Antithrombotics

Antithrombotic
drugs
l e v e l 1 S E M 2
Nehal M. Ramadan
A s s o c i a t e p r o f e s s o r o f c l i n i c a l p h a r m a c o l o g y
F a c u l t y o f m e d i c i n e , M a n s o u r a u n i v e r s i t y , E g y p t

AG E N DA
1. Anticoagulant drugs  prevent blood coagulation to prevent the formation or expansion of a
thrombus.
2. Antiplatelet drugs  inhibit platelet activation/aggregation to prevent unwanted thrombi
3. Fibrinolytic drugs  stimulate lysis of an already-formed clot following a thromboembolic event
2
1
3

M a j o r cl a s s e s & t h e r a p e u t i c
i n d i c at i o n s
Drug class Therapeutic indication
Anticoagulant drugs
• Warfarin
• Unfractionated Heparin
• Low molecular weight Heparins (LMWHs)
• Fondaparinux (Heparin Pentasaccharide)
• Direct Thrombin inhibitors
• Factor Xa inhibitors
Coronary artery disease (acute myocardial infarction)
Coronary artery bypass surgery, coronary
angioplasty/stenting
Atrial fibrillation (AF)
Valvular heart disease (natural & artificial valves)
Orthopedic surgery & mechanical prothesis
Deep Venous Thrombosis (DVT)
Antiplatelet drugs
• Aspirin
• P2Y12 blockers: Clopidogrel, Cangrelor, Prasugrel,
Ticagrelor
• Glycoprotein IIb/IIIa inhibitors
Coronary artery disease (stable angina or acute myocardial
infarction)
Coronary artery bypass surgery, coronary
angioplasty/stenting
Stroke & transient ischemic attack
Fibrinolytic drugs
• Streptokinase, Urokinase, tissue plasminogen activator
and its derivatives
Acute myocardial infarction
DVT & pulmonary embolism

A
n
t
i
c
o
a
g
u
l
a
n
t
s
P R E S E N T A T I O N T I T L E
4
Anticoagulant drugs
function by either
• Blocking thrombin
formation (inhibition
factor Xa)
• Indirect factor Xa
inhibitors
• Direct factor Xa
inhibitors
• or by inhibiting the
activity of thrombin
after it is formed.
• Indirect thrombin
inhibitors
• Direct thrombin
inhibitors
• Vit K antagonists

A n t i c o a g u l a n t
d r u g s
C l a s s i f i c at i o n
Anticoagulants
Parenteral
Indirect thrombin
inhibitors
Unfractionated Heparin
(UFH)
Low molecular weight
Heparins (LMWHs)
Indirect factor Xa
inhibitors
Fondaparinux
Direct thrombin
inhibitors
Lepirudin
Bivalirudin
Argatroban
Oral
Vit K
antagonist
Warfarin
Direct factor Xa
inhibitors
Rivaroxaban
Apixaban
Direct thrombin
inhibitors
Dabigatran

Pa r e n t e r a l i n d i r e c t
a n t i c o a g u l a n t s
Heparins  linear sulphated mucopolysaccharides derived from animal sources.
1. Unfractionated heparin (UFH) 
• A heterogeneous compound.
• it is a collection of large and variable polysaccharides (over a 100 sugar units, MW as
as 30 kDa)
• With limited bioavailability.
2. Low-molecular-weight heparins (LMWHs): Enoxaparin & dalteparin
• Have an average MW of ~ 5 kDa and
• Have been size-selected (uniform in size) to provide a more predictable
profile.
Fondaparinux
• A synthetic pentasaccharide corresponding to the minimal five-residue active
oligosaccharide of heparin required for anticoagulation

Mechanism of action:
UFH  acts by ↑ the activity of anti-thrombin III
It binds to anti-thrombin III  a conformational change that renders the
reactive site on anti-thrombin more accessible to thrombin & factor X 
inactivation of thrombin (factor IIa) and factors Xa
• Heparin-anti-thrombin complex is a very efficient inhibitor of free thrombin,
clot-bound thrombin is resistant to inhibition.
LMWHs  inhibit factor Xa >> thrombin
Fondaparinux  Because of its short chain length  does not promote
thrombin inhibition, making it an anti-thrombin-dependent selective
factor Xa inhibitor.
P a r e n t e r a l i n d i r e c t t h r o m b i n / X a i n h i b i t o r s

Pharmacokinetics:
UFH, LMWHs & fondaparinux  not absorbed from the gut  must be
given parenterally.
1. UFH  administered by continuous IV infusion or SC.
• It is removed from the circulation by the reticuloendothelial system
• Has a half-life of ~90 minutes.
• The dosage of UFH is monitored using the activated partial
time (aPTT) and is considered adequate when the aPTT is 1.5 to 2
normal.
2. Enoxaparin and dalteparin administered SC
• Their maximal effect occurs 3 - 5 hours after injection.
• The aPTT does not need to be monitored because the anticoagulant
activity of LMWH is more predictable than the activity of UFH.

Side effects:
1. The major problem of all anticoagulants, even when used in therapeutic doses, is bleeding
2. UFH  Heparin Induced Thrombocytopenia (HIT)  either;
a) Type I  Transient thrombocytopenia  in 25% of ptns, non-immune mechanisms,
asymptomatic  reversible within 4 days despite continued heparin treatment.
b) Type II  Clinically-significant thrombocytopenia  if the platelet count falls <
more serious  immune mechanisms  Heparin must be discontinued
• Type II involve formation of complexes of heparin, platelet factor 4, and IgG.
• Its incidence ranges from 0.3%–3% in patients exposed to UFH for > 4 days
• Platelet counts should be monitored at regular intervals in patients receiving UFH for
periods.
• May be associated with arterial or venous thrombosis in a small but significant subset of
can be extremely serious and even fatal.
• Reversible  When heparin is discontinued, the platelet count usually returns to normal within
• Less common with the LMWHs than with UFH & fondaparinux.
3. UFH  occasionally causes hyperkalemia due to suppression of aldosterone secretion.

I N T RO
Treatment of
anticoagulant-
induced
bleeding side
effects
(Specific antidotes)
UFH or LMWH-
induced bleeding
Protamine sulfate
• A positively charged
protein that binds to the
negatively charged
heparin and inactivates it.
• Administered IV
• aPTT is measured 2-4 h
after administration  to
guide the need for further
protamine treatment.
Severe bleeding caused by
heparin-type drugs  require
administration of fresh
plasma or clotting factors.
Warfarin-
induced bleeding
Dabigatran-
induced bleeding
P
R
E
S
E
N
T
A
T
I
O
N
T
I
T
L
E
10
Phytonadione (vitamin K 1 )
1. Warfarin should be
stopped until the bleeding
can be evaluated
2. The patient’s INR should
be determined.
3. Administration of
phytonadione (vitamin
K1).
Serious bleeding or if the
INR is markedly elevated
(>20)  administration of
fresh plasma or factor IX
concentrate
Idarucizumab
• In cases of life-
threatening bleeding or
emergency surgery.
• A monoclonal antibody
to dabigatran 
immediately inactivates it
• Administered IV
Patients should also receive
activated charcoal orally 
prevent absorption of
dapigatran from GIT

T
h
e
m
o
r
e
t
h
a
n
i
d
e
a
l
c
o
m
p
a
r
i
s
o
n
b
e
t
w
e
e
n
U
F
H
&
L
M
W
H
s
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S
11
No need for therapeutic monitoring
Therapeutic monitoring is needed
using aPTT

Bivalirudin & Argatroban  synthetic  administered intravenously  directly
block the active site of thrombin and does not require AT-III as a cofactor 
• Both drugs have a more predictable anticoagulant effect than heparin.
• Unlike heparin  both are efficient inhibitors of free thrombin, as well as, clot-
bound thrombin.
• Like Heparin  the most serious adverse effect is bleeding.
• Unlike heparin  it does not cause thrombocytopenia  can be used in Heparin
induced thrombocytopenia (HIT)
P a r e n t e r a l d i r e c t t h r o m b i n i n h i b i t o r s

O r a l a n t i c o a g u l a n t s
V i t K a n t a g o n i s t ( Wa r f a r i n )
• Warfarin is structurally related to vitamin K.
• It inhibits the synthesis of coagulation factors whose formation is
dependent on vitamin K, factors II (prothrombin), VII, IX, and X.
• Warfarin inhibits the enzyme vitamin K epoxide reductase (VKORC1) 
blocks recycling of the oxidized form of vitamin K (epoxide form) to its
reduced form (which acts as a cofactor in the carboxylation of
coagulation factors)  prevents the biosynthesis of factors II, VII, IX, and
X.
• Warfarin has no effect on the already-synthesized factors  plasma levels of
vitamin K-dependent factors must decline before the anticoagulant effect of
becomes apparent, typically requiring several days (3 to 5d) after therapy is
Patients with acute thromboembolic diseases should be initially treated with a
+ plus warfarin, and the LMWH is then withdrawn after warfarin effects are

Pharmacokinetics:
• Warfarin  well absorbed from the gut  given orally.
• Warfarin is extensively metabolized in liver by CYP2C9 before being
excreted in the urine.
• Unlike heparin, warfarin crosses the placenta and can cause fetal
hemorrhage  CI in pregnancy
• Warfarin has a delayed onset of action WHY????
• A period of several days is also required for coagulation factor levels to
return to normal after warfarin has been discontinued  the recovery of
clotting factors can be ↑ by administration of phytonadione (vitamin K 1 )
• The dosage of Warfarin is monitored using the prothrombin time (PT)

Side effects and drug interactions:
1. The major problem, even when used in therapeutic doses, is bleeding  educate
patients to report any signs of bleeding.
2. CI in pregnancy  causes fetal hemorrhage and structural bone malformations
“the fetal warfarin syndrome”  chondrodysplasia punctata, skeletal deformities,
nasal hypoplasia, malformation of ears and eyes, optic atrophy, mental retardation
3. Warfarin serum levels are altered by a large number of drugs  drug-drug
interactions  patients should consult a doctor before starting or discontinuing
any other medication.
↑ anticoagulant effect of warfarin  bleeding ↓ anticoagulant effect of warfarin  thrombosis
Drugs that inhibit cytochrome P450 (CYP2C9)
Amiodarone, cimetidine, antibiotics (erythromycin,
metronidazole)
Drugs that induce cytochrome P450 (CYP2C9)
Rifampin or barbiturates
Displacement of warfarin from plasma albumin
Salicylates
Decreased warfarin absorption from the gut
Cholestyramine
Other anticoagulant drugs
Antiplatelet drugs
Non-steroidal anti-inflammatory (NSAIDs)

I N R ( I n t e r n a t i o n a l n o r m a l i z e d r a t i o )
I N R = ( P a t i e n t P T / C o n t r o l P T ) I S I
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S
16
• The dosage of warfarin is based on the patient’s PT (which measure
the extrinsic coagulation pathway).
• For most clinical indications, an INR of 2 to 3 is desirable.
• The patient’s PT should be monitored daily during the initiation of
warfarin therapy and whenever another drug is added to or
withdrawn from the treatment regimen.
• Once the patient’s INR has stabilized, it should be monitored every
4 to 6 weeks.

I N T RO
Treatment of
anticoagulant-
induced
bleeding side
effects
UFH or LMWH-
induced bleeding
Protamine sulfate
negatively charged
• Administered IV
Warfarin-
induced bleeding
Dabigatran-
induced bleeding
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S
17
can be evaluated
be determined.
K1).
concentrate
Idarucizumab
emergency surgery.
to dabigatran 
• Administered IV
dapigatran from GIT

D i r e c t t h r o m b i n i n h i b i t o r s
( D a b i g at r a n )
• Administered orally
• A prodrug  activated in the gut, blood, and liver.
• Primarily eliminated by renal excretion  Renal impairment prolongs the t1/2 of the
drug  doses should be reduced in renal dysfunction
• Dabigatran is a potent, competitive, reversible inhibitor of thrombin  blocks
conversion of fibrinogen to fibrin in the final step of blood coagulation.
• Unlike heparin  Dabigatran inhibits both fibrin-bound and unbound (free) thrombin.

D i r e c t t h r o m b i n i n h i b i t o r s
( D a b i g at r a n )
Side effects and drug interactions:
• Dabigatran increases the risk of bleeding
• Compared to warfarin  gastrointestinal bleeding is ↑
• Compared to warfarin  intracranial hemorrhage & stroke are ↓
• Unlike warfarin  Dabigatran does not interact with food and most other drugs
• However, dabigatran is a substrate for the excretory transporter; P-glycoprotein (Pgp)
transporter in the gut and kidneys  it should not be coadministered with inducers of Pgp 
↑ dabigatran excretion  ↓ dabigatran effect
• Dabigatran can be given with Pgp inhibitors (verapamil, amiodarone)  but these drugs
should be given 2h before or after dabigatran.
• Unlike warfarin  Dabigatran does not require laboratory monitoring

I N T RO
Treatment of
anticoagulant-
induced
bleeding side
effects
UFH or LMWH-
induced bleeding
Protamine sulfate
negatively charged
• Administered IV
Warfarin-
induced bleeding
Dabigatran-
induced bleeding
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S
20
can be evaluated
be determined.
K1).
concentrate
Idarucizumab
emergency surgery.
to dabigatran 
• Administered IV
dapigatran from GIT

D i r e c t Fa c t o r X i n h i b i t o r s
( A p i x a b a n a n d R i v a r ox a b a n )
• They bind to the active catalytic site of Xa  inhibiting the activity of both free Xa and
that bound in the prothrombinase complex.
• Xa is formed at the convergence of the extrinsic and intrinsic pathways  then Xa
combines with factor Va to form a prothrombinase complex that converts prothrombin
to thrombin
Side effects:
• Bleeding is the most common adverse effect
• There are no reversal agents  Experts suggest administering coagulation factor
preparations such as prothrombin complex concentrate
Unlike warfarin  Factor X inhibitors do not require laboratory monitoring

T
h
e
m
o
r
e
t
h
a
n
i
d
e
a
l
c
o
m
p
a
r
i
s
o
n
b
e
t
w
e
e
n
o
r
a
l
a
n
t
i
c
o
a
g
u
l
a
n
t
s
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S
22

T
h
e
m
o
r
e
t
h
a
n
i
d
e
a
l
c
o
m
p
a
r
i
s
o
n
b
e
t
w
e
e
n
U
F
H
a
n
d
w
a
r
f
a
r
i
n
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S
23

A
n
t
i
p
l
a
t
e
l
e
t
d
r
u
g
s
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S
24
Thrombin receptor blockers
(PAR-1 blocker)
Vorapaxar
GP-IIb/IIIa receptor blockers
abciximab, tirofiban, and
eptifibatide
Antiplatelet drugs
function by either
• Inhibiting
thromboxane A2
formation
(low dose Aspirin)
• Blocking ADP
receptors (P2Y12)
Clopidogrel,
prasugrel &
ticagrelor
• Blocking GP Iib/IIIa
glycoproteins
Abciximab
• Blocking thrombin
receptors (PAR1)
Voraxapar

• Aspirin (high dose) is a non-steroidal anti-inflammatory drug (NSAID)  has
analgesic, antipyretic, and anti-inflammatory effects
• Aspirin (low dose 75-100 mg/d)  also inhibits platelet aggregation  used to
prevent/treat arterial thromboembolic disorders (MI and stroke).
Mechanisms of action:
• Low doses of aspirin  selectively & irreversibly inhibit platelet cyclooxygenase-1
(COX1) enzyme  ↓ synthesis of thromboxane A2 (TXA2)  inhibit platelet
aggregation
• Aspirin inhibits platelet aggregation for the life of the platelet  effective when
administered once/day.
Side effects:
• Bleeding, especially in the GIT, why???
Aspirin inhibits the synthesis of stomach prostaglandins that ↑ secretion of bicarbonate and
mucus  These substances protect the stomach mucosa from the damaging effects of
stomach acid and pepsin.
L ow d o s e a s p i r i n

A D P r e c e p t o r b l o cke r s
C l o p i d o g r e l , P r a s u g r e l & T i c a g r e l o r
• They block ADP receptors on platelet (P2Y12 receptors)  inhibit activation
ADP-induced platelet aggregation.
• Clopidogrel and prasugrel are irreversible P2Y12 antagonists that inhibit
platelet function for the life of the platelet.
• Ticagrelor are reversible P2Y12 antagonists.
Pharmacokinetics:
• Clopidogrel and prasugrel  prodrugs metabolized to active drugs by
CYP450 enzymes.
• Prasugrel  has a more rapid onset of action than Clopidogrel and it produces a
higher and more consistent level of platelet inhibition than Clopidogrel
• Ticagrelor does not require activation  has a more rapid onset of action &
action wears off more rapidly after discontinuation of Ticagrelor

T
h
e
m
o
r
e
t
h
a
n
i
d
e
a
l
c
o
m
p
a
r
i
s
o
n
b
e
t
w
e
e
n
o
r
a
l
A
D
P
r
e
c
e
p
t
o
r
b
l
o
c
k
e
r
s
27
• Activation of Clopidogrel is
dependant on CYP2C19
• CYP2C19 is inhibited by proton
pump inhibitors (PPIs), esp.
omeprazole, that are used in
treating peptic ulcer
• PPIs  inhibit Clopidogrel
activation  significantly
increasing the risk of
thrombotic events
• Avoid omeprazole in patients
on Clopedogrel therapy
• Prasugrel is activated primarily
by CYP3A4 and CYP2B6 and is
not significantly affected by
PPIs
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S

Fibrinolytic drugs breakdown the already-formed
blood clot by:
Enhancing convertion of plasminogen to plasmin 
degrades both fibrin and fibrinogen  clot
dissolution
• Fibrin-specific drugs
Recombinant forms of human tissue plasminogen
activator (t-PA): alteplase, reteplase, and tenecteplase
• Nonfibrin-specific drugs
streptokinase
F
i
b
r
i
n
o
l
y
t
i
c
d
r
u
g
s
28
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S

Classification:
1. Fibrin-specific drugs
• Recombinant forms of human tissue plasminogen activator (t-PA):
alteplase, reteplase, and tenecteplase
• Mild-moderate specificity for target fibrin-bound plasminogen in clots
2. Nonfibrin-specific drugs
• Streptokinase (a protein obtained from streptococci bacteria)
• Lower specificity for fibrin-bound plasminogen in clots  causes
greater degradation of systemic fibrinogen
F i b r i n o l y t i c d r u g s
STREPTOKINASE ALTEPLASE RETEPLASE TENECTEPLASE
Administration Infusion Infusion Bolus Bolus
Allergic reactions Yes No No No
Systemic
fibrinogen
depletion
Marked Mild Moderate Minimal
Fibrin specificity − ++ + +++

Side effects:
1. The most common adverse effect is bleeding  indicated in
treatment of ischemic stroke but, CI in hemorrhagic stroke
• Because the recombinant forms of t-PA selectively activate
plasminogen bound to fibrin  they cause less bleeding than
streptokinase.
2. Arrhythmias (e.g., bradycardia and tachycardia) may occur in MI
patients treated with fibrinolytic drugs
3. treptokinase can cause various types of hypersensitivity
reactions, including fatal anaphylactic shock  it should not be
used repeatedly in the same patient.
Treatment of Bleeding due to fibrinolytic drugs
Aminocaproic acid & tranexamic acid  these drugs bind plasmin
plasmin thereby prevent it from degrading fibrin.
F i b r i n o l y t i c d r u g s

THANK YOU
Nehal M. Ramadan
Associate professor of clinical pharmacology
Faculty of medicine, Mansoura university, Egypt
A
N
T
I
T
H
R
O
M
B
O
T
I
C
D
R
U
G
S
31

Antithrombotics

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Antithrombotics

Similar to Antithrombotics (20)

More from Nehal M. Ramadan

More from Nehal M. Ramadan (17)

Recently uploaded

Recently uploaded (20)

Antithrombotics