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Pharm-Spring > Antiplatelets/Antifibrinolytics > Flashcards

Antiplatelets/Antifibrinolytics Flashcards

1
Q

Antiplatelets:

Medication Classes and Agents

A
  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)
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2
Q

COX-1 vs. COX-2: Platelet Function

A
  • 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
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3
Q

Aspirin Mechanism of Action (MOA)

A
  • 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
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4
Q

Aspirin

Doses

A
  • 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
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5
Q

Aspirin: Anti-platelet Indications

A
  • Indications:
    • TIA/ischemic stroke
    • Stable and unstable angina
    • Prevent/treat MI
    • Maintenance of patent coronary stents
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6
Q

Aspirin: Anti-platelet

Adverse Effects

A
  • GI bleed
  • Hemorrhagic stroke
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7
Q

P2Y12 Adenosine Diphosphate (ADP) Receptor Antagonists: Thienopyridines

A
  • 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
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8
Q

ADP Receptor Antagonists:

Agents

A
  • 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
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9
Q

ADP receptor antagonists: Clopidogrel

Indications

A
  • 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
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10
Q

ADP receptor antagonists: Clopidogrel

Pk

A
  • 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
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11
Q

ADP receptor antagonists: Clopidogrel

Drug:Drug Interactions

A
  • 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
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12
Q

ADP receptor antagonists: Clopidogrel

Adverse Reactions

A
  • 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)
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13
Q

Dipyridamole

Action, Pk

A
  • A pyrimidopyrimidine derivative w/ vasodilator and antiplatelet properties
  • MOA not clear
    • Increases plasma adenosine levels
  • Half Life: 10 hrs
    • Requires BID dosing
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14
Q

Dipyridamole

Indication

A
  • 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)
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15
Q

Dipyridamole

Adverse Events

A
  • Headache (most common)
  • Nausea/dizziness
  • Hypotension (vasodilator properties)
  • Rash/flushing
  • Bronchospasm/dyspnea
  • Myocardial ischemia/infarction
  • Arrhythmias
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16
Q

Glycoprotein IIb/IIIa Receptor Antagonists

Agents

A
  • Abciximab (IV only)
  • Tirofiban (IV only)
  • Eptifibatide (IV only)
17
Q

Glycoprotein IIb/IIIa Receptor Antagonists

MOA

A
  • 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
18
Q

Glycoprotein IIb/IIIa Receptor Antagonists

Indications

A
  • Unstable angina
  • Acute MI
  • Percutaneous coronary intervention (angioplasty, etc.)
19
Q

Glycoprotein IIb/IIIa Receptor Antagonists

Prototype

A
  • 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
20
Q

Fibrinolytic Therapy

A
  • Streptokinase
  • Urokinase
  • Tissue plasminogen activator tPA (alteplase)
21
Q

Fibrinolysis

A
  • 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
22
Q

Alteplase/tPA

Action, Pk

A
  • 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
23
Q

Alteplase/tPA

Indications

A
  • Acute MI
  • Acute ischemic stroke
  • Symptomatic PE
24
Q

Alteplase/tPA

When do you give it?

A
  • 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%
25
Q

Alteplase/tPA

Adverse Effects

A
  • 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)
26
Q

Alteplase/tPA

Absolute Contraindications

A
  • Absolute
    • Intracranial hemorrhage/brain tumor/cerebral vascular lesion
    • Known source of internal bleeding
    • Aortic dissection
27
Q

Alteplase/tPA

Relative Contraindications

A
  • 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
28
Q

Procoagulants

A
  • Antifibrinolytic Agents
  • Lysine analogs
  • Aprotinin (not currently available in US secondary to safety concerns)
29
Q

Antifibrinolytics: Lysine analogs

Agents

A

Transexamic acid (TXA) & aminocaproic acid

30
Q 
Antifibrinolytics: Lysine analogs
Transexamic acid (TXA) & aminocaproic acid

MOA

A
  • 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
31
Q

When do you give TXA?

A

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

32
Q

TXA dose

A
  • 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
33
Q

TXA: Pharmacokinetics

A
  • 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
34
Q

TXA: Adverse Effects

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

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