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

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 1

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:
 Blood vessel constriction
 Platelet aggregation
 Fibrin generation
 Vessel repair and fibrin
degradation

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 2

MECHANISM OF BLOOD COAGULATION

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 3

PLATELET PLUG

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 4

COAGULATION CASCADE

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 5

COAGULATION CASCADE

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 6

INHIBITION OF COAGULATION

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 7

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)
• 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)

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 8

ANTICOAGULANT

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 9

 ANTICOAGULANT DRUGS

Vitamin K Direct thrombin

Heparins antagonists inhibitors

 Unfractionated  Warfarin  Hirudin

heparin (UFH)
 Coumarin  Recombinant
 Low molecular - Lepirudin
weight heparin - Bivalirudin
(LMWH)
 Synthetic
 Synthetic - Argatroban
pentasaccharides
- Melagatran
(fondaparinux,
- Dabigatran
idraparinux)
-
 ANTICOAGULANT
I. INDIRECT TROMBIN INHIBITOR

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 12

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

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 13

INDIRECT THROMBIN INHIBITOR (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.

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 14

INDIRECT THROMBIN INHIBITOR (HEPARIN)
 Routine monitoring aPTT need for used of UHF, just adjusment
needed. Maintain prolongation of the aPTT to 2–2.5 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.

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 15

INDIRECT THROMBIN INHIBITOR (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 1–4% of individuals
treated with UFH for a minimum of 7 days.

KI: patient with bleeding or risk of bleeding.

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 16

 ANTICOAGULANT
II. DIRECT TROMBIN INHIBITOR

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 17

DIRECT THROMBIN INHIBITOR
 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 heparin-induced 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.

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 18

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
• 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,

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 19

DIRECT TROMBIN INHIBITOR
Dabigatran
• 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%

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 20

 ANTICOAGULANT
III. VITAMIN K ANTAGONIST

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 21

VITAMIN K ANTAGONISTS – MECHANISM OF
ACTION
VITAMIN K ANTAGONISTS – MECHANISM OF
ACTION

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 23

VITAMIN K-DEPENDENT CLOTTING FACTORS

 Varying half-life (6-72 hours)

 Anticoagulant effect of vitamin K antagonists starts after
several days
VIT K ANTAGONIST (WARFARIN)
• 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.

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 25

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
Paper 1; pharmacodynamic and kinetic drug interaction of warfarin
RIVAROXABAN (NEW ORAL ANTICOAGULAN)
• 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

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 27

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

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 28

ANTIPLATELET DRUG
1. Inhibition of PGI2 (TXA2)….prevent paltelet aggregation…aspirin
2. Inhibition of ADP…no effect of PGI2 (TXA2)….clopidrogel
3. Blockage of platelet glycoprotein II A/III A receptor…abciximab, tirofiban, and
eptifibatide
4. Additional antiplatelet…dypiridamol, cilostazol (phospodiesterase inhibitor ,
promote vasodilatation)

Paper II: Pharmacology antiplatelet drug !!!!

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 29

SYSTEMIC HEMOSTATIC

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 30

PLASMA FRACTION
 Cryoprecipitate
 FFP
 Prothrombin complex concentrates (intermediate purity factor IX concentrates)
 Recombinant factor VIII products
 Recombinant factor IX products

PAPER 3 clinical used?

+ desmopresisn asetat…synthetic vasopresin…increased Fc VIII and vWf…

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 31

VIT K
 Vit K related cascade factor IIa, VII, IX, and X
 K1: leafy green vegetables…..orally and parenteral
 Onset 6 h…completely action 24 hours, newborn routine
administration to prevent hemorrage.
 K2: synt by bacteria in human intestine

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 32

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 g…2-3x/daily…slowly IV injc…
 Th/ for bleeding ec fibrinolitic therapy….avoid used for DIC

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 33

TERIMAKASIH

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT. 34