Flashcards in Anti-platelets & fibrinolytics Deck (64)
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1
Platelet aggregation is physiologically facilitated by
- thromboxane (TXA2)
- ADP receptor stimulation
- GP IIb/IIIa receptor stimultation
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platelet aggregation is pharmacologically inhibited by
- TXA2 synthesis inhibitor aspirin
- ADP receptor antagonists Ticlopidine and Clopidogrel
- dipyridamole
- GP IIb/IIIa receptor antagonists Abciximab
3
Use of aspirin & MOA
low dose aspirin (81-325)
Use: antiplatelet
MOA: irreversibly inhibit platelet COX enzyme by acetylating the enzyme and also inhibits thromboxane synthetase
- as platelets cannot synthesize new COX (no nucleus)
- no thromboxane TXA2 synthesis
- antithrombotic effect lasts for 3 days
High dose aspirin = COX 1 and 2
Use: low dose daily prevents ischemic attack and MI
>1000mg/day has NO anti platelet effect
- high dose is anti-inflammatory dose
- high dose inhibits prostacyclin (PGI) synthesis
- PGI normally prevents platelet aggregation
- therefore prophylactic benefit of aspirin as an anti platelet drug is always in low doses
MC use of aspirin = coronary artery disease
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COX 1
COX1 = housekeeping; important with PG in mucous production
aspirin-induced ulcers result from inhibition of this --> not seen much with low-dose aspirin
Remember: aspirin acetylates serine residue on COX --> inhibits TXA2 synthetase
5
Ticlopidine: MOA, use, A/E
ADP receptor antagonist
MOA: blocks platelet ADP receptor and prevents platelet aggregation
Uses:
- for prevention of TIA, post MI, unstable angina and as an alternative to aspirin
- adjunct therapy with aspirin following coronary stent implantation to decrease incidence of stent thrombosis
A/E:
- severe neutropenia, thrombocytopenic purpura
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GP IIb/IIIa receptor antagonists
- Abciximab
- Eptifibatide
- Tirofiban
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Fibrinolytics / Thrombolytics
- streptokinase
- urokinase
- tissue plasminogen activator (tPA)
fibrinolytic therapy should be used ASAP to reestablish blood flow following AMI; >60% decrease in mortality post-MI if used within 3 hours!
8
Antifibrinolytics
aminocaproic acid
tranexamic acid
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Clopidogrel: MOA, use, A/E
ADP receptor antagonist
MOA: blocks platelet ADP receptor and prevents platelet aggregation
Uses:
- for prevention of TIA, post MI, unstable angina and as an alternative to aspirin
- adjunct therapy with aspirin following coronary stent implantation to decrease incidence of stent thrombosis
A/E:
- less incidence of neutropenia or thrombocytopenia
10
Eptifibatide: MOA and use
GP IIb/IIIa receptor antagonist
MOA: Inhibit binding of fibrinogen to the GPIIb/IIIa receptor --> thereby inhibiting the final, common pathway of platelet aggregation
Use: given along with aspirin and heparin during coronary angioplasty (PTCA)
- markedly reduce the incidence of restenosis
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Streptokinase
thrombolytic/fibrinolytic
- obtained from streptococci
MOA: binds to circulating plasminogen--> converts to plasmin
A/E: bleeding, allergic reactions, hypotension, fever
12
alteplase
tPA
MOA: binds to & activates fibrin bound plasminogen (more local action on the thrombus)
13
Dipyridamole MOA
Inhibits phosphodiesterase --> increased cAMP --> prevents aggregation
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Abciximab:
GP IIb/IIIa receptor antagonist
MOA: monoclonal antibodies directed against GP IIb/IIIa receptor complex
Use: given along with aspirin and heparin during coronary angioplasty (PTCA)
- markedly reduce the incidence of restenosis
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urokinase
fibrinolytic/thrombolytic
- derived from human tissue
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reteplase
tPA
MOA: binds to & activates fibrin bound plasminogen (more local action on the thrombus)
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aminocaproic acid: MOA, Uses
antifibrinolytic
MOA: Inhibits the plasminogen activation
Uses: to treat excessive bleeding due to overdose of fibrinolytic agents
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Tissue plasminogen activator (tPA)
fibrinolytic/thrombolytic
- Alteplase, reteplase (recombinant DNA technology)
MOA: binds to & activates fibrin bound plasminogen (more local action on the thrombus)
used to help re-canalize bv after AMI
19
Tirofiban: MOA and use
GP IIb/IIIa receptor antagonist
MOA: monoclonal antibodies directed against GP IIb/IIIa receptor complex
Use: given along with aspirin and heparin during coronary angioplasty (PTCA)
- markedly reduce the incidence of restenosis
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tranexamic acid: MOA, Uses
antifibrinolytic
MOA: Inhibits the plasminogen activation
Uses: to treat excessive bleeding due to overdose of fibrinolytic agents
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Anticoagulants
- Heparin
- warfarin (Oral anticoagulant)
- dicumarol (Oral anticoagulant)
- hirudin (direct thrombin inhibitor)
- bivalirudin (direct thrombin inhibitor)
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heparin: MOA, Pharmacokinetics,
Anticoagulant: indirect thrombin inhibitor
- unfractionated Heparin (UFH)
- low molecular weight heparins (LMWH)--longer DOA
- monitor via aPTT
MOA: activates ATIII --> inactivates clotting factors in intrinsic pathway
- thrombin IIa, IXa, Xa
Pharmacokinetics:
- hepatin is a strong acid and can be neutralized by basic compounds like protamine***
- highly ionized --> not absorbed orally
--> does not cross placenta; safe in pregnancy*
- given via IV/ S.C.
- dose monitored by aPTT (activated partial thromboplastin time) --> normally 25-39 sec
- with heparin: 45-75 sec; beyond this-->bleeding!
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warfarin
Oral Anticoagulant
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intrinsic coagulation system
Intrinsic pathway: factors XII, XI, IX, and VIII
- begins with activation of factor XII (Hageman factor)
- exposed sub-endothelial collagen and HMWK activate factor XII to form factor XIIa
- factor XIIa is also known as activated Hageman factor
- factor XIIa activates factor XI to form factor XIa
- factor XIIa activates 3 substances:
---> factor XI to form factor XIa
---> plasminogen to form plasmin
---> kininogen system to produce chalkier and bradykinin
- XIa activates factor IX to form IXa
- IXa complexes with factor VIII, CA2+, and PF3 to form a four component complex: factor IXa, factor VIII, PF3 and Ca2+
- in the final common pathway this complex activates factor X
_____________________________________________
XII --> XIIa
XI --> XIa
IX --> IXa
VIII + IXa + PF3 + Ca2+ --->common pathway
Common pathway:
X --> Xa
V + Xa + PF3 + Ca2+
prothrombin --> thrombin
fibrinogen --> fibrin monomer
fibrin monomer aggregate--> soluble fibrin --> cross-linked insoluble fibrin
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extrinsic coagulation pathway
Extrinsic pathway: factor VII
- begins with activation of factor VII
- Tissue Thromboplastin released from injured tissue activates factor VII resulting in formation of factor VIIa
- in the final common pathway factor VIIa activates factor X
_______________________________________
VII --> VIIa
----> common pathway:
X --> Xa
V + Xa + PF3 + Ca2+
prothrombin --> thrombin
fibrinogen --> fibrin monomer
fibrin monomer aggregate--> soluble fibrin --> cross-linked insoluble fibrin
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dicumarol
Oral anticoagulant
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Common Pathway
Factors X, V, II (prothrombin) and I (fibrinogen)
- begins with activation of factor X by:
--> factor VIIa (extrinsic pathway)
--> four component complex [(factor IXa, factor VIII, PF3, Ca2+) intrinsic pathway]
-activated factor Xa complexes with factor V, PF3, and Ca2+ to form a complex = the Prothrombin complex
----> prothrombin complex cleaves prothrombin to the enzyme thrombin
_____________________________________
X --> Xa
V + Xa + PF3 + Ca2+
prothrombin --> thrombin
fibrinogen --> fibrin monomer
fibrin monomer aggregate--> soluble fibrin --> cross-linked insoluble fibrin
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LMW heparins: names, MOA, Advantages, A/E
enozaparin
dalteparin
tinzaparin
- selectively inhibit Xa, less effect on thrombin
- given subcutaneously
advantages:
- less hemorrhagic complication, less thrombocytopenia
- equally efficacious
- increased bioavailability
- less frequent dosing, bc longer half life
- less effect on aPTT
A/E: BLEEDING!
- close monitoring of activated partial thromboplastin time (aPTT)
- PROTAMINE is used to stop bleeding due to heparin
- Moderate & transient thrombocytopenia --> immune mediated
- Osteoporosis on prolonged use
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Hemopoietic agents used in treatment of anemias and hemopoietic growth factors
- iron
- vitamin B12
- folic acid
- erythropoietin
- myeloid growth factors
- platelet growth factor
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