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IHO Week 6 - WLB > Thrombolytics, Anticoagulants, & Antiplatelet Drugs - Regal > Flashcards

Thrombolytics, Anticoagulants, & Antiplatelet Drugs - Regal Flashcards

1
Q

What is the principal complication of anticoagulant therapy?

A

BLEEDING

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2
Q

When should we interfere with hemostasis?

A
  • 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
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3
Q

What are the therapeutic uses of antiplatelet therapy?

A
  • Venous thromboembolism
  • Unstable angina
  • Acute myocardial infarction
  • Stroke
  • Prevent thrombosis during angioplasty and cardiopulmonary bypass
  • Etc.
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4
Q

What is the general MOA of antiplatelet drugs?

A
  • prevent platelet activation
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5
Q

What is the MOA of Aspirin (Acetylsalicylate)?

A

Irreversible inhibitor of COX

  • Antipyretic
  • Analgesic
  • Anti-inflammatory
  • Anti-Thromboxane A2
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6
Q

Do platelets have COX-2?

A

No

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7
Q

Can platelets make more COX?

A

NO

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8
Q

Why don’t the other NSAIDs work well as anti-platelet agents?

A

They are REVERSIBLE!

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9
Q

What are the adverse effects of Aspirin?

A
  • Bleeding
  • GI disturbances
  • Tinnitus
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10
Q

What is the difference between low dose and high dose Aspirin treatment?

A
  • Low dose
    • antiplatelet
  • High dose
    • antiplatelet
    • anti-inflammatory
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11
Q

What is the MOA of ADP Receptor Antagonists?

A
  • Irriversible ADP receptor antagonists
    • prevent activaiton of ADP receptor
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12
Q

What are the three ADP Receptor Antagoinst drugs that we need to know?

A
  1. Clopidogrel
  2. Prasugrel
  3. Ticlopidine
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13
Q

When are ADP Receptor Antagonists used?

A
  • During stenting
  • Recommended for patients that don’t tolerate Aspirin
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14
Q

What are the adverse side effects of ADP Receptor Antagonists?

A
  • 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
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15
Q

How are ADP Receptor Antagonists administered?

A

Orally

(with duration of days)

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16
Q

What is unique about Ticlopidine compared to the other ADP Receptor Antagonists?

A

has more side effects

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17
Q

What is unique about Clopidogrel compared to the other ADP Receptor Antagonists?

A
  • may require activation via CYP2C19
    • drugs that impair this isoform should be used with caution (e.g. omeprazole)
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18
Q

What is the reversibility of the effects of ADP Receptor Antagonists?

A
  • ALL are Irreversible
  • Effect lasts the life of the platelet (8-9 days)
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19
Q

What is the MOA of GPIIb/IIIa Receptor Inhibitors?

A
  • Prevent binding of adhesive glycoproteins such as fibrinogen and vWF to become activated platelets
  • Inhibits the final common pathway for platelet aggregation
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20
Q

What are the three GPIIb/IIIa Receptor Inhibitor drugs that we need to know?

A
  • Abciximab
    • humanized MAB against GPIIb/IIIa
  • Eptifibatide
    • fibrinogen analogue
  • Tirofiban
    • non-peptide competitive inhibitor (where fibrin is binding)
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21
Q

How/When are GPIIb/IIIa Receptor Inhibitors administered?

A
  • How
    • IV
  • When:
    • during angioplasty (with aspirin and heparin)
    • for acute coronary syndromes
22
Q

What are the adverse side effects of GPIIb/IIIa Receptor Inhibitors?

A
  • Bleeding
  • Thrombocytopenia
    • with chronic use
23
Q

What is the MOA of Dipyridamole?

A
  • 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
  • Also a vasodilator
24
Q

When is Dipyridamole used?

A
  • 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
25
Q

What is the adverse side effect of Dipyridamole?

A

headache

26
Q

What is the MOA of Indirect Thrombin Inhibitors?

A
  • 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
27
Q

What are the three Indirect Thrombin Inhibitor drugs that we need to know?

A
  • Unfactionated Heparin
    • UFH = high molecular weight (HMW) heparin
    • obtained from porcine (pig) intestine
  • Low Molecular Weight (LMW) Heparin
  • Fondaparinux
    • a pentasacharide
28
Q

What is the relationship between the size of Heparin and its activity?

A

Heparin’s activity against thrombin is

size dependent.

29
Q

What are the differences in the activity between the three Indirect Thrombin Inhibitors?

A
  • 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
30
Q

How closely should patient’s on Heparin be monitored?

A
  • 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
31
Q

What does PTT (aPTT) test?

A
  • clotting time
    • specifically intrinsic pathway
  • Normal PTT times require the presence of coag factors:
    • I
    • II
    • V
    • VIII
    • IX
    • X
    • XI
    • XII
32
Q

What does the PT/derived INR test?

A
  • clotting time
    • specifically extrinsic pathway
    • measures factors:
      • I (fibrinogen)
      • II (prothrombin)
      • V
      • VII
      • X
33
Q

What are the adverse side effects of Indirect Thrombin Inhibitors?

A
  • 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
34
Q

What is the antedote for Heparin?

A
  • 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
35
Q

What is the MOA of Direct Thrombin Inhibitors?

A
  • Bind to and directly inhibit thrombin enzyme
    • derivative of leech salivery gland hirudin
36
Q

What are the three Direct Thrombin Inhibitor drugs that we need to know?

A
  • Bivalirudin (IV)
  • Argatroban (IV)
  • Diabigatran etexilate
    • oral, new
37
Q

What is the MOA of Warfarin?

A
  • 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)
38
Q

Why does Warfarin require close monitoring?

A
  • Tricky drug - NARROW THERAPEUTIC INDEX
  • Tons of drug interactions
  • slow to act because it affects the synthesis of proteins
39
Q

How is Warfarin activity monitored?

A
  • clotting times
    • PT and derived INR
      • extrinsic pathway specifically
      • measures factors:
        • I (fibrinogen)
        • II (prothrombin)
        • V
        • VII
        • X
40
Q

What are the adverse effects of Warfarin?

A
  • BLEEDING
  • flatulence and diarrhea
  • cutaneous necrosis
  • chondrodysplasia punctata
41
Q

What Warfarin enantiomer is more active?

A
  • S is the more active enantiomer
42
Q

How is Warfarin metabolized?

A
  • S-warfarin
    • CYP2C9
      • if you give drug that alters this it will affect the activity/dose of warfarin
  • R-warfarin
    • CPYs 1A1, 1A2, 3A4
43
Q

Why does Warfarin dosing vary so widely?

A
  • 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.
44
Q

What are the pharmacokinetic drug interactions of Warfarin due to?

A
  • Absorption, distribution, metabolism, elimination (ADME)
  • For oral anticoagulants, pharmacokinetic drug interactions are primarily due to:
    • enzyme induction
    • enzyme inhibition
    • reduced plasma protein binding
45
Q

What are the pharmacodynamic drug interactions of Warfarin due to?

A
  • 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
46
Q

How can bleeding be stopped in the context of too much Warfarin?

A
  • Stop the drug immediately
  • Add Vitamin K
    • Phytonadione (vitamin K1)
    • Prothrombin complex concentrates
    • Recombinant factor VIIa
47
Q

What are the other type of oral anticoagulants besides Warfarin?

A
  • Direct Factor Xa Inhibitors
    • Rivaroxaban
    • Apixaban
    • Edoxaban
48
Q

What is the MOA of Direct Factor Xa Inhibitors?

A
  • Inhibit Factor Xa directly
49
Q

What is the benefit/disadvantage of Direct Factor Xa Inhibitors compared to Warfarin?

A
  • 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
50
Q
A

IHO Week 6 - WLB (8 decks)

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