Haemostasis

adalah …

Antithrombotik
• proses penghentian perdarahan dari pembuluh darah yang
terluka atau luka yang terbuka dan sangat diperlukan untuk
pertahanan tubuh,
FARMAKOLOGI II — Semester IV/2016-2017
Azizah Vonna, M. Pharm. Sci., Apt. • proses yang bertujuan untuk memelihara keenceran darah
Farmasi - UNSYIAH

@AzizahVonna,MPharmSci.,Apt

Proses Haemostasis PROSES HEMOSTASIS

Proses utama yang terjadi meliputi … 1 2

▪ Vasokonstriksi (misalnya melibatkan
Tromboksan –A2)

▪ Adhesi, Aktivasi, dan Agregasi (AAA)

Platelet
3 4
▪ Pembentukan fibrin + Platelet – AAA =
koagulasi darah
http://www.youtube.com/watch?v=-F73CMjVuqg
@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
 Pada saat terjadi luka thd pembuluh darah maka tubuh akan
PROSES HEMOSTASIS meresponnya dengan melakukan:

! vasokonstriksi akibat dari perangsangan saraf simpatik dan pelepasan endothelin dari
endothelium
! Kolagen terpapar dg darah → platelet terikat kpd kolagen (adhesi platelet) → aktivasi
platelet
! Aktivasi platelet → mediator yang ada dalam granul2 platelet dibebaskan → terjadi ikatan
antara satu platelet dg yg lain (agregasi platelet= platelet plug) (Pembentukan sumbatan oleh
platelet)
! Agregasi platelet kemudian diikat oleh fibrin dan vWF (luka pada pembuluh darah tertutup)

http://www.youtube.com/watch?v=-F73CMjVuqg
@AzizahVonna,MPharmSci.,Apt

Fungsi Koagulasi
Adhesi platelet, dibantu oleh ikatan Glicoprotein pada GP Ia pada kolagen
▪ Mencegah infeksi, kehilangan darah, membantu penyembuhan
Agregasi platelet, dibantu oleh ikatan Glicoprotein pada reseptornya (GP IIb/IIIa) jaringan, menjaga TD
(ikatan platelet ke platelet lainnya)
▪ Untuk koagulasi dibutuhkan:
Agregasi platelet distimulasi oleh: ADP, TXA2 dan dihambat oleh agen inflamasi ▪ Platelet
seperti Prostacyclin (PGI2 dan PGD2) dan NO ▪ Fibrinogen
▪ Thrombokinase
TXA2 dihasilkan oleh proses sintesis Asam arakhidonat yang dicetuskan oleh
platelet yg teraktivasi
▪ Ion calcium
▪ Vitamin K
@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
Komponen dalam plasma darah

Pembuluh darah dan

komponen darah

10

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt

Coagulation
Contoh:
 12

Faktor I = Fibrinogen

Pembuluh darah melepaskan Thrombokinase
Faktor II = Prothrombin


Faktor III = Tissue factor
 …Dengan adanya ion Kalsium + Vitamin K (larut lemak) dalam darah…
Faktor IV = Calcium

Prothrombin (inaktif) → thrombin (aktif) (difasilitasi oleh thrombokinase)
... etc = total 13 faktor pembekuan

Fibrinogen (larut) → fibrin (tidak larut) (difasilitasi oleh thrombin)

Fibrin: merupakan jaring-jaring yang menutupi platelet

Platelet-AAA + fibrin = bekuan darah (blood clot)

11

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
 Coagulation
13

Keadaan Patologi dari pembekuan darah:

▪ Defisiensi kalsium atau Vitamin K
▪ Haemophilia
▪ Thrombocytopenia (sedikitnya jumlah platelet)
▪ Thrombocytosis (tingginya jumlah platelet)
▪ Thrombosis (kecenderungan darah membeku didalam pembuluh darah)

14

@AzizahVonna,MPharmSci.,Apt

Thrombosis Thrombosis
15 16

▪ Bahaya dari keadaan thrombosis, bagian dari thrombus

▪ Pembentukan gumpalan darah di dalam pembuluh darah, dapat pecah dan menghambat aliran darah
tanpa disertai alasan yang jelas e.g; luka jaringan (THROMBOEMBOLISM)
….keadaan patologis yang diakibatkan oleh ativasi ▪ Contoh keadaan yang dapat disebabkan oleh
mekanisme haemostasis yang tidak seharusnya… thromboembolism:
▪ Contoh: Myocardial infarction, stroke, deep vein thrombosis,
Venous thrombosis, arterial thrombosis, artrial fibrilation pulmonary embolus, dll

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
 Apa yang terjadi jika “Blood Clot/Koagulasi” 
 Apa yang terjadi jika “Blood Clot/Koagulasi” 

terus terjadi terus terjadi

@AzizahVonna,MPharmSci.,Apt

Thrombosis
Thrombosis
Terapi dengan Anti thrombotik
19

Virchow’s triad: Blood flow

Three factors Obat-obatan dapat mempengaruhi haemostasis dan thrombosis
contributing to dg 3 cara yang berbeda:
thrombosis
▪ Koagulasi darah (mis. pembentukan fibrin)
▪ Fungsi platelet & Agregasi platelet
▪ Melarutkan fibrin (fibrinolysis)

Atherosclerosis Abnormalities

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
Terapi dg Antithrombotic Warfarin
▪ Obat yg digunakan untuk mencegah bekuan (thrombus) yang kaya fibrin : ❖ Merupakan inhibitor kompetitif Vitamin K reduktase
ANTIKOAGULAN ▪ Mencegah pematangan Faktor pembekuan (clotting factors) II, VII, IX dan X yang disintesis di hati,
Cont. warfarin, heparin sehingga faktor2 tersebut bersifat tidak aktif
▪ Obat yg digunakan untuk mengobati bekuan (thrombus) yang kaya platelet : ❖ Faktor koagulasi ini mengalami aktivasi setelah proses dekarboksilasi dengan bantuan
FIBRINOLYTICS CO2, O2 dan Vitamin K reductase
cont. streptokinase, alteplase ❖ Warfarin berkerja dengan cara berikatan dg Vitamin K
▪ Obat yg digunakan untuk mencegah bekuan yang kaya platelet: reduktase secara kompetitif → menghambat aktivitas
ANTIPLATELET ❖ Akibatnya penurunan aktivitas faktor koagulasi →
cont. aspirin, clopidogrel, dypiridamole, abciximab penghambat aktivitas pembekuan darah

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt

(-)

(-)

(-)
Dihambat oleh warfarin
melalui gangguan sintesis
Vitamin K

(-)
24

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
Warfarin Warfarin
❖ merupakan vitamin-K antagonist kompetitif, sehingga aktivitas akan terhambat ❖ Penanganan perdarahan dengan pemakaian Warfarin:
apabila konsentrasi Vitamin K dalam tubuh banyak
‣ Hentikan pemakaian warfarin
❖ Indikasi
▪ Pencegahan VTE
‣ Diberikan Vitamin K oral atau injeksi
❖ Adverse Effects ‣ Diberikan plasma
▪ Perdarahan ‣ Diberikan faktor pembekuan darah
▪ Bersifat teratogen, tidak boleh diberikan untuk ibu hamil (kategori keamanan D)
❖ Efek baru tercapai ~1-2 hari (onset lama), OKI penggunaan awal digunakan
bersama heparin

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt

Warfarin International Normalized Ratio (INR) Test

28

❖ Selama penggunaan Warfarin, perlu dilakukan monitoring INR

(International Normalised Ratio)
❖ Prothrombin Time (PT) digunakan untuk mengukur waktu untuk darah
menggumpal (clotting), normal 12-13 detik (tergantung metode
pemeriksaan)

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
 International Normalized Ratio (INR) Test Heparin
29

Berikatan dengan Anti Thrombin III → aktivitas penghambatan faktor

aktivasi pembekuan darah
Heparin tidak dapat diabsorbsi scr oral → diberikan secara inta vena
atau subkutan
Untuk pemakaian lokal tersedia
heparin dlm bentuk gel

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt

Heparin

Activation of AT = inactivation of thrombin

Activation of AT = inactivation of Xa
Heparin
No thrombin = fibrinogen does NOT become fibrin =
no clotting
AT

Xa

32

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
 Heparin
❖ Penggunaan Klinis (secara i.v): Pencegahan VTE, dan pada pasien yg
beresiko tinggi mengalami thrombosis

❖ Adverse Effects
▪ Bleeding
▪ Heparin-induced thrombocytopenia (HIT)
▪ Osteoporosis
308 22. Anticoagulants and Antiplatelet Agents

charged protamine interacts with the negatively charged heparin,

Fibrinogen Fibrin forming a stable complex without anticoagulant activity. Adverse
effects of drug administration include hypersensitivity as well as dys-
pnea, flushing, bradycardia, and hypotension when rapidly injected.
Streptokinase– @AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
plasminogen
+

complex C. Vitamin K
Vitamin K1 (phytonadione) administration can stop bleeding problems
Fibrinogen Fibrin
due to warfarin by increasing the supply of active vitamin K1, thereby
degradation degradation inhibiting the effect of warfarin. Vitamin K1 may be administered via the
products products oral, subcutaneous, or intravenous route. [Note: Intravenous vitamin K
should be administered by slow IV infusion to minimize the risk of
hypersensitivity or anaphylactoid reactions.] For the treatment of
Lytic state Clot dissolution bleeding, the subcutaneous route of vitamin K1 is not preferred, as it
Antidotum Antikoagulan
Figure 22.22
is not as effective as oral or IV administration. The response to vitamin
K1 is slow, requiring about 24 hours to reduce INR (time to synthesize LMW Heparin
35 Streptokinase degrades both fibrin new coagulation factors). Thus, if immediate hemostasis is required, 36
and fibrinogen. fresh frozen plasma should be infused.

Enoxaparin (Lovenox®)
Antidote for Bleeding Monitoring
Medication Adverse Effects
Caused by Parameters
Aminocaproic acid Fibrinolytic state Muscle necrosis CBC
Thrombosis Muscle enzymes
Tranexamic acid CVA Blood pressure
Seizure
Protamine sulfate Heparin Flushing Coagulation monitoring
Nausea/vomiting Blood pressure
Dyspnea Heart rate
Bradyarrhythmia
Hypotension
Anaphylaxis

Vitamin K1 Warfarin Skin reaction PT/INR

Anaphylaxis

CBC=complete blood count, CVA = cerebrovascular accident, PT=prothrombin time, INR=international normalized ratio

Figure 22.23
Summary of drugs used to treat bleeding. @AzizahVonna,MPharmSci.,Apt

Study Questions
 LMW Heparin Streptokinase
37

Fondaparinux (Arixtra®) Plasmin adalah komponen dalam darah yang berfungsi untuk melarutkan fibrin (agen
Merupakan pentasakarida sintetik yang berkerja sbg inhibitor antikoagulan) yang diperoleh dari konversi plasminogen → Streptokinase meningkatkan
produksi plasmin dengan cara mengaktivasi plasminogen → meningkat aktivitas
faktor Xa, dengan cara terikat kuat dg antithrombin III (ATIII) penguraian bekuan darah “blood clot”

Diberikan secara IV

Diberikan pada pasien yang

menderita infark miokardium

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt

39 40

@AzizahVonna,MPharmSci.,Apt
 New Oral Anti Coagulant Oral Anticoagulant Comparison
41
42

Mechanism of
Medication Metabolism Monitoring Parameters
Action
Warfarin Inhibits formation of CYP2C9 PT/INR (individualized; depends on INR
vitamin K-dependent CYP1A2 stability)
clotting factors II,VII, IX, X, CYP3A4
and proteins C and S CYP2C19

Dabigatran Directly inhibits thrombin Hepatic Routine lab monitoring not required;
(Pradaxa) glucuronidation aPTT, TT
P-gp substrate Renal function

Rivaroxaban Directly inhibits factor Xa CYP3A4 Routine lab monitoring not required; may
(Xarelto) CYP3A5 use PT to detect presence of rivaroxaban
CYP2J2 Renal and hepatic function
P-gp substrate

Proses Hemostasis Proses Hemostasis

Mengandung:
ENDOTHELIUM ! Glikogen
! Granul-granul yang berisi ADP/ATP,
Ca++, 5HT, faktor vWF, fibrinogen,
faktor koagulasi V dan XIII
• Endothelium disusun o/sel endotel

• Dalam keadaan fisiologis, endotel melepaskan NO, PGI2, endotelADP-ase untuk

mencegah aktivasi platelet
• Sel endotel → mgd kolagen, faktor vWF, endothelin dan “tissue faktor” PLATELET

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
Lanjutan… Sistem Koagulasi
Aktivitas Thrombin dihambat oleh
Trombin Antithrombin III (ATIII)

Fibrinogen Fibrin

Pada keadaan fisiologis, fibrin yang mengikat platelet dapat dilarutkan oleh
plasmin

@AzizahVonna,MPharmSci.,Apt

Sistem Koagulasi & 


Tapak Kerja Antikoagulan Antiplatelet

Anti platelet adalah obat-obat yang menurunkan agregasi platelet dan

menghambat pembentukan thrombus di sirkulasi arteri

Agregasi platelet adalah salah satu bagian dari sistem koagulasi, dimana
ketika endotelium di pembuluh darah mengalami kerusakan, akan tejadinya
aktivasi platelet sebagai bentuk tubuh dalam melakukan homeostatisnya.

@AzizahVonna,MPharmSci.,Apt
 294 22. Anticoagulants and Antiplatelet Agents

Resting platelet such as ADP and serotonin that activate other platelets; 2) activation
of thromboxane A2 synthesis; and 3) activation of glycoprotein
(GP) IIb/IIIa receptors that bind fibrinogen and, ultimately, regulate
HAEMOSTASIS AND THROMBOSIS 24
platelet–platelet interaction and thrombus formation. Fibrinogen, a
soluble plasma GP, simultaneously binds to GP IIb/IIIa receptors Ruptured atherosclerotic plaque

on two separate platelets, resulting in platelet cross-linking and

platelet aggregation. This leads to an avalanche of platelet aggre-
gation, because each activated platelet can recruit other platelets
Adhesion of platelets to
thrombogenic surface
50
(Figure 22.4).
Exposure of
Activation of platelets acidic

E. Formation of a clot
phospholipids

Local stimulation of the coagulation cascade by tissue factors released AA generation Coagulation
processes
from the injured tissue and by mediatorsAspirin
on the surface of platelets
results in the formation of thrombin (factor IIa). In turn, thrombin, a Production of cyclic
endoperoxides Thrombin
serine protease, catalyzes the hydrolysis of fibrinogen to fibrin,TXA which 2

is incorporated into the clot. Subsequent cross-linking of the

synthesis
inhibitorsfibrin

Activated platelet strands stabilizes the clot and forms a hemostatic platelet–fibrin
Release of ADP etc.

TXA -
plug Synthesis of TXA2

2
Direct thrombin
inhibitors
(e.g. hirudin)
(Figure 22.2). Ticlopidine
Clopidogrel
receptor
antagonists

Figure 22.3 Expression of GP

IIb/IIIa receptors

Scanning electron micrograph of F. Fibrinolysis Antagonists of GP

IIb/IIIa receptors (e.g.
platelets. Epoprostenol abciximab, tirofiban)

During clot formation, the fibrinolytic pathway is locally activated. Linkage of adjacent platelets
by fibrinogen binding to
GP IIb/IIIa receptors
Plasminogen is enzymatically processed to plasmin (fibrinolysin) by
Antiplatelet dan tapak kerjanya plasminogen activators in the tissue (Figure 22.2). Plasmin limits the
Epoprostenol, NO AGGREGATION of
growth of the clot and dissolves the fibrin network as wounds heal. platelets
@AzizahVonna,MPharmSci.,Apt
Fig. 24.7 Platelet activation. Events involved in platelet adhesion and aggregation are shown, with the sites of action of drugs and
endogenous mediators. AA, arachidonic acid; ADP, adenosine bisphosphate; GP, glycoprotein; NO, nitric oxide; TXA2, thromboxane A2.

IV. PLATELET AGGREGATION INHIBITORS ASPIRIN

Low-dose aspirin (see Ch. 26) profoundly (> 95%) inhibits
until the affected cohort of platelets is replaced in 7–10
days. Clinical trials have demonstrated the efficacy of
platelet TXA2 synthesis, by irreversible acetylation of a aspirin in several clinical settings (e.g. Fig. 24.8). Adverse
serine residue in the active site of cyclo-oxygenase I (COX- effects of aspirin, mainly on the gastrointestinal tract, are,
I). Oral administration is relatively selective for platelets however, clearly dose related, so a low dose (often 75 mg
Platelet aggregation inhibitors decrease the formation of a platelet-rich
because of presystemic elimination (Ch. 9). Unlike nucle-
ated cells, platelets cannot synthesise proteins, so after
once daily) is usually recommended for thromboprophy-
laxis. Thromboprophylaxis is reserved for people at high
303
clot or decrease the action of chemical signals that promote platelet
administration of aspirin, TXA2 synthesis does not recover cardiovascular risk (e.g. survivors of myocardial

aggregation (Figure 22.5). The platelet aggregation inhibitors described

below inhibit cyclooxygenase-1 (COX-1) or block GP IIb/IIIa or ADP
Aktivasi
294 dan Agregasi Platelet Aspirin (Asam Asetil Salisilat)
receptors, thereby interfering with the signals that promote platelet aggre-
22. Anticoagulants and Antiplatelet Agents
gation. Because these agents have different mechanisms of actions, syn-
ergistic or additive effects may be achieved when agents from different
Resting platelet such as ADP and serotonin that activate other platelets; 2) activation
classes are combined.
of thromboxane A2 synthesis; and 3) activation of glycoprotein
These agents are beneficial in the prevention and
▪ Pada saat platelet diaktivasi, maka jalur asam arakidonat (yang terlibat dalam proses inflamasi tubuh) juga
treatment
(GP) IIb/IIIa receptors that bind fibrinogen and, ultimately, of occlusivediaktivasi
regulate cardiovascular diseases, in the maintenance of
platelet–platelet interaction
Platelet vascular
and thrombus formation.
activation graftsaand arterial patency, and as adjuncts to thrombin inhibi-
Fibrinogen,
soluble plasma GP, simultaneously binds to GP tors or thrombolytic
IIb/IIIa receptors ▪ Aktivasiin
therapy dari
MI.jalur asam arakidonat ini menghasilkan Tromboksan A2 (TXA2), yang mempunyai aktifitas
on two separate platelets, resulting in platelet cross-linking and protrombotik.
platelet aggregation. This leadsFibrinogen
to an avalanche of platelet aggre-
A. Aspirin
gation,Platelet
because each activated platelet can recruit other platelets
aggregation aktifitas protrombotik meningkatkan pembentukan platelet baru dan agregasi
(Figure 22.4). 1. Mechanism of action: Stimulation of platelets by thrombin, platelet
colla-
gen, and ADP results in activation of platelet membrane phospholi-
E. Formation of a clot ▪ Jalur asam arakidonat yang mensintesis TXA2 di  bantu oleh enzim siklooksigenase (COX)
pases that liberate arachidonic acid from membrane phospholipids.
Local stimulation of the coagulation cascade by tissue factorsArachidonic acid
released ▪ Aspirin berkerja
is first menghambat
converted enzim siklooksigenase
to prostaglandin (inhibitor COX) → sintesis TXA2 terhambat →
H2 by COX-1
fromActive
the injured tissue and by mediators on the surface of platelets
(Figure pembentukan platelet
22.6). Prostaglandin dan agregasi
H2 is further metabolized to thrombox-
results in the formation of thrombin (factor IIa). In turn, thrombin, a
GP IIb/IIIa ✓platelet into
ane A2, which is released juga akan dihalangi
plasma. → membantuAmencegah
Thromboxane promotes bekuan
receptors
serine protease, catalyzes the hydrolysis of fibrinogen to fibrin, which ✓clot (bekuan darah) 2
the aggregation
is incorporated into the clot. Subsequent cross-linking of the fibrin process that is essential for the rapid formation of
Activated platelet a hemostatic
strands stabilizes the clot and forms a hemostatic platelet–fibrin plug plug. Aspirin [AS-pir-in] inhibits thromboxane A2 syn-
(Figure 22.2). thesis by acetylation of a serine residue on the active site of COX-1,
@AzizahVonna,MPharmSci.,Apt
Figure 22.3 Figure 22.4 thereby irreversibly inactivating the enzyme (Figure 22.7). This
Scanning electron micrograph of F. Fibrinolysis
Activation and aggregation of shifts the balance of chemical mediators to favor the antiaggrega-
platelets.
Duringplatelets. the fibrinolytic pathway is locallytory
GP = glycoprotein.
clot formation, effects of prostacyclin, thereby preventing platelet aggregation.
activated.
 Aspirin (Asam Asetil Salisilat)
▪ Aspirin secara parsial juga menghambat agregasi oleh adenosine diphosphat
(ADP)
▪ Pemakaian klinis: untuk pencegahan dan terapi infark miokardium, juga
menurunkan resiko terjadinya serangan jantung
▪ Efek samping: bronkospasme, gangguan (hingga perdarahan) saluran
pencernaan
▪ Dosis tunggal 150 – 300 mg diberikan segera mungkin setelah terjadinya
serangan yang dilanjutkan dengan dosis penjagaan 80-100 mg sehari.
Clopidogrel
Berkerja dengan cara menghambat reseptor platelet adenosin diphosphat (ADP) yaitu
reseptor P2Y12 yang terletak pada sel platelet. Penghambatan ini terjadi secara
ireversibel.
Penghambatan kerja ADP pada reseptornya akan menghalangi terjadinya agregasi
platelet → menurunkan aktivitas pembetukan bekuan darah (blood clot)
Clopidogrel merupakan prodrug, yang aktif setelah diaktivasi oleh sitokrom di hati
Dosis awal 300-600mg, yang diikuti dengan dosis pemeliharaan 75 mg sehari sekali.
Efek samping rasa kurang enak di perut, nyeri perut, diare, perdarahan, sakit kepala dll.

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt

IV. Platelet Aggregation Inhibitors 295

55 56

Clopidogrel Prasugrel Ticagrelor Monitoring

Medication Adverse Effects Drug Interactions
Loading Dose 300-600 mg 60mg 180mg Parameters
Maintenance Dose 75 mg daily 10 mg daily 90 mg twice daily Oral Agents:
Aspirin Angioedema ketorolac—increased bleeding CBC
Bleeding cidofovir—nephrotoxicity LFT
Route Oral Oral Oral Bronchospasm probenecid—decreased uricosuric effects
GI disturbances
Binding to P2Y12 Irreversible Irreversible Reversible Reye syndrome
SJS
Prodrug Yes Yes No
Cilostazol Bleeding Food (administer on CBC
Hepatic Metabolism CYP C219 CYP 3A, 2B6,2C19 None GI disturbances empty stomach)
Headache
Peripheral edema
SJS
Platelet Inhibition 40% ~70% 95%
Clopidogrel Bleeding Strong CYP2C19 inhibitors reduce CBC
SJS antiplatelet effect (e.g., omeprazole) LFT
Onset 2 hours 30- 60 minutes 2 hours Dipyridamole Bleeding Salicylates None for oral
Dizziness Thrombolytic agents administration
GI discomfort
Rash
@AzizahVonna,MPharmSci.,Apt Prasugrel Angioedema Anticoagulants CBC
Bleeding Other antiplatelets
Headache
Hyperlipidemia
Hypertension
 Aspirin Angioedema ketorolac—increased bleeding CBC
Bleeding cidofovir—nephrotoxicity LFT
Bronchospasm probenecid—decreased uricosuric effects
GI disturbances
Reye syndrome
SJS
Cilostazol Bleeding Food (administer on CBC
GI disturbances empty stomach)
Headache
IV. Platelet Aggregation Peripheral edema
Inhibitors 295
SJS
Clopidogrel Bleeding Strong CYP2C19 inhibitors reduce CBC
SJS antiplatelet effect (e.g., omeprazole) LFT
Monitoring
Medication
Dipyridamole Adverse Effects
Bleeding Drug Interactions
Salicylates None for oral
Dizziness Thrombolytic agents Parameters
administration
GI discomfort
57 Oral Agents: Rash
Aspirin
Prasugrel Angioedema ketorolac—increased
Anticoagulants bleeding CBC
CBC
Bleeding cidofovir—nephrotoxicity
Other antiplatelets LFT
Bronchospasm
Headache probenecid—decreased uricosuric effects
GI disturbances
Hyperlipidemia
Reye syndrome
Hypertension
SJS
Ticlopidine Abnormal LFT Antacids—decreases levels CBC
Cilostazol Bleeding Food (administer on clearance
Cimetidine—reduces CBC
LFT
GI disturbances
Dizziness empty stomach) platelet count
Headache
GI disturbances
Peripheral
SJS edema
SJS
Ticagrelor Bleeding Strong CYP3A4 inhibitors CBC
Clopidogrel Bleeding
Dyspnea Strong CYP2C19 inhibitors reduce
(e.g., ketoconazole) CBC
LFT
SJS
Headache antiplatelet
Strong CYP3A4effect (e.g., omeprazole)
inducers LFT
Raised SCr (e.g., rifampin)
Dipyridamole Bleeding Salicylates None for oral
Injectable Agents: Dizziness Thrombolytic agents administration
GI discomfort
Abciximab For all agents:
Rash For all agents: For all agents:
Prasugrel Angioedema
Hypotension Anticoagulants
Increased bleeding: CBC clotting time
APTT
Eptifibatide Bleeding
Nausea Other antiplatelets
Ginkgo biloba H/H
Headache
Vomiting Antiplatelets platelet count
Hyperlipidemia
Thrombocytopenia Salicylates thrombin time
Tirofiban Hypertension SSRIs and SNRIs
Ticlopidine
APTT=activated Abnormal
partial thromboplastin LFT
time, CBC=complete Antacids—decreases
blood count, GI levels
= gastrointestinal, H/H=hemoglobin CBC LFT=liver function
and hematocrit,
Bleeding
test, SCr=serum creatinine, SJS=Stevens–Johnson Cimetidine—reduces
Syndrome, SNRI = serotonin–norepinephrine clearance
reuptake LFT serotonin reuptake
inhibitor, SSRI = selective
inhibitor Dizziness platelet count end of lecture…
GI disturbances
SJS
Figure 22.5
Ticagrelor Bleeding Strong CYP3A4 inhibitors CBC
Summary of characteristics ofDyspnea
platelet aggregation inhibitors. (e.g., ketoconazole) LFT
Headache Strong CYP3A4 inducers
Raised SCr (e.g., rifampin)
The inhibitory
Injectable Agents: effect is rapid, and aspirin-induced suppression of Thromboxane A2
thromboxane A and the resulting suppression of platelet aggrega-
2
Abciximab For all agents: For all agents: For all agents:
tion last for the life of the platelet, which is approximately 7 to 10 days.
Repeated administration Hypotension
of aspirin has a cumulative Increased
effect bleeding:
on the APTT clotting
Prostaglandin H2time
Eptifibatide Nausea Ginkgo biloba H/H
function of platelets. Aspirin is the only antiplatelet agent
Vomiting that irre-
Antiplatelets Cyclooxygenase-1platelet count
Thrombocytopenia
versibly inhibits platelet function. Salicylates (COX-1) Aspirin
thrombin time
Tirofiban SSRIs and SNRIs Arachidonic acid
2. Therapeutic
APTT=activated use: Aspirin
partial thromboplastin isCBC=complete
time, used in theblood
prophylactic treatment of H/H=hemoglobin and hematocrit, LFT=liver
count, GI = gastrointestinal, function
Membrane
test, SCr=serum creatinine,
transient cerebral SJS=Stevens–Johnson Syndrome,the
ischemia, to reduce SNRIincidence
= serotonin–norepinephrine
of recurrent reuptake inhibitor, SSRI = selective serotonin reuptake
phospholipids
inhibitor
MI, and to decrease mortality in the setting of primary and second-
ary prevention of MI. Complete inactivation of platelets occurs with Figure 22.6
Figure 22.5
75 mg of aspirin given daily. The recommended dose of aspirin Aspirin irreversibly inhibits platelet
Summary of characteristics of platelet aggregation inhibitors.
ranges from 50 to 325 mg daily. cyclooxygenase-1.

The inhibitory effect is rapid, and aspirin-induced suppression of Thromboxane A2

thromboxane A2 and the resulting suppression of platelet aggrega-
tion last for the life of the platelet, which is approximately 7 to 10 days.
Repeated administration of aspirin has a cumulative effect on the Prostaglandin H2
function of platelets. Aspirin is the only antiplatelet agent that irre- Cyclooxygenase-1
versibly inhibits platelet function. (COX-1) Aspirin
Arachidonic acid
2. Therapeutic use: Aspirin is used in the prophylactic treatment of
0002116801.INDD 295
Membrane
6/24/2014 9:42:04 AM

transient cerebral ischemia, to reduce the incidence of recurrent phospholipids

MI, and to decrease mortality in the setting of primary and second-
ary prevention of MI. Complete inactivation of platelets occurs with Figure 22.6
75 mg of aspirin given daily. The recommended dose of aspirin Aspirin irreversibly inhibits platelet
ranges from 50 to 325 mg daily. cyclooxygenase-1.