Lecture 23 - Anticoagulants, Antiplatelet Drugs, Thrombolytics, and Hemostatics Flashcards
Antiplatelet Agents
- Aspirin
- Dipyridamole
- Clopidogrel
- Tirofiban HCl
Anticoagulants
- Heparin
- Enoxaparin Sodium
- Protamine Sulfate
- Warfarin sodium
- Dabigatran etexilate
- IdaruCIZUmab
- Rivaroxaban
- Andexanet alfa
Fibrinolytics
- Alteplase
- Aminocaproic acid
Hemostatics
- Factor VIII
- Factor IX
- Phytonadione
Hemostasis
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
Plasminogen to Plasmin conversion is stimulated by? is inhibited by?
Stimulated: t-PA (Drug), Prokinase
Inhibited: Aminocaproic acid
Actions of antiplatelet agents
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
Clopidogrel
Inhibitor of adenosine (ADP) binding to prevent platelet aggregation.
- Binds irreversibly to platelet P2Y12 purinergic receptor.
- Antagonism of platelet glycoprotein IIb/IIIa
Tirofiban
Reversible antagonist of fibrinogen binding to glycoprotein IIb/IIIa receptor
Aspirin
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
Anticoagulants
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
Heparin (What it is and MOA)
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
Heparin (Uses and adverse effects)
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
Protamine sulfate
Positively charged and originates from fish.
Instantaneous inactivator of heparin (positive charge neutralize negative charge)
Adverse effect
- Anaphylactic reaction for patients allergic to fish
Warfarin (Info, uses, adverse effects)
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
Warfarin (Drug interactions and reversal of action)
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
Dabigatran etexilate
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
IdaruCIZmab
Humanized monoclonal antibody that binds and reverses action of dabigatran etexilate.
Does not reverse anticoagulant effects of factor Xa inhibitors
Rivaroxaban
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
Andexanet Alfa
Sequesters FXa inhibitor rivaroxaban
Fibrinolytics
Lyses fibrin to restore vessel patency and flow
- Promotes conversion of plasminogen to plasmin
Alteplase
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
Aminocaproic acid
Similar to amino acid lysine, synthetic inhibitor of fibrinolysis by competitively inhibiting plasminogen activation (such as from alteplase)
Hemostatics
Replacements of certain clotting factors or platelet deficiencies.
- Factor VIII: For hemophilia A
- Factor IX: For hemophilia B (less common)
- Phytonadione: For vitamin K1
Factor VIII
Used for hemophilia A; X linked factor VIII deficiency
Factor IX
Used for hemophilia B; X linked factor IX deficiency
Phytonadione
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
Vitamin K types
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
