Week 2: Thrombolysis and Antiplatelet Therapy for Ischemic heart disease

Question 1

Review of the functions of thrombin.

Answer 1

1. Acts as serine protease and converts fibrinogen to fibrin
2. activates platelets
3. amplifies coagulation steps by converting XI, V, VIII, XIII to their activated forms.

Question 2

List the anticoagulants.

Answer 2

1. Warfarin
2. Unfractionated Heparin
3. Low molecular weight heparins (LMWHs)
4. Factor Xa Inhibitors: direct and indirect
5. Direct Thrombin Inhibitors (DTIs)

Question 3

Describe warfarin.

Answer 3

• inhibits synthesis of vitamin k dependent clotting factors: II, VII, IX, X, Protein C and S.
• because it inhibits the anti-coagulant protein C and S, must have bridge to therapy from heparin. C+S deplete faster compared to the clotting factors, and time for full anticoagulant effect can take up to 5 days
• R and S enantiomers, the S enantiomer is much stronger
• monitored by PT/INR (factor VII has shortest half life, so PT is more sensitive)

Question 4

Describe unfractionated Heparin (UFH).

Answer 4

• inactivates thrombin and Xa in 1:1 ratio
• binds to antithrombin (AT) which catalyzes inactivation of thrombin and Xa.
• monitor aPTT, CBC (platelets), antiXa, osteoporosis
• adverse effects: type II thrombocytopenia-autoimmune

Question 5

Describe low molecular weight heparins.

Answer 5

-similar to UFH, requires AT for activity.
-greater selectivity for Xa because of shorter chain length
e.g.
Enoxaparin
Dalteparin

Question 6

Describe Factor Xa inhibitors.

Answer 6

1. indirect (Fondaparinux)
   - Antithrombin mediated selective inhibition of Xa
   - potentiates innate neutralization of Xa by ATIII (300x)
   - is a synthetic analog of the AT binding pentasaccharide found in UFH
2. direct (Rivaroxaban)
   - reversible binding oral
   - P-glycoprotein substrate, active site of Xa
   - direct Xa inhibitors approved for AF and VTE, not IHD
   - T1/2=5-9 hrs
3. Direct (Apixaban)
   - reversible binding oral
   - similar to Rivaroxaban, T1/2=6-12 hrs
4. Direct (Edoxaban)
   - reversible binding oral
   - not approved yet

Question 7

Describe Direct Thrombin Inhibitors (DTIs)

Answer 7

-binds to either active site (univalent) or to active site and exosite (bivalent), blocking enzymatic activity
IV DTIs: used for HIT (heparin induced thrombocytopenia)
-monitor by aPTT, additive effect on PT/INR when used in patient on warfarin
e.g. Lepirudin (bivalent, renal elim), Bivalirudin (bivalent, renal elim), Argatroban (univalent, hepatic elim)
PO DTIs
Dabigatran Etexilate
-reversible binding of free and clot bound thrombin
-Prodrug converted by plasma esterases to active form, poor bioavailability
-P-gp substrate

Question 8

Describe thrombolytics.

Answer 8

-MOA: facilitates conversion of plasminogen to plasmin, which leads to breakdown of fibrin strands.
-limited use in ACS
-therapeutic uses: STEMI, PE, peripheral VTE and arterial TE, catheter occlusions, ischemic stroke
1st Generation
-Streptokinase (not used), anistreplase, urokinase
2nd Generation
-tPA or Alteplase (rt-PA)
-tissue specificity
3rd Generation
-Reteplase (RPA) [double bolus] and Teneteplase (TNK) [single bolus]
-modified t-PA for longer half life and bolus admin

Question 9

List the different types of anti-platelet drugs.

Answer 9

1. Aspirin
2. P2Y12 Receptor Antagonists
   - prevents ADP from binding and prevents activation of platelet
   - used in combo with aspirin in ACS
   - alternative to aspirin in IHD
3. Thrombin Receptor Antagonists
   - platelet effects of thrombin are mediated be protease activated receptors (PAR-1 and PAR-2, with 1 being more important). Blocks PAR-1 receptors.
4. Glycoprotein IIb/IIIa receptor inhibitors
   - prevent fibrinogen from binding to receptor on activated platelets, preventing aggregation

Question 10

Describe the different P2Y12 receptor antagonists.

Answer 10

1. Clopidogrel
   - only 15% to active form by CYP, 85% by esterases to inactive form
   - disulfide bridge to cysteine residues on P2Y12
   - most widely used
   - concern about inconsistent anti platelet effects based on genetics, DDI (drug drug interactions)
2. Prasugrel
   - prodrug
   - more efficient conversion to active form than clopidogrel
   - consistency of effect, rapid time to onset
   - higher bleeding risks, narrower indications
3. Ticlopidine: not used anymore, risk of agrunulocytosis
4. Ticagrelor
   - ATP analog
   - direct competitive/reversible inhibitor of P2Y12
   - short acting
   - PO

Question 11

Describe the different thrombin receptor antagonists.

Answer 11

1. Vorapaxar
   - oral competitive reversible PAR-1 receptor antagonist
   - for reducing risk of heart attack, stroke, CV death, and need for revascularization procedures in patients with previous MI or PAD

Question 12

Describe the different glycoprotein IIb/IIIa receptor inhibitors

Answer 12

1. Abciximab
   - monoclonal antibody, irreversibly binds to GP IIb/IIIa receptor, renal excretion
2. Eptifibitide and Tirofiban
   - reversible, competitive binding to receptor, renal elimination
   - used in broader range of patients