Flashcards in PMT, Konorev - Drugs Used in Thromboembolic Disorders Deck (51):
What is a white thrombus, where do they form, and what pathologic conditions are associated with it?
Drug class used to prevent this.
-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
What is a red thrombus, where do they form, and what pathologic conditions are associated with it?
Drug class used to prevent this.
-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
What class is used to destroy clots?
THROMBOLYTICS - reestablish flow through vessel
MOA of indirect thrombin and FXa inhibitors (anticoag) (3)
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.
Admin route and indications/use of HMW v. LMW heparin.
LMW requires less frequent injections from SC injection site.
Route: IV and SC
1) protects against pulm. emboli;
2) DVT, atrial arrhythmias >>any condition that will PREDISPOSE TOWARDS RED THROMBI
What is a heparin lock?
Prevents clot formation in catheters.
What are two ways to monitor patients of heparin?
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
AE of heparin.
-Heparin Induced Thrombocytopenia (HIT)
Mechanism of HIT.
Tx for HIT
MOA: immunogenicity of the complex of heparin with platelet factor 4 (PF4).
Tx: discontinue hep and administer DTI
What are two things to look for in a patient on heparin?
1) Thrombocytopenia due to platelet removal by macrophages.
2) Thrombosis due to platelet activation and aggregation.
CI of Heparin.
Severe HTN, active TB, ulcers of GI, patients with recent surgery.
What do you use to reverse heparin action?
What is fondaparinux, its admin, and its MOA.
MOA - binds antithrombin to indirectly inhibit FXa by being and antithrombin III catalyst
How is fondaparinux different than heparins and what are its clinical indications?
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
Name the Parenteral anticoagulants:
1) Indirect thrombin and FXa-i: HMW, LMW, and synthetic pentasaccharide
2) Direct thrombin inhibitors
- HMW: heparin sodium
- LMW: enoxaparin, tinzaparin, dalteparin
- Synthetic - fondaparinux
2) Lepirudin, bivalirudin, argatroban
MOA of Direct thrombin inhibitors
Directly inhibit protease activity of thrombin.
Lepirudin, bivalirudin - bind both active site and substrate recognition site.
Argatroban - bind only at thrombin active site.
Which Direct thrombin inhibitors are irr/reversible.
Lepirudin - irreversible thrombin inhibitor
Bivalirudin - reversible thrombin inhibitor (also inhibits platelet aggregation
Argatroban - IV, short acting
Indications and AE of Direct thrombin inhibitors.
Indications - HIT, coronary angioplasy (BIVALIRUDIN and ARGATROBAN).
AE - bleeding, anaphylactic reaction in repeated LEPIRUDIN use.
Name to oral anticoagulants
1) coumarin anticoags - Warfarin
2) Novel Oral AntiCoagulants - FXA-I (Rivaroxaban, Apixaban, Edoxaban); Direct thrombin inhibitor (Dabigatran)
MOA of Warfarin
Inhibits vitK-epoxide reductase whic inhibits reactivaiton of vitK >> inhibiting carboxylation of gamma-glutamyl-carboxylase.
Proteins affected - factor 2 (protrombin). factors 7/9/10 (hemostatic)
What is the normal function of carboxylation of glutamate residues - what is warfarin effective at preventing?
Converts hypofunctional hemostatic factors into functional ones.
Warfarin - Pharmacokinetics, indications, AE
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
Warfarin dose titration - INR
High chance of thrombosis?
High chance of bleeding?
Range for patients on warfarin?
0.5 - high chance of thrombosis
0.9-1.3 - normal
4.0-5.0 - high chance of bleeding
2.0-3.0 - range for patients on warfarin.
What is VKORC1? What race is high dose v. low dose haplotype more common in?
What is CYP2C9 responsible for?
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
What are the pharmacokinetic and pharmacodynamic interactions of Warfarin. What disease states are affected?
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.
What reverses warfarin?
Fresh frozen plasma or prothrombin complex concentrate (more rapid than VitK).
Clinical use for NOAC - FXa-I
Prevention of thromboembolism (Riva and Apix).
Prevention of stroke in people with afib.
NOAC - FXa-I Advantages v. Drawbacks
Advantage: Fixed dose, no monitoring. Rapid onset compared to Warfarin.
Drawbacks: no antidotes, excreted by kidneys>>dose adjustment in renal patients.
Clinical use of Dabigatran.
First oral NOAC approved by FDA.
Use - Reduce risk of stroke and systemic embolism in people wit non-valvular afib. Tx of venous thromboembolism.
Dabigatran Advantages v. Drawbacks
Advantage - antidote (idarucizumab), rapid on/off, no P450 interaction, fixed dosing.
Drawback - 80% renal excretion - may not be suitable for renal patients!
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?*
2) Dipyridamole, cilostazol.
3) Abciximab, eptifibatide, tirofiban.
4) Clopidogrel, prasugrel, *ticlopidine*, ticagrelor.
Aspirin: MOA, clinical use, AE
MOA - inhibit COX >> decrease TXA2 production
Use - prevention of heart attack
AE - peptic ulcer, GI bleeding
Inhibitors of phosphodiesterases: MOA
Inhibit cAMP degradation, increasing the levels of cAMP in platelets, thereby affecting platelet aggregation.
ADP Receptor Blockers: MOA
Relieve inhibition of Adenylyl Cyclase by alpha-i, resulting in increased cAMP production.
Clopidogrel: metabolism, and alleles
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.
Ticlopidine (ADP Receptor Blocker): Clinical Use and AE
Use - prevents arterial thrombosis in stroke patients.
AE - throbotic thrombocytopenic purpura, GI (NVD), bleeding, leukopenia.
Clopidogrel, prasugrel, ticagrelor (ADP Receptor Blocker): Clinical Use and AE
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
Dipyridamole (Inhibitors of phosphodiesterases): Clinical Use
Combine with aspirin to prevent cerebrovascular ischemia. Combine with warfarin to prevent thromboemboli in prosthetic heart valves.
Cilostazol (Inhibitors of phosphodiesterases): Clinical Use
Treat intermittent claudication
Platelet glycoprotein receptor blockers: MOA
Target Arg-Gly-Asp (RGD) sequence to prevent binding of ligands to CP IIb/IIIa receptro to inhibit platelet aggregation.
What is Platelet GP IIb/IIIIa receptor for?
fibrinogen, vitronectin, fibronectin, vWF - common platelet aggregation pathway.
What is each Platelet glycoprotein receptor blockers - GP2b/3ai?
Abciximab - anti-GP IIb/IIIa monoclonal antibody.
Tirofiban, eptifibatide - GP IIb/IIIa antagonist
Platelet glycoprotein receptor blockers: Use
IV influsion dt short half life.
Prevents thrombosis in unstable angina and acute coronary syndromes, pts undergoing percutaneous coronary angioplasty.
Platelet glycoprotein receptor blockers: AE
All = hypotension
Abciximab = myalgia
Abciximab and Thirfiban = thrombocytopenia (rare)
Thrombolytic (fibrinolytic) drugs: MOA
Induce fibrinolysis - lyse fibrin (and fibronectin, laminin, thrombospondin, vWf) in thrombi.
Activate endogenous fibrinolytic system (after clot has formed).
Types of fibrinolytic drugs and what they result in.
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)
Names of fibrinolytic drugs, where they're produced, and their MOA.
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)
Fibrinolytic drugs: Used for what and within what timeframe?
**Within 3 hours of acute embolic/thrombotic stroke.*
Within 3-6 hours of acute myocardial infarction.
Pulm embolism, DVT, ascending thrombophlebitis.
What fibrinolytic drug is best used after a cerebral artery stroke?
What can this drug exacerbate?
tPA within 3 hours.
Can exacerbate damage produced by hemorrhagic stroke.
Fibrinolytic drugs: AE
Streptokinase and urokinase - Bleeding from systemic fibrinogenolysis.
Stretokinase - allergic reactions.