,000 Daltons
Heterogeneous mixture of polysaccharide chains
with varying effects on anticoagulant activity
Accelerates the action of circulating antithrombin
(AT), a proteolytic enzyme which inactivates
factors IIa (thrombin), IXa, Xa
Prevents thrombus propagation, but does not
lyse existing thrombi

Heparin

Sulphated carbohydrate
Purified from pork or bovine lungs
Different size
Active in vitro and in vivo
Administration - parenteral Do not inject IM - only IV or deep s.c.

Half-life 1 - 5 hrs - monitor aPTT

Adverse effect - hemorrhage - antidote protamine sulphate
Toxicity of heparin - Heparin-induced Platelet
Aggregation

Low-Molecular-Weight Heparin (LMWH)

4,200-6,000 Daltons
Obtained through chemical or enzymatic
depolymerization of polysaccharide chains of
UFH
>18 saccharide units inactivate Xa and thrombin
<18 saccharide units inactivate Xa (25-50% of chains)

Relatively more inhibition of Xa than thrombin

Ratios of anti-factor Xa:IIa from 1.9-12.

Fondaparinux

Factor Xa inhibitor
Synthetic pentasaccharide
t1/2 = 17-21 hrs
Inactive against thrombin already generated
Advantages over UFH

Decreased plasma protein, endothelial cell binding

More predictable, sustained anticoagulation
Once-daily dosing
No laboratory monitoring

Low Molecular Weight Heparin

Potential Advantages:
Lack of binding to plasma proteins
and endothelium
Good bioavailability
Stable dose response
Long half-life
Resistance does not develop

Low Molecular Weight Heparin

Venous Thromboembolism
- prophylaxis
- treatment
Ischaemic heart disease
unstable angina
acute MI
coronary stenting

Cerebrovascular disease
ischaemic stroke
embolic stroke

Peripheral vascular disease

reconstructive surgery

Comparison UFH vs
LMWH
Standard
Parameter
LMWH
Heparin
Molecular Weight ~15,000 Daltons ~5,000 Daltons
Bioavailability

Poor

Good

Lab Monitor

aPPT

None

IV or SQ

SQ

Bleeding Risk

3+

2+

Antithrombotic
Effect

3+

4+

Route

Heparin vs Warfarin
Heparin

Warfarin

Absorption

Parentral only

Oral

Vol of distribution

Plasma vol (0.07 L/kg)

7.6-13.9 L

Metabolism/Clearance

Hepatic metabolism & uptake by

reticulo endothelial system
Also by thrombin & other
clotting factors

Hepatic

Elimination t1/2

50-90 min

36-42 hr

Protein binding

Bound to antithrombin III &

other serine proteases

99.4% bound to albumin

Plasma concentration
(therapeutic)

0.2-0.4 U/ml

1.5 mg/L

Side effects

Bleeding
Thrmbocytopenia
Osteoporosis

Bleeding
Skin necrosis
Drug interactions

Treatment of bleeding

Mild: Slow or stop infusion

Severe: Protamine 1 mg/100 u
of estimated heparin remaining
in body

Mild: hold 1-2 doses, observe,

restart at lower dose
Severe: Vit K or fresh frozen
plasma

Oral anticoagulants :
warfarin, dicumarol

Coumarins - warfarin, dicumarol

Isolated from clover leaves
Structurally related to vitamin K
Inhibits production of active clotting factors
Absorption rapid - binds to albumin
Clearance is slow - 36 hrs
Delayed onset 8 - 12 hrs
Overdose - reversed by vitamin K infusion
Can cross placenta - do not use during late
pregnancies

Mechanism of action
Descarboxy
Prothrombin

Prothrombin

Reduced
Vitamin K

Oxidized
Vitamin K

NAD

NADH

Warfarin

Therapeutic range for warfarin in

AF and stroke

a specified international sensitivity index (ISI)

The variability of warfarin dosage

age, body size
genetic polymorphism of :
CYP2C9 the enzyme that metabolize S-warfarin
VKOR (vit. K epoxide reductase) the target enzyme
for warfarin
ethnicity (warfarin dose in Asian < Caucasian)
concurrent disease
(hepatocellular damage, cardiac disease, pyrexia)

dietary vitamin K intake

drug interactions

Drug interaction - Warfarin

Drugs that
promote
bleeding

Drugs that
decrease
warfarin
activity

Decrease synthesis of
Clotting Factors

Antibiotics (oral)

Decrease binding to
Albumin

Aspirin
Sulfonamide

Inhibition of clotting factors

Heparin
antimetabolites

Inhibit metabolizing enzymes

Cimetidine,
Disulfiram

Induction of metabolizing enzymes

Barbiturates
Phenytoin

Promote clotting factor synthesis

Vitamin K
OC

Reduced absorption

Cholestyramin

Limitations of VKA Therapy

sell J, et al. Chest 2008;133:1605-85, Nutescu EA, et al. Cardiol Clin 2008;26:169-87,
Umer Ushman MH, et al. J Interv Card Electrophysiol 2008;22:129-37

New Anticoagulant Targets

ORAL

PARENTERAL

TTP889

TFPI (tifacogin)

TF/VIIa
X

Warfari
n

IX
VIIIa

Va

Rivaroxaban
Apixaban
Betrixaban

Xa

APC (drotrecogin alfa)

sTM (ART-123)

IXa

AT

II (thrombin)
Dabigatran
Ximelagatra
n

IIa
Fibrinogen

Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7.

Heparin
Idraparinux

Otamixaban
Melagatran

Fibrin

APC
AT
sTM
TF
TFPI

activated protein C
antithrombin
soluble thrombomodulin
tissue factor
tissue factor pathway

Comparison of Features:
Warfarin vs. NOACs
Feature

Warfarin

NOAC

Onset

Slow

Rapid

Half-life

Long

Short

Elimination

Hepatic

Renal

Therapeutic Window

Narrow

Wider

Polymorphism

Yes

No

Racemic

Yes

No

Many

Few

Food effect

Yes

No

Monitoring

Yes

No

Antidote

Yes

No

Dosing

Variable

Fixed

Drug interactions

New Oral Anticoagulants

Potential Alternatives to Warfarin
Thrombin inhibitors Factor Xa inhibitors

Ximelagatran
Dabigatran
Dabigatran
Rivaroxaban

2010

Apixaban

2011

Rivaroxaban
Apixaban
Edoxaban
Others
Otomaxiban

2012

2013

Chemical Structure of
Anticoagulants

Dabigatran Etexilate (Pradaxa)

Pro-drug: Dabigatran Etexilate Dabigatran
Direct thrombin inhibitor (fIIa inhibitor)
Absorption: requires acidic environment

Bioavailability ~6%

~35% protein bound;

Vd = 0.85 1.0 L/kg
Metabolism:

by esterase-catalyzed hydrolysis; not a CYP450 substrate,

inducer, or inhibitor.
P-glycoprotein substrate:

avoid use with P-gp inducers (i.e. rifampin);

may use with concominant P-gp inhibitors (i.e. ketoconazole, verapamil,
amiodarone, clarithromycin) bioavailability of dabigatran is decreased

Elimination: t1/2 = 12-17 hours;

80% excreted unchanged in the urine via glomerular filtration

Dabigatran
150 and 75 mg dose approved by FDA
Dosing
CrCl > 30 mL/ml 150mg BID
CrCl 15-30mL/ml 75 mg BID
CrCl < 15 not indicated
The US FDA dabigatran should not be used to
prevent stroke or major thromboembolic events in
patients with mechanical (also known as mechanical
prosthetic) heart valves
Not to be used in patients with:
Valvular atrial fibrillation
Advanced liver disease
Severe renal failure

Why thrombin is an excellent

target?
PROTHROMBIN

Resting Platelet
THROMBIN
Active Platelet

DTI

Fibrinogen
Fibrin
CLOT

Factor Xa inhibitors
fXa may be a better target than thrombin
Has few functions outside coagulation
(compared with thrombin)
Has a wider therapeutic window than
thrombin (separation of efficacy and
bleeding), in vitro
Thrombin inhibitors are associated with
rebound thrombin generation no
evidence with fXa inhibitors

Rivaroxaban and Apixaban

They are direct factor Xa inhibitors.
Both XABANs bind to the catalytic/active site
of factor X and directly interfere with the
coagulation cascade.
The two drugs interact slightly differently with the
S4 region of factor X

Similar to dabigatran
they have predictable pharmacokinetics and
allow for fixed oral dosing.
their half-lives are under 12 hours.

Rivaroxaban (Xarelto)
Absorption: complete, take with or without food
bioavailability of 80-100%,

~95% protein bound;

Metabolism: P-glycoprotein, CYP3A4 substrate

Concomitant use + inhibitors anticoagulant effect

Concomitant use + inducers anticoagulant effect

Elimination: t1/2 = 5-9 h (young), 11-13 h (elderly)

66% (renal), 34% (feces)
Contraindications/Warnings Black Box Warning:
Epidural or spinal hematomas can occur in patients who are
anticoagulated and are receiving neuraxial anesthesia or
undergoing spinal puncture

avoid use in patients with moderate or severe hepatic

impairment

Apixaban (Eliquis)
Direct-acting, reversible factor Xa inhibitor.
inhibit the conversion of prothrombin to thrombin

Dose: 2.5 mg
Absorption: complete, take with or without food
bioavailability of 66%, peak concentrations 3-4 hrs

~80% protein bound;

Metabolism: P-glycoprotein, CYP3A4 substrate
to inactive metabolite O-demethyl-apixaban.
does not induce or inhibit enzymes

Elimination: t1/2 = 12 (9-14) hours;

25% renally and 55% fecally eliminated.

Apixaban (Eliquis)
Drug interaction

+ Potent 3A4 inhibitors ADR

ADRs:

Bleeding (6%), nausea (7%), vomiting (5%),

constipation (5%) in ADVANCE trials.
Elevation of LFTs (the incidence rate was no different
from the comparator groups)

Monitoring:

No routine monitoring is required

Prothrombin time/INR

Reversal agent:

No standard antidote

Pharmacokinetics of NOACs
Parameter

Apixaban

Rivaroxaban

Dabigatran E

MW (Dalton)

460

436

628

Pro-drug

No

No

Yes

Peak conc. (hour)

2 (ACIDIC)

Bioavailability (%)

66

> 80

Food effect

None

Delays absorption Delays absorption

Effect of age

Not reported

Variable

None29

Effect of BW

Not reported

None

None

80

95

35

9-14

5-9 (young)
11-13 (elderly)

12-17

Plasma protein (%)

Half-life (hour)
Elimination

Renal (25%)

Renal (66%);
half is inactive

Renal (85%)

Transporters

P-gp

P-gp/BCRP

P-gp

Involv. of CYP

CYP3A4 (15%)

CYP3A4 (32%)

No

Lab. monitoring

Dil. PT

PT

Thrombin time

Pharmacodynamics of NOACs
Parameter

Apixaban

Rivaroxaban

Dabigatran

MoA

FXa inhibitor

Fxa inhibitor

Thrombin inhibitor

Dosing

ARISTOTLE

ROCKET-AF

RE-LY

Dosing

BID all indication

(VTEp, VTEL, AF,
ACS)
5.0 (2.5)

OD (VTEp,
VTEL, AF)
BID (ACS)
20 (15)

OD (VTEp)
BID (VTEL, AF)

Linear PK

Yes

Drug interaction

Intersubject
variability

Strong CYP3A4
and P-gp
inhibitors and
inducers

150, 110
Yes

No
Strong CYP3A4
and P-gp
inhibitors
Strong CYP3A4
inducers
35%

P-gp inhibitors
(Amiodaron) and
inducers
(Verapamil)
PPI decrease
absorption
30%

Hot Topics in Cardiology 2010;4:7-14; Clin Pharmacokinet 2009;48:1-22;

Thromb Haemost 2010; 103: 34-39; Thromb Haemost 2010;103: 572-585