Download Factor Xa inhibitors

Dr.Hardik Patel
 Arterial
thrombus
Rich in platelets
 Venous
thrombus
Rich in fibrin and RBC
 Aspirin
produces its antithrombotic effect by
irreversibly acetylating and inhibiting platelet
COX -1, a critical enzyme in the biosynthesis of
thromboxane A2
 Aspirin
is widely used for secondary
prevention of cardiovascular events in patients
with coronary artery, cerebrovascular,or
peripheral vascular disease.

Dosage:
75-325 mg/day
Higher dose not more effective than lower dose

Side effects:
Gastritis, peptic ulcer
Bleeding

Aspirin resistance
Poor absorption, drug interaction, overexpression
of cox-2
Theinopyridine (Clopidogrel & Prasugrel)
 They
selectively inhibit ADP-induced
platelet
aggregation by irreversibly blocking P2Y12
 Clopidogrel
and prasugrel are prodrugs that
require metabolic activation by the hepatic
cytochrome P450 (CYP) enzyme system

Clopidogrel is more effective than aspirin in
patients with recent ischemic stroke, recent MI, or a
history of peripheral arterial disease

Clopidogrel and aspirin are combined to capitalize
on their capacity to block complementary
pathways of platelet activation in certain situations

The combination of clopidogrel and aspirin should
only be used when there is a clear benefit
 Prasugrel
has better role in treatment of MI and
prevention of stent rethrombosis , but at the
cost of high bleeding tendency

The drug is generally avoided in patients with
age > 75 years and contraindicated in those
patient with history of CVD
Clopidogrel
Loading 300mg f/b 75mg OD
Prasugrel
Loading dose of 60 mg f/b 10mg OD
Side effects
Bleeding , more common with prasugrel than
clopidogrel
Thienopyridine Resistance

The ability of Clopidogrel to inhibit ADP activity
varies among individuals

This is mainly due to genetic polymorphism of CYP
(mainly CYP2C19) enzyme involved the metabolic
activation of Clopidogrel.

PPI are inhibitors of CYP2C19 enzymes

This CYP polymorphism is less significant with
Prasugrel activation

Orally active inhibitor of P2Y12

Not a prodrug and its produces reversible
inhibition of ADP receptor

Rapid onset and offset of action

Studies
have
found
Ticagrelor
superior
clopidogrel for MI

Dosage : Loading 180 mg, f/b 90mg BD
to
 Dipyridamole
is a relatively weak antiplatelet
agent on its own

An
extended-release
formulation
of
dipyridamole combined with low dose aspirin
(Aggrenox), is used for prevention
of stroke in patients with TIA

Abciximab, Eptifibatide and Tirofiban

All target GpIIb/IIIa receptor

Mainly
used
in
patients
undergoing
percutaneous coronary interventions and in
high-risk patients with unstable angina.
 Dosing
All drugs given as IV bolus f/b infusion
Drug
Bolus
(ugm/kg)
Infusion
(Ugm/kg/min)
Abciximab
0.25
0.125
Eptifibatide
180 +180
2
Tirofiban
0.4 for 30 min
0.1
 Side
effects
Bleeding, thrombocytopenia (immune mediated)
 New
agents in advanced stages of development
include Cangrelor, a parenteral, rapidly acting,
reversible inhibitor of P2Y12

Vorapaxar,
an
orally
active
inhibitor
of
protease-activated receptor 1 (PAR-1), the
major thrombin receptor on platelets
Parenteral anticoagulants
Heparin, LMWH
Fondaparinux
Lepirudin, Desirudin, Bivalirudin, Argatroban.
Oral anticoagulants
Warfarin
Oral thrombin inhibitor - Dabigatran etexilate)
Oral factor Xa inhibitors- Rivaroxaban, Apixaban,
Edoxaban
Heparin


A sulphated polysachharide, isolated from mast cells
Heparin acts by activating antithrombin and
accelerating the rate at which antithrombin inhibits
clotting enzymes, particularly thrombin and factor
Xa.

Heparin has equal capacity to promote the
inhibition of thrombin and factor Xa
anti-factor Xa to anti-factor IIa ratio of 1:1

In the circulation, heparin binds to the endothelium
and to plasma proteins other than antithrombin

Heparin binding to endothelial cells explains its
dose-dependent clearance

Clearance is mainly extrarenal; heparin binds to
macrophages,which internalize and depolymerize the
long heparin chains and secrete shorter chains
back into the circulation.

Because of its dose-dependent clearance mechanism,
the plasma half-life of heparin ranges from 30 to 60 min
with bolus IV doses of 25 and 100
units/kg, respectively

Activated platelets also release PF4, a highly cationic
protein that binds heparin with high affinity. The large
amounts of PF4 found in the vicinity of platelet-rich
arterial thrombi can neutralize
the anticoagulant activity of heparin.

This phenomenon may attenuate heparin’s
capacity to suppress thrombus growth.
 Monitored
using the aPTT or anti-factor Xa level
 Therapeutic
heparin levels are achieved with a
two- to three fold prolongation of the aPTT
For prophylaxis :

5000 units SC two or three times daily

Coagulation monitoring is not necessary
Therapeutic dose
Coronary disease : IV heparin bolus of 5000 units or 70
units/kg, a heparin infusion rate of 12–15 U/kg per/hr
PTE: Initial bolus of 5000 units or 80 units/kg, followed by
an infusion of 18 units/kg per h.
 Bleeding
 Thrombocytopenia
 Osteoprosis
 Elevated
transaminases
 Small
fragments of heparin, mean molecular
weight 1/3 of UH
 Acts
by activating antithrombin, but more
affinity towards Xa than thrombin
 Longer
and predictable half life, doesn't need
coagulation monitoring
Dosing
 For
prophylaxis: OD SC doses of 4000–5000U
 Venous
thromboembolism:100U/kg BD
 Unstable
angina: 100-120U/kg BD
Monitoring
Anti factor Xa monitoring required in certain
situations
 Aa
synthetic analogue of the antithrombin-
binding pentasaccharide sequence
 Acts
by inhibiting factor Xa , no activity against
thrombin
 Dosage
:
2.5 mg OD for prophylaxis and ACS
7.5 mg OD for VTE
 Approved
parenteral direct thrombin inhibitors
include recombinant hirudins (lepirudin and
desirudin), argatroban, and bivalirudin
 Mainly
used in patients with HIT. Usually given
as IV infusion
 Monitoring
done using aPTT
 Vit
K Antagonists
Warfarin
 Thrombin inhibitors
Dabigatran
 Factor Xa inhibitors
Rivoroximab, Apixaban, Edoxaban
 Warfarin
interferes with the synthesis of the
vitamin K–dependent clotting proteins, which
include prothrombin (factor II) and factors VII,
IX, and X.
 The
synthesis of the vitamin K–dependent
anticoagulant proteins, proteins C and S are
also reduced

Warfarin is a racemic mixture of R and S isomers

CYP polymorphism alters metabolism of warfarin

Because of the variability in the anticoagulant
response to warfarin,coagulation monitoring is
essential to ensure that a therapeutic response is
obtained

For most indications, warfarin is administered in
doses that produce a target INR of 2.0–3.0

Warfarin is usually started at a dose of 5-10mg

A
minimum
5-day
course
of
parenteral
anticoagulation is recommended to ensure that the
levels of factor Xa and prothrombin have been
reduced into the therapeutic range with warfarin
 Bleeding
:
Narrow therapeutic range
 Skin
necrosis :
Occurs 2-5 days after start of treatment
 Contraindicated
 To
during pregnancy
be stopped 5 days before elective surgery

Dabigatran, rivaroxaban, and apixaban are licensed as
alternatives to warfarin for stroke prevention in nonvalvular
atrial fibrillation

Rivaroxaban, and apixaban have been approved for use in
elective hip or knee arthroplasty.

Rivaroxaban and dabigatran are also licensed for treatment
of DVT or PE

In Europe Rivaroxaban along with dual antiplatelets for ACS
 For
stoke prevention
Rivaroxaban ; 20mg OD
Dabigatran : 150mg BD
Apixaban
: 5mg BD
 For treatment of DVT or PTE
Rivaroxaban 15mg BD for 3 weeks f/b 20mg OD
 Post surgical prophylaxis
Rivaroxaban 10mg OD
Apixaban 2.5mg BD
 Not
routinely required
 For Xa inhibitors: aPTT
 Dabigatran : PT
 Bleeding
Reduced incidence compared to Warfarin
GI bledding common
 Contraindicated
during pregnancy
Thank
you