Anticoagulants Part 2 Flashcards

1
Q

How do direct thrombin inhibitors work?

When are they useful?

A
  • Directly bind thrombin at both the catalytic and fibrinogen binding site, suppressing platelet function.
  • Useful in pt with history of HIT
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2
Q

Dabigatran (Pradaxa)

MOA

Use

Onset

How long before surgery should it be stopped?

How is effect measured?

A
  • 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
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3
Q

What are the adverse effects of dabigatran?

Drug interactions?

Reversal?

A
  • 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
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4
Q

What is Rivaroxaban (Xarelto)

use?

metab?

adverse effect?

A
  • 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
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5
Q

Rivaroxaban

Contraindications

Reversal agent

How long held before surgeyr?

A
  • 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
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6
Q

What are the ASRA guidelines for regional anesthesia preoperatively?

What about resuming drug after neuraxial procedures?

A
  • 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
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7
Q

What are the three major classes of antiplatelet medications?

A
  • Thromboxane inhibitor
    • ASA
  • P2Y12 ADP antagonists
    • Clopidogrel, Aspirin/dipyridamole
  • GIIb/IIIa antagonists
    • abciximab
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8
Q

COX-1 Vs COX-2 regarding platelet function

A
  • 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
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9
Q

ASA MOA

A
  • 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
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10
Q

What does aspirin do in the different dose ranges?

A
  • 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
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11
Q

When is ASA indicated for use as an antiplatelet?

A
  • 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
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12
Q

P2Y12 adenosine diphosphate receptor antagonists are all ________

A

prodrugs; converted in vivo to thiol-containing active metabolites

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13
Q

Inhibition of the P2Y12 ADP receptor blocks _____________.

For how long?

What does this cause?

A

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
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14
Q

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

Which one is reversible?

A
  • 1st- Ticlopidine
  • 2nd- Clopidogrel- most commonly used
  • 3rd- Pasugrel
    • black box warning >75 years old in TIA/stroke patients <60 kg
  • Reversible: Ticagrelor
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15
Q

Clopidogrel:

Class

indications

A
  • 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
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16
Q

Clopidogrel

pharmacokinetics

drug:drug interactions

A
  • 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
17
Q

Clopidogrel

Adverse reactions

A
  • severe rash
  • diarrhea
  • bleeding
  • thrombocytopenia
  • TTP- thrombotic thrombocytopenia purpura
  • no significan neutropenia- unlike ticlopidine
18
Q

What did the CURE & COMMIT trials find?

A
  • that combination of Clopidogrel and aspirin is better than aspirin alone
  • They have complementary mechanisms, causing additive effect
19
Q

Dipyridamole

structure

MOA

Indication

half life

A
  • 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
20
Q

Dipyridamole

Adverse effects

A
  • HA
  • hypotension (vasodilator properties)
  • bronchospasm
  • myocardial ischemia/infarction
  • arhythmias
  • nausea/dizziness
  • rash/flushing
21
Q

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

MOA?

A
  • 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
22
Q

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

Which is the prototype?

A
  • 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
23
Q

What are the different fibrinolytic drugs?

A

Streptokinase

urokinase

tPA

24
Q

How does fibrinolysis work?

A
  • 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
25
Q

Alteplase/tPA

What is it?

administration?

E1/2t?

MOA?

indications?

A
  • 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
26
Q

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

What trial was this?

A
  • 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
27
Q

Contraindications for tPA

absolute

relative

A
  • 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