Thrombolytics, Anticoagulants, & Antiplatelet Drugs - Regal Flashcards
What is the principal complication of anticoagulant therapy?
BLEEDING
When should we interfere with hemostasis?
- Treat bleading disorders due to deficiencies and disease, etc.
- Prevention and treatment of thrombosis
- Venous thrombosis
- Inherited disorders
- Increased risk due to prolonged bed rest, surgery, cancer, afib, etc.
- Arterial thrombosis
- platelet activation is central
- Venous thrombosis
What are the therapeutic uses of antiplatelet therapy?
- Venous thromboembolism
- Unstable angina
- Acute myocardial infarction
- Stroke
- Prevent thrombosis during angioplasty and cardiopulmonary bypass
- Etc.
What is the general MOA of antiplatelet drugs?
- prevent platelet activation
What is the MOA of Aspirin (Acetylsalicylate)?
Irreversible inhibitor of COX
- Antipyretic
- Analgesic
- Anti-inflammatory
- Anti-Thromboxane A2
Do platelets have COX-2?
No
Can platelets make more COX?
NO
Why don’t the other NSAIDs work well as anti-platelet agents?
They are REVERSIBLE!
What are the adverse effects of Aspirin?
- Bleeding
- GI disturbances
- Tinnitus
What is the difference between low dose and high dose Aspirin treatment?
- Low dose
- antiplatelet
- High dose
- antiplatelet
- anti-inflammatory
What is the MOA of ADP Receptor Antagonists?
- Irriversible ADP receptor antagonists
- prevent activaiton of ADP receptor
What are the three ADP Receptor Antagoinst drugs that we need to know?
- Clopidogrel
- Prasugrel
- Ticlopidine
When are ADP Receptor Antagonists used?
- During stenting
- Recommended for patients that don’t tolerate Aspirin
What are the adverse side effects of ADP Receptor Antagonists?
- Bleeding
- Nausea
- Diarrhea
- Rash (10-15% of patients)
- Severe leukopenia (1% of patients)
- Thrombotic Thrombocytopenic Purpura (TTP)
- very rare (Ticlopidine)
- results in low platelets, & purple spots
How are ADP Receptor Antagonists administered?
Orally
(with duration of days)
What is unique about Ticlopidine compared to the other ADP Receptor Antagonists?
has more side effects
What is unique about Clopidogrel compared to the other ADP Receptor Antagonists?
- may require activation via CYP2C19
- drugs that impair this isoform should be used with caution (e.g. omeprazole)
What is the reversibility of the effects of ADP Receptor Antagonists?
- ALL are Irreversible
- Effect lasts the life of the platelet (8-9 days)
What is the MOA of GPIIb/IIIa Receptor Inhibitors?
- Prevent binding of adhesive glycoproteins such as fibrinogen and vWF to become activated platelets
- Inhibits the final common pathway for platelet aggregation
What are the three GPIIb/IIIa Receptor Inhibitor drugs that we need to know?
- Abciximab
- humanized MAB against GPIIb/IIIa
- Eptifibatide
- fibrinogen analogue
- Tirofiban
- non-peptide competitive inhibitor (where fibrin is binding)
How/When are GPIIb/IIIa Receptor Inhibitors administered?
- How
- IV
- When:
- during angioplasty (with aspirin and heparin)
- for acute coronary syndromes
What are the adverse side effects of GPIIb/IIIa Receptor Inhibitors?
- Bleeding
- Thrombocytopenia
- with chronic use
What is the MOA of Dipyridamole?
- Increases cAMP and Inhibits platelet activation
- phosphodiesterase 3 inhibitor
- increases cAMP by preventing its breakdown to 5’AMP by phosphodiesterase
- inhibits platelet uptake of adenosine and thus increases adenosine interaction with Adenosine A2 receptor → increases cAMP
- phosphodiesterase 3 inhibitor
- Also a vasodilator
When is Dipyridamole used?
- In combination with aspirin or warfarin
- unclear if the combination of dipyridamole and aspirin is more beneficial than aspirin alone
- Little or no beneficial effect by itself
What is the adverse side effect of Dipyridamole?
headache
What is the MOA of Indirect Thrombin Inhibitors?
- Bind to antithrombin to have their effect
- increase activity of antithrombin
- antithrombin normally inactivates both thrombin and Factor Xa → prevent secondary hemostasis/fibrin mesh clot formation
What are the three Indirect Thrombin Inhibitor drugs that we need to know?
- Unfactionated Heparin
- UFH = high molecular weight (HMW) heparin
- obtained from porcine (pig) intestine
- Low Molecular Weight (LMW) Heparin
- Fondaparinux
- a pentasacharide
What is the relationship between the size of Heparin and its activity?
Heparin’s activity against thrombin is
size dependent.
What are the differences in the activity between the three Indirect Thrombin Inhibitors?
- Heparin (HMW/UFH)
- targets Xa and thrombin (IIa)
- 30% bioavailability (less predictable, only short term use)
- short half-life, not renally excreted
- complete antidote effect
- cause <5% thrombocytopenia
- LMW Heparin
- targets Xa and thrombin (IIa)
- 90% bioavailability (more preditable for long term use)
- moderate half-life, renally excreted
- partial antidote effect
- cause <1% thrombocytopenia
- Fondaparinux
- targets Xa only
- 100% bioavailability (very predictable)
- long half-life, renally excreted
- no antidote effect (can’t reverse it)
- cause <1% thrombocytopenia
How closely should patient’s on Heparin be monitored?
- UFH/HMW Heparin
- requires close monitoring of activated partial thromboplastin time (PTT)
- LMW Heparin
- more predictable pharmacokinetics
- no monitoring req’d in most patients
- fewer non-hemorrhagic side effects
What does PTT (aPTT) test?
- clotting time
- specifically intrinsic pathway
- Normal PTT times require the presence of coag factors:
- I
- II
- V
- VIII
- IX
- X
- XI
- XII
What does the PT/derived INR test?
- clotting time
- specifically extrinsic pathway
- measures factors:
- I (fibrinogen)
- II (prothrombin)
- V
- VII
- X
What are the adverse side effects of Indirect Thrombin Inhibitors?
- Bleeding
- Heparin-induced thrombocytopenia
- thrombotic complications may precede the drop in platelets
- 2x as likely in women than men
- probably due to development of IgG antibodies against complexes of heparin with platelet factor 4
What is the antedote for Heparin?
- Protamine
- highly basic (+) charged peptide
- combines with (-) charged Heparin
- forms stable complex that lacks anticoagulant activity
- ONLY binds long heparin molecuse
- incompletely reverse activity of LMW heparin
- will not reverse the activity or fondaparinux
What is the MOA of Direct Thrombin Inhibitors?
- Bind to and directly inhibit thrombin enzyme
- derivative of leech salivery gland hirudin
What are the three Direct Thrombin Inhibitor drugs that we need to know?
- Bivalirudin (IV)
- Argatroban (IV)
- Diabigatran etexilate
- oral, new
What is the MOA of Warfarin?
- Blocks synthesis of Vitamin K dependent clotting factors
- inhibits synthesis of oxidized Vitamin K epoxide into its reduced form (vitamin K hydroquinone)
- via stopping vitamin K dependent epoxide reductase
- consequently inhibits vitamin K-dependent gamma-carboxylation of factors:
- II
- VII
- IX
- X
- Protein C & S (inhibitors)
- inhibits synthesis of oxidized Vitamin K epoxide into its reduced form (vitamin K hydroquinone)
Why does Warfarin require close monitoring?
- Tricky drug - NARROW THERAPEUTIC INDEX
- Tons of drug interactions
- slow to act because it affects the synthesis of proteins
How is Warfarin activity monitored?
- clotting times
- PT and derived INR
- extrinsic pathway specifically
- measures factors:
- I (fibrinogen)
- II (prothrombin)
- V
- VII
- X
- PT and derived INR
What are the adverse effects of Warfarin?
- BLEEDING
- flatulence and diarrhea
- cutaneous necrosis
- chondrodysplasia punctata
What Warfarin enantiomer is more active?
- S is the more active enantiomer
How is Warfarin metabolized?
- S-warfarin
- CYP2C9
- if you give drug that alters this it will affect the activity/dose of warfarin
- CYP2C9
- R-warfarin
- CPYs 1A1, 1A2, 3A4
Why does Warfarin dosing vary so widely?
- Polymorphisms in the C1 subunit of vitamin K reductase (VKORC1)
- can affect the susceptibility of the enzyme to warfarin-induced inhibition
- affects warfarin pharmacodynamics
- Common genetic polymorphisms in CYP2C9 can influence metabolism
- 30% of pop’n = slow metabolizers
- affects warfarin pharmacokinetics
- Overall these cause 20-70% change in dosage in different people.
What are the pharmacokinetic drug interactions of Warfarin due to?
- Absorption, distribution, metabolism, elimination (ADME)
- For oral anticoagulants, pharmacokinetic drug interactions are primarily due to:
- enzyme induction
- enzyme inhibition
- reduced plasma protein binding
What are the pharmacodynamic drug interactions of Warfarin due to?
- Biochemical and physiological effects of drugs and their MOA
- For oral anticoagulants pharmacodynamic drug interactions are primarily due to:
- reduced clotting factor synthesis
- competitive antagonism with Vitamin K
- hereditary resistance to oral anticoag
How can bleeding be stopped in the context of too much Warfarin?
- Stop the drug immediately
- Add Vitamin K
- Phytonadione (vitamin K1)
- Prothrombin complex concentrates
- Recombinant factor VIIa
What are the other type of oral anticoagulants besides Warfarin?
- Direct Factor Xa Inhibitors
- Rivaroxaban
- Apixaban
- Edoxaban
What is the MOA of Direct Factor Xa Inhibitors?
- Inhibit Factor Xa directly
What is the benefit/disadvantage of Direct Factor Xa Inhibitors compared to Warfarin?
- Benefit:
- Rapid onset of action
- Shorter half life
- Doesn’t require monitoring
- Disadvantages:
- No antidote
- New drugs so their place in treatment and as a replacement for warfarin is TBD