Pharmacology of Anticoagulation Therapy

Question 1

Name the anticoagulant drugs that interfere with the coagulation cascade and prevent formation of thrombin, which converts fibrinogen to fibrin.

Answer 1

Heparin and oral anticoagulants

Question 2

What agent promotes lysis of clots by increasing formation of plasmin, a serine protease that degrades fibrin?

Answer 2

Fibrinolytic agents

Question 3

What drug inhibits the formation of platelet products or blocks platelet adhesion thus preventing platelet aggregation and clot formation?

Answer 3

Anti-platelet agents

Question 4

What are the three forms of Heparin?

Answer 4

1. Unfractionated Heparin
2. Low molecular weight heparins
3. Fondaparinux

Question 5

Describe unfractionated heparin.

Answer 5

• Proteoglycans containing covalently linked sulfated polysaccharide chains
• 12,000 Daltons
• Highest negative charge density

Question 6

Describe low molecular weight heparins like

• lovenox
• enoxaparin
• dalteparin
• nadroparin

Answer 6

• produced by chemical or enzymatic depolymerization of heparin
• 4,500 Daltons

Question 7

Describe Fondaparinux (Arixtra)

Answer 7

Synthetic pentasacharide

Minimal sequence in heparin for binding antithrombin

Question 8

What is the mechanism of action of heparin?

Answer 8

Heparins bind antithrombin III

Antithromin III is a natural protease inhibitor that inactivates coagulation factors

Heparin accelerates the rate of decay of IXa, Xa, and XIIa by antithrombin III

Question 9

Which type of heparin is able to bind to the antithrombin/thrombin complex?

Answer 9

Unfractionated

LMWH and Fondaparinux can only bind AT-III

Question 10

Which drug does not absorb well from the GI tract and can’t be given orally. This drug also has poor bioavailability and relatively short half-life?

Hint: Requires careful monitoring in hospital but can be given to pregnant women.

Answer 10

Unfractionated heparin

Question 11

What drug is given SQ, has a long half life, requires less monitoring, and has a better bioabailability than unfractionated heparin?

Answer 11

Low molecular weight heparins and fondaparinux

Question 12

What conditions would you use heparins to treat?

Answer 12

-Venous thrombosis and pumonary embolism
-management of unstable angina or acute myocardial infarction
-During and after coronary angioplasty or stent placement
During surgery requiring cardiopulmonary bypass
-Kidney dialysis

Question 13

What drug can you use to reverse the toxic affects of heparin?

Answer 13

Protamine sulfate, a positively charged compound that neutralizes heparin

Question 14

Name three toxic effects of heparin.

Answer 14

1. Bleeding
2. Heparin-induced thrombocytopenia syndrome (HIT)
3. Allergic Events

Question 15

Describe the onset of heparin-induced thrombocytopenia syndrome.

Answer 15

Platelet cound decreases 5-10 after heparin

Caused by development of antibodies that bind to and activate platelets resulting in a prothrombotic state

Question 16

What is the treatment for patients who have heparin-induced thrombocytopenia syndrome?

Answer 16

TX with direct thrombin inhibitors:

• Argatroban (Novastan): a small molecule inhibitor
• Lepirudin (Refludan): recombinant form of hirudin, the antivoagulant from leeches

Question 17

Allergic reactions are sometimes seen in patients on Heparin. What is the root cause of thos allergic reaction?

Answer 17

Contaminant over sulfated chondroitin sulfate

Question 18

What drug is a derivative of dicumarol and is a vitamin K analogue?

Answer 18

Warfarin

Question 19

What is the mechanism of action of warfarin?

Answer 19

Warfarin inhibits reductases that reduce vitamin K.

Reduced vitamin K is used as a cofactor for certain enzymes

These enzymes undergo vitamin K-dependent gamma carboxylation of N-terminal glutamate

Question 20

What are the pharmacokinetic characteristics of warfarin?

Answer 20

It is readily absorbed
Good bioavailability
Does not achieve affect until 2-3 days

Question 21

What are the clinical uses of warfarin?

Answer 21

Used to prevent:

• Venous thromboembolism
• Systemic embolism in patients with prosthetic heart valves or atrial fibrillation
• Stroke, recurrent infarction, or death in patients with acute myocardial infarction

Question 22

What are some of the adverse effects of warfarin?

Answer 22

Hemorrhage
TX: Drug stopped, Vitamin K administered, Plasma can be transfused to replace coag. factors

Teratogenic

Question 23

What drugs can increase the action of warfarin?

Answer 23

1. Drugs that inhibit platelet function (aspirin)
2. Drugs that decrease vit. K synthesis by intestinal microbes (antibiotics)
3. Drugs that replace warfarin from plasma proteins (clofibrate, phenytoin)
   - Drugs that reduce the metabolism and elimination of warfarin in the liver

Question 24

What drug decrease the effect of warfarin?

Answer 24

• Drugs that increase the metabolism by inducing metabolic enzymes in the liver (barbiturates, rifampin)
• Drugs that decrease warfarin absorption from the GI tract (cholestyramine)

Question 25

There are new oral anticoagulants that are direct thrombin or Factor Xa inhibitors. Name some advantages of these drugs.

Answer 25

- Rapid onset of action - Absence of food interactions - Do not require monitoring

Question 26

There are new oral anticoagulants that are direct thrombin or Factor Xa inhibitors. Name some disadvantages of these drugs.

Answer 26

- Contraindicated with kidney disease - Greater GI bleeding than with warfarin - Short half-life - Cost - No antidote available to reverse effects

Question 27

There are new oral anticoagulants that are direct thrombin or Factor Xa inhibitors. Name three of these new drugs.

Answer 27

- Dabigatran etexilate: Prodrug, lowers rate of stroke and systemic embolism, less intracranial hemorrhage. More myocardial infarctions - Apixaban - Rivaroxaban- Synthetic, lower rates of strokes and emboli for the TX or atrial fibrillation All three have been approved for the treatment of atrial fibrillation

Question 28

What is the mechanism of action for fibrinolytic agents?

Answer 28

Convert plasminogen to plasmin, a protease that degrades fibrin clots.

Question 29

What is tissue plasminogen activator and what is its mechanism of action?

Answer 29

- Serine protease | - Fibrinolytic drug that binds to fibrin, which increases cleavage of plasminogen to plasmin.

Question 30

What is urokinase (u-PA)?

Answer 30

Enzyme obtained from renal cells in culture that converts plasminogen to plasmin DOES NOT BIND FIBRIN

Question 31

What is streptokinase?

Answer 31

Non-enzymatic protein obtained from beta-hemolytic streptococci. -forms a complex with plasminogen which becomes activated and converts plasmin

Question 32

What are fibrinolytic agents used in the the treatment for?

Answer 32

-Acute myocardial infarction -Ischemic stroke -Deep vein thrombosis Pulmonary embolism

Question 33

What are some adverse effects of fibinolytic agents?

Answer 33

Hemorrhage Induced systemic lytic state Allergic reaction due to antibodies against Streptokinase

Question 34

What are antiplatelet drugs used to treat?

Answer 34

Acute coronary syndrome

Question 35

What are the three classes of anti-platelet drugs?

Answer 35

- Those that inhibit formatio of platelet products (Aspirin) - Those that prevent activation/aggregation (ADP receptor antagonist) - Those that block adhesion proteins (Glycoprotein IIb/IIIa Inhibitors)

Question 36

What is the mechanism of action of aspirin?

Answer 36

Irreversibly inactivates cyclooxygenase preventing thromboxane A2 formation by platelets Permanent- for the lifespan of the platelet 7-10 days Used in prevention of AMI of patients with artherosclerosis

Question 37

What are two ADP receptor antagonist?

Answer 37

Thienophyridines - Clopidogrel (Plavix)-used in pts. w/ aspirin intol. - Ticlopidine - Prasugrel- most potent

Question 38

What is the mechanism of action of ADP receptor antagonists?

Answer 38

They block platelet activation by ADP which inhibits secretion of alpha granules and blocks expression of adhesion proteins GPIIb/IIa

Question 39

What is the pharmacokinetics of ADP receptor antagonists?

Answer 39

slow onset of action because they are prodrugs that have to be metabolized by the liver

Question 40

Is the action of ADP receptor antagonists permanent?

Answer 40

Yes so for the lifespan of that platelet

Question 41

What is ADP receptor antagonist used to treat?

Answer 41

Preventing cardiac events in patients with atherosclerosis

Question 42

Describe Ticagrelor.

Answer 42

Oral ATP analogue that binds reversibly to ADP receptor Rapid action Greater platelet inhibition Reduced rate of death from MI without increasing major bleeding

Question 43

What are glycoprotein IIb/IIIa inhibitors?

Answer 43

Adhesion protein on the surface of platelets that is a receptor for fibrinogen Inhibitors block the receptor and prevent platelet aggregation

Question 44

Name three glycoprotein IIb/IIIc inhibitors.

Answer 44

Abciximab-Monoclonal antibody agains the glycoprotein receptor. Used in coronary angioplasty. Prevents restenosis, recurrent AMI Eptifibatide- Cyclic peptide inhibitor used for unstable angina Tirofiban- small molecule inhibitor used or treatment of unstable angina

Question 45

What are the adverse affects of glycoprotein IIb/IIIc inhibitors?

Answer 45

Bleeding and thrombocytopenia | Reverse by platelet infusion