Antiplatelets/Antifibrinolytics

Question 1

Antiplatelets:

Medication Classes and Agents

Answer 1

1. Thromboxane inhibitor
   
   • Aspirin (ASA)
2. P2Y12 ADP Antagonists
   
   • Ticlopidine (Ticlid)
   • Clopidogrel (Plavix)
   • Aspirin/dipyridamole (Aggrenox)
3. GIIb/IIIa Antagonists
   
   • Abciximab (Reopro)
   • Tirofiban (Aggrestat)
   • Eptifibatide (Integrilin)

Question 2

COX-1 vs. COX-2: Platelet Function

Answer 2

• COX-1: Produced by platelets
  
  • No nuclei, so once inhibited, plts 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 plt aggregation and promotes vasodilation via prostacylcin

Question 3

Aspirin Mechanism of Action (MOA)

Answer 3

• Arachidonic pathway uses cyclooxygenase (COX) to produce thromboxane A2 (TXA2) and prostacyclin I2 (PGI2)
• ASA irreversibly inhibits COX pathway
  
  • 7-10 days (hold for this period before surgery unless risk of bleeding < benefit of continuing)
    
    • TXA2 inhibition decreases vasoconstriction and decreases degranulation of platelets
    • PGI2 inhibition reduces vasodilation and promotes platelet degranulation

Question 4

Aspirin

Doses

Answer 4

• Low doses (75 to 81 mg/day):
  
  • irreversibly inhibit (COX)-1 → inhibits generation of thromboxane A2 → antithrombotic effect
• Intermediate doses (650 mg to 4 g/day):
  
  • inhibit COX-1 and COX-2 → blocking prostaglandin (PG) production → analgesic and antipyretic effects
• High doses (4 and 8 g/day):
  
  • anti-inflammatory effect - COX-2 dependent PGE2
  • Limited by toxicity: tinnitus, hearing loss, and gastric intolerance

Question 5

Aspirin: Anti-platelet Indications

Answer 5

• Indications:
  
  • TIA/ischemic stroke
  • Stable and unstable angina
  • Prevent/treat MI
  • Maintenance of patent coronary stents

Question 6

Aspirin: Anti-platelet

Adverse Effects

Answer 6

• GI bleed
• Hemorrhagic stroke

Question 7

P2Y12 Adenosine Diphosphate (ADP) Receptor Antagonists: Thienopyridines

Answer 7

• Structurally related class of compounds reduce plt aggregation
• Inhibition of the P2Y12 ADP receptor
  
  • Blocks stimulated adenylyl-cyclase activity
• Prodrugs: Converted in vivo to thiol-containing active metabolites
  
  • Metabolism pathways are different for each member of this class

Question 8

ADP Receptor Antagonists:

Agents

Answer 8

• Irreversible blockade for life of plt:
  
  • 7-10 days
  • Ticlopidine – 1st generation
    
    • Use less common
  • Clopidogrel – 2nd generation
    
    • Most commonly used
  • Pasugrel – 3rd generation
    
    • Black Box Warning for bleed risk in >75 year
    • < 60 kg /TIA/Stroke patients
• Reversible blockade:
  
  • Ticagrelor

Question 9

ADP receptor antagonists: Clopidogrel

Indications

Answer 9

• Inhibits plt aggregation ~50%
  
  • Maintenance of coronary stent patency
  • Prevent MI/Stroke/vascular occlusion in high risk pts (usually combined w/ ASA in acute coronary syndromes)
  • Alternative primary prevention in ASA intolerant pts

Question 10

ADP receptor antagonists: Clopidogrel

Pk

Answer 10

• Rapid oral absorption
• Onset 2 hrs
• Peak at 3-7 days
• Once daily dosing regimen considered sufficient
• Pro-drug: Must undergo metabolism by CYP2C19 to become active
  
  • “Poor metabolizers” (variant CYP2C19) may fail therapy; carries a Black Box Warning
    
    • Consider prasugrel or ticagrelor in these pts

Question 11

ADP receptor antagonists: Clopidogrel

Drug:Drug Interactions

Answer 11

• Other meds that increase bleeding
• Proton-pump inhibitors inhibit CYP2C19
• Clopidogrel + aspirin vs aspirin alone: combo better
  
  • Complimentary mechanisms → additive effect
  • Effective for pts undergoing PCI and med mgmt

Question 12

ADP receptor antagonists: Clopidogrel

Adverse Reactions

Answer 12

• Severe rash
• Diarrhea
• Bleeding complications
• Thrombocytopenia (rate similar to aspirin)
• TTP – usually w/in first two weeks of therapy
• No significant rate of neutropenia (contrast with ticlopidine)

Question 13

Dipyridamole

Action, Pk

Answer 13

• A pyrimidopyrimidine derivative w/ vasodilator and antiplatelet properties
• MOA not clear
  
  • Increases plasma adenosine levels
• Half Life: 10 hrs
  
  • Requires BID dosing

Question 14

Dipyridamole

Indication

Answer 14

• Used in combo w/ warfarin and indicated for prevention of thrombus following heart valve replacement
• Aggrenox: Combined w/ aspirin to reduce risk of ischemic stroke
  
  • FDA approved as combo med for stroke prevention
• No intrinsic antiplatelet activity or increased bleeding risk noted when used alone (w/o aspirin)

Question 15

Dipyridamole

Adverse Events

Answer 15

• Headache (most common)
• Nausea/dizziness
• Hypotension (vasodilator properties)
• Rash/flushing
• Bronchospasm/dyspnea
• Myocardial ischemia/infarction
• Arrhythmias

Question 16

Glycoprotein IIb/IIIa Receptor Antagonists

Agents

Answer 16

• Abciximab (IV only)
• Tirofiban (IV only)
• Eptifibatide (IV only)

Question 17

Glycoprotein IIb/IIIa Receptor Antagonists

MOA

Answer 17

• Reversible blockade of GP-IIb/IIIa receptors = final step of plt aggregation
  
  • This prevents plts from attaching to each other despite TXA2, ADP, thrombin or plt activation factor stimulation
  • Most effective form of antiplatelet activity

Question 18

Glycoprotein IIb/IIIa Receptor Antagonists

Indications

Answer 18

• Unstable angina
• Acute MI
• Percutaneous coronary intervention (angioplasty, etc.)

Question 19

Glycoprotein IIb/IIIa Receptor Antagonists

Prototype

Answer 19

• Prototype: Abciximab
  
  • Purified Fab fragment of monoclonal antibody that binds near the GPIIb/III receptor occluding the binding of fibrinogen.
  • Adverse effects:
    
    • Bleeding risk 2X increase

Question 20

Fibrinolytic Therapy

Answer 20

• Streptokinase
• Urokinase
• Tissue plasminogen activator tPA (alteplase)

Question 21

Fibrinolysis

Answer 21

• Fibrinolytic system dissolves intravascular clots
  
  • Plasminogen converted to → plasmin (active form)
  • Plasmin is a nonspecific protease, digests fibrin clots and other proteins
• Fibrinolytic drugs are also non-specific
  
  • Both protective thrombi and target thromboemboli are broken down
  • Potential for hemorrhage is high

Question 22

Alteplase/tPA

Action, Pk

Answer 22

• A version of tissue plasminogen activator (tPA) produced by recombinant DNA technology
• IV infusion
• E½t = 5 min
• Binds plasminogen catalyzing the reaction: plasminogen → plasmin
  
  • Plasmin digests fibrin (breaks down thrombi)
  • Plasmin breaks down fibrinogen and other clotting factors (increasing r/f subsequent hemorrhage

Question 23

Alteplase/tPA

Indications

Answer 23

• Acute MI
• Acute ischemic stroke
• Symptomatic PE

Question 24

Alteplase/tPA

When do you give it?

Answer 24

• Must administer quickly after symptom onset
• GUSTO-I trial (coronary artery occlusion)
  
  • Administered within 2 hours death rate: ~5%
  • Administered within 2-4 hours death rate ~6.7%
  • Administered within 4-6 hours death rate ~ 9.4%

Question 25

Alteplase/tPA Adverse Effects

Answer 25

* Bleeding!!!! 5-30% * **Intracranial hemorrhage** (r/o hemorrhagic stroke) 1.7-8% * Healing area w/ previous clot formation (wounds, IV & art lines, invasive procedure) * May need to administer blood products to restore hemostasis * **Angioedema** (especially if also on ACEI’s)

Question 26

Alteplase/tPA Absolute Contraindications

Answer 26

* Absolute * **Intracranial hemorrhage**/brain tumor/cerebral vascular lesion * Known source of **internal bleeding** * **Aortic dissection**

Question 27

Alteplase/tPA Relative Contraindications

Answer 27

* Relative * Severe HTN (\>180/110 mmHg) * Intracerebral issues not noted in absolute contraindications * Other anti-coags/anti-plt drugs (increase bleeding risk) * Known bleeding pathophysiology/non-compressible vascular puncture * History of traumatic injury major surgery, internal bleeding ~ 3 wks * Pregnancy * PUD

Question 28

Procoagulants

Answer 28

* Antifibrinolytic Agents * Lysine analogs * Aprotinin (not currently available in US secondary to safety concerns)

Question 29

Antifibrinolytics: Lysine analogs Agents

Answer 29

Transexamic acid (TXA) & aminocaproic acid

Question 30

``` Antifibrinolytics: Lysine analogs Transexamic acid (TXA) & aminocaproic acid ``` MOA

Answer 30

* **Competitively inhibits plasminogen activation** (binds to kringle domain in place of lysine on plasminogen), **_reducing plasmin concentration and fibrinolytic activity_**. TXA will directly inhibit plasmin at high doses. * Basic science still examining exact MOA * Alternative hypothesis has been suggested: TXA improves survival via reduction of pro-inflammatory plasmin activity * **Blood loss and need for transfusion are reduced** in surgical patients * **_No increase r/f thromboembolic events_** based on current evidence

Question 31

When do you give TXA?

Answer 31

Give within **3 hours** (of injury or birth) for reduced risk of death due to bleeding in trauma &OB hemorrhage

Question 32

TXA dose

Answer 32

* **1 g in 100 mL/NSS** given over **10 min** (loading dose) – Followed by **1g in 100 mL/NSS over 8 hrs** * Do not administer in same line as blood products, rFVIIa or Penicillin * Should be stored between **15-30 C** or 56-86 F

Question 33

TXA: Pharmacokinetics

Answer 33

* 3% protein bound (does not bind to albumin) * Vd 9-12 L * 95% excreted unchanged * Reduce dose in renal disease (see below) * Onset: 5-15 min * DOA: 3 hrs * E½t= 2-11 hrs

Question 34

TXA: Adverse Effects

Answer 34

* Seizures * GABA blockade in frontal cortex *(inhibition of inhibitory signals)* * Vision changes – particularly color vision * Ureteral obstruction and bleeding * Renal toxicity