Anticoagulants Part 2 Flashcards
How do direct thrombin inhibitors work?
When are they useful?
- Directly bind thrombin at both the catalytic and fibrinogen binding site, suppressing platelet function.
- Useful in pt with history of HIT
Dabigatran (Pradaxa)
MOA
Use
Onset
How long before surgery should it be stopped?
How is effect measured?
- 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
What are the adverse effects of dabigatran?
Drug interactions?
Reversal?
- Adverse effects:
- bleeding (17% all types, 3% major)
- warfarin > risk of life-threatening bleed
- GI- dyspepsia, gastritis
- bleeding (17% all types, 3% major)
- Drug interactions:
- P-glycoprotein inhibitors will increase drug levels of dabigatran
- ketoconazole, amiodarone, verapamil, quinidine
- P-glycoprotein inhibitors will increase drug levels of dabigatran
- Reversal: None
- can try recombinant VIIa and/or dialysis
What is Rivaroxaban (Xarelto)
use?
metab?
adverse effect?
- 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
- CYP3A4 and substrate for P-glycoprotein
- Adverse effect:
- bleeding (potentially fatal)
- lower risk compared to warfarin
Rivaroxaban
Contraindications
Reversal agent
How long held before surgeyr?
- 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
What are the ASRA guidelines for regional anesthesia preoperatively?
What about resuming drug after neuraxial procedures?
- 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
What are the three major classes of antiplatelet medications?
- Thromboxane inhibitor
- ASA
- P2Y12 ADP antagonists
- Clopidogrel, Aspirin/dipyridamole
- GIIb/IIIa antagonists
- abciximab
COX-1 Vs COX-2 regarding platelet function
- 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
ASA MOA
- 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
What does aspirin do in the different dose ranges?
- 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
When is ASA indicated for use as an antiplatelet?
- 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
P2Y12 adenosine diphosphate receptor antagonists are all ________
prodrugs; converted in vivo to thiol-containing active metabolites
Inhibition of the P2Y12 ADP receptor blocks _____________.
For how long?
What does this cause?
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
What are the 1st, 2nd, and 3rd generation drugs of ADP receptor antagonists?
Which one is reversible?
- 1st- Ticlopidine
- 2nd- Clopidogrel- most commonly used
- 3rd- Pasugrel
- black box warning >75 years old in TIA/stroke patients <60 kg
- Reversible: Ticagrelor
Clopidogrel:
Class
indications
- 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
- inhibits about 50% of platelet aggregation
Clopidogrel
pharmacokinetics
drug:drug interactions
- 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
Clopidogrel
Adverse reactions
- severe rash
- diarrhea
- bleeding
- thrombocytopenia
- TTP- thrombotic thrombocytopenia purpura
- no significan neutropenia- unlike ticlopidine
What did the CURE & COMMIT trials find?
- that combination of Clopidogrel and aspirin is better than aspirin alone
- They have complementary mechanisms, causing additive effect
Dipyridamole
structure
MOA
Indication
half life
- 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
Dipyridamole
Adverse effects
- HA
- hypotension (vasodilator properties)
- bronchospasm
- myocardial ischemia/infarction
- arhythmias
- nausea/dizziness
- rash/flushing
What are the different Glycoprotein IIb/IIIa receptor antagonist drugs?
MOA?
- 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
What are the indications for the Glycoprotein IIb/IIIa receptor antagonists?
Which is the prototype?
- 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
What are the different fibrinolytic drugs?
Streptokinase
urokinase
tPA
How does fibrinolysis work?
- 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
Alteplase/tPA
What is it?
administration?
E1/2t?
MOA?
indications?
- 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
What are the statistics regarding death rate and administration times of tPA after symptom onset of coronary artery occlusion?
What trial was this?
- 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
Contraindications for tPA
absolute
relative
- 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
