PMT, Konorev - Drugs Used in Thromboembolic Disorders Flashcards

1
Q

What is a white thrombus, where do they form, and what pathologic conditions are associated with it?

Drug class used to prevent this.

A
  • A platelet-rich thrombus
  • Form in high-pressure arteries.
  • Associated with local ischemia due to arterial occulsion - MI/unstable angina in coronary a.) Little fibrin involvement.
  • ANTIPLATELET drugs to inhibit platelet function
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2
Q

What is a red thrombus, where do they form, and what pathologic conditions are associated with it?

Drug class used to prevent this.

A
  • A fibrin rich with trapped RBCs.
  • Form in low pressure veins.
  • Associated with embolic stroke - pain and severe swelling, embolism, distal pathology. Fibrin involvement.
  • ANTICOAGULANTS to regulate function and synthesis of clotting factors
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3
Q

What class is used to destroy clots?

A

THROMBOLYTICS - reestablish flow through vessel

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4
Q

MOA of indirect thrombin and FXa inhibitors (anticoag) (3)

A

Overall: Bind plasma serine protease inhibitor ANTITHROMBIN (III)

  • HMW Heparin - inhibits activity of thrombin and FXa.
  • LMW Heparin - inhibits FXa, little effect on thrombin.
  • Fondaparinux - inhibits FXa (indirectly), no effect on thrombin.
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5
Q

Admin route and indications/use of HMW v. LMW heparin.

A

Anticoagulants.
LMW requires less frequent injections from SC injection site.
Route: IV and SC
Use:
1) protects against pulm. emboli;
2) DVT, atrial arrhythmias&raquo_space;any condition that will PREDISPOSE TOWARDS RED THROMBI

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6
Q

What is a heparin lock?

A

Prevents clot formation in catheters.

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7
Q

What are two ways to monitor patients of heparin?

A
  1. Activated Partial Thromboplastin Time (aPTT) - normal range is 30-50sec; goal in heparin-patients is 50-75sec
  2. Anti-Xa assay - therapeutic range is 0.3-0.7units/mL
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8
Q

AE of heparin.

A
  • Bleeding

- Heparin Induced Thrombocytopenia (HIT)

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9
Q

Mechanism of HIT.

Tx for HIT

A

MOA: immunogenicity of the complex of heparin with platelet factor 4 (PF4).
Tx: discontinue hep and administer DTI

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10
Q

What are two things to look for in a patient on heparin?

A

1) Thrombocytopenia due to platelet removal by macrophages.

2) Thrombosis due to platelet activation and aggregation.

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11
Q

CI of Heparin.

A

Severe HTN, active TB, ulcers of GI, patients with recent surgery.

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12
Q

What do you use to reverse heparin action?

A

Protamine sulfate.

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13
Q

What is fondaparinux, its admin, and its MOA.

A

Synthetic pentasaccharide
SC admin
MOA - binds antithrombin to indirectly inhibit FXa by being and antithrombin III catalyst

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14
Q

How is fondaparinux different than heparins and what are its clinical indications?

A

Different bc - does not inhibit thrombin actiivty, rarely induces HIT, action NOT reversed by Protamine Sulfate.
Indications - DVT prevention, tx of acute DVT, tx of pulmonary embolism

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15
Q

Name the Parenteral anticoagulants:

1) Indirect thrombin and FXa-i: HMW, LMW, and synthetic pentasaccharide
2) Direct thrombin inhibitors

A

1)
- HMW: heparin sodium
- LMW: enoxaparin, tinzaparin, dalteparin
- Synthetic - fondaparinux
2) Lepirudin, bivalirudin, argatroban

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16
Q

MOA of Direct thrombin inhibitors

A

Directly inhibit protease activity of thrombin.
Lepirudin, bivalirudin - bind both active site and substrate recognition site.
Argatroban - bind only at thrombin active site.

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17
Q

Which Direct thrombin inhibitors are irr/reversible.

A

Lepirudin - irreversible thrombin inhibitor
Bivalirudin - reversible thrombin inhibitor (also inhibits platelet aggregation
Argatroban - IV, short acting

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18
Q

Indications and AE of Direct thrombin inhibitors.

A

Indications - HIT, coronary angioplasy (BIVALIRUDIN and ARGATROBAN).
AE - bleeding, anaphylactic reaction in repeated LEPIRUDIN use.

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19
Q

Name to oral anticoagulants

A

1) coumarin anticoags - Warfarin

2) Novel Oral AntiCoagulants - FXA-I (Rivaroxaban, Apixaban, Edoxaban); Direct thrombin inhibitor (Dabigatran)

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20
Q

MOA of Warfarin

Proteins affected

A

Inhibits vitK-epoxide reductase whic inhibits reactivaiton of vitK&raquo_space; inhibiting carboxylation of gamma-glutamyl-carboxylase.
Proteins affected - factor 2 (protrombin). factors 7/9/10 (hemostatic)

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21
Q

What is the normal function of carboxylation of glutamate residues - what is warfarin effective at preventing?

A

Converts hypofunctional hemostatic factors into functional ones.

22
Q

Warfarin - Pharmacokinetics, indications, AE

A

Kinetics - oral, long half life, dose varies in each person.
Indications - prevent thrombosis or tx thromboembolism afib, prosthetic heart valve
AE - TERATOGENIC (bleeding in fetus), skin necrosis/breasts, intestins, osteoperosis, bleeding

23
Q
Warfarin dose titration - INR
Normal?
High chance of thrombosis?
High chance of bleeding?
Range for patients on warfarin?
A
  1. 5 - high chance of thrombosis
  2. 9-1.3 - normal
  3. 0-5.0 - high chance of bleeding
  4. 0-3.0 - range for patients on warfarin.
24
Q

What is VKORC1? What race is high dose v. low dose haplotype more common in?
What is CYP2C9 responsible for?

A

VKORC1 - responsible for 30% of variation in dose: high dose haplotype = more warfarin resistant = African American; low dose haplotype = less warfarin resistant = Asian Americans
CYP2C9 - responsible for 10% of variation in dose, Caucasians

25
Q

What are the pharmacokinetic and pharmacodynamic interactions of Warfarin. What disease states are affected?

A

Pharmacokinetic - CYP enzyme indiction/inhibiton, reduced plasma protein binding.
Pharmacodynamic - synergism with other antithrombotic drugs, competitive antagonism (vitK reverses it), clotting factor concentration (diuretics).
Disease states - liver disease (reduced clotting factor synthesis) and thyroid status.

26
Q

What reverses warfarin?

A

Vit k

Fresh frozen plasma or prothrombin complex concentrate (more rapid than VitK).

27
Q

Clinical use for NOAC - FXa-I

A

Prevention of thromboembolism (Riva and Apix).
Tx thromboembolism.
Prevention of stroke in people with afib.

28
Q

NOAC - FXa-I Advantages v. Drawbacks

A

Advantage: Fixed dose, no monitoring. Rapid onset compared to Warfarin.
Drawbacks: no antidotes, excreted by kidneys»dose adjustment in renal patients.

29
Q

Clinical use of Dabigatran.

A

First oral NOAC approved by FDA.

Use - Reduce risk of stroke and systemic embolism in people wit non-valvular afib. Tx of venous thromboembolism.

30
Q

Dabigatran Advantages v. Drawbacks

A

Advantage - antidote (idarucizumab), rapid on/off, no P450 interaction, fixed dosing.
Drawback - 80% renal excretion - may not be suitable for renal patients!

31
Q

Name the antiplatelet drugs:

1) Inhibitors of TXA2 synthesis (1)
2) Inhibitors of phosphodiesterases (2)
3) Platelet glycoprotein receptor blockers - GP2b/3ai (3)
4) ADP Receptor Blockers (4) Which is less preferred?

A

1) Aspirin.
2) Dipyridamole, cilostazol.
3) Abciximab, eptifibatide, tirofiban.
4) Clopidogrel, prasugrel, ticlopidine, ticagrelor.

32
Q

Aspirin: MOA, clinical use, AE

A

MOA - inhibit COX&raquo_space; decrease TXA2 production
Use - prevention of heart attack
AE - peptic ulcer, GI bleeding

33
Q

Inhibitors of phosphodiesterases: MOA

A

Inhibit cAMP degradation, increasing the levels of cAMP in platelets, thereby affecting platelet aggregation.

34
Q

ADP Receptor Blockers: MOA

A

Relieve inhibition of Adenylyl Cyclase by alpha-i, resulting in increased cAMP production.

35
Q

Clopidogrel: metabolism, and alleles

A

Metabolized by CYP2C19 isoenzyme - cyto.p450 status does not affect use of other ADP receptor antagonists.
Nonfunctional CYP2C19 allele present in: 50% Chinese, 34% African American, 1/4 Caucasians, 19% Mexican Americans.

36
Q

Ticlopidine (ADP Receptor Blocker): Clinical Use and AE

A

Use - prevents arterial thrombosis in stroke patients.

AE - throbotic thrombocytopenic purpura, GI (NVD), bleeding, leukopenia.

37
Q

Clopidogrel, prasugrel, ticagrelor (ADP Receptor Blocker): Clinical Use and AE

A

Use - ALL prevent thrombosis in patients with ACS and recent AMI, stroke, and peripheral arterial disease; Prasugrel, Ticagrelor = pts undergoing stenting and PCI)
AE - ALL cause bleeding; Ticagrelor=dyspnea

38
Q

Dipyridamole (Inhibitors of phosphodiesterases): Clinical Use

A

Combine with aspirin to prevent cerebrovascular ischemia. Combine with warfarin to prevent thromboemboli in prosthetic heart valves.

39
Q

Cilostazol (Inhibitors of phosphodiesterases): Clinical Use

A

Treat intermittent claudication

40
Q

Platelet glycoprotein receptor blockers: MOA

A

Target Arg-Gly-Asp (RGD) sequence to prevent binding of ligands to CP IIb/IIIa receptro to inhibit platelet aggregation.

41
Q

What is Platelet GP IIb/IIIIa receptor for?

A

fibrinogen, vitronectin, fibronectin, vWF - common platelet aggregation pathway.

42
Q

What is each Platelet glycoprotein receptor blockers - GP2b/3ai?

A

Abciximab - anti-GP IIb/IIIa monoclonal antibody.

Tirofiban, eptifibatide - GP IIb/IIIa antagonist

43
Q

Platelet glycoprotein receptor blockers: Use

A

IV influsion dt short half life.

Prevents thrombosis in unstable angina and acute coronary syndromes, pts undergoing percutaneous coronary angioplasty.

44
Q

Platelet glycoprotein receptor blockers: AE

A

All = hypotension
Abciximab = myalgia
Abciximab and Thirfiban = thrombocytopenia (rare)

45
Q

Thrombolytic (fibrinolytic) drugs: MOA

A

Induce fibrinolysis - lyse fibrin (and fibronectin, laminin, thrombospondin, vWf) in thrombi.
Activate endogenous fibrinolytic system (after clot has formed).

46
Q

Types of fibrinolytic drugs and what they result in.

A

All: result in activation of plasminogen to form plasmin, which degrades fibrin.

1) Tissue-type plasminogen activator (tPA)
2) Urokinase-type plasminogen activator (urokinase, uPA)
3) Streptokinase

47
Q

Names of fibrinolytic drugs, where they’re produced, and their MOA.

A

1) tPA - produced in endothelium; cleaves plasminogen to form plasmin (Alteplase, Reteplase, Tenecteplase)
2) uPA - produced in kidneys; converts plasminogen to plasmic (Urokinase)
3) Streptokinase - released by beta-hemolytic streptococci; converts plasminogen by non-proteolytic mechanism (Streptokinase)

48
Q

Fibrinolytic drugs: Used for what and within what timeframe?

A

**Within 3 hours of acute embolic/thrombotic stroke.*
Within 3-6 hours of acute myocardial infarction.
Pulm embolism, DVT, ascending thrombophlebitis.

49
Q

What fibrinolytic drug is best used after a cerebral artery stroke?
What can this drug exacerbate?

A

tPA within 3 hours.

Can exacerbate damage produced by hemorrhagic stroke.

50
Q

Fibrinolytic drugs: AE

A

Streptokinase and urokinase - Bleeding from systemic fibrinogenolysis.
Stretokinase - allergic reactions.

51
Q

What fibrinolytic classes affect.

A

1) tPA - Fibrin-Specific Plasminogen Activator
2) uPA - Nonfibrin-Specific or Less Fibrin-Specifc Plasminogen Activators
3) Streptokinase - Nonfibrin-Specific or Less Fibrin-Specifc Plasminogen Activators