Drugs used in coagulation disorders
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Drugs used in coagulation disorders. By S.Bohlooli, Ph.D. 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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Drugs used in coagulation disorders

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Drugs used in coagulation disorders

Drugs used in coagulation disorders

By S.Bohlooli, Ph.D.


Mechanism of blood coagulation

Mechanism of blood coagulation

  • Thrombogenesis

  • Blood coagulation

  • Regulation of coagulation and fibrinolysis

    • Fibrin inhibition: 1-antiprotease, 2-macroglobulin, 2-antiplasmin, antithrombin

    • Fibrinolysis: plasmin


Thrombogenesis

Thrombogenesis


Blood coagulation

Blood coagulation


A model of blood coagulation

A model of blood coagulation


Fibrinolysis

Fibrinolysis


Basic pharmacology of the anticoagulant drugs

Basic pharmacology of the anticoagulant drugs

  • Indirect thrombin inhibitors

  • Direct thrombin inhibitors

  • Warfarin and the Coumarin anticoagulants


Indirect thrombin inhibitors

Indirect thrombin inhibitors

  • Unfractioned heparin

  • Low molecular-weight heparin:

    • Enoxoparin, daltaparin, tinzaprin

  • foundaparinux


Differences between fondaparinux lmwh and hmwh heparin

Differences between fondaparinux, LMWH and HMWH heparin


The antithrombin binding structure of heparin

The antithrombin-binding structure of heparin


Toxicity

Toxicity

  • Bleeding

  • Thrombocytopenia

  • Caution in patient with allergy

  • Contraindicated in:

    • Hypersensitive

    • Actively bleeding

    • Hemophilia

    • Thrombocytopenia

    • Sever Hypertension

    • Intracranial hemorrhage

    • Advanced renal or hepatic disease


Direct thrombin inhibitors

Direct thrombin inhibitors

  • Hirudin, lepirudin

  • Bivalirudin

  • Agatroban

  • Melagatran

    • Ximelagatran: oral prodrug


Warfarin and the coumarin anticoagulants

Warfarin and the Coumarin anticoagulants


Warfarin mechanism of action

Warfarin :Mechanism of action

  • 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 action1

Warfarin :Mechanism of action


Warfarin toxicity

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


Basic pharmacology of the fibrinolytic drugs

Basic pharmacology of the Fibrinolytic drugs


Contraindications to thrombolytic therapy

Contraindications to Thrombolytic Therapy

  • Surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious trauma, cardiopulmonary resuscitation

  • Serious gastrointestinal bleeding within 3 months

  • History of hypertension (diastolic pressure >110 mm Hg)

  • Active bleeding or hemorrhagic disorder

  • Previous cerebrovascular accident or active intracranial process

  • Aortic dissection

  • Acute pericarditis


Basic pharmacology of antiplatelet agents

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


Structure of ticlopidine and clopidogrel

Structure of ticlopidine and clopidogrel


Toxicity ticlopidine

Toxicity:Ticlopidine

  • nausea, vomiting, and diarrhea

  • severe neutropenia: 2.4% patients

  • Fatal agranulocytosis with thrombopenia


Clinical pharmacology of drugs used to prevent clotting

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


Drugs used in bleeding disorders

Drugs used in bleeding disorders

  • Vitamin K

  • Plasma fractions

  • Fibrinolytic inhibitors: aminocaproic acid

  • Serine protease inhibitors: aprotinin


Vitamin k

Vitamin K


Vitamin k1

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


Vitamin k deficiency

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


Toxicity1

Toxicity

  • Phylloquinone and the menaquinones are nontoxic

  • menadione and its derivatives:

    • hemolytic anemia and kernicterus in neonates, especially in premature infants


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