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PDA Block 2 > Anticoagulants & Thrombolytics > Flashcards

Anticoagulants & Thrombolytics Flashcards

1
Q

How are anti-coagulants involved in hemostasis?

A
  1. Vascular wall
  2. Platelets
  3. Soluble coagulation proteins
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2
Q

Steps in Blood Coagulation:

A
  1. Activation of factor X ⇒ Xa
  2. Conversion of prothrombin (factor II) ⇒ thrombin (IIa)
  3. Thrombin - mediated transformation of fibrinogen ⇒ fibrin
    • involves activation of factor XIII
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3
Q

Other effects of thrombin:

A
  • promotes platelet aggregation
  • converts factors V and VIII to active forms
  • initiates the anticoagulant protein C pathway
    • ​thrombin bound to thrombomodulin on the surface of endothelial cells
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4
Q

Describe the protein C pathway:

A
  1. Thrombin cleaves protein C ⇒ activated protein
    C (APC)
  2. APC then cleaves factors Va and VIIIa to give inactive products
  3. Process is accelerated in the presence of protein S and platelets
  4. Protein C and S are vitamin K dependent
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5
Q

Factor V Leiden:

A
  • factor V Leiden mutation is the most common genetic risk factor for thrombosis
    • ​90% of cases with APC resistance
    • **only a risk factor **
  • ​factor Va Leiden is inactivated about 10 times more slowly than normal factor Va
    • ​substantially reduced anticoagulant response to APC
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6
Q

Two ways to measure clotting time:

A
  1. **aPTT: **activated partial thromboplastin time
  2. **PT: **prothrombin time
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7
Q

Heparin (unfractionated, UFH):

Physical Properties

A
  • Heterogeneous mixture of sulfated polysaccharides
  • Large & highly negatively charged because of multiple sulfate and carboxylic acid residues
  • Commercial source: porcine intestine
    • heterogeneity in composition among different commercial preparations
    • biological activities are similar
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8
Q

Heparin (unfractionated, UFH):

Mechanism of Action

A
  1. No intrinsic anticoagulant properties
  2. Catalyzes the inhibition of several coagulation factors (proteases) **by antithrombin **
  3. Antithrombin **inhibits activated coagulation factors: **thrombin, Xa, IXa
    • “suicide substrate”
    • attacks a specific Arg-Ser peptide bond in the reactive site of antithrombin and becomes trapped as a stable 1:1 complex
  4. Binding of heparin induces a conformational change in antithrombin making reactive site more accessible to the protease (coagulation factor)
  5. Heparin increases the rate of the thrombin-antithrombin reaction at least 1000 fold by serving as a catalytic template
    • both the inhibitor (antithrombin) and protease (coagulation factor) bind
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9
Q

Both heparin and LMWH catalyze inhibition of Xa by
____________.

A

antithrombin

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10
Q

How does heparin affect clotting?

A
  • does not affect the synthesis of clotting factors
  • does not lyse the existing clot
  • does prevent further clot formation
  • does prevent the further extension of the clot
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11
Q

Heparin (unfractionated, UFH):

Absorption & Metabolism

A
  • not absorbed from the GI tract because of size and polarity
    • given by i.v. infusion or subcutaneously
  • does not cross the placenta
    • anticoagulant of choice in pregnancy
  • immediate onset of action when given IV
    • More variable with subq.
  • half-life in plasma depends on dose administered
    • Heparin is cleared by the reticuloendothelial system and liver
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12
Q

How do you monitor the action of heparin?

A
  • **aPTT **
  • **clot-based test: **time for a fibrin clot to form is measured
  • clotting time of 1.5x to 2.5x the normal mean aPTT (usually 50 to 80 sec) is therapeutic
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13
Q

Administration and Monitoring of Heparin:

A
  • Venous thromboembolism
    • Bolus injection/followed by continuous i.v. infusion
    • aPTT 1.8 to 2.5 times normal is assumed to be therapeutic response/decreased risk of recurrence if within 24 hours
  • Cardiopulmonary bypass
    • Very high dose
    • aPTT prolonged indefinitely
  • Prophylactic use of heparin to prevent venous thrombosis
    • Subq administration, low dose, no effect on aPTT
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14
Q

Heparin (unfractionated, UFH):

Adverse Reactions

A
  • Bleeding: MAJOR ADVERSE REACTION
    • major bleeding: treated for venous thromboembolism
    • mild bleeding: controlled with administration of an antagonist
  • Heparin-induced thrombocytopenia:
    • can occur in about 0.5% of patients 5-10 days
      after initiation of therapy
    • higher in surgical patients
    • Women are twice as likely as men to develop this condition
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15
Q

Heparin (unfractionated, UFH):

Contraindications

A
  • Active bleeding.
  • Recent surgery - intracranial, spinal cord, eye
  • Severe uncontrolled hypertension
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16
Q

Heparin (unfractionated, UFH):

Therapeutic/Clinical Indications

A
  1. initial treatment of deep venous thrombosis or pulmonary embolism
  2. initial management of unstable angina or acute MI, during and after coronary angioplasty or stent placement, or during surgery requiring cardiopulmonary bypass
  3. low dose heparin used prophylactically to prevent DVT and thromboembolism
  4. hemodialysis
  5. anticoagulation during pregnancy
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17
Q

**Low molecular weight heparins (LMWH): **

Enoxaparin [trade name: Lovenex®]; Dalteparin [trade name: Fragmin®]

Mechanism of Action

A
  • LMWH has greater capacity to potentiate factor Xa inhibition by antithrombin than thrombin inhibition
    • too short to bridge both
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18
Q

Enoxaparin; Dalteparin (LMWHs):

Pharmacokinetics

A
  • not absorbed through the GI mucosa
    • given parenterally
  • absorbed more uniformly than heparin after subcutaneous injection
  • longer biological half-lives than heparin (4-6 hours)
  • cleared almost exclusively by the kidneys
    • can accumulate in patients with renal impairment
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19
Q

Enoxaparin; Dalteparin (LMWHs):

Adverse Effects

A
  • Incidence of bleeding is somewhat less
  • Incidence of thrombocytopenia lower compared to heparin
    • platelet counts should still be monitored
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20
Q

Enoxaparin; Dalteparin (LMWHs):

Contraindications

A
  • Active bleeding.
  • Recent surgery - intracranial, spinal cord, eye.
  • Severe uncontrolled hypertension.
  • Renal impairment
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21
Q

Enoxaparin; Dalteparin (LMWHs):

Clinical Uses

A
  • treatment of acute DVT
  • prophylaxis of DVT
  • acute unstable angina and MI
  • hip replacement surgery, during and following hospitalization
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22
Q

**Direct Thrombin Inhibitors (2): **

A
  1. Lepirudin [REFLUDAN]
  2. Bivalirudin [ANGIOMAX]
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23
Q

Direct Thrombin Inhibitors:

Mechanism of action

A
  • inhibts thrombin by blocking the substrate binding site in a 1 : 1 complex
  1. lepirudin: 65–amino acid polypeptide
    • binds tightly to both the catalytic site and the extended substrate recognition site (exosite I) of thrombin
  2. bivalirudin: synthetic, 20–amino acid polypeptide
    • contains the sequence Phe1–Pro2–Arg3–Pro4, which occupies the catalytic site of thrombin
    • tetraglycine linker and a hirudin-like sequence that binds to exosite I
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24
Q

Direct Thrombin Inhibitors:

Pharmacokinetics

A
  • administered intravenously
  • excreted by the kidneys
  • t1/2 ≈ 1.3 hours for lepuridin
  • t1/2 ≈ 25 minutes for bivalirudin
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25
Q

Direct Thrombin Inhibitors:

  • Adverse Effects:
  • Contraindications:
  • Clinical Use:
A
  • Adverse Effects:
    • ​bleeding
    • use cautiously in patients with renal failure
      • drugs can accumulate ⇒ cause bleeding
  • Contraindications:
    • Active bleeding
    • Recent surgery - intracranial, spinal cord, eye
    • Severe uncontrolled hypertension
    • Renal disease
  • Clinical Use:
    • alternative to heparin to patients undergoin coronary angioplasty and cardiopulmonary bypass surgery
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26
Q

**What is a direct factor Xa inhibitor? **

A

fondaparinux [ARIXTRA]

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27
Q

Direct Factor Xa Inhibitor:

  • Mechanism of Action
  • Pharmacokinetics
  • Adverse Effects
A
  • Mechanism of Action: Fondaparinux causes an antithrombin-mediated selective inhibition of factor Xa
    • does not allow thrombin to bind
  • Pharmacokinetics:
    • ​administered by subcutaneous injection
    • reaches peak plasma levels in 2
      hours
    • excreted in the urine (t1/2 ≈ 17 h)
    • should not be used in patients with renal failure
  • **Adverse Effects: **
    • ​bleeding is the major edverse effect
    • hemorrhage can occur at any site
    • much less likely than heparin or LMWH to trigger the syndrome of heparin-induced
      thrombocytopenia
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28
Q

Dirtect factor Xa Inhibitor:

  • Contraindications:
  • Clnical Use:
A
  • Contraindications:
    • Active bleeding
    • Recent surgery - intracranial, spinal cord, eye.
    • Severe uncontrolled hypertension.
    • Renal impairment
  • Clinical Use:
    • FDA approved:
      1. ​Prophylaxis of deep vein thrombosis (DVT) in patients undergoing surgery for hip replacement, knee replacement, hip fracture or abdominal surgery
      2. treatment of acute PE
      3. treatment of acute DVT without PE
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29
Q

Protamine Sulfate (heparin antagonist):

A
  1. Positively charged molecule derived from fish sperm
  2. High affinity for negatively charged molecules
    • 1:1 binding with heparin ⇒ formation of an inactive complex
  3. Has weak anti-coagulant properties in high doses and if used alone
  4. May cause anaphylactic reactions
    • Observed in persons with fish hypersensitivity
    • previous protamine exposure in insulin products
  5. May also result in severe pulmonary hypertension.
  6. Used most commonly to reverse heparin following cardiopulmonary bypass
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30
Q

Warfarin [trade name: Coumadin®]:
Physical Properties

A
  • Fat soluble derivative of 4-hydroxycoumarin
  • Structural analog of Vitamin K
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31
Q

How are clotting factors activated?

A
  • Warfarin is a vitamin K antagonist
  • Vitamin K is required:
    • catalyze the conversion of inactive precursors of the clotting factors II, VII, IX, and X into active forms
  • γ−carboxylation of glutamic acid residues ⇒ formation of Ca2+ binding sites required for the coagulation process
  • γ−carboxylation is linked to vitamin K metabolism
    • Vitamin K is supplied to liver from dietary sources or as a metabolite of intestinal flora
  • Reduced form of vitamin (KH2) is required for enzymatic conversion of factor precursors
    • KH2 is oxidized ⇒ vitamin K epoxide (KO)
  • Oxidized form (KO) is coupled to the carboxylation of the glutamate residues in the precursor clotting factors
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32
Q

Warfarin:

Mechanism of Action

A
  • interferes with post-translational modification of vitamin K-dependent clotting factors (II, VII, IX, X)
  • inhibits the vitamin K epoxide reductase (VKORC1)
    • traps vitamin K in the KO form
  • KH2 must be regenerated from the KO form for the sustained synthesis of biologically active clotting factors
  • KH2 is not formed
  • Competitive inhibition:
    • can be overcome by administration of vitamin K
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33
Q

Why is the therapeutic effect of Vitamin K delayed for several hours to days?

A
  • Warfarin does not act on activated clotting factors
    • ​cicrulating clotting factors are not affected
  • Kinetics is dependent upon the breakdown of already activated clotting factors
    • 2-3 days for prothrombin (factor II)
    • 5 hrs for factor VII​
34
Q

How is warfarin absorbed and metabolized?

A
  • Rapidly and completely absorbed after oral administration
  • Extensively bound to plasma albumin (>99%)
  • Converted to inactive metabolites by the liver (CYP2C9)
35
Q

Warfarin:

Adverse Reactions/Contraindications

A
  • risk of bleeding increases with:
    • intensity and duration of warfarin therapy
    • other medications
    • anatomical source of bleeding.
  • metabolism by CYP2C9 & CYP2C9 polymorphisms:
    • cause a narrow therapeutic window
    • increased risk of bleeding.
  • genetic variations in VKORC1
  • contraindicated in pregnancy
  • patients with liver/kidney disease or Vitamin K deficiency
  • purple toe syndrome (3-8 weeks after)
36
Q

International Normalized Ratio (INR):

A

ratio of patient PT to a control PT

  • standardized by WHO
37
Q

When would reversal of warfarin be necessary? How is reversal achieved?

A

INR > 5

  • Minor bleeding: discontinuation of the drug
  • Excessive anticoagulation: administration of vitamin K
    • reversal may take days
  • Immediate reversal: requires exogenous administration of active clotting factors
  • Reversal of the anti-coagulant effects of warfarin is correlated with re-establishment of normal clotting factor activity
38
Q

Warfarin:

Drug Interactions

A
  • Drug interactions are very common with warfarin and often lead to poor control of anti-coagulation
  • Most serious drug interactions:
    • those that increase the anti-coagulant effect of the drug and increase the risk of bleeding
  • Other drug interactions involve those that decrease the action of warfarin
39
Q

Warfarin:

Clinical Indications

A
  • Long-term treatment of venous thromboembolic disease
  • Prophylaxis against thromboembolism in patients with:
    • atrial fibrillation
    • prosthetic heart valves
    • dilated cardiomyopathy
40
Q
  1. ______ variants affect warfarin pharmacokinetics
  2. ______ variants affect warfarin pharmacodynamics
A
  1. CYP2C9
    • ​decreased activity; higher drug concentrations; reduced warfarin dose
  2. VKORC1
    • ​​haplotypes A and B; more prevalent than those of CYP2C9;
41
Q

Other (new) Oral Anticoagulants (2):

A
  1. Dabigatran
  2. Rivaroxaban
42
Q

Dabigatran:

Mechanism of Action

A
  • prodrug (dabigatran etexilate):
    • converted to dabigatran
    • specific, reversible, direct thrombin inhibitor
    • inhibits both free and fibrin-bound thrombin
  • inhibits coagulation by preventing thrombin-mediated effects:
    • cleavage of fibrinogen ⇒ fibrin
    • activation of factors V, VIII, XI and XIII
    • inhibition of thrombin-induced platelet aggregation
  • inhibition of fibrin-bound thrombin provides an advantage over heparins:
    • bound thrombin can continue to trigger thrombus expansion
43
Q

Dabigatran:

Pharmacokinetics

A
  • orally available
  • rapidly absorbed and converted by esterases to its active form
  • Plasma levels peak within 2 hours of administration
    half-life is 14 to 17 hours
  • eliminated mainly via the kidneys
44
Q

How are Pgps involved in dabigtran kinetics?

A
  • Dabigatran etexilate, but not dabigatran (its active metabolite), is a substrate for the P-glycoprotein (Pgp) transporter in the gut and kidneys
  • should not be coadministered with inducers of Pgp
  • Pgp inducers (rifampin) = decrease plasma concentration
  • Pgp inhibtors (verapamil) = increase plasma concentrations
45
Q

Dabigatran:

  • Adverse Effects:
  • Therapeutic Uses:
A
  • Adverse Effects:
    • risk of bleeding
    • GI upset
  • Therapeutic Uses:
    • ​postoperative thromboprophylaxis
    • nonvalvular atrial fibrillation
46
Q

Rivaroxaban:

Mechanism of Action

A
  • selective direct-acting factor Xa inhibitor
  • binds directly and reversibly to Factor Xa via the S1 and S4 pockets
  • S1 subpocket determines the major component of selectivity and binding
47
Q

Rivaroxaban:

  • Pharmacokinetics
  • Adverse Effects
  • Clinical Uses:
A

Pharmacokinetics:

  • oral administration
  • half-life of 5 to 9 hours
  • dual mode of elimination:
    • 1/3 is eliminated unchanged by the kidneys
    • 2/3 is metabolized by the liver
    • CYP3A4/5 & CYP2J2​​

Adverse Effects:

  • bleeding, although are lower than with other anticoagulants

Clinical Uses:

  • stroke and systemic embolism (non-valvular a-fib)
  • prophylaxis DVT
48
Q

Describe the action of plasmin and its components:

A
  • Plasmin: an enzyme that digests fibrin
  • Plasminogen (inactive precursor of plasmin): converted to plasmin by cleavage of a single peptide bond
  • N-terminus (heavy chain): contains 5 disulfide-bonded loops (“kringles”) which act as lysine-binding sites and are responsible for binding of plasminogen and plasmin to specific lysine residues in polymerized fibrin
  • C-terminus (light chain): contains the active catalytic site of the molecule
  • Activation of plasminogen to plasmin:
    • initiated by endogenous or exogenous activators
49
Q

Endogenous t-PA:

Mechanism

A
  • endogenous activator synthesized by vascular endothelial cells and released at local sites of thrombosis

Mechanism:

  1. t-PA binds to binding sites on fibrin that are in close
    proximity to plasminogen binding sites
  2. activates fibrin-bound plasminogen ⇒ fibrin-bound
    plasmin ⇒ initiates clot resolution
  3. During the early stage of clot formation:
    • very little t-PA is released because plasminogen activator inhibitors (PAI-1 and PAI-2)
  4. PAI production decreases ⇒ t-PA production increases ⇒ breakdown of the clot ⇒ recanalization of the injured vessel
  • plasma prourokinase ⇒ urokinase by _kallikrein _
    • enhances fibrin-bound plasminogen activation
50
Q

Plasmin is a ___________ protease, digests fibrin clots and other plasma proteins

A

nonspecific

51
Q

Describe the regulation of free plasmin. What happens if plasmin exceeds this regulation?

A
  • Normally free plasmin becomes inactivated by α2-antiplasmin
  • Protects circulating fibrin and other clotting factors (like factors VIII and V)
  • When plasmin generation exceeds the capacity of the α2-antiplasmin system ⇒ systemic lytic state
    • consumption of fibrinogen, factor VIII and V
52
Q

Regulation of fibrinolysis:

A

unwanted fibrin thrombi are removed, while fibrin in
wounds persists to maintain hemostasis

53
Q

t-PA; Alteplase [trade name: Activase®]:

A
  1. Serine protease with one polypeptide chain
  2. Poor enzyme in the absence of fibrin
  3. Binds fibrin with high affinity via lysine binding sites in the amino terminus
    • **activates fibrin-bound plasminogen several **hundred-fold more rapidly than circulating plasminogen
  4. High affinity of t-PA/Alteplase for plasminogen in the presence of fibrin allows efficient degradation of clot fibrin
  5. Rapid hepatic clearance (t1/2 = 1 to 4 minutes)
    • requires continuous intravenous administration
  6. Nonantigenic
54
Q

Complications of thrombolytic therapy:

A
  • Hemorrhage — an indiscriminant phenomenon
  • Systemic lytic state resulting from systemic formation of plasmin
    • ​Produces fibrinogenolysis.
    • Destroys clotting factors (especially V and VIII)
  • **Minor bleeding: **(3-4%)
    • ​puncture or injection sites
  • Major bleeding requiring transfusion (1%)
  • Incidence of bleeding is similar when patients receive streptokinase or t-PA/alteplase
  • Incidence of hemorrhagic complications may be higher when combined with heaprin or aspirin
  • Incidence of hemorrhage is proportional to the dose of the thrombolytic agent used and the duration of therapy
55
Q

Indications for Thrombolytic Therapy:

A
  1. Management of ST-elevation myocardial infarction (STEMI) for the lysis of thrombi in coronary arteries
  2. Management of acute ischemic stroke
    • Recommended criteria for treatment:
      • Onset of stroke symptoms within 3 hours of treatment
  3. Management of acute pulmonary embolism
56
Q

Contraindications to Thrombolytic Therapy:

A
  • Active bleeding
  • Recent surgery within 10 days, including major surgery, organ biopsy, trauma, CPR
  • GI bleeding within 3 months
  • Recent CVA, intracranial surgery, or known intracranial mass or aneurysm
  • Hemorrhagic disorder
  • Hypersensitivity
  • Severe, uncontrolled hypertension
  • Pregnancy or postpartum period
57
Q

PROCOAGULANT DRUGS:

A

Aminocaproic acid [trade name: Amicar®]

  • potent inhibitor of fibrinolysis
58
Q

Aminocaproic acid:

A
  1. A synthetic lysine analog that **binds to the lysine binding sites of plasminogen and plasmin **⇒ blocks the binding of plasmin to fibrin
    • competitive inhibitor of plasmin(ogen) to fibrin
  2. Can reverse states associated with an excessive breakdown of fibrin
  3. Effective in decreasing hemorrhage with surgical procedures
  4. Concentration in urine can be 100-fold that in plasma
    • useful for treating urinary tract bleeding
59
Q

What is the platelets role in vascular injury? How are platelets involved pathologically?

A
  • provide the initial hemostatic plug
  • involved in pathological thromboses that lead to:
    • MI, stroke and peripheral vascular thromboses
60
Q

What causes platelets to adhere to the subendothelium?

A
  • GPIa/IIa and GPIb are platelet membrane proteins (integrins) that bind to collagen and vWF
    • ​causes platelets to adhere to the subendothelium of a damaged blood vessel
61
Q
  1. _________ are protease-activated receptors that **respond to thrombin (IIa) **
  2. __________ are purinergic receptors for ADP
  3. When either of these receptors are stimulated, they activate the fibrinogen-binding protein __________ (also an integrin) and _____ to promote platelet aggregation and secretion
A
  1. Protease activated: PAR1/PAR4
  2. Purinergic: P2Y1/P2Y12
  3. Fibrinogen-binding: GPIIb/IIIa and COX-1
62
Q

What does fibrinogen binding result in?

A

cross-linking of adjacent platelets

63
Q
  1. ____ is major product of COX-1
  2. ____ is synthesized by endothelial cells to inhibit platelet activation
A
  1. TXA2
  2. PGI2
64
Q

Aspirin [trade name: Bayer®]

Mechanism of action

A
  • irreversible inhibition of platelet COX-1 & 2
  • acetylation of serine residue near active site of the enzyme
  • blocks thromboxane formation in platelet
65
Q

Aspirin:

Pharmacokinetics

A
  • rapidly absorbed by the upper GI tract
    • ​measurable platelet effects within 1 hour
  • plasma half-life is only 20 minutes
    • effect on COX-1 and the platelet is permanent
    • anucleate platelet cannot synthesize new enzyme
  • life span of a platelet is ~ 7-10 days
  • may take 10 days for renewal of the platelet population
66
Q

Asprin:

Adverse Effects

Therapeutic Uses

A
  • Adverse Effects:
    • ​bleeding and GI irritation
    • side effects are dose-related
  • Therapeutic Uses:
    1. ​​MI prophylaxis
    2. alone or in combination with thrombolytics in
    3. acute MI
    4. acute phase of ischemic stroke
    5. stroke prophylaxis
    6. unstable angina
    7. preeclampsia prophylaxis
67
Q

Dipyridamole [trade name: Persantine®]:

A
  1. Mechanism of Action
    1. phosphodiesterase inhibition and/or blockade of uptake of adenosine increases cAMP
    2. **inhibits platelet aggregation **
    3. oral administration
  2. Adverse Effects
    • Headache
    • GI upset
    • Dizziness
  3. Therapeutic Uses
    • prevention of thromboemboli (with warfarin) in patients with prosthetic heart valves
68
Q

Drugs that inhibit ADP binding to the P2Y1/P2Y12 receptor (4):

A
  1. Clopidogrel
  2. Ticlopidine
  3. Prasugrel
  4. Ticagrelor
69
Q

What is the overall effect of platelet ADP receptor binding?

A

a further increase in platelet activation and aggregation

70
Q

All platelet ADP blockers are irreversible antagonists except:

A

Ticagrelor

71
Q

When would it be advantageous to use ticagrelor?

A

in patients about to undergo surgery

72
Q

Which platelet ADP blockers are **prodrugs **and what enzyme converts them to their active metabolites?

A
  • Prodrugs: Clopidogrel, ticlopidine & prasugrel
  • Clopidogrel and ticlopidine are metabolized by CYP2C19
  • Prasugrel is metabolized by CYP3A4 and CYP2B6
    • ​undergoes esterase-mediated hydrolysis to a thiolactone (inactive), then is converted to active metabolite
73
Q

Compare the pharmacokinetics of prasugrel vs. clopidogrel:

A
  • Prasugrel:
    • higher potency and a more rapid onset of action
    • more efficient generation of its active metabolite
    • produces a higher and more consistent level of platelet inhibition
    • less response variability and a decreased
      prevalence of nonresponsiveness
74
Q

All ADP blockers increase the risk of ________.

A

bleeding

75
Q

Other Adverse Effects of ADP blockers:

A
  • ticagrelor may cause dyspnea
  • ticlopidine can cause severe neutropenia
  • activation of clopidogrel by CYP2C19 is potentially inhibited by proton pump inhibitors (PPIs)
    • omeprazole
76
Q

ADP Blockers:

Therapeutic Use

A
  • Clopidogrel:
    • patients with unstable angina or NSTEMI in
  • *combination with aspirin**
    • patients with STEMI
    • recent MI, stroke, or established peripheral arterial disease
  • Prasugrel:
    • reduce rate of thrombotic cardiovascular events in patients who are to be managed with percutaneous coronary intervention (PCI)
  • Ticagrelor:
    • used in conjunction with aspirin for secondary prevention of thrombotic events
77
Q

Glycoprotein IIb/IIIa receptor blockers (2):

A
  1. Abciximab [trade name: Reopro®]
  2. Eptifibatide [trade name: Integrilin]
78
Q

Glycoprotein IIb/IIIa receptor blockers:
Mechanism of action

A
  1. Abciximab
    • Fab fragment of a chimeric human-murine monoclonal antibody
    • noncompetitive inhibitor
    • prevents platelet aggregation by binding to platelet GP IIb/IIIa receptors to prevent fibrinogen binding and cross-linking of platelets
  2. Eptifibatide
    • prevent platelet aggregation by preventing fibrinogen crosslinking of platelets
    • competitive, reversible inhibitor
    • highly specific for the GP IIb/IIIa receptor
79
Q

Glycoprotein IIb/IIIa receptor blockers:
Pharmacokinetics

A
  1. Abciximab
    • biphasic plasma half-life,
      • initial half-life < 10 minutes
      • second-phase halflife ≈ 30 minutes
    • biological half-life of 12 to 24 minutes
    • slow clearance
    • functional half-life up to 7 days
  2. Eptifibatide
    • ​achieves peak plasma concentrations by 5 minutes with maximal inhibition of platelet aggregation by 15 minutes
    • returns to normal within 4-8 hours after discontinuing drug
    • Renal clearance
  • ​both drugs are administered via IV
80
Q

Glycoprotein IIb/IIIa receptor blockers:

  • Adverse Effects
  • Clincal Uses
A
  • Adverse Effects:
    • most common adverse effect is bleeding
  • Clinical Use:
    • Abciximab
      • prevent platelet aggregation and thrombosis
      • administered in combination with aspirin and heparin or LMWH
      • shown to significantly prevent vessel restenosis, reinfarction, and death
    • Eptifibatide used in two ways:
      1. to prevent coronary thrombosis in persons with unstable angina or NSTEMI
      2. to prevent thrombosis in persons having coronary angioplasty or stent placement for STEMI

PDA Block 2 (15 decks)

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