Drugs used in coagulation disorders

Question 1

Antiplatelet drugs

Answer 1

• Inhibition of COX-1 (Aspirin)
• Inhibitors of phosphodiesterase 3 (Dipyridamole, Cilostazol)
• ADP receptors antagonists (Ticlopidine, Clopidogrel, Prasugrel)
• Glycoprotein IIb/IIIa receptor inhibitors (Abciximab, Tirofiban, Eptifibatide)

Question 2

Aspirin

Answer 2

• Block COX-1 –> inhibit thromboxane A2 synthesis (platelet aggregation stimulator) from arachidonic acid by irreversible acetylation of a serine
• Used to prevent further infarcts in patients that have had 1 or more MI, and reduce incidence of first infarcts
• Used to prevent TIA, ischemic strokes, and other thrombotic events
• Adverse effects; GI and CNS

Question 3

Clopidogrel, Ticlopidine, Prasugrel

Answer 3

• Irreversible inhibition of ADP receptor, thereby inhibit the activation of GP IIb/IIIa
• Prevent TIAs and ischemic strokes, especially in patients who can not tolerate aspirin

Question 4

Abciximab

Answer 4

• Reversible inhibits the binding of fibrin and other ligands to GP IIb/IIIa
• A monocona antibody
• Prevent restenosis after coronary angioplasty and used in acute coronary syndrome

Question 5

Eptifibatide and Tirofiban

Answer 5

• Reversible block GP IIb/IIIa
• Bind to the site that interacts with the arginine-glycine-aspartic acid sequence of fibrinogen
• Prevent restenosis after coronary angioplasty and used in acute coronary syndrome

Question 6

Dipyridamole and Cilostazol

Answer 6

• Increase intracellular cAMP by inhibiting cyclic nucleotide phosphodiesterase 3 –> decreased thromboxane A2 synthesis
• Coronary vasodilators, used to treat intermittent claudication
• Dipyridamole: used prophylactically to treat angina pectoris
• Cilostazol: treat Buerger disease, vascular sclerosis complicating DM, chronic cerebral ischemia

Question 7

Thrombolytic agents

Answer 7

• Forms of tissue plasminogen activator (t-PA) (Alteplase, Tenecteplase, Reteplase)
• Plasminogen activation (Urokinase)
• Plasminogen-complex (Streptokinase)
• Anisoylated plasminogen-streptokinase activator complex (APSAC) (Anistreplase)

Question 8

Alteplase, Reteplase, Tenecteplase

Answer 8

• Active tissue plasminogen activator (t-PA)
• Converts plasminogen to plasmin
• Results in hydrolyzing of fibrin –> breakdown and dissolution of clots
• Alteplase: IV, normal human plasminogen activator
• Reteplase, Tenecteplase: bolus doses, mutated form of human t-PA

Question 9

Thrombolytic agents; indication

Answer 9

• Used in emergency treatment of coronary artery thrombosis
• Better outcome in ischemic strokes
• Used in multiple PE
• Cerebral hemorrhage must be ruled out before use

Question 10

Streptokinase

Answer 10

• Combine with plasminogen. The complex converts plasminogen into plasmin
• IV infusion
• May cause allergic reactions
• Antibodies may neutralize its fibrinolytic properties

Question 11

Urokinase

Answer 11

• Directly converts plasminogen to plasmin

- Extracted from cultured human kidney cells

Question 12

Anistreplase

Answer 12

• Prodrug

- Slowly releases streptokinase-activated plasminogen

Question 13

Anticoagulants

Answer 13

• Antithrombin III activatiors (Heparin, Enoxaparin, Fondaparinux, Dalteparin)
• Direct thrombin inhibitors (Lepirudin, Biyalirudin, Argatroban)
• Vitamin K antagonist (Warfarin, Dicumarol)

Question 14

Heparin can be neutralized by…

Answer 14

Protamine

- Heparin is highly acidic and can be neutralized by basic molecules

Question 15

Mechanism of Heparin

Answer 15

• Bind to endogenous ATIII
• The heparin-ATIII complex combines with and irreversible inactivates thrombin (factor II) and factor Xa
• ATIII proteolysis factor II and Xa, 1000-fold faster when combine to heparin

Question 16

Differences between Heparin and LMWH

Answer 16

• Heparin weight 15,000-20,000, LMWH weight 2000-6000
• Heparin inhibit factor II and Xa, LMWH selectively inhibit factor Xa
• LMWH have higher bioavailability and longer duration of action
• Heparin is monitored with aPTT, LMWH is not reliably measured
• Heparin is administrated IV or subcutaneously, LMWH is administrated subcutaneously
• Heparin cause moderate transient thrombocytopenia and osteoporosis when long-term therapy

Question 17

Heparin; indications

Answer 17

• Treatment of DVT, PE, and acute MI
• Used in combination with thrombolytics for revascularization
• Used in combination with GP IIb/IIIa inhibitors during angioplasty and placement of coronary stents
• Prophylactically to prevent postoperative DVTs
• Anticoagulant drug of choice in pregnancy

Question 18

Anticoagulants

Answer 18

• Antithrombin III activatiors (Heparin, Enoxaparin, Fondaparinux, Dalteparin)
• Direct thrombin inhibitors (Lepirudin, Biyalirudin, Argatroban, Dabigatran etexilate)
• Vitamin K antagonist (Warfarin, Dicumarol)

Question 19

Mechansim of direct thrombin inhibitors

Answer 19

• Lepirudin and Bivalirudin bind simultaneously to the active site of thrombin and to thrombin substrates
• Argatroban bind solely to thrombin
• Bivalirudin also inhibit platelet activation
• Monitored with aPTT (dabigatran etexilate does not require INR)

Question 20

Direct thrombin inhibitors; indications

Answer 20

• Lepirudin and Argatroban; used as alternatives to heparin in patients with heparin-induces thrombocytopenia
• Bivalirudin used in combination with Aspirin during percutaneous transluminal coronary angioplasty
• Dabigatran etexilate approved for prevention of stroke and systemic embolism in patients with AF

Question 21

Vitamin K antagonists; mechanism

Answer 21

• Site of action: liver
• Interfere with the normal post translational modification of clotting factor that requires vitamin K; II, VII, IX and X
• Prevent -carboxylation by inhibiting vitamin K epoxide reductase
• The factor is produced with diminished activity (10-40% of normal)
• Monitored with the prothrombin time (PT)

Question 22

Warfarin; indications

Answer 22

• Used to prevent progression or recurrence of acute DVT or PE after initial Heparin treatment
• Used to prevent venous thromboembolism during orthopedic or gynecologic surgery
• Used prophylactically in patients with acute MI, prosthetic heart valves, and chronic AF
• Contraindicated in pregnancy - can cause bone defect and hemorrhage

Question 23

Drugs used to treat bleeding disorders

Answer 23

• Vitamin K deficiency (Phyotonadione)
• Hemophilia (factor VIII and IX)
• Inhibiton of plasminogen activation (Aminocaproic acid, Tranexamic acid)
• Plasmin inhibitor (Aprotinin)