Drugs Affecting Blood Cloting

dr. Anati Purwakanthi, MSc.

Bagian Farmakologi FKIK UNJA
 Warfarin

Anticoagulants Heparin

Direct thrombin inhibitors

COX Inhibitors

Antiplatelet ADP Antagonist

Anticloting Drugs
agents
Glycoprotein IIa/IIIb Inhibitors

PDE/Adenosin Uptake Inhibitors

Thrombolytics t-PA Derivates

Streptokinase

Replacement factors
Drugs that
Vitamin K
facilitate cloting
Antiplasmin Drugs
Anticoagulant
Warfarin

Heparin

Direct Thrombin
Inhibitors
 Anticoagulant
Mechanisms of Action:
1. Activation of anticlotting factors (especially
antithrombin III)  HEPARIN, DALTEPARIN,
ENOXAPARIN, FONDAPARINUX
2. Direct inhibition of thrombin
3. Inhibition of synthesis of blood coagulation
factor precursors (zymogens)
4. Activated Protein C
 Heparin
• Antikoagulan yang paling umum diberikan
untuk penggunaan jangka pendek.
• Merupakan kompleks mucopolysaccharide
• MOA: berikatan dengan antitrombin
• DALTEPARIN, ENOXAPARIN: low MW fragment
HEPARIN
• Harus diberikan IV (tidak aktif secara oral;
pemberian IM menyebabkan hematoma)
 Therapeutic Indications
• Untuk respons hipotrombik segera:
- Massive DVT
- Infark paru
- MI akut akut pasca operasi (kecuali otak,
sumsum tulang belakang, atau mata)
-Sebelum kardioversi atrial fibrilasi
 Adverse Effect
• HEMORRHAGE (esp. hemorrhagic stroke)
• Hypersensitivity
• Transient thrombocytopenia
• prolonged administration of high doses may
cause :
– Osteoporosis
– Progressive reduction in antithrombin III 
decreased effectiveness, increased clotting
– Mineralocorticoid deficiency
 4-HYDROXYCOUMARIN, WARFARIN

• Mechanism of Action
– Inhibit synthesis of coagulation factor precursors
– Inhibit epoxide hydrase
– Interfere with the synthesis of vitamin K and thus
inhibits activation of vitamin k-dependent clotting
factors (II, VII, IX, X)
– Also decreases the activity of protein C (activated
by thrombin)
 Pharmacokinetics
• Has a narrow therapeutic index
• Is nearly completely (99%) bound to plasma
albumin
• Is eliminated by hepatic metabolism
 Therapeutic Indications
• Long-term oral treatment of deep-vein
thrombosis
• For 2-6 months following myocardial infarction
• Atrial fibrillation
 Adverse Effects
• Hemorrhage
• Flatulence and diarrhea are common
• Penurunan protein C menyebabkan nekrosis kulit yang
disebabkan selama minggu-minggu pertama pengobatan;
jarang dapat berkembang menjadi infark (trombosis vena)
pada jaringan lemak, usus dan ekstremitas
• Bone defects(chondrodysplasia punctata) dan gangguan
hemoragik pada neonates dari ibu yang menggunakan
obat selama trimester pertama kehamilan 
ABSOLUTELY CONTRAINDICATED IN PREGNANCY
DIRECT THROMBIN INHIBITORS (DTIs):

• BIVALIRUDIN, HIRUDIN, LEPIRUDIN

– Inhibiting fibrin binding to thrombin
– Interacting with the thrombin active site
inhibiting thrombin activity even in the presence
of bound fibrin
• XIMELAGATRAN, ARGATROBAN  bind
reversibly to the thrombin active site
 Advantages Over HEPARIN:
• Inhibition of coagulation via a single mechanism of
action
• Actions are independent of antithrombin III, which
means they can reach and inactivate fibrin-bound
thrombin inside clots
• Little effect on platelets or bleeding time
• Not inactivated by platelet or plasma proteins
• More uniform potency and increased safety
• Rebound coagulation after discontinuation of the drug
is less likely with direct thrombin inhibitors
 ACTIVATED PROTEIN C
• Drotrecogin alfa
• Recombinant version of protein c; activated by thrombin; requires ca2+,
phospholipid and protein s as cofactors
• Anti-coagulant actions:
– Destroys activated factors Va and VIIIa, resulting in ↓ thrombin
formation
– Inhibits platelet activation
– Suppresses tissue factor expression
• Fibrinolytic actions
– Attenuates thrombin-catalyzed activation of tpa inhibitors
– Decreases pai-1 concentrations
• Anti-inflammatory actions:
– Inhibits synthesis of tumor necrosis factor
– Inhibits neutrophil activation
– Blocks the release of cytokines from macrophages
Antiplatelet Agents
COX Inhibitors

ADP Antagonist

Glycoprotein IIa/IIIb
Inhibitors

PDE/Adenosin Uptake
Inhibitors
antiplatelet

Ticlopidine

Phosphodiester
ase inhibitors
COX Inhibitor :
Aspirin
 Indication of Aspirin
• Prophylaxis against transient ischemic attacks,
myocardial infarction and thromboembolic
disorders.
• Treatment of acute coronary syndromes and
in the prevention of reoclusion in coronary
revascularization procedures. 
 Side Effects
• GI bleeding
• Acute renal insufficiency.
 ADP antagonist (Thienopyridines)
• Actions : Inhibiting the ADP-dependent
pathway of platelet activation  block ADP
receptors.
• Ticlopidine, clopidogrel
 Clopidogrel
• Digunakan u/ pencegahan kejadian aterosklerotik
setelah infark miokard, stroke atau penyakit
arteri perifer, untuk digunakan dalam sindrom
koroner akut yang diobati dengan pencangkokan
bypass arteri koroner atau PCI.
• profil keamanan yang lebih baik daripada
ticlopidine.
• Berinteraksi dengan Inhibitor Pompa Proton
mengurangi efektivitas clopidrogel
 GPIIb/IIIa Inhibitors
• The glycoprotein IIb/IIIa inhibitors are used
parenterally in patients with acute coronary
syndromes by specialists, this class of drugs is
not used in an outpatient setting by non-
specialists.
• Adverse effects of GPIIB-IIIa antagonists
include major bleeding, intracerebral
hemorrhage and thrombocytopenia.
 Continue...
• Abciximab is a chimeric human-murine
monoclonal antibody directed against GPIIb/IIIa
– Indications include unstable angina that does not
respond to conventional therapy in patients that
undergo percutaneous coronary intervention.
• The peptide derivatives (eptifibatide  and 
tirofiban)  are  more selective towards the
GPIIb/IIIa receptor and have a shorter effect
than abciximab.
 Phosphodiesterase/Adenosine Uptake
Inhibitors
• Dipyridamol
• MoA: Ini menghambat uptake adenosin dan
aktivitas siklik GMP fosfodiesterase 
menurunkan agregasi platelet.
• bertindak sebagai vasodilator
• Dipyridamole memiliki sedikit efek antiplatelet
kombinasi dengan aspirin atau warfarin
dalam profilaksis gangguan tromboemboli
THROMBOLYTIC DRUGS

Streptokinase

t-PA Derivates
• Thrombolytic drugs dissolve existing
lifethreatening thrombi
• Actions : Activate plasminogen to plasmin 
hydrolysis of fibrin and several other coagulation
factors.
• short activation times, and short half-lives
• tPAs (tissue Plasminogen Activators) Derivates:
ALTEPLASE, RETEPLASE, TENECTEPLASE,
• STREPTOKINASE, ANISTREPLASE, UROKINASE
 Indication of Thrombolytics
• Indications : recent acute MI (selection of
patients is critical!!! Some can be harmed),
extensive pulmonary emboli, severe deep vein
thrombosis, thromboembolic stroke (tPAs
only)
 Side Effects of Thrombolytics
• Cause bleeding (particularly hemorrhagic
stroke)  can be antagonized by
aminocaproic acid (for tpas) or aprotinin (for
streptokinase)
Contraindication of Thrombolytics
• Recent surgery (10 days)
• GI bleeding (3 months)
• Active bleeding or hemorrhagic disorder
• Previous cerebrovascular accident or active
intracranial process
• History of hypertension (diastolic > 110 mmhg)
• Pregnancy
• Aortic dissection
• Acute pericarditis
 ANISTREPLASE, STREPTOKINASE
• Mechanism of action
– Mengikat dan menginduksi perubahan
plasminogen  plasmin
– Anistreplase adalah kompleks streptokinase dan
lys-plasminogen pada manusia - lebih nyaman
(waktu infus lebih pendek) tetapi jauh lebih mahal
dengan kecenderungan trombolisis sistemik
• Adverse effects : allergic hypersensitivity
reactions, fever and anaphylaxis.
 UROKINASE
• MoA: enzim ginjal yang secara langsung
mengubah plasminogen menjadi plasmin
• diindikasikan hanya untuk pasien yang alergi
terhadap STREPTOKINASE
• Adverse Effects : febrile episodes, infusion
reactions and hypersensitivity (anaphylaxis).
 TISSUE PLASMINOGEN ACTIVATORS
(tPAs):
Merupakan hasil rekayasa genetik dari sel melanoma
manusia
• ALTEPLASE adalah tPA manusia yang tidak dimodifikasi
• RETEPLASE menghapus beberapa sekuens asam amino
• TENECTEPLASE adalah versi rekombinan dari TPA
manusia dengan 3 pengganti asam amino.

MoA
• Menyebabkan aktivasi "selektif" plasminogen yang
terikat fibrin
 Antiplatelet recommendation in Updated
ACS Guidelines:
• Aspirin should be given to all patients without
contraindications at an initial loading dose of 150–300
mg, and at a maintenance dose of 75–100 mg daily long-
term regardless of treatment strategy.
• A P2Y12 inhibitor (clopidrogel, ticagrelor) should be
added to aspirin as soon as possible and maintained over
12 months, unless there are contraindications such as
excessive risk of bleeding. Clopidogrel initial loading dose
is 300 mg, and at a maintenance dose of 75 mg daily.
Ticagrelor initial loading dose 180mg, maintenance
2x90mg/d
SEKIAN
 Tuliskan resep
• Aspirin dan ticagrelor, untuk terapi inisial IMA!

• Aspirin dan clopidrogel untuk terapi

maintenance penderita IMA SELAMA 1
MINGGU!