20150529-his-pharmacology of anticoagulant final

8/9/2019 20150529-His-Pharmacology of Anticoagulant FINAL

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AzL & YSP

Dep. Farmakologi & Terapeutik, Fakultas Kedokteran

29 Mei 2015 HIS KK FK !S! Medan


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"#e alan$e

leedin% lottin%


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Intrinsi$ 'at#(a)Blood disturbances andplatelet phospholipidsactivate factor XII toinitiate the intrinsiccoagulation pathwa,

which leads to theactivation of !factorX".

*

+trinsi$ 'at#(a)#hen a vessel is in$ured,

!tissue factor, orthromboplastin" isreleased from theendothelium initiating

the e%trinsic coagulationpathwa, which leads tothe activation of!factor X".

"F

*

Common pathway

!factor II, or prothrombin" isconverted b factor Xa into factor IIa, or

thrombin.

Thrombin cleaves !factor I, orbrinogen" to form brin !factor Ia", ake component of clot formation.

II

I

lood oa%ulation as$ade-./er/ie(

'dapted from 'nsell (. J Thromb Haemost . )**+-!suppl"/0*102.

3uton '4, 5all (6. 5emostasis and blood coagulation. In/ Textbook of Medical Physiology. *th ed. 7hiladelphia, 7'/ #B 8aunders 4o )***/2912)9.:oake (;. 5emostasis. In/ 7orter >www.merck.com>mmpe>sec>ch?2>ch?2a.html. 'ccessed :arch 2,)**@.

Fibrin 4lot

Xll

Xl

lX

AIIIa AII

"F

Aa

I

Fa$tor *a- ccupies a critical

$uncture of the

coagulation cascade,common to both theintrinsic and e%trinsicpathwas

'n attractive target foranticoagulation


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Thrombosis

• Arterial Thrombosis : – Adherence of platelets to arterial walls –

– White in color - Often associated withMI, stroke and ischemia

• Venous Thrombosis : – Develops in areas of stagnated blood flow

(deep vein thrombosis), – ed in color- Associated with

Con!esti"e #eart $ailure, Cancer,%ur!ery&


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mocardial

infarction

stroke

deep veinthrombosis

pulmonarembolism

red

t#rous

t#roosisbrinoltic

anti1

coagulant

anti'latelet

(#itet#rous

%econdarypre"ention

'rimarypre"ention


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Clinical Manifestations ofAtherothrombosis

8troke TI'Intracranial stenosis

4arotid arter stenosisCEACarotid stenting


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Prin$i'les Mana%eent andPrin$i'les Mana%eent and

"#era') o3 "#roosis"#era') o3 "#roosis

"#rool)ti$ A%ent"#roosis

Anti$oa%ulantlood oa%ulation

Platelet A%%re%ation

Anti'lateletPlatelet Ad#esion

4edu$ed .3 4isk Fa$torProt#rooti$ State

"#era')Pat#o%enesis

Anti

"#rooti$A%ent


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Antithrombotic dru!s to treat

thrombo-embolism

(ru! Class 'rototype Action )ffect

AnticoagulantParenteral

#eparin Inactivation ofclotting

actors

Prevent venous

!hrombosis

Anticoagulant"ral

Warfarin Decreases#nthesis of$lotting factors

Prevent venous

!hrombosis

Antiplateletdrugs

Aspirin Decreaseplatelet

aggregation

Prevent arterial!hrombosis

!hrombol#ticDrugs

%treptokinase ibrinol#sis %rea&down ofthrombin


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urrentl) A/ailaleAntit#rooti$ ru%s

"H4.M.LY"IA6+7"s

A7"IPLA"+L+"A6+7"s

A7"I.A6!LA7"s

8treptokinaserokinase

t7'

PA4+7"+4AL

4oumarin#arfarrin

:elagatran

5eparin;:#55irudin

'rgatrobanFondaparino%

.4AL PA4+7"+4AL

6PII8IIIaAnta%onists

'bci%imab Tiroban

6ptibatide

.4AL PA4+7"+4AL

'spirinDipridamol Ticlopidin

lo'ido%rel4ilostaEol

8ulnpraEone


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Anticoa!ulant Tar!ets

TF7I !tifacogin"

Idraparinu%


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Anticoa!ulant

• A substance that prevents coagulation'

that is which stop blood from clotting

• educe blood clotting

• !his prevents: – Deep vein thrombosis

– Pulmonar# embolism

– #ocardial infarction

– *tro&e


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urrent Anti$oa%ulants

Classes )*amples

+itamin Antagonist -arfarin

.nfractionated /eparin

(./)

/eparin

0ow olecular -eight/eparin (0-/)

1no2aparin

Direct !hrombin Inhibitors %ivalirudin,Dabigatran,

actor 3a Inhibitors Api2aban,ivaro2aban


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+nfractionated #eparin +$#

• 4,555675,555 Daltons

• /eterogeneous mi2ture of pol#saccharide chains

with var#ing effects on anticoagulant activit#

• Accelerates the action of circulating antithrombin(A!), a proteol#tic en8#me which inactivates

factors IIa (thrombin), I3a, 3a

• Prevents thrombus propagation, but does notl#se e2isting thrombi


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#eparin

• *ulphated carboh#drate• Purified from pork or bovine lungs• Different si8e

• Active in vitro and in vivo• Administration 6 parenteral6

– Do not in9ect I 6 onl# I+ or deep sc

•/alf6life ; 6 4 hrs 6 monitor aP!!• Adverse effect 6 hemorrhage 6 antidote 6protamine sulphate

• To*icity of heparin - /eparin6induced Platelet

Aggregation


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.ow-Molecular-Wei!ht #eparin .MW#

• ,555 Daltons

• "btained through chemical or en8#matic

depol#meri8ation of pol#saccharide chains of

./ – ?;@ saccharide units inactivate 3a and thrombin

– ;@ saccharide units inactivate 3a (=4645B of chains)

•elativel# more inhibition of 3a than thrombin

• atios of anti6factor 3a:IIa from ;C6;=


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$ondaparinu*

• actor 3a inhibitor

• *#nthetic pentasaccharide

• t;D= E ;F6=; hrs

• Inactive against thrombin alread# generated

• Advantages over ./

– Decreased plasma protein, endothelial cell binding

– ore predictable, sustained anticoagulation – "nce6dail# dosing

– Go laborator# monitoring


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.ow Molecular Wei!ht #eparin

Potential Advantages:• 0ac& of binding to plasma proteins

and endothelium• Hood bioavailabilit#

• *table dose response

• 0ong half6life• esistance does not develop


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.ow Molecular Wei!ht #eparin

• +enous !hromboembolism 6 proph#la2is

6 treatment• Ischaemic heart disease

– unstable angina – acute I – coronar# stenting

• $erebrovascular disease

– ischaemic stro&e – embolic stro&e• Peripheral vascular disease

– reconstructive surger#


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o'arison !FH /s

LM:H'arameter %tandard#eparin

.MW#

olecular -eight ;4,555 Daltons 4,555 Daltons

%ioavailabilit# Poor Hood

0ab onitor aPP! Gone

oute I+ or *J *J

%leeding is& 7K =K

Antithrombotic1ffect

7K


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#eparin "s Warfarin/eparin -arfarin

Absorption Parentral only Oral

Vol of distribution Plasma vol (0.07 L/kg) 7.!"#.$ L

etabolism$learance /epatic metabolism L upta&e b#reticulo endothelial s#stem

Also b# thrombin L otherclotting factors

/epatic

1limination t;= 456C5 min 7>6


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Oral anticoa!ulants /warfarin, dicumarol

$oumarins 6 warfarin, dicumarol

Isolated from clover leaves

*tructurall# related to vitamin

Inhibits production of active clotting factors Absorption rapid 6 binds to albumin

$learance is slow 6 7> hrs

Dela#ed onset @ 6 ;= hrs

"verdose 6 reversed b# vitamin infusion

$an cross placenta 6 do not use during latepregnancies


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Mechanism of action

es$aro)Prot#roin

Prot#roin

4edu$editain K

.idizeditain K

7AH7A

:ar3arin


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Therapeutic ran!e for warfarin in

A$ and stroke

a specied international sensitivit inde% !I8I"


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The "ariability of warfarin dosa!e

• age, bod# si8e• genetic pol#morphism of :

– $MP=$C – the en8#me that metaboli8e *6warfarin

– +" (vit epo2ide reductase) – the target en8#mefor warfarin

→ethnicit# (warfarin dose in Asian $aucasian)→concurrent disease→ (hepatocellular damage, cardiac disease, p#re2ia)

• dietar# vitamin inta&e• drug interactions


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(ru! interaction - Warfarin

Drugs thatpromote

bleeding

Decrease s#nthesis of $lotting actors

Antibiotics (oral)

Decrease binding to

Albumin

Aspirin

*ulfonamide

Inhibition of clotting factors /eparinantimetabolites

Inhibit metaboli8ing en8#mes $imetidine,Disulfiram

Drugs that

decrease

warfarin

activit#

Induction of metaboli8ing en8#mes %arbiturates

Phen#toin

Promote clotting factor s#nthesis +itamin

"$

educed absorption $holest#ramin


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.imitations of V0A Therapy

ell (, et al. 4hest )**@??/0*-1@-, Cutescu 6', et al. 4ardiol 4lin )**@)0/091@+,

mer shman :5, et al. ( Interv 4ard 6lectrophsiol )**@))/)91?+


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1ew Anticoa!ulant Tar!ets

TF7I !tifacogin"

Idraparinu%


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Comparison of $eatures/Warfarin "s& 1OACs

$eature Warfarin 1OAC

"nset *low apid

/alf6life 0ong *hort

1limination /epatic enal

!herapeutic -indow Garrow -ider

Pol#morphism Mes Go

acemic Mes Go

Drug interactions an# ew

ood effect Mes Go

onitoring Mes Go

Antidote Mes Go

Dosing +ariable i2ed


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1ew Oral Anticoa!ulants'otential Alternati"es to Warfarin

Thrombin inhibitors

3imela!atran

Dabi!atran

$actor 2a inhibitors

ivaro*aban

Api*aban1do*aban

"thers

Dabigatran

Rivaroxaban Apixaban

2010 2011 2012 2013

Otomaxiban


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#ei$al Stru$ture o3Anti$oa%ulants


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(abi!atran )te*ilate 'rada*a3

• 'ro-dru!: Dabigatran 1te2ilate Dabigatran• Direct thrombin inhibitor (fIIa inhibitor)• Absorption: re4uires acidic en"ironment

• %ioavailabilit# >B

• 74B protein bound'• +d E 5@4 – ;5 0&g• etabolism:

• b# esterase6catal#8ed h#drol#sis' not a $MP


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(abi!atran

• ;45 and F4 mg dose approved b# DA• Dosing

– $r$l ? 75 m0ml ;45mg %ID – $r$l ;4675m0ml F4 mg %ID

– $r$l ;4 not indicated• !he .* $(A dabi!atran should not be used toprevent stro&e or ma9or thromboembolic events inpatients with mechanical also &nown as mechanicalprosthetic heart "al"es

• Got to be used in patients with: – +alvular atrial fibrillation – Advanced liver disease – *evere renal failure


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'OT#OM5I1

C.OT

$ibrino!en

$ibrin

Acti"e 'latelet

estin! 'latelet

T#OM5I1

"I

:#) t#roin is an e$ellenttar%et;


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$actor 2a inhibitors

f2a ma# be a better tar!et than thrombin – /as few functions outside coagulation

(compared with thrombin)

– /as a wider therapeutic window thanthrombin (separation of efficac# and

bleeding), in vitro

– Thrombin inhibitors are associated withrebound thrombin !eneration – no

evidence with f3a inhibitors


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i"aro*aban and Api*aban

• !he# are direct factor 3a inhibitors

• %oth 2A5A1s bind to the catal#ticactive siteof factor 3 and directl# interfere with the

coagulation cascade• !he two drugs interact slightl# differentl# with the

*< region of factor 3

• *imilar to dabigatran

• the# have predictable pharmaco&inetics andallow for fi2ed oral dosing

• their half6lives are under ;= hours


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i"aro*aban 2arelto3

• Absorption: complete% ta&e with or without food• bioavailabilit# of @56;55B,

• C4B protein bound'• etabolism: P6gl#coprotein, $MP7A< substrate

• $oncomitant use K inhibitors anticoagulant effect• $oncomitant use K inducers anticoagulant effect

• 1limination: t;D= E 46C h (#oung), ;;6;7 h (elderl#)• >>B (renal), 7


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Api*aban )li4uis3

• Direct6acting, reversible factor 3a inhibitor• inhibit the conversion of prothrombin to thrombin

• Dose: =4 mg• Absorption: complete% ta&e with or without food

• bioavailabilit# of >>B, pea& concentrations 76< hrs• @5B protein bound'

• etabolism: P6gl#coprotein, $MP7A< substrate

to inactive metabolite "6demeth#l6api2aban

• does not induce or inhibit en8#mes• 1limination: t;= E ;= (C6;


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Api*aban )li4uis3

• (ru! interaction• K Potent 7A< inhibitors A(

• A(s/ • %leeding (>B), nausea (FB), vomiting (4B),

constipation (4B) in AD+AG$1 trials• 1levation of 0!s (the incidence rate was no different

from the comparator groups)• Monitorin!/

• Go routine monitoring is reNuired• Prothrombin timeIG

• e"ersal a!ent/ • Go standard antidote


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'harmacokinetics of 1OACs'arameter 'arameter Api*abanApi*aban i"aro*abani"aro*aban (abi!atran )(abi!atran )

- (Dalton) 5 >=@

Pro6drug Go Go 7es

Pea& conc (hour) 7 < = (ACI(IC)

%ioavailabilit# (B) >> ? @5 8

ood effect Gone Dela#s absorption Dela#s absorption

1ffect of age Got reported +ariable Gone=C

1ffect of %- Got reported Gone Gone

Plasma protein (B) @5 9: 74

/alf6life (hour) C6;< 46C (#oung);;6;7 (elderl#)

;=6;F

1limination enal (=4B)enal (88B)'half is inactive

enal (;:B)

!ransporters P6gp '-!p65C' P6gp

Involv of $MP C7':? C7'


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'harmacodynamics of 1OACs'arameter 'arameter Api*abanApi*aban i"aro*abani"aro*aban (abi!atran(abi!atran

oA 3a inhibitor 2a inhibitor !hrombin inhibitor

Dosing AI*!"!01 "$1!6A 160M

Dosing %ID all indication(+!1p, +!10, A, A$*)45 (=4)

O( (+!1p,+!10, A)%ID (A$*)=5 (;4)

"D (+!1p)%ID (+!10, A) ;45, ;;5

0inear P Mes Go Mes

Drug interaction *trong $MP7A<and P6gpinhibitors and

inducers

*trong $MP7A<and P6gpinhibitors

*trong $MP7A<inducers

'-!p inhibitors(Amiodaron) andinducers

(+erapamil)''I decreaseabsorption

Intersub9ectvariabilit#

O 74B 75B

5 t T i i 4 di l )** 2 + 2 4li 7h ki t )**9 2@ ))

20150529-his-pharmacology of anticoagulant final

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