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

Thrombogenesis

Blood coagulation

A model of blood coagulation

Fibrinolysis

Basic pharmacology of the anticoagulant drugs

Indirect thrombin inhibitors Direct thrombin inhibitors Warfarin and the Coumarin

anticoagulants

Indirect thrombin inhibitors

Unfractioned heparin Low molecular-weight heparin:

Enoxoparin, daltaparin, tinzaprin foundaparinux

Differences between fondaparinux, LMWH and HMWH heparin

The antithrombin-binding structure of heparin

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

Hirudin, lepirudin Bivalirudin Agatroban Melagatran

Ximelagatran: oral prodrug

Warfarin and the Coumarin anticoagulants

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

Warfarin :Mechanism of action

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

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

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

Toxicity:Ticlopidine

nausea, vomiting, and diarrhea severe neutropenia: 2.4% patients Fatal agranulocytosis with

thrombopenia

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

Vitamin K Plasma fractions Fibrinolytic inhibitors:

aminocaproic acid Serine protease inhibitors:

aprotinin

Vitamin K

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 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

Toxicity

Phylloquinone and the menaquinones are nontoxic

menadione and its derivatives: hemolytic anemia and kernicterus in

neonates, especially in premature infants