Drugs for Thromboembolic Disorders (Wolff) Flashcards
1
Q
White (platelet-rich) thrombi form in arteries under what type of pressure?
A
High-pressure arteries
2
Q
What are 2 pathologic conditions of coronoary arteries associated w/ white thrombi?
A
- MI
- Unstable angina
3
Q
Red (fibrin-rich) thrombi form in vessels under what type of pressure and in which location?
A
Low-pressure veins and in the heart
4
Q
Anticoagulants are primarily used to prevent clots form forming where?
Which specific type of thrombi?
A
- Venous system and heart
- Red (fibrin) thrombi
5
Q
Antiplatelet drugs are primarily used to preven clots from forming in which vessels?
What specific type of thrombi?
A
- Arteries
- White thrombi
6
Q
What are the 3 classes and drugs in each of parenteral anticoagulants which act as indirect thrombin and factor Xa (FXa) inhibitors?
A
- Unfractionated (HMW) heparin = Heparin sodium
- LMW heparins = Enoxaparin, Tinzaparin, and Dalteparin
- Synthetic pentasaccharide = Fondaparinux
7
Q
Which 3 drugs belong to the direct thrombin inhibitor class and are used as parenteral anticoagulants?
A
- Lepirudin
- Argatroban
- Bivalirudin
8
Q
The indirect thrombin and factor Xa (FXa) inhibitors bind to what in the plasma?
A
Serine protease inhibitor antithrombin III
9
Q
Unfractionated (HMW) heparin inhibits the activity of?
A
Thrombin and factor Xa
10
Q
LMW heparins inhibit what?
A
Factor Xa w/ little effect on thrombin
11
Q
Which 2 drugs in the parenteral direct thrombin inhibitor class are bivalent and bind at both the active site and substrate recognition site of thrombin?
A
- Lepirudin
- Bivalirudin
12
Q
Which parenteral class of heparin has increased bioavailability from the SC injection site and allows for less frequent injections and more predictable dosing?
A
LMW Heparin (-aparin’s)
13
Q
Heparins are used during surgery or in hospitalized patients to reduce the risk of what?
A
Reduces risk of emboli
14
Q
Heparin is administered to patients with what disorders?
A
- DVT
- Atrial arrhythmias
15
Q
Why must heparins be given via IV or SC routes?
A
Very hydrophilic
16
Q
What are 2 AE’s associated with Heparin?
A
- Bleeding
- Heparin-induced thrombocytopenia (HIT)
17
Q
What are heparin locks used for?
A
Prevents clots from forming in catheters
18
Q
What 2 lab studies are used to monitor patients on Heparin?
A
- Activated partial thromboplastin time (aPTT)
- Anti-Xa assay
19
Q
Heprain-induced thrombocytopenia (HIT) is due to what underlying mechanism?
A
Immunogenicitiy of the complex of heparin with platelet factor 4 (PF4)
20
Q
What 2 things should you be looking for in a patient on Heparin?
A
- Thrombocytopenia
- Thrombosis
21
Q
Treatment for hepain-induced thrombocytopenia?
A
Discontinue heparin and administer DTI
22
Q
What are 4 contraindications for using Heparin?
A
- Severe HTN
- Active TB
- Ulcers of GI tract
- Patients w/ recent surgeries
23
Q
What is used clinically for reversal (antidote) of heparin action?
A
Protamine sulfate
24
Q
The synthetic pentasaccharide, Fondaparinux, used as an anticoagulant binds to and inhibits what?
A
Acts as antithrombin III catalyst –> indirectly inhibit factor Xa (NO effect on thrombin)
25
In what 3 ways does the anticoagulant, Fondaparinux, differ from heparins?
- Does **not** inhibit thrombin acitivity
- **Rarely** induces HIT (thrombocytopenia)
- Action is **not** reversed by Protamine sulfate
26
What are 3 clinical indications for the use of Fondaparinux?
- **Prevention** of DVT's
- Tx of **acute** DVT (in conjunction w/ Warfarin)
- Tx of **pulmonary embolism**
27
Which **parenteral** direct thrombin inhibitor binds **only** at the thrombin active site?
Argatroban
28
Which parenteral direct thrombin inhibitor is an **irreversible** inhibitor of thrombin?
Lepirudin
29
Which parenteral direct thrombin inhibitor is a **reversible** inhibitor of thombin and also **inhibits** platelet aggregation?
**Bi**valirudin
## Footnote
\*Think **Bi** = **2 mechanisms!**
30
Which parenteral direct thrombin inhibitor is short acting and used IV?
Argatroban
31
What are the clinical indications for the parenteral direct thrombin inhibitors?
What are bivalirudin and argatroban used for specifically?
- HIT
- Coronary angioplasty (bivalirudin and argatroban)
32
Repeated lepirduin use may cause what?
Anaphylactic rxn
33
Bleeding is an adverse effect of parenteral direct thrombin inhibitors and why may this potentially be a big deal?
No antidote exists
34
What is the MOA of Warfarin?
- **Inhibits** reactivation of **vitamin K**, by inhibiting **vit K epoxide reductase**
- **Inhibits** **carboxylation** of glutamate residues by **GGCX** in prothrombin and factors VII, IX, and X
35
List 4 causes of high variability in therapeutic warfarin concentrations between individuals?
- Genetic make-up
- Disease states
- Drug-Drug interactions
- Diet
36
Warfarin has a **narrow** therapeutic window therefore the dose is titrated based on what lab testing?
At what range should patients be at?
- Prothrombin time **(PT/INR)**
- **2.0-3.0** range for pt's on Warfarin
- **INR is monitored** a patients visit the clinic regularly
37
Which stereoisomer of Warfari in 3-5x more potent?
S-isomer
38
Which steroisomer of Warfarin is metabolized primarily by CYP2C9?
S-isomer
39
What is the bioavailability of Warfarin when administered orally?
Onset and half-life?
- 100% bioavailability
- **Delayed** onset of action (12 hours)
- **Long** half-life (**36 hrs**)
40
99% of Warfarin is bound to what in the plasma?
Plasma **albumin**
41
What are 3 clincial uses for Warfarin?
- **Prevent thrombosis** or **prevent/treat** thromboembolism
- Atrial fibrillation
- Prosthetic heart valves
42
What are the major AE's associated with Warfarin?
- **Teratogenic effect** (bleeding disorder in fetus, abnormal bone formation)
- **Skin necrosis**, infarction of breasts, intestines, extremities
- **Osteoporosis**
- **Bleeding**
43
Individual variability in the action of Warfarin may be to genetic factors including a high dose and low dose haplotype of what?
VKORC1
44
The high dose haplotype of VKORC1 for warfarin is more common in which ethnic group?
African Americans = more resistant to warfarin
45
The low dose haplotype of VKORC1 for warfarin is more common in which ethnic group?
Asian Americans = less resistant to warfarin
46
Which CYP is responsible for the individual variations in warfarin dose seen in some Caucasian pt's?
CYP2C9
47
What are 3 pharmacokinetic interactions of Warfarin?
- CYP enzyme **induction**
- CYP enzyme **inhibition**
- **Reduced** plasma protein binding
48
What are 3 pharmacodynamic interactions associated with Warfarin?
- **Synergism** with other antithrombotic drugs
- **Competitive** antagonism (**Vit K**)
- Clotting factor concentration (**diurectics**)
49
Which 2 disease states must be accounted for when treating with Warfarin due to possibility of **increased** prothrombin time?
- **Liver** diseases (reduced clotting factor synthesis)
- Thyroid status --\> **Hyper**thyroidism
50
What are 3 pharmacodynamic drug interactions of warfarin associated with **increased** prothrombin time?
- Aspirin (high doses)
- Cephalosporins, 3rd Gen.
- Heparin
51
What are 3 pharmacokinetic drug interactions of warfarin associated with decreased prothrombin time?
- Barbituates
- Cholestyramine
- Rifampin
52
What are 2 pharmacodynamic drug interactions of warfarin associated with **decreased** prothrombin time?
- Diuretics
- Vitamin K
53
List 4 advantages of using Warfarin.
- **Oral** administration
- **Long** duration of action
- **Drug clearance** is **independent** of renal function
- **Reversal** of action strategy has been developed
54
How can reversal of Warfarin action be accomplished?
What if rapid reversal needed?
- **Vit K** administration will reverse action in **12-24 hours**
- More **rapid** reversal give **fresh frozen plasma** or **prothrombin complex concentrate**
55
What are 3 drawbacks of using Warfarin?
- Very high dosing variability, hard to maintain optimal concentration
- May lead to **bleeding complications**, such as intracranial hemorrhages
- Requires INR monitoring
56
Direct **ORAL** anticoagulants consist of three **factor Xa inhibitors** and a **direct thrombin inhibitor**, what are the drugs in these classes?
- **Factor Xa inhibitors**: Rivaro**xaban**, Api**xaban**, and Edo**xaban**
- **Direct thrombin inhibitor**: Dabigatran
57
What are the 3 clinical uses of the **direct oral anticoagulants**, which are Factor Xa inhibitors (Rivaroxaban, Apixaban, Edoxaban)?
- Prevention of thromboembolism
- Treatment of thromboembolism
- Prevention of stroke in patients w/ atrial fibrillation
58
What are 4 clinical advantages of using direct oral anticoagulants, which are Factor Xa inhibitors (Rivaroxaban, Apixaban, Edoxaban)?
- Given orally
- Administered at **fixed doses** and do NOT require monitoring
- Show **non-inferiority** compared with Warfarin
- **Rapid** onset of action as compared to warfarin
59
What is one drawback of direct oral anticoagulants, which are Factor Xa inhibitors (Rivaroxaban, Apixaban, Edoxaban)?
**Excreted by kidneys**; dose adjustment is needed in renal pts
60
What are the 2 clinical uses of the **oral** direct thrombin inhibitor, Dabigatran?
- Reduce the risk of stroke and systemic embolism in patients w/ **non-valvular atrial fibrillation**
- Tx of venous thromboembolism
61
What is the approved antidote for the oral direct thrombin inhibitor, Dabigatran?
Idarucizumab
62
What is a disadvantage associated w/ the oral direct thrombin inhibitor, Dabigatran?
**80% renal excretion** - may not be suitable in renal pt's
63
What are some of the advantages of the oral direct thrombin inhibitor, Dabigatran?
- Predictable pharmacokinetics and bioavailability
- Fixed dosing and predictable anticoagulant action (no INR monitoring required)
- Rapid onset and offset of actions
- No interaction w/ P-450 metabolized drugs
64
What is the antidote for the DOAC - FXa inhibitors (rivaroxaban, apixaban, and edoxaban)?
Andexanet alfa
65
Which blood coagulation test is used for the direct oral anticoagulants, which are FXa inhibitors (rivaroxaban, apixaban, edoxaban)?
Anti-Xa
66
Which blood coagulation test is used for the oral direct thrombin inhibitor, Dabigatran?
Diluted thrombin time (TT)
67
Which antiplatelet drug is an inhibitor of thromboxane A2 synthesis?
Aspirin
68
What are the 4 ADP receptors blockers used as antiplatelet drugs?
- Clopidogrel
- Prasugrel
- Ticlopidine
- Ticagrelor
69
What are the 3 platelet glycoprotein receptor (GP IIb/IIIa) antagonists used as antiplatelet drugs?
- Abciximab
- Eptifibatide
- Tirofiban
70
What are the 2 inhibitors of phosphodiesterases used as antiplatelet drugs?
- Dipyridamole
- Cilostazol
71
What are the clinical uses of Aspirin as an antiplatelet?
- Primary and seconday prevention of a heart attack
- And other vascular events --\> ischemic stroke, arterial thrombosis of the limbs resulting in intermittent claudication
72
What are 2 AE's associated with Aspirin?
- Peptic Ulcer
- GI bleeding
73
What is the MOA of the antiplatelets which are blockers of ADP receptors?
- Inhibition of AC by αi is relieved
- Increased production of cAMP
74
What is the MOA of the antiplatelet drugs which are inhibitors of phosphodiesterase?
- Inhibition of cAMP degradation
- Levels of cAMP in platelets are increased
75
The high variability of action of the antiplatelet drug, Clopidogrel is related to metabolism by what?
CYP2C19
76
Nonfunctional CYP2C19 allele is present in which ethnicities and has an effect on the action of the antiplatelet drug, Clopidogrel?
- Chinese (50%)
- African Americans (25%)
- Caucasians and Mexican-Americans (19%)
77
Cilostazol (inhibitor of phosphodiesterase) is primarily used for what?
Treat intermittent claudication
78
Dipyridamole (PDE inhibitor) is used with aspirin to prevent what?
Cerebrovascular ischemia
79
Dipyridamole (PDE inhibitor) is used with warfarin in which patients?
Those w/ **prosthetic heart valves**
80
What is the MOA of the fibrinolytic (thrombolytic) drugs?
**Activate** endogenous **fibrinolytic system** by converting **plasminogen ---\> plasmin**
81
What are the 3 tissue-type plasminogen activator drugs which are fibrinolytic?
- Alt**eplase**
- Ret**eplase**
- Tenect**eplase**
82
What is the Urokinase-type plasminogen activator drug used as a fibrinolytic?
Urokinase
83
Which 3 classes of drugs are used as thrombolytic (fibrinolytic) drugs?
- Tissue-type plasminogen activator
- Urokinase-type plasmingoen activator
- Streptokinase preparations
84
What are 5 clinical uses for the thrombolytic (fibrinolytic) drugs?
- Acute embolic/thrombotic stroke (within 3 hrs)
- Acute MI (withing 3-6 hrs)
- Pulmonary embolism
- DVT
- Ascending thrombophlebitis
85
What is an AE associated with the fibrinolytic drugs, streptokinase and urokinase?
**Bleeding** from the **systemic fibrinogenolysis**
86
Allergic reactions are an AE associated with what fibrinolytic drug?
Streptokinase
87
Which fibrinolytic drugs need fibrin as coactivator?
tPA
