Drugs Affecting Blood

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• ?????????????
• Drugs Affecting Blood

• Thrombosis

• Platelet inhibitor
• Anticoagulants
• Thrombolytic agents

• Treatment of Bleeding
• Treatment of Anemia

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• ??????????????B12??????????????

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Hemostasis

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??????? ??????????????

• ????

???Protein C S Va, VIIIa, Xa AT-III IIa, IXa,
Xa, XIa, XIIa
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???????(Intrinsic)
???????(Extrinsic)
???AT-??????
?????????
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• ???? Thrombosis

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Formation of a hemostatic plug
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Damage to vessel expose collagen to subendothelium
Prothrombin (II)

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Thrombin (IIa)
Platelet adhesion and release of granules
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Fibrinogen(I)
Fibrin
Activation of coagulation factors in plasma
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Chemical mediators Released by platelets
Platelets cover and adhere to exposed
subendothelial surface
Platelet aggregation and formation of fibrin plug
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TXA2 binds to receptors on other platelets
thereby initiating release of additional
aggregating agents.
5-HT ADP
Balance between levels of PGI2 and TXA2
influences whether platelet aggregates or
circulates freely
Platelet
TXA2
PGG2, PGH2
Granules
DAG IP3
Aspirin
cAMP
ATP
AA
Dipyridamole

• Healthy, intact endothelium releases PGI2 into
  plasma.
• PGI2 binds to platelet membrane receptors causing
  synthesis of cAMP.
• cAMP inhibits release of granules containing
  aggregating agents.

5-AMP

• Thrombin, TXA2 and exposed collagen cause release
  of AA from platelet membrane.
• TXA2 is synthesized from AA and released from the
  platelet.
• This pathway is inhibited by aspirin.

PGI2
TXA2
Endothelial cells
Collagen fibers
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????
????? ????
??? ??
ATP
AC
ADP
cAMP
????? ????
?????
??

IIa
PLA2
?????
?????
????
??
COX
????
???
PGG2 PGH2
TXA2
PGI2
XIIa,Ka,???? SK,UK,t-PA
????
????
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• ???(Antithrombotic drugs)

??????(Anticoagulants)
????????? (Fibrinolytics)
???????(Antiplatelet drugs)
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• ???(antithrombotic drugs)

??????(Anticoagulants)

• ?? Heparin
• ??? Hirudin
• ???? Coumarin

????????? (Fibrinolytics)

• ??? Streptokinase
• ??? Urokinase
• ????????????? t-pA,
• (Human tissue-type plasminogen activator)

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? ???? (Anticoagulants)
?? (Heparin) ???????
???????,?????(??????)?
?????????(??,????)?
?????????,???????????
??????????????
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Sensitivity of coagulation screening tests to
factor deficiency
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Fig. Effects of TET and FAN on the human plasma
coagulation time.

• ????????? activated partial thromboplastin time
  (APTT) ??????.Cephaline CaCl2
• ????? prothrombin time (PT) ??????.Calcium-thromb
  oplastin
• ????? thrombin time (TT) ????????Thrombin

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???????????AT-III
??AT-???? (???????a??a??a??a??a?Ka????). ??-AT-?-?
??????(???????).
?????? (LMWH)Low Molecular Weight Heparin

• 1????AT-III???????a?
• 2?T ½ gt heparin
• 3????heparin,??????????.

??????
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• No Heparin

• With Heparin

Active clotting factors (IIa, IXa, Xa, XIIa,
XIIIa) (Serine residue)
Active clotting factors (IIa, IXa, Xa, XIIa,
XIIIa) (Serine residue)
Antithrombin III (arginine-residue)
Rapid
Slow
Inactive factors
Inactive factors
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? ???? (Anticoagulants)
?????? ????(Coumarin) ???(Warfarin)
????
?????K???,??????????????????????C?S??-????????????
???,???????
??!
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Coumarin
Warfarin
Dicoumarin
O2
V-k
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????????? ???????
??????

• ??????????????????4??
• ??????1?2??????,??????????
• ??? Prothrombin time (PTT)

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????????????? 1)?????,????????????
2)????????????????K 3)????,????????
???????????????????(?????????) ????,????,????
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? ??????? Fibrinolytics
???(Streptokinase,SK)
???????
??????????? ? ?????? ? ?????
?????????????(????)?
?????
?????,????,?????,???????,?????????
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? ??????? Fibrinolytics
??? (urokinase)
???????
??????? ????????,??????????????????????
?????????? (human tissue-type plasminogen
activator,t-pA)
??????
???????????????????????????
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???
?????????
????????
?????
????
????????????????????
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• ???? Coagulants

???K ?? Human plasma VIII ??? ????
Cryoprecipitate ??? Thrombin ???????
Desmopressin acetate ???? Aminomethylbenzoic
acid, PAMBA ???? Tranexamic acid, AMCHA, ???
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• ???(Antithrombotic drugs)

???????(Antiplatelet drugs)

• ??????????
• ??????cAMP???????(???)
• ??ADP??????GPIIb/IIIa??????
• ???? Ticlopidine (????)
• ?????????
• ????GP IIb/IIIa?????????
• ???? PGI2

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? ???? (Aspirin) ??????
??
???(40 -80 mg/?) ??????COX?TXA2?
????????,??????? ????(300 mg/?) ?????
??????????COX? PGI2 ??? ???????? ?
??
1)?????????????
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• Effect of aspirin on AA pathway

AA

COX
AcO-
PGG2
AcO-COX Inactive
TXA2
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FDA ?EMEA ?????????? ????????( celecoxib ,
???,Celebrex)????????(CV)????(GI)???????????? ????
???? ??FDA COX-2????????????????? ??EMEA
?????????????????COX-2???,????????,???????????????
?????????????COX-2????????
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• ?????????8?21???,????????????????????????6???
  ????????8?19?,??????????????????????????2.53????
  ????,??????????2001?5?????????

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(No Transcript)
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• ??????cAMP???

???? (dipyridamole ,???persantin)
??????
???????(???????????)?

• ??PDE?cAMP?????????
• ??PGI2??,?????
• ???????AC ?cAMP?
• ???????COX ? TXA2?

????
???????????
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(No Transcript)
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? ??ADP????????
????(Ticlid)
????
???????,????????
????
??????
ADP????GPIIb/IIIa(receptor)?? ? ?????(ligand)?? ?
??????
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(No Transcript)
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? ???GP IIb/IIIa?????
???? Abciximab (????) (GP IIb/IIIa??????)
????
??GP IIb/IIIa?? ? ????????????? ?????????
???(Hirudin) ?????????(IIa)???? ??????????PTCA????
?????
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Plaque Disruption
Collagen
vWF
Platelet Adhision and Activation
Aspirin
Procoagulant Activity
?
TXA2
ADP
Thrombin
Thrombin Inhibitors
Ticlopidine Clopidogrel
?
?
Conformational Activation of GPIIb/IIIa
GPIIb/IIIa Antagonists
?
Platelet Aggregation
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Sites where common antiplatelet drug therapies
work
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• ??????????

????????
?????? Erythropoitin (EPO) ????? Stem cell
factor(SCF) ??? 112 Interleukins
(IL-112) ???-?????????? Granulocyte-macrophage
colony stimulating factor (GM-CSF) ?????????
Granulocyte colony stimulating factor
(G-CSF) ????-?????????? Monocyte-macrophage
colony stimulating factor (M-CSF)
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• ???? Antianemia drugs

??
???Ferrous sulfate?Iron dextran?
Ferric ammonium citrate ??? Folic acid ???B12

• ??????

???? Dextran70?40?20?10 ???