Lecture 23 - Anticoagulants, Antiplatelet Drugs, Thrombolytics, and Hemostatics

Question 1

Antiplatelet Agents

Answer 1

• Aspirin
• Dipyridamole
• Clopidogrel
• Tirofiban HCl

Question 2

Anticoagulants

Answer 2

• Heparin
• Enoxaparin Sodium
• Protamine Sulfate
• Warfarin sodium
• Dabigatran etexilate
• IdaruCIZUmab
• Rivaroxaban
• Andexanet alfa

Question 3

Fibrinolytics

Answer 3

• Alteplase
• Aminocaproic acid

Question 4

Hemostatics

Answer 4

• Factor VIII
• Factor IX
• Phytonadione

Question 5

Hemostasis

Answer 5

Mechanism that minimizes or prevents blood loss
Four interrelated events:
1) Vasoconstriction of local blood vessels
2) Platelet aggression: Uses COX1 to convert arachidonic acid to thromboxane A2.
3) Coagulation: Enzyme called thrombin (factor 2) converts fibrinogen, a soluble plasma protein, to fibrin, an insoluble plasma protein.
4) Fibrinolysis: Natural anticoagulant and fibrinolytic systems to restore blood flow

Question 6

Plasminogen to Plasmin conversion is stimulated by? is inhibited by?

Answer 6

Stimulated: t-PA (Drug), Prokinase
Inhibited: Aminocaproic acid

Question 7

Actions of antiplatelet agents

Answer 7

Inhibition of Thromboxane (TXA2) synthesis
- Aspirin irreversibly acetylates COX1

Inhibition of phosphodiesterase and activation of adenylate cyclase
- Rise of cAMP blocks TXA2 production
- Dipyridamole blocks platelet adhesion to vascular subendothelium by inhibition of phosphodiesterase to increase cAMP

NOTE: phosphodiesterase breaks down cAMP to AMP

Question 8

Clopidogrel

Answer 8

Inhibitor of adenosine (ADP) binding to prevent platelet aggregation.
- Binds irreversibly to platelet P2Y12 purinergic receptor.
- Antagonism of platelet glycoprotein IIb/IIIa

Question 9

Tirofiban

Answer 9

Reversible antagonist of fibrinogen binding to glycoprotein IIb/IIIa receptor

Question 10

Aspirin

Answer 10

Inactivates the enzyme COX1 to prevent TXA2 synthesis by platelets.
- Platelets cant resynthesize COX1, therefore irreversible

Uses
- Prevention of myocardial infarction, ischemic attacks and stroke.
- Prevent arterial thrombotic events
- Prevents vein graft occulsion

Adverse reactions
- Abdominal discomfort, epigastric pain, heartburn, nausea and gastrointestinal bleeding
- Stomach and intestine uses COX1 for prostaglandin synthesis

Question 11

Anticoagulants

Answer 11

Interfere with fibrin formation and used to prevent thrombus development.
- Major therapeutic application: venous thromboembolic disorders

Precautions: Bleeding is a hazard

Contraindications: Avoid pregnancy due to teratogenicity and intrauterine hemorrhage.
- If anticoagulants must be used: HEPARIN for first trimester

Question 12

Heparin (What it is and MOA)

Answer 12

Heterogenous mixture of sulfated mucopolysaccharides
- Negative charge
- Synthesized in mast cells

MOA
- Binds to some of the lysine residues of the protease inhibitor antithrombin III (AT-III) due to its negative charge.
- AT-III inactivates factor Xa and thrombin (factor IIa)
- Interacts with platelets to cause thrombocytopenia

Question 13

Heparin (Uses and adverse effects)

Answer 13

Uses:
- Drug of choice when rapid effect is desired
- Venous and Arterial Thromboembolic Diseases
- FOR PREGNANCY instead of oral anticoagulants

Adverse effects:
- CLINICALLY SIGNIFICANT BLEEDING
- Drug related thrombocytopenia cause by heparin-related and platelet-activating antibodies
- Hypersensitivity: of animal origin and can cause a reaction
- Local capillary rupture: at injection site when administered intramuscularly (DO NOT USE THIS ROUTE)

Drug Interactions:
- Suppresses aldosterone
- May interact with insulin receptors

Question 14

Protamine sulfate

Answer 14

Positively charged and originates from fish.
Instantaneous inactivator of heparin (positive charge neutralize negative charge)

Adverse effect
- Anaphylactic reaction for patients allergic to fish

Question 15

Warfarin (Info, uses, adverse effects)

Answer 15

Coumarin derivative anticoagulant blocks vitamin K, which is essential for post-translational modification of clotting factors II, VII, IX, and X and anticoagulant proteins C and S.
- Vitamin K epoxide reductase inhibition
- Onset of anticoagulation requires clearance of already existing factors (72-96 hours)

Uses: Prophylaxis of thromboembolic and prevention of thrombosis.

Adverse effects:
- Hemorrhage
- Hypertension
- Necrotic lesions of the skin and/or gangrene
- Occasional gastrointestinal disturbances and other
- WARFARIN CROSSES PLACENTA, DO NOT USE IF PREGNANT OR LACTATING

Question 16

Warfarin (Drug interactions and reversal of action)

Answer 16

Drug interactions
- Prolong or intensify oral anticoagulants (aspirin for example)
- Diminish oral anticoagulants (Corticosteroids or excessive vitamin K intake)

Reverse action with vitamin K1 and fresh frozen plasma

Question 17

Dabigatran etexilate

Answer 17

Direct, reversible thrombin (F2a) inhibitor

Used for deep venous thrombosis and pulmonary embolism treatment, nonvascular atrial fibrillation, and hip replacements.

BLACK BOX WARNINGS:
- Thrombotic events
- Spinal/Epidural hematoma

Other effects:
- GI bleeding

Question 18

IdaruCIZmab

Answer 18

Humanized monoclonal antibody that binds and reverses action of dabigatran etexilate.

Does not reverse anticoagulant effects of factor Xa inhibitors

Question 19

Rivaroxaban

Answer 19

Factor Xa inhibitor which inhibits both coagulation pathways. Does not inhibit thrombin

For deep venous thrombosis and pulmonary embolism and nonvalvular atrial fibrillation.

BLACK BOX WARNINGS:
- Thrombotic events
- Spinal/Epidural hematoma

Other effects:
-Bleeding

Question 20

Andexanet Alfa

Answer 20

Sequesters FXa inhibitor rivaroxaban

Question 21

Fibrinolytics

Answer 21

Lyses fibrin to restore vessel patency and flow
- Promotes conversion of plasminogen to plasmin

Question 22

Alteplase

Answer 22

human tissue-type plasminogen activator (rt-PA)
- Naturally occurring serine protease that binds to fibrin to increase the enzymes affinity for it’s substrate plasminogen.
- Alterplase activates fibrin-bound plasminogen to plasmin

Question 23

Aminocaproic acid

Answer 23

Similar to amino acid lysine, synthetic inhibitor of fibrinolysis by competitively inhibiting plasminogen activation (such as from alteplase)

Question 24

Hemostatics

Answer 24

Replacements of certain clotting factors or platelet deficiencies.
- Factor VIII: For hemophilia A
- Factor IX: For hemophilia B (less common)
- Phytonadione: For vitamin K1

Question 25

Factor VIII

Answer 25

Used for hemophilia A; X linked factor VIII deficiency

Question 26

Factor IX

Answer 26

Used for hemophilia B; X linked factor IX deficiency

Question 27

Phytonadione

Answer 27

Fat soluble naphthoquinone identical to Vitamin K1, which is required for the synthesis of blood coagulation factors II, VII, IX, and X

Used for hypoprothrombinemia caused by coumarins and newborn hemorrhagic disease

Nontoxic however anaphylaxis has been observed

Question 28

Vitamin K types

Answer 28

Vitamin K1: phytonadione. Produced synthetically and occurs in a variety of foods.

Vitamin K2: produced by bacteria in gastrointestinal tract

Vitamin K3: synthetically for therapeutic replacement