drugs used in coagulation disorders by s.bohlooli, ph.d
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Drugs used in coagulation disorders
By S.Bohlooli, Ph.D.
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Mechanism of blood coagulation
Thrombogenesis Blood coagulation Regulation of coagulation and
fibrinolysis Fibrin inhibition: 1-antiprotease, 2-
macroglobulin, 2-antiplasmin, antithrombin
Fibrinolysis: plasmin
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Thrombogenesis
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Blood coagulation
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A model of blood coagulation
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Fibrinolysis
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Basic pharmacology of the anticoagulant drugs
Indirect thrombin inhibitors Direct thrombin inhibitors Warfarin and the Coumarin
anticoagulants
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Indirect thrombin inhibitors
Unfractioned heparin Low molecular-weight heparin:
Enoxoparin, daltaparin, tinzaprin foundaparinux
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Differences between fondaparinux, LMWH and HMWH heparin
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The antithrombin-binding structure of heparin
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Toxicity Bleeding Thrombocytopenia Caution in patient with allergy Contraindicated in:
Hypersensitive Actively bleeding Hemophilia Thrombocytopenia Sever Hypertension Intracranial hemorrhage Advanced renal or hepatic disease
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Direct thrombin inhibitors
Hirudin, lepirudin Bivalirudin Agatroban Melagatran
Ximelagatran: oral prodrug
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Warfarin and the Coumarin anticoagulants
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Block the -carboxylation of several glutamate residue in prothrombine and factors VII, IX, and X
As well as the endogenous antigoagulant proteins C and S
There is 8- to 12-hour delay in the action of warfarin
Warfarin :Mechanism of action
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Warfarin :Mechanism of action
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Warfarin: Toxicity bleeding Readily crosses the placenta
Hemorrhagic disorders Abnormal bone formation
Cutaneous necrosis Frank infarction of breast, fatty
tissues intestine, and extremities Venous thrombosis
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Basic pharmacology of the Fibrinolytic drugs
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Contraindications to Thrombolytic Therapy
1. Surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious trauma, cardiopulmonary resuscitation
2. Serious gastrointestinal bleeding within 3 months
3. History of hypertension (diastolic pressure >110 mm Hg)
4. Active bleeding or hemorrhagic disorder5. Previous cerebrovascular accident or active
intracranial process6. Aortic dissection7. Acute pericarditis
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Basic pharmacology of Antiplatelet agents
Clyclooxygenase inhibitors:Aspirin ADP receptor antagonists:
Clopidogrel, ticlopidine Blockers of GP IIB/IIIA receptors:
abciximab, eptifibatide, tirofiban Phosphodiesterase inhibitors:
dipyridamole, cilostazol
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Structure of ticlopidine and clopidogrel
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Toxicity:Ticlopidine
nausea, vomiting, and diarrhea severe neutropenia: 2.4% patients Fatal agranulocytosis with
thrombopenia
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Clinical pharmacology of drugs used to prevent clotting Venous thrombosis
Risk factors: Inherited disorders Acquired diseases
Anithrombotic management Prevention Treatment of established disease
Arterial thrombosis Antiplatelet drugs
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Drugs used in bleeding disorders
Vitamin K Plasma fractions Fibrinolytic inhibitors:
aminocaproic acid Serine protease inhibitors:
aprotinin
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Vitamin K
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Vitamin K to promote the biosynthesis of the -
carboxy-glutamate (Gla) forms of: factors II (prothrombin), VII, IX, and X anticoagulant proteins C and S, protein Z (a
cofactor to the inhibitor of Xa) the bone Gla protein osteocalcin, matrix
Gla protein, growth arrest-specific protein 6 (Gas6)
four transmembrane monospans of unknown function
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Vitamin K Deficiency increased tendency to bleed Ecchymoses, epistaxis, hematuria,
gastrointestinal bleeding, and postoperative hemorrhage
fetal warfarin syndrome: vitamin K-dependent protein in bone
deficits in bone mineral density and fractures
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Toxicity
Phylloquinone and the menaquinones are nontoxic
menadione and its derivatives: hemolytic anemia and kernicterus in
neonates, especially in premature infants