OBAT YANG

MEMPENGARUHI
PEMBEKUAN DARAH

dr.I Made Jawi, M.Kes

Bagian Farmakologi FK Unud
 Hemostatic Plug Formation
PRIMARY
AGGREGATION

Platelet Aggregation Clotting

Hemostatic
Clot

Fibrin
SECONDARY
COAGULATION Thrombin

0 min 5 min 10 min

Adapted from Ferguson JJ, et al. Antiplatelet Therapy in Clinical Practice. 2000:15-35.
 Platelets Role in Thrombosis
1. Platelet Adhesion
Platelet

GP Ib 2. Platelet Activation

Plaque rupture Activated Platelet

GP IIb/IIIa
3. Platelet Aggregation
TxA2
ASA,
ASA,
Clopidogrel/Ticlopidine
Clopidogrel/Ticlopidine

GPIIb/IIIa
GP IIb/IIIaInhibitors
Inhibitors

ASA, acetylsalicyclic acid. Fibrinogen

Cannon and Braunwald, Heart Disease. 2001.
Pharmacological Manipulation
ANTI-PLATELET DRUGS
Aspirin, dipyridamole
Glycoprotein IIb/IIIa Inhibitors
Pharmacological Manipulation
ANTI-COAGULANTS
Warfarins (coumarins)
Heparins
Pharmacological Manipulation
THROMBOLYTICS (fibrinolytics)
Tissue Plasminogen Activator
Streptokinase
Alteplase, urokinase

CLOT
BREAKDOWN
 Anti-platelet Drugs
• Aspirin
– COX-1 inhibition
• Dipyridamole
– Phosphodiesterase Inhibitors
• Clopidogrel
– ADP antagonists
• Glycoprotein IIb / IIIa Inhibitors
Anti-platelet Agents – Mechanism of action
T
Thrombin
T

cAMP ADP

ADP

COX-1
ADP
ADP release
TBX A2

G IIb / IIIa R

G IIb / IIIa
 Anti-platelet Agents – Mechanism of action
T
T
Thrombin
Clopidogrel

Dipyridamole cAMP ADP

ADP

Aspirin COX-1
ADP
ADP release
TBX A2

G IIb / IIIa R

G IIb / IIIa

G IIb / IIIa Inhibitors

 Anti-platelet Therapeutics
• IHD, MI, ACS
– Aspirin
– Clopidogrel
– GP IIb/IIIa (in high risk angina)

• CVA, TIA
– Aspirin
– Dipyridamole SR

• AF
– Occasionally aspirin - more usually warfarin

• Plus…

Clinical Trial Evidence ++++

 Anti-platelet drug cautions
• Risk of bleeding
• Drug interactions
• Contra-indications

• Aspirin
– Hypersensitivity
– Gout with low-dose aspirin
– Reye’s Syndrome

• Dipyridamole
– Vasodilator
Anticoagulants: Warfarin
Mechanism of action
 Vitamin K Antagonist
(Coumarin)
• Structurally similar to vitamin K
• Inactivates vitamin K in hepatic microsomes
• Prevent reduction of vitamin K essential for post-
translational carboxylation of vitamin K dependent
clotting factors (VI,IX,X,prothrombin (II))
Warfarin: Action
 Summary of Action

Vitamin K

Antagonism VII
Synthesis of Non
of IX Functional
Vitamin K X Coagulation
Factors
II

Warfarin
Pharmacokinetics
 GI absorption

• Oral Preparation
• High bio-availability taken orally
• Rapid absorption
 Dose-dependent reduction in
Vit K dependent factors
• Individuals vary greatly in dose requirements
for anticoagulation
– PK
• Absorption
• Metabolism
– PD
• Nutrition (Vit K)
• Co-existing illness (liver, malignancy, fever, thyroid)
• Drugs
 Drug Interactions
See the BNF!
• Effects on Anticoagulation
– Majority increase anticoagulant effect
– But some decrease effect

N.B: Perhaps more than with any

other drug:
INTERACTIONS WITH WARFARIN
ARE HIGHLY SIGNIFICANT !!!!
 Drugs potentiating Warfarin
Alcohol,
Amiodarone,
Antibiotics (Erythromycin / Clarithromycin, metronidazole,
ciprofloxacin, tetracycline)
Anti-fungals (Fluconazole)
Anticonvulsants (Sodium Valproate)
Antacids (Cimetidine, Omeprazole)
Anti-lipid Agents (Simvastatin, Fibrates)
Analgesics (Paracetamol, NSAIDS,
Dextropropoxyphene in cocodamol, Aspirin)
Allopurinol,
Anabolic Steroids (possibly corticosteroids also)
 Drugs inhibiting Warfarin
Alcohol
Azathioprine
Barbiturates
Carbamazepine
Contraceptives (OCP)
Griseofulvin
Rifampicin
 Hepatic metabolism

• Microsomal enzymes
• Metabolites excreted via kidneys

• Caution with Liver Disease!

 Slow onset of action

• Takes several days for maximal effect

• Persistent action after cessation (slow offset)
• Half life approximately 48 Hours
Uses
 Uses of Warfarin

• Treatment of Venous or Arterial Thrombosis

– DVT/PE
– Mural Thrombus (post MI)-reduce risk of embolisation
• Prevention of Venous or Arterial Thromboembolism
– Mechanical heart valves
– AF (Risk of systemic emboli)
– CVA-Especially in AF

•Treatment is 3-6 months for DVT, 6 for PE

•Lifelong if preventive, high risk or > 1 episode
HEPARIN
 Obat untuk menghentikan
perdarahan( Hemostatic Drugs)
• Vit K
• Faktor pembekuan darah
• Tranexamic acid: prevent fibrinolysis
Terima Kasih