04-15 L2 Anti-coagulation and antithrombotics

Question 1

name the vitamin K dependent factors

Answer 1

• Factor 7 (6h) Protein C
• Factor 9 (24h)
• Factor 10 (48h)
• Factor 2 (72h) Protein S

Question 2

Vit K is need to carboxylated what aa

where does this occur?

Answer 2

• Vit K carboxylation: glutamic acid residue
• producing gama-carboyxglutamic acid

Question 3

What are the sources of Vit K

Answer 3

• Diet (30-40%)
• Intestinal flora (60-70%)

Question 4

what are the categories of

anticlotting durgs (3)

&

Drugs that facilatate clotting (3)

Answer 4

• Anticlotting
  
  • Anticoagulants
  • Thrombolytics
  • Antiplatelet drugs
• Drugs that facilitate clotting
  
  • Replacement factors
  • Vit K
  • Antiplasmin drugs

Question 5

Name the subtypes of the following 3 anticlotting drugs

• Anticoagulants
• Thrombolytics
• Antiplatelets

Answer 5

• Anticoagulants
  
  • ​Heprains
  • Direct thrombin inhibitors
  • Warfarin
• Thrombolytics
  
  • t-PA derivatives
  • Steptokinase
• Antiplatelets
  
  • Aspirin
  • Glycoprotien 2b/3a inhibitors
  • ADP inhibitors (clopidogrel)
  • PDE/adenosine uptake inhibitors

Question 6

Anticoagulant drugs

UnFractionated Hep

• MOA
• Batch to batch
• Clinical indiciation
• Antidote

Answer 6

UnF hep

• Antithrombin III: pentasaccharide binding motif of heparin
• MOA: clotting factor attachs (Anti TIII: a serine protease inhibitor) and becomes trapped in the complex and activates
• differs from batch to batch not all the same
  
  • ​binds to plasma proteins or vascular endothelial cell surface__​
• _​_CI: DVt and PE (can be used in pregnancy but LMW Hep perfered).
• Antidote: Protamine sulfate **heavily pos charged, binds UFH and prevents UFH antithormbin 3 interaction

Question 7

What is the difference bt UFH and LMWH

Answer 7

• UFH: binds to factors 2 and 10
• LMWH: binds to factor 10
  
  • (binds to ATIII but not thormbin)

Question 8

what are the clinical indications of LMWH

Answer 8

clincial indications

• Prophylaxis and treatment of DVT/PE
• Management of acute coronary syndrome
• Pregnant pts (due to lack of need to monitor)

Question 9

Warfarin

• half life
• mode of monitoring

Answer 9

Warfarin

• half life: 20-60 hrs
  
  • so you need to be careful b/c pt will clot b/c Protein C and factor 7 & X go quickly before the other factors thus initial clotting then thnning of blood)
• ​INR: international normalized ratio (target: 2-4)
  
  • falls below 2: thromboiss risks increase
  • above 4: bleeding risk increase

Question 10

Warfarin drug-drug interactions

Answer 10

• need to monitor drug-drug interactions
• A low TI index
• hghly protein bound
• Sm changes in dosage can result in lg changes in anticoagulation.

Question 11

Dabigatran

or argatroban

Answer 11

Dabigatran

• MOA: direct thrombin (factor 2) inhibitors
• unlike warfarin, Dabigatron does not require routine plasma concentration monitoring.

Question 12

Name 3 clot busters

MOA

Answer 12

• clot busters
  
  • Streptokinase/Urokinase
  • Tissue plasminogen activator (t-PA)
  • tenecteplase (TNK t-PA)
• MOA
  
  • Plasminogen –>plasmin
  • plasmin cuts fibrin & fibrinogen, factors 5, 8

Question 13

Streptokinase

• MOA
• mode of ingestion
• origion

Answer 13

Streptokinase

• MOA: does not have intrinsic enzymatic activity, binds to plasminogen, expose active site, and promotes conversion of additional plasminogen to plasmin
• mode of ingestion: IV (to overwhelm antibody) followed by infusion
• origin: bacterial origin, possibiilty of anaphylactic response.

Question 14

t-PA

• MOA
• admin
  *

Answer 14

t-PA (2nd gen)

• MOA:
  
  • serine protease, naturally occuring regulator of thrombolysis
  • converts plasminogen to plasmin
  • human recombinant protein for RX use
• admin: IV bolus followed by infusion

Question 15

Tenecteplase

• MOA
• 3 point mutations
• CI
• C-toxicities
• antidote

Answer 15

Tenecteplase (prototypical 3rd generation)

• T-PA genetically engineered to improve efficacy and bioavailability
• 3 point mutations
  
  • incraese t1/2
    
    • T (threonine) mutation
    • N (asparagine) mutation
  • incraese activity
    
    • K (lys)-His-R-R
• CI: rapid lysis of occlusive thrombi
  
  • admin early (w/in 3-4 hrs)
  • emergent, life threating PE
  • Stroke
    
    • in the absence of intracranial hemorrhage admin early (w/in 3 hr of onset)
• Clinical toxicity
  
  • Mechanism: lyse physiological thrombi
  • contraindicated or extreme caution
    
    • active bleeding, recent surgery, recent GI bleeding, orevious cerebral vascular accident, hypertnesion
  • bleeding
    
    • increase risk w/concomitant heparin
    • to manage
      
      • D/c thormbolytic drug (short t1/2)
      • transfusion of plasma whoel blood and fibrinogen
      • antidote: ** Aminocaproic acid**:
      • binds to plasminogen and plasmin blocks theri access to fibrin

Question 16

What is the antidote of thromblytic drugs (Tenecteplase)

What is its MOa

Answer 16

• drug: Aminocaproic acid
• MOA: binds to plasminogen and plasmin and inhibits its interaction with fibrin.

Question 17

What are the 3 antiplatelet drgus

Answer 17

• ASA:
  
  • MOA: irreversible COX inhibitor (COX-1 platelets) inhibits the synthesis of plateelt agonists against TXA2 (7-10 days)
  • non-competitive inhibitor
• Clopidorgrel
  
  • MOA: irreverisble platelet purinergic (P2Y12) receptor
  • antagonist (a prodrug) blocks ADP platelet stimuation (4 day effect)
• Abciximab
  
  • FAB fragment of a_ntibody against GP2a/3b blocks_ binding to fibrinogen
• other sm inhibitors of G2a/3b (both IV)
  
  • eptifibatide: a cyclic peptide
  • Tirofaban (nonpeptide)

Question 18

ASA

Important Drug-drug interactions

Answer 18

ASA

• Other NSAIDs (ibuprofen)
  
  • should be used with great caution in patients taking low dosing aspirin pophylactically, or post-MI avoid concomitant use, since the competitve inhibition may interfere wiht aspirins irreversible inhibitors
• acetaminophen (1st choice non-opioid analgesic for these patients)
  
  • 2-4 days anticoagulant effect for many NSAIDs