Anti-Thrombotics Flashcards
(116 cards)
1
Q
Importance of the GP IIb/IIIa conformation change
A
Allows receptors to bind to fibrinogen for aggregations
2
Q
Biggest side effect of anti-thrombotics
A
Bleeding
3
Q
Mechanism of ASA
A
- COX inhibitor
- Dec TxA2
- Dec platelet activation
4
Q
Therapeutic uses of ASA
A
- Atherothrombosis (primary and secondary prevention of ACS/CAD)
- Venous thromboembolism
- Colorectal cancer
5
Q
Primary prevention
A
At risk
6
Q
Secondary prevention
A
past medical history
7
Q
Onset of ASA
A
- Platelet inhibition <1 hour (<20 minutes if chewed)
- Delayed with enteric-coated tablets: 3-4 hours
8
Q
Duration of ASA
A
- Platelet inhibitory effect lasts entire platelet lifespan
- Rapid absorption in stomach and upper intestine
9
Q
Metabolism of ASA
A
- High first pass
- Hydrolyzed to salicylic acid (inactive) by carboxylesterase-2 in GI mucosa, liver, synovial fluid, blood
- half life of parent drug is 15 minutes; acetyl salicylate 3 hours
10
Q
How is oral ASA effective if it has high first pass metabolism?
A
ASA comes into contact with 100% of blood supply in short period of time in portal system
11
Q
How does ASA interact with NSAIDs?
A
- NSAID is competitive w/ASA, prevents it from binding
- Give ASA first and wait about 2 hours to give ibuprofen
12
Q
Inhibition of ___ of the capacity of the platelets to generate TxA2 is necessary to inhibit platelet function
A
> 95-98%
13
Q
Contraindication to ASA
A
- TRUE hypersensitivity
- Active bleeding
- Severe bleeding risk
14
Q
Side effects of ASA
A
- GI (dyspepsia, erosive gastritis, peptic ulcers)
- Prostaglandin depletion causing topical injury to mucosa
- Increases risk of hemorrhagic stroke in men by a factor of 1.7
15
Q
P2Y12 ADP inhibitor drugs
A
- Clopidogrel (Plavix)
- Prasugrel
- Ticagrelor
- Cangrelor
16
Q
Mechanism of P2Y12 inhibitors
A
Inhibits P2Y12 receptor from releasing granules, which prevents activation of GPIIb/IIIa and inhibits platelet aggregation
17
Q
Pharmacologic class of clopidogrel
A
Thienopyridine
18
Q
Is plavix reversible or irreversible?
A
Irreversible receptor blockade
19
Q
Administration of clopidogrel
A
Oral
20
Q
Frequency of clopidogrel dose
A
Once a day, but requires loading dose
21
Q
Is clopidogrel a prodrug?
A
Yes
22
Q
Onset of action of Plavix
A
2-8 hours, max effect 15-24 hours
23
Q
Offset of action of Plavix
A
7-10 days
24
Q
CYP drug interactions of plavix
A
CYP2C19
25
Why is Ticlopidine never used?
Causes diarrhea, rashes, neutropenia, thrombotic thrombocytopenic purpura
26
What percentage of clopidogrel is an inactive metabolite?
85%
27
Would a drug that inhibits CYP2C19 amplify or reduce clopidogrel antiplatelet effect?
Reduce
28
True/false: poor metabolizers of clopidogrel means clopidogrel as a preventative therapy is reduced
True
29
Clopidogrel clinical uses
- ACS +/- PCI (percutaneous coronary intervention)
- Dual antiplatelet therapy
- CAD, CVD and/or PAD comparable to ASA in secondary prevention of atherothrombotic disease
30
Onset of action of Prasugrel
30 min-4hrs
31
CYP drug interaction of prasugrel
None
32
Faster onset of action and more potent platelet inhibition than clopidogrel
Prasugrel and Ticagrelor
33
Contraindications to Prasugrel
- Patients <60 kg (half dose recommended)
- hx stroke/TIA
- pts >75 y/o (unless high-risk ischemic features such as DM)
- Pts who do NOT undergo revascularization/PCI (due to inc in CABG related bleeding)
34
Pharmacologic class of Ticagrelor
CPTP
35
Receptor blockade of Ticagrelor
Reversible receptor blockade
36
Frequency of Ticagrelor
BID
37
Is Ticagrelor a prodrug?
No, it's active right away
38
Onset of action of Ticagrelor
30 min-4 hrs
39
Offset of action of Ticagrelor
3-5 days
40
CYP drug interaction of Ticagrelor
CYP3A
41
Difference between Ticagrelor active metabolite and others
Ticagreor AM has a longer half life, but is otherwise the same
42
Why does Ticagrelor cause a sensation of dyspnea
- P2Y12 inhibitors increases neuronal signaling, increasing conductivity of pulmonary vagal C-fibers
- Because Ticagrelor is BID, the second dose binds to the newly created receptors
43
Pharmacologic class of cangrelor
ATP analogue
44
Receptor blockade of Cangrelor
Reversible
45
Administration route of Cangrelor
IV
46
Frequency of Cangrelor
Bolus plus infusion
47
Is Cangrelor a prodrug?
No
48
Onset of action of cangrelor
2 min
49
Offset of action of cangrelor
30-60 min
50
CYP drug interaction of Cangrelor
None
51
Indications for cangrelor
P2Y12 receptor inhibitor-naive patients undergoing PCI
52
True/false cangrelor has higher bleeding rates than clopidogrel
True
53
Causes dyspnea sensation
Ticagrelor and Cangrelor
54
Mechanism of Cilostazol
- Phosphodiesterase 3 inhibitor (inc cAMP levels, reduces Ca++, inhibits platelets
- Inhibits vascular smooth muscle cell proliferation
- Improves peripheral blood flow
55
Indications of cilostazol
- FDA: PAD (increases exercise tolerance)
- stroke/TIA
- Post-PCI
- PVD
56
Contraindications of cilostazol
Heart failure
57
Mechanism of vorapaxar
- Blocks the platelet thrombin receptor (PAR-1)
| - inhibits thormbin induced platelet aggregation
58
Indications for vorapaxar
-Post MI patients at risk for secondary atherothrombotic events (initiated in stable patients >2 weeks after an MI on antiplatelet therapy
59
Contraindications for vorapaxar
- first time in patients presenting with ACS
| - Hx stroke, TIA, ICH, active pathological bleeding
60
Use vorapaxar with caution in patients with:
- low body weight (<60kg)
- older age
- hx bleeding diathesis
61
Half life of vorapaxar
5-13 days
62
Vorapaxar is eliminated by
Metabolism by CYP3A
| -Avoid use with strong CYP3A4 inhibitors
63
GP IIb/IIIa inhibitor mechanism of action
-Prevents platelet aggregation
64
Administration of GP IIb/IIIa inhibitors
-IV or intra-coronary
65
Indications for GPIIb/IIIa inhibitors
PCI
66
Onset of action for GP IIb/IIIa inhibitors
Rapid
67
Potent platelet inhibition
GPIIb/IIIa inhibitors
68
GP IIb/IIIa inhibitor drugs
- Abciximab
- Eptifibatide
- Tirofiban
69
Contraindications of GP IIb/IIIa inhibitors
- Active or recent bleeding (4-6 weeks)
- Severe hypertension (?180-200/110)
- Any hemorrhagic CVA or CVA within 30 days-2 years
- Major surgery or trauma within 4-6 weeks
- Thrombocytopenia
- Bleeding diathesis/warfarin with elevated INR
70
Abciximab characteristics
- Fab fragment of humanized mouse monoclonal antibody
- Not specific for GP IIb/IIIa
- Plasma half life is short
- Platelet bound half life is long
- No renal clearance
71
Eptifibatide characteristics
- Cyclical KGD-containing heptapeptide
- Specific for GP IIb/IIIa
- Long plasma half life
- Short platelet bound half life
- Renal clearance
72
Tirofiban characteristics
- Nonpeptidic RGD-mimetic
- Specific for GPIIb/IIIa
- Long plasma half life
- Short platelet bound half life
- Renal clearance
73
Parenteral Anticoagulant drugs
- Unfractioned Heparin
- Low molecular weight heparins
- Synthetic pentasaccharides
- Direct thrombin inhibitors
74
Uses for parenteral anticoagulants
- treatment and prophylaxis of venous thrombosis and pulmonary embolism
- initial management of ACS
75
Mechanism of parenteral anticoagulants
- Induce a conformational change in antithrombin that accelerates its interaction with clotting factors
- To inhibit thrombin, heparin must bind to both the coagulation enzyme and AT
- only heparin chains >18 saccharide units are of sufficient length to bind thrombin
- Small heparin fragments catalyze inhibition of factor Xa by antithrombin
76
Heparin administration
IV or subcutaneous
77
Heparin mechanism of action
- Heparin interacts with antithrombin to change its conformation and enhance its ability to
inactivate clotting factor proteases, especially thrombin (IIa), IXa and Xa
78
Heparin metabolism
Cleared and degraded by the reticuloendothelial system (dose-dependent clearance)
79
Heparin reversal
Protamine sulfate
80
Protamine sulfate mechanism of action
Acts as heparin antagonist by complexing with the strongly acidic heparin to form a stable complex devoid of anticoagulation action
81
Onset of protamine sulfate
5 minutes
82
Dosing of protamine sulfate
1mg for 100 units of heparin to neutralize, but no faster than 50mg/10min
83
Triggered by antibodies directed against neoantigens of PF4
| Binding activates platelets and generates prothromotic platelet microparticles, promoting thrombin generation
Heparin-Induced Thrombocytopenia
84
Low molecular weight heparin characteristics
- mean MW 4500-5000 d
- <18 saccharide units are unable to bind simultaneously to ATIII and IIa and are unable to accelerate thrombin inactivation by ATIII
- LMWH catalyzes inhibition of Xa by ATIII
- Anti-Xa: IIa ratio of 2-4:1
85
LMWH drugs
- Enoxaparin (Lovenox)
- dalteparin (fragmin)
- tinzaparin (innohep)
86
Pharmacokinetics of LMWH
- subcutaneous with 91% bioavailability
- Less binding to endothelial cells, macrophages, heparin-binding plasma proteins
- longer half life
- minimal need for monitoring
- cleared renally
- lower risk HIT
- partially reversed by protamine
87
LMWH uses
- DVT prophylaxis
- Surgery, abdominal, hip/knee replacement
- Medical patients with severe mobility restrictions
- Acute DVT or PE
- ACS
88
LMWH boxed warning
Epidural or spinal hematomas may occur
89
Synthetic pentasaccharide drug
Fondaparinux (arixtra)
90
Pharmacokinetics of fondaparinux
- SubQ bioavailability is 100%
- Half life 17-21 hours (dose Q24hr)
- major bleeding in 2-3%
- thrombocytopenia in 2.9%
- No HIT risk
- do not use if CrCl 30ml/min
- black box warning for spinal or epidural hematomas
91
Agratroban characteristics
- Treatment for HIT
- Metabolized by hepatic CYPs & excreted in bile
- Continuous IV infusion
- Plasma half life 45 min
- Monitoring goal: aPTT 1.5-3x baseline
- Prolongs INR
92
Direct thrombin inhibitor drugs
- Agratroban
| - Bivalirudin
93
Bivalirudin characteristics
- Bivalent
- IV infusion as alternative to heparin in pts undergoing PCI
- plasma half life of 25 minutes
- degraded by peptidases & partially excreted by kidneys
94
Oral anticoagulants
- Warfarin
- Direct thrombin inhibitor (dabigatran)
- Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)
95
Oral anticoagulants
- Warfarin
- Direct thrombin inhibitor (dabigatran)
- Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)
96
Common clinical uses for oral anticoagulants
- Treatment and prophylaxis of venous thromboembolism and pulmonary embolism
- Prevention of stroke and venous thromboembolism in patients with afib
97
Warfarin mechanism
interferes with the synthesis of vitamin K dependent clotting factors (II, VII, IX, X)
98
Warfarin characteristics
- Anticoagulant effect is observed after elimination of normal preformed clotting factors 48-72 hours after administration
- Recovery requires the synthesis of new normal clotting factors
99
INR for patients on warfarin
- 2.0-3.0 is recommended to balance safety and efficacy for most patients
- You want to be in this range 66% of the time
100
Factors that correlate with warfarin dose
- Age
- Body surface area/weight
- amiodarone
- acetaminophen
- race
- sex
- plasma vitamin K level
- decompensated CHF
- chemotherapy
- genetic status
101
Adverse effects of warfarin
- bleeding
| - skin necrosis (3-10 days after initiation, widespread thrombosis, protein C depletion -leads to coagulation
102
Potential warfarin reversal
- Recombinant factor VIIa (immediate)
- PCC (immediate)
- fresh frozen plasma (immediate)
- IV vitamin K (8-12 hours)
- Oral vitamin K (24 hours)
103
Direct oral anticoagulant drugs
- Dabigatran
- Rivaroxaban
- Apixaban
- Edoxaban
104
Direct oral anticoagulant drug characteristics compared to warfarin
- Rapid onset
- Fixed dosing
- No food effect
- Few drug interactions
- No monitoring
- No antidote
105
Dabigatran characteristics
- Factor IIa target (thrombin)
- prodrug
- 3-7% bioavailability
- 1-3 hrs to cmax
- 12-17 hr half life
- 80% renal clearance
- 5-10% dyspepsia
106
Rivaroxaban characteristics
- Factor Xa target
- 66% bioavailability (100% w/food)
- 2-4hrs to cmax
- 5-13 hr half life
- 33% renal clearance
- CYP3A4 elimination
- absorbs w/food
107
Apixaban characteristics
- Factor Xa target
- 50% bioavailabiity
- 3-4 hours to cmax
- 9-14 hr half life
- 27% renal clearance
- Minor CYP3A4 elimination
108
Edoxaban characteristics
- Factor Xa target
- 62% bioavailability
- 1-2 hrs to cmax
- 10-14 hr half life
- 50% renal clearance
- minimal CYP3A4 metabolism
- absorbs w/food
109
Boxed warning for factor Xa inhibitors
- Place pts at increased risk of thrombotic events
| - inc risk of stroke with discontinuing meds w/nonvalvular afib
110
DOAC antidotes
- Idarucizumab (monoclonal antibody for dabigatran)
| - Andexanet alfa (inactivated factor Xa for factor Xa inhibitors)
111
Thrombolytic drugs
Streptokinase
112
Streptokinase mechanism of action
- bind to fibrin on the surface of the clot
- activates fibrin-bound plasminogen
- plasmin cleaved from plasminogen associated with the fibrin
- fibrin molecules are broken apart by the plasmin and the clot dissolves
113
Thrombolytics indications
- STEMI
- DVT
- PE
- acute ischemic stroke
- acute peripheral arterial occlusion
114
Thrombolytic adverse reactions
- ICH
| - Other serious bleeding <5%
115
Absolute contraindications to thrombolysis
- prior ICH
- known cerebral vascular leasion
- known malignant intracranial neoplasm
- ischemic stroke within 3 mos except acute ischemic stroke w/in 3 hours
- suspected aortic dissection
- active bleeding
- significant closed head or facial trauma within 3 mos
116
Relative contraindications to thrombolysis
- Hx chronic or severe poorly controlled HTN (and acute)
- Hx prior ischemic stroke >3 mos, dementia or known intracranial pathology
- Traumatic or prolonged (>10 min) CPR or major surgery (<3 wks)
- Recent (w/in24hrs) internal bleeding
- noncompressible vascular punctures
- pregnancy
- active peptic ulcer
- current use of anticoagulants
