Agent Used in Disorder in Coagulation

Drug Used in Disorder of
Coagulation
(Including drug used to limit abnormal bleeding and to inhibit
thrombosis)
ANGGELIA P, MD
PHARMACOLOGY AND THERAPEUTIC DEPT.
FACULTY OF MEDICINE
UNIVERSITY OF JAMBI, INDONESIA
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A N G G E L I A P , M D . P H A R M AC O LO GY A N D
T H E R A P E U T I C D E P T.
NORMAL HEMOSTATIC MECHANISM

Hemostasis refers to the finely regulated
dynamic process of maintaining fluidity of
the blood, repairing vascular injury, and
limiting blood loss while avoiding vessel
occlusion (thrombosis) and inadequate
perfusion of vital organs.
There are four phases to

the normal coagulation
cascade:
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Blood vessel
constriction
Platelet aggregation
Fibrin generation
Vessel repair and fibrin
A Ndegradation
G G E L I A P , M D . P H A R M AC O LO GY A N D
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MECHANISM OF BLOOD COAGULATION
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COAGULATION CASCADE
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COAGULATION CASCADE
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INHIBITION OF COAGULATION
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C:\Users\Start\Downloads\Video\Coagulation cascade.mp4
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INTRODUCTION
Human body controlling coagulation process by activated plasmin,
antithrombine synthesized and activating protein C and S.
Antitrombotic:
I. anticoagulation
Indirect thrombin inhibitor (heparin : UFH, LMWH, synthetic heparin derivates

fondaparinux)
Direct trombin inhibitor (hirudin_lepirudine, bivalirudin, argatroban, melagatran,

dabigatran)
Vit K antagonist (warfarin and coumarin derivates)
Direct Xa inhibitor (rivaroxaban)
II. Fibrinolytic drug (streptokinase, urokinase, t-Pas_alteplase, reteplase, teneplase)

III. Antiplatelet drug (aspirin, clopidrogel, abciximab, dypiridamol+aspirin,
cilostazol)
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ANTICOAGULANT
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ANTICOAGULANT
I. INDIRECT TROMBIN INHIBITOR
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INDIRECT THROMBIN INHIBITOR

(HEPARIN)
Heparin is a heterogeneous mixture of sulfated
mucopolysaccharides
Mechanism of action
Biologic activity is dependent upon the endogenous
anticoagulant antithrombin.
Cofactor that accelerated by 1000-fold antithrombin
inhibits clotting factor proteases, especially thrombin (IIa),
IXa, and Xa, by forming equimolar stable complexes with
them.
Heparin extract from porcine intestinal mucosa or bovine lung
Antidotum: protamine sulfate
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(HEPARIN)
Consist of:
Unfractionated heparin (height weight moleculer
heparin)_UFH
Low weight moleculer heparin (enoxaparin,
dalteparin, and tinzaparin) _LMH
Synthesized derivated heparin (Fondaparinux ).
LMH inhibit activated factor X but have less effect on
thrombin than the HMW species
LMH have equal efficacy with UHF, increased
bioavailability by SC inj and less frequent
doses.
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(HEPARIN)
Routine monitoring aPTT need for used of UHF,
just adjusment needed. Maintain prolongation
of the aPTT to 22.5 times
Coagulation monitoring for LMH used is not done
routinely, LMH giving once/twice/day with fixed dose
or /kgbb
Fondaparinux can be given once a day at a fixed dose
without coagulation monitoring.
Precaution for renal failure patient.
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(TOXICITY)
Bleeding (Increased risk in elder women and renal
failure)
Allergy reaction
Alopesia or increased loss of hair
Long term therapy: osteoporosis, spontaneous
fracture and deficiency of mineralocorticoid.
Heparin induced trombocitopenia, occurs in 14%
of individuals treated with UFH for a minimum of 7
days.
KI: patient with bleeding or risk of bleeding.
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ANTICOAGULANT
II. DIRECT TROMBIN INHIBITOR
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DIRECT THROMBIN INHIBITOR
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Mechanism of action by directed binding to the active site of thrombin
Hirudin and bivalirudin are bivalent DTIs in that they bind at both the catalytic
or active site of thrombin as well as at a substrate recognition site.
Argatroban and melagatran are small molecules that bind only at the
thrombin active site.
Hirudin recombinant_lepirudin. approved by the Food and Drug

Administration for use in patients with thrombosis related to heparininduced thrombocytopenia.
Parenterally used
Lepirudin is excreted by the kidney and should be used with great

caution in patients with renal insufficiency as no antidote exists
Bivalirudin also inhibits platelet activation and has been FDA-approved for use
in percutaneous coronary angioplasty.
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DIRECT TROMBIN INHIBITOR

Argatroban
FDA-approved for use in patients with HIT with or without thrombosis and
coronary angioplasty in patients with HIT.
Has a short half-life, is given by continuous intravenous infusion, and is

monitored by aPTT.
Its clearance is not affected by renal disease but is dependent on liver function.
Ximelagatran
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Oral prodrug that is metabolized to the DTI melagatran.
Potential advantages of ximelagatran include predictable pharmacokinetics and

bioavailability.
This allows for fixed dosing and predictable anticoagulant response; no need for
routine coagulation monitoring; lack of interaction with P450-interacting drugs;
and rapid onset and offset of action,
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DIRECT TROMBIN INHIBITOR

Dabigatran
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Direct competitive inhibition of trombin, inhibit free and clot bound

trombin and trombin induced platelet aggregation
Not a substrate, inhibitor or inducer of CYP450 enzyme
T1/2 12-17 h, oral dosing form, BID
Urine excretion up to 80%
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ANTICOAGULANT
III. VITAMIN K ANTAGONIST
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VITAMIN K-DEPENDENT CLOTTING FACTORS
Varying half-life (6-72 hours)

Anticoagulant effect of vitamin K
antagonists starts after several days
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VIT K ANTAGONIST (WARFARIN)
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Warfarin is generally administered as the sodium salt and has 100%

bioavailability.
Over 99% of racemic warfarin is bound to plasma albumin, which

may contribute to its small volume of distribution (the albumin
space), its long half-life in plasma (36 hours), and the lack of urinary
excretion of unchanged drug.
Warfarin crosses the placenta readily and can cause a hemorrhagic

disorder in the fetus.
Treatment with warfarin should be initiated with standard doses of

5-10 mg rather than the large loading doses formerly used.
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Warfarin - Pharmacokinetics Pharmacodynamics
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
Slow onset and offset of action. This takes about 3-4

days.
The initial treatment with VKAs, such as warfarin, must

therefore always be combined with heparin
When rapid reversal is required, fresh frozen plasma or
coagulation factor concentrates can be administered.
Vitamin K can also be administered but the effect of this
treatment is delayed.
Numerous interactions with alcohol, foods
containing vitamin K, with foods and drugs
metabolised by cytochrome P450 enzymes and
with foods and drugs which interfere with
gastrointestinal absorption
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RIVAROXABAN (NEW ORAL

ANTICOAGULAN)
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Factor Xa inhibitor that inhibit platelet activation by selectively

blocking the active site of factor Xa without requiring cofactor (eg.
Antitrombin) fir activity
Bioavailability : 80-100% ; Protein 92-95%; metabolized by oxidative

degradation catalyzed by CYP3A4/5; T1/2 5-9 h; excreted in feces
and urine.
PO dosing form
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FIBRINOLYTIC DRUG
Lyse thrombin by catalyzing of plasmin
Consist of: Streptokinase, urokinase, t-Pas(alteplase, reteplase,
tenecteplase)
Streptokinase enzym synthesized by streptococci that combines with the
proactivator plasminogen.
Urokinase is a human enzyme synthesized by the kidney that directly converts
plasminogen to active plasmin.
Plasminogen can also be activated endogenously by tissue plasminogen
activators (t-PAs). Human t-PA is manufactured as alteplase by means of
recombinant DNA technology.
Indication : pulmonary embolism with hemodynamic instability, severe deep
venous thrombosis such as the superior vena caval syndrome, and ascending
thrombophlebitis of the iliofemoral vein with severe lower extremity
edema.
Golden period, 6 hours after symptom onset of MCI
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ANTIPLATELET DRUG
1. Inhibition of PGI2 (TXA2).prevent paltelet aggregationaspirin
2. Inhibition of ADPno effect of PGI2 (TXA2).clopidrogel
3. Blockage of platelet glycoprotein II A/III A receptorabciximab,
tirofiban, and eptifibatide
4. Additional antiplateletdypiridamol, cilostazol (phospodiesterase
inhibitor , promote vasodilatation)
Paper I: Pharmacology antiplatelet drug !!!!
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C:\Users\Start\Downloads\Video\Platelet Adhesion and Aggreg

ation mechanism explained.mp4
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SYSTEMIC HEMOSTATIC
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PLASMA FRACTION
Cryoprecipitate
FFP
Prothrombin complex concentrates (intermediate purity

factor IX concentrates)
Recombinant factor VIII products
Recombinant factor IX products

PAPER 2 clinical used?
+ desmopresisn asetatsynthetic vasopresinincreased Fc VIII

and vWf
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VIT K
Vit K related cascade factor IIa, VII, IX, and X
K1: leafy green vegetables..orally and parenteral
Onset 6 hcompletely action 24 hours, newborn
routine administration to prevent hemorrage.
K2: synt by bacteria in human intestine
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FIBRINOLITIC INHIBITOR
Aminocaproic acid (EACA).competitively Inhibit
plasminogen activation
Rapidly orally absorbed and excretion via urine.
Adverse effect: skin rash, hipotensi, nose stifness be
aware of general trombosis
Tranexamid acid (analog aminocaproic acid)10x more
potent and less side effect. Available in indonesia
Rapidly absorbed, dose 0,5-1 g2-3x/dailyslowly IV injc
Th/ for bleeding ec fibrinolitic therapy.avoid used for
DIC
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TERIMAKASIH
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Agent Used in Disorder in Coagulation

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Agent Used in Disorder in Coagulation

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Drug Used in Disorder of

NORMAL HEMOSTATIC MECHANISM

There are four phases to

MECHANISM OF BLOOD COAGULATION

Indirect thrombin inhibitor (heparin : UFH, LMWH, synthetic heparin derivates

Direct trombin inhibitor (hirudin_lepirudine, bivalirudin, argatroban, melagatran,

Vit K antagonist (warfarin and coumarin derivates)

Direct Xa inhibitor (rivaroxaban)

II. Fibrinolytic drug (streptokinase, urokinase, t-Pas_alteplase, reteplase, teneplase)

INDIRECT THROMBIN INHIBITOR

INDIRECT THROMBIN INHIBITOR

INDIRECT THROMBIN INHIBITOR

INDIRECT THROMBIN INHIBITOR

DIRECT THROMBIN INHIBITOR

Mechanism of action by directed binding to the active site of thrombin

Hirudin recombinant_lepirudin. approved by the Food and Drug

Lepirudin is excreted by the kidney and should be used with great

DIRECT TROMBIN INHIBITOR

Has a short half-life, is given by continuous intravenous infusion, and is

Oral prodrug that is metabolized to the DTI melagatran.

Potential advantages of ximelagatran include predictable pharmacokinetics and

DIRECT TROMBIN INHIBITOR

Direct competitive inhibition of trombin, inhibit free and clot bound

Not a substrate, inhibitor or inducer of CYP450 enzyme

T1/2 12-17 h, oral dosing form, BID

Urine excretion up to 80%

VITAMIN K-DEPENDENT CLOTTING FACTORS

Varying half-life (6-72 hours)

VIT K ANTAGONIST (WARFARIN)

Warfarin is generally administered as the sodium salt and has 100%

Over 99% of racemic warfarin is bound to plasma albumin, which

Warfarin crosses the placenta readily and can cause a hemorrhagic

Treatment with warfarin should be initiated with standard doses of

Warfarin - Pharmacokinetics Pharmacodynamics

Racemic mixture of two optical

Slow onset and offset of action. This takes about 3-4

The initial treatment with VKAs, such as warfarin, must

RIVAROXABAN (NEW ORAL

Factor Xa inhibitor that inhibit platelet activation by selectively

Bioavailability : 80-100% ; Protein 92-95%; metabolized by oxidative

C:\Users\Start\Downloads\Video\Platelet Adhesion and Aggreg

Prothrombin complex concentrates (intermediate purity

Recombinant factor VIII products

Recombinant factor IX products

+ desmopresisn asetatsynthetic vasopresinincreased Fc VIII

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