Thrombolytics, Anticoagulants, & Antiplatelet Drugs - Regal Flashcards
1
Q
What is the principal complication of anticoagulant therapy?
A
BLEEDING
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
- Venous thrombosis
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.
4
Q
What is the general MOA of antiplatelet drugs?
A
- prevent platelet activation
5
Q
What is the MOA of Aspirin (Acetylsalicylate)?
A
Irreversible inhibitor of COX
- Antipyretic
- Analgesic
- Anti-inflammatory
- Anti-Thromboxane A2
6
Q
Do platelets have COX-2?
A
No
7
Q
Can platelets make more COX?
A
NO
8
Q
Why don’t the other NSAIDs work well as anti-platelet agents?
A
They are REVERSIBLE!
9
Q
What are the adverse effects of Aspirin?
A
- Bleeding
- GI disturbances
- Tinnitus
10
Q
What is the difference between low dose and high dose Aspirin treatment?
A
- Low dose
- antiplatelet
- High dose
- antiplatelet
- anti-inflammatory
11
Q
What is the MOA of ADP Receptor Antagonists?
A
- Irriversible ADP receptor antagonists
- prevent activaiton of ADP receptor
12
Q
What are the three ADP Receptor Antagoinst drugs that we need to know?
A
- Clopidogrel
- Prasugrel
- Ticlopidine
13
Q
When are ADP Receptor Antagonists used?
A
- During stenting
- Recommended for patients that don’t tolerate Aspirin
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
15
Q
How are ADP Receptor Antagonists administered?
A
Orally
(with duration of days)
16
Q
What is unique about Ticlopidine compared to the other ADP Receptor Antagonists?
A
has more side effects
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)
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)
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
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)
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
- phosphodiesterase 3 inhibitor
- 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
What is the adverse side effect of Dipyridamole?
headache
26
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
27
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
28
What is the relationship between the size of Heparin and its activity?
Heparin's activity against thrombin is
**size dependent**.
29
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
30
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
31
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
32
What does the PT/derived INR test?
* clotting time
* specifically extrinsic pathway
* measures factors:
* I (fibrinogen)
* II (prothrombin)
* V
* VII
* X
33
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
34
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
35
What is the MOA of Direct Thrombin Inhibitors?
* Bind to and directly inhibit thrombin enzyme
* derivative of leech salivery gland hirudin
36
What are the three Direct Thrombin Inhibitor drugs that we need to know?
* Bivalirudin (IV)
* Argatroban (IV)
* Diabigatran etexilate
* oral, new
37
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)
38
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
39
How is Warfarin activity monitored?
* clotting times
* PT and derived INR
* extrinsic pathway specifically
* measures factors:
* I (fibrinogen)
* II (prothrombin)
* V
* VII
* X
40
What are the adverse effects of Warfarin?
* BLEEDING
* flatulence and diarrhea
* cutaneous necrosis
* chondrodysplasia punctata
41
What Warfarin enantiomer is more active?
* S is the more active enantiomer
42
How is Warfarin metabolized?
* 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
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.
44
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
45
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
46
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
47
What are the other type of oral anticoagulants besides Warfarin?
* Direct Factor Xa Inhibitors
* Rivaro**xaban**
* Api**xaban**
* Edo**xaban**
48
What is the MOA of Direct Factor Xa Inhibitors?
* Inhibit Factor Xa directly
49
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
50
