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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

2

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

4

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

6

GP IIb/IIIa receptor antagonists

- Abciximab
- Eptifibatide
- Tirofiban

7

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

9

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

11

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

14

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

15

urokinase

fibrinolytic/thrombolytic
- derived from human tissue

16

reteplase

tPA

MOA: binds to & activates fibrin bound plasminogen (more local action on the thrombus)

17

aminocaproic acid: MOA, Uses

antifibrinolytic

MOA: Inhibits the plasminogen activation

Uses: to treat excessive bleeding due to overdose of fibrinolytic agents

18

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

20

tranexamic acid: MOA, Uses

antifibrinolytic

MOA: Inhibits the plasminogen activation

Uses: to treat excessive bleeding due to overdose of fibrinolytic agents

21

Anticoagulants

- Heparin
- warfarin (Oral anticoagulant)
- dicumarol (Oral anticoagulant)
- hirudin (direct thrombin inhibitor)
- bivalirudin (direct thrombin inhibitor)

22

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!

23

warfarin

Oral Anticoagulant

24

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

25

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

26

dicumarol

Oral anticoagulant

27

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

28

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

29

Hemopoietic agents used in treatment of anemias and hemopoietic growth factors

- iron
- vitamin B12
- folic acid
- erythropoietin
- myeloid growth factors
- platelet growth factor

30

hirudin

direct thrombin inhibitor