Thrombolytics, anticoagulants, and anti platelet Rx for IHD

Question 1

Anticoagulants: Warfarin

Answer 1

• Targeting any of the coagulation cascade factors (warfarin, LMW or HMW heparin, factor Xa inhibitors, DTIs)
• Warfarin (vit K antagonist) depletes the vit K-dependent factors (2, 7, 9, 10, C and S) by inhibition of Vit K epoxide reductase (VKORC)
• Since these factors have variable T1/2s, the ones with the shorter T1/2 will be decreased faster (C, S, 7)
• Warfarin contains both R and S enantiomers, but the S enantiomer is 2-5 times more potent (CYP2C9 metabolizes S warfarin- liver)
• Adverse reactions (ADR): bleeding, cat X
• Monitor using PT (VII)

Question 2

Anticoagulants: HMW and LMW Heparin

Answer 2

• HMW or unfractionated heparin (UFH) contains long heparin strands that inhibit thrombin and Xa equally
• Both UFH and LMW heparin require antithrombin to have any effect (cofactor)
• LMW heparin only affects Xa as its anticoagulation effect
• Renally excreted, monitor using aPTT
• ADRs: bleeding, thrombocytopenia, HIT
• HIT: heparin-induced thrombocytopenia
• In HIT there are antibodies made against heparin (usually HMW), there is thrombocytopenia and thrombosis timed after heparin is given (3 Ts)
• Rx for HIT: discontinue heparin, use warfarin or DTI

Question 3

Anticoagulants: factor Xa inhibitors

Answer 3

• Indirect inhibitor: fondaparinux, which potentiates the neutralization of factor Xa by antithrombin (binds to AT allosterically)
• Direct Xa inhibitors (rivaroxaban, apixaban, edoxaban): directly bing to active site of Xa

Question 4

Anticoagulants: direct thrombin inhibitors (DTIs)

Answer 4

• Do not require a cofactor, bind directly to thrombin active site or to active site+fibrinogen binding site
• IV names: bivalirudin, argatroban
• PO: Dabigatran, reversible binding (shorter duration), renal excretion
• ADR: bleeding
• Monitor using aPTT

Question 5

Thrombolytics

Answer 5

• Facilitate the conversion of plasminogen into plasmin
• Are used for some situations (STEMI in less than 12 hrs), but generally percutaneous interventions (PCI) are favored in ACS
• First generation: streptokinase and urokinase
• Second and third generations: tPA (continuous) and modified tPAs (reteplase, tenecteplase) for bolus
• Indications: STEMI, PE, thromboembolism, catheter occlusions, ischemic stroke (contraindications vary)

Question 6

Antiplatelets: activation inhibitors 1

Answer 6

• Can either prevent recruitment/activation (most types) or adhesion (GP IIb/IIIa inhibitors)
• Aspirin: irreversibly inhibits COX1, thus reducing TXA2 synthesis and reducing platelet activation
• Low doses (<100mg) used for prevention of coronary events in IHD

Question 7

Antiplatelets: activation inhibitors 2

Answer 7

• P2Y12 (ADP receptor) antagonists: prevents ADP-induced platelet activation, can be reversible (Ticagrelor) or irreversible binding (ticlopidine, clopidogrel, prasugrel)
• Used as alternative to aspirin in IDH, in combination w/ aspirin during ACS
• Prasugrel has more efficient conversion from prodrug->drug than clopidogrel, but also a higher bleeding risk
• Thrombin receptor (PAR) antagonists: prevent binding of thrombin to platelets, reduces platelet activation
• Vorapaxar: oral, reversible binding, contraindicated in stroke/TIA

Question 8

Antiplatelets: aggregation inhibitors

Answer 8

• These bind to GPIIb/IIIa receptor on platelets, preventing them from binding to fibrinogen and aggregating to form clots
• Used with aspirin and P2Y12 inhibitors in select ACS pts
• Abciximab: Ab against GPIIb/IIIa, removed by RES (not renal cleared)
• Eptifibitide and tirofiban: small molecule GPIIb/IIIa inhibitor, reversible, renal eliminated

Question 9

Rx regimen for IHD

Answer 9

• 1-3 antiplatelets
• +/- an anticoagulant
• +/- a fibrinolytic