Anticoagulants Part 2

Question 1

How do direct thrombin inhibitors work?

When are they useful?

Answer 1

• Directly bind thrombin at both the catalytic and fibrinogen binding site, suppressing platelet function.
• Useful in pt with history of HIT

Question 2

Dabigatran (Pradaxa)

MOA

Use

Onset

How long before surgery should it be stopped?

How is effect measured?

Answer 2

• Pro-drug: binds and reversibly inhibits circulating thrombin and clot integrated thrombin
• Use: Afib only
• Onset: rapid; E1/2 = 13 hours
• Stop 48 hours before surgery with normal renal function
  
  • 72-96 hours with abnormal renal function
  • 5 days for high risk for bleed surgery
• effect measured by TT and aPTT

Question 3

What are the adverse effects of dabigatran?

Drug interactions?

Reversal?

Answer 3

• Adverse effects:
  
  • bleeding (17% all types, 3% major)
    
    • warfarin > risk of life-threatening bleed
  • GI- dyspepsia, gastritis
• Drug interactions:
  
  • P-glycoprotein inhibitors will increase drug levels of dabigatran
    
    • ketoconazole, amiodarone, verapamil, quinidine
• Reversal: None
  
  • can try recombinant VIIa and/or dialysis

Question 4

What is Rivaroxaban (Xarelto)

use?

metab?

adverse effect?

Answer 4

• Highly selective direct factor Xa inhibitor
  
  • can inhibit free Factor Xa or bound Xa
• Use:
  
  • hip and knee surgery for DVT/PE prophylaxis
  • afib
• Metabolized:
  
  • CYP3A4 and substrate for P-glycoprotein
    
    • about 35% eliminated unchanged by kidneys
• Adverse effect:
  
  • bleeding (potentially fatal)
  • lower risk compared to warfarin

Question 5

Rivaroxaban

Contraindications

Reversal agent

How long held before surgeyr?

Answer 5

• Contraindicated:
  
  • renal, hepatic disease, bleeding risk
• No reversal; try recombinant VIIa or dialysis
• Hold 48 hours preop, 5 days for high risk for bleeding surgery
  
  • no blood test that reliably estimates effect

Question 6

What are the ASRA guidelines for regional anesthesia preoperatively?

What about resuming drug after neuraxial procedures?

Answer 6

• Stop oral anticoagulants 5 half lives before the regional or pain intervention
• For resumption after a neuraxial procedure:
  
  • ASRA recommends 6 hours
  • pain recommends 24 hours

Question 7

What are the three major classes of antiplatelet medications?

Answer 7

• Thromboxane inhibitor
  
  • ASA
• P2Y₁₂ ADP antagonists
  
  • Clopidogrel, Aspirin/dipyridamole
• GIIb/IIIa antagonists
  
  • abciximab

Question 8

COX-1 Vs COX-2 regarding platelet function

Answer 8

• COX-1: Produced by platelets
  
  • no nuclei, so once inhibited, platelets cannot produce more cox-1
  • Induces platelet aggregation and vasoconstriction via thromboxane A2
• COX-2: Produced by vascular endothelial cells
  
  • have nuclei, can replace inhibited enzyme
  • Inhibits platelet aggregation and promotes vasodilation via prostacyclin

Question 9

ASA MOA

Answer 9

• Arachidonic pathway uses cyclooxygenase to produce thromboxane A2 (TXA2) and prostacyclinI2 (PGI2)
• ASA irreversibly inhibits the COX pathway
• Hold before surgery 7-10 days (unless risk of bleeding is < benefit of continuing)
  
  • TXA2 inhibition decreases vasoconstriction and decreases degranulation of platelets
  • PGI2 inhibition reduces vasodilation and promotes platelet degranulation

Question 10

What does aspirin do in the different dose ranges?

Answer 10

• Low dose: 74-81 mg/day
  
  • irreversibly inhibit COX-1, inhibiting generation of thromboxane A2, having antithrombotic effect
• Intermediate dose: 650 mg- 4 g/day
  
  • Inhibit COX1 and COX2, blocking prostaglandin (PG) production
  • analgesic and antipyretic effects
• High dose: 4-8 grams/day
  
  • anti-inflammatory effect- COX2 dependent PGE2
  • limited by toxicity, tinnitus, hearing loss, and gastric intolerance

Question 11

When is ASA indicated for use as an antiplatelet?

Answer 11

• Indications:
  
  • transient ischemic attach/ischemic stroke
  • stable and unstable angina
  • prevention and treatment of MI
    
    • maintain patency of stents
• Adverse effects
  
  • GI bleed
  • hemorrhagic stroke

Question 12

P2Y12 adenosine diphosphate receptor antagonists are all ________

Answer 12

prodrugs; converted in vivo to thiol-containing active metabolites

Question 13

Inhibition of the P2Y12 ADP receptor blocks _____________.

For how long?

What does this cause?

Answer 13

stimulated adenylyl cyclase activity

For 7-10 days (irreversible)

• ADP is released once platelets are activated and usually comes back to same or neighboring platelet to P2Y12 receptor which activates adenylyl cyclase to change the shape of the GIIa/IIIb receptor, allowing it to bind to fibrinogen
• P2Y12 antagonist prevents the release of the adenylyl cyclase and the changing shape of the GIIa/IIIb receptor

Question 14

What are the 1st, 2nd, and 3rd generation drugs of ADP receptor antagonists?

Which one is reversible?

Answer 14

• 1st- Ticlopidine
• 2nd- Clopidogrel- most commonly used
• 3rd- Pasugrel
  
  • black box warning >75 years old in TIA/stroke patients <60 kg
• Reversible: Ticagrelor

Question 15

Clopidogrel:

Class

indications

Answer 15

• ADP receptor antagonist
• Indications:
  
  • inhibits about 50% of platelet aggregation
    
    • maintenance of coronary stent patency
    • prevention of MI/stroke in high risk patients
    • alternative for ASA intolerant pts

Question 16

Clopidogrel

pharmacokinetics

drug:drug interactions

Answer 16

• Pharmacokinetics:
  
  • rapid oral absorption; onset 2 hours; peak at 3-7 days
  • once daily dosing
• Pro-drug: must undergo metabolism by CYP2C19 to become active
  
  • Black box warning for poor metabolizers- consider prasugrel or ticagrelor in these pts
• Drug:drug interactions
  
  • other meds that increase bleeding
  • PPIs inhibit CYP2C19

Question 17

Clopidogrel

Adverse reactions

Answer 17

• severe rash
• diarrhea
• bleeding
• thrombocytopenia
• TTP- thrombotic thrombocytopenia purpura
• no significan neutropenia- unlike ticlopidine

Question 18

What did the CURE & COMMIT trials find?

Answer 18

• that combination of Clopidogrel and aspirin is better than aspirin alone
• They have complementary mechanisms, causing additive effect

Question 19

Dipyridamole

structure

MOA

Indication

half life

Answer 19

• pyrimidopyrimidine derivative with vasodilator and antiplatelet properties
• MOA not clear- increases plasma adenosine levels
  
  • no antiplatelet activity when used alone
• Indication:
  
  • used in combo with warfarin to prevent thrombus following heart valve replacement
  • Aggrenox- combined with ASA to reduce the risk of ischemic stroke
• Half life 10 hours, BID dosing

Question 20

Dipyridamole

Adverse effects

Answer 20

• HA
• hypotension (vasodilator properties)
• bronchospasm
• myocardial ischemia/infarction
• arhythmias
• nausea/dizziness
• rash/flushing

Question 21

What are the different Glycoprotein IIb/IIIa receptor antagonist drugs?

MOA?

Answer 21

• Abciximab (IV only)
• Tirofiban (IV only)
• Eptifibatide (IV only)
• MOA
  
  • reversible blockade of GP-IIb/IIIa receptors, the final step of platelet aggregation
  • platelets cant attach to each other
• **Most effective form of antiplatelet activity

Question 22

What are the indications for the Glycoprotein IIb/IIIa receptor antagonists?

Which is the prototype?

Answer 22

• Indications:
  
  • unstable angina, acute MI
  • Percutaneous coronary intervention
• Prototype: Abciximab
  
  • Purified fab fragment of monoclonal antibody that binds near the GPIIb/IIIa receptor occluding the binding of fibrinogen
• SE
  
  • 2x bleeding risk

Question 23

What are the different fibrinolytic drugs?

Answer 23

Streptokinase

urokinase

tPA

Question 24

How does fibrinolysis work?

Answer 24

• Plasminogen becomes active form plasmin
• plasmin is a non-specific protease, it digensts fibrin clots and other proteins
• Fibrinolytic drugs are nonspecific!
  
  • both protective thrombi and target thromboemboli will be broken down!
  • high potential for hemorrhage

Question 25

Alteplase/tPA What is it? administration? E1/2t? MOA? indications?

Answer 25

* A version of tissue plasminogen activator produced by recombinant DNA technology * IV infusion * E1/2t = 5 minutes * MOA: binds plasminogen catalyzing the reaction of plasminogen into plasmin * plasmin digests fibrin and breaks down fibrinogen and other clotting factors * Indications: * acute MI * acute ischemic stroke * symptomatic PE

Question 26

What are the statistics regarding death rate and administration times of tPA after symptom onset of coronary artery occlusion? What trial was this?

Answer 26

* within 2 hours, death rate about 5% * within 2-4 hours, death rate about 6-7% * within 4-6 hours, death rate about 9.4 % * The GUSTO-1 trial

Question 27

Contraindications for tPA absolute relative

Answer 27

* Absolute contraindications: * intracranial hemorrhage/brain tumor/cerebral vascular lesion * known source of internal bleeding * aortic dissection * Relative * severe HTN \>180/110 * intracerebral issues not noted above * other anti coags or anti platelt drugs * known bleeding pathophysiology * hx of traumatic surgery or internal bleeding within 3 weeks * pregnancy * PUD