Anticoagulants & Thrombolytics

Question 1

How are anti-coagulants involved in hemostasis?

Answer 1

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

Question 2

Steps in Blood Coagulation:

Answer 2

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

Question 3

Other effects of thrombin:

Answer 3

• 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

Question 4

Describe the protein C pathway:

Answer 4

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

Question 5

Factor V Leiden:

Answer 5

• 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

Question 6

Two ways to measure clotting time:

Answer 6

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

Question 7

Heparin (unfractionated, UFH):

Physical Properties

Answer 7

• 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

Question 8

Heparin (unfractionated, UFH):

Mechanism of Action

Answer 8

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

Question 9

Both heparin and LMWH catalyze inhibition of Xa by
____________.

Answer 9

antithrombin

Question 10

How does heparin affect clotting?

Answer 10

• 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

Question 11

Heparin (unfractionated, UFH):

Absorption & Metabolism

Answer 11

• 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

Question 12

How do you monitor the action of heparin?

Answer 12

• **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

Question 13

Administration and Monitoring of Heparin:

Answer 13

• 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

Question 14

Heparin (unfractionated, UFH):

Adverse Reactions

Answer 14

• 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

Question 15

Heparin (unfractionated, UFH):

Contraindications

Answer 15

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

Question 16

Heparin (unfractionated, UFH):

Therapeutic/Clinical Indications

Answer 16

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

Question 17

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

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

Mechanism of Action

Answer 17

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

Question 18

Enoxaparin; Dalteparin (LMWHs):

Pharmacokinetics

Answer 18

• 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

Question 19

Enoxaparin; Dalteparin (LMWHs):

Adverse Effects

Answer 19

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

Question 20

Enoxaparin; Dalteparin (LMWHs):

Contraindications

Answer 20

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

Question 21

Enoxaparin; Dalteparin (LMWHs):

Clinical Uses

Answer 21

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

Question 22

**Direct Thrombin Inhibitors (2): **

Answer 22

1. Lepirudin [REFLUDAN]
2. Bivalirudin [ANGIOMAX]

Question 23

Direct Thrombin Inhibitors:

Mechanism of action

Answer 23

• 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

Question 24

Direct Thrombin Inhibitors:

Pharmacokinetics

Answer 24

• administered intravenously
• excreted by the kidneys
• t_1/2 ≈ 1.3 hours for lepuridin
• t_1/2 ≈ 25 minutes for bivalirudin

Question 25

Direct Thrombin Inhibitors:

• Adverse Effects:
• Contraindications:
• Clinical Use:

Answer 25

• 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

Question 26

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

Answer 26

fondaparinux [ARIXTRA]

Question 27

Direct Factor Xa Inhibitor:

• Mechanism of Action
• Pharmacokinetics
• Adverse Effects

Answer 27

• 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 (t_1/2 ≈ 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

Question 28

Dirtect factor Xa Inhibitor:

• Contraindications:
• Clnical Use:

Answer 28

• 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

Question 29

Protamine Sulfate (heparin antagonist):

Answer 29

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

Question 30

Warfarin [trade name: Coumadin®]:
Physical Properties

Answer 30

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

Question 31

How are clotting factors activated?

Answer 31

• 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

Question 32

Warfarin:

Mechanism of Action

Answer 32

• 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

Question 33

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

Answer 33

• 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​

Question 34

How is warfarin absorbed and metabolized?

Answer 34

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

Question 35

Warfarin:

Adverse Reactions/Contraindications

Answer 35

• 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)

Question 36

International Normalized Ratio (INR):

Answer 36

ratio of patient PT to a control PT

• standardized by WHO

Question 37

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

Answer 37

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

Question 38

Warfarin:

Drug Interactions

Answer 38

• 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

Question 39

Warfarin:

Clinical Indications

Answer 39

• Long-term treatment of venous thromboembolic disease
• Prophylaxis against thromboembolism in patients with:
  
  • atrial fibrillation
  • prosthetic heart valves
  • dilated cardiomyopathy

Question 40

1. ______ variants affect warfarin pharmacokinetics
2. ______ variants affect warfarin pharmacodynamics

Answer 40

1. CYP2C9
   
   • ​decreased activity; higher drug concentrations; reduced warfarin dose
2. VKORC1
   
   • ​​haplotypes A and B; more prevalent than those of CYP2C9;

Question 41

Other (new) Oral Anticoagulants (2):

Answer 41

1. Dabigatran
2. Rivaroxaban

Question 42

Dabigatran:

Mechanism of Action

Answer 42

• 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

Question 43

Dabigatran:

Pharmacokinetics

Answer 43

• 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

Question 44

How are Pgps involved in dabigtran kinetics?

Answer 44

• 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

Question 45

Dabigatran:

• Adverse Effects:
• Therapeutic Uses:

Answer 45

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

Question 46

Rivaroxaban:

Mechanism of Action

Answer 46

• 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

Question 47

Rivaroxaban:

• Pharmacokinetics
• Adverse Effects
• Clinical Uses:

Answer 47

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

Question 48

Describe the action of plasmin and its components:

Answer 48

• 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

Question 49

Endogenous t-PA:

Mechanism

Answer 49

• 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

Question 50

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

Answer 50

nonspecific

Question 51

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

Answer 51

• 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

Question 52

Regulation of fibrinolysis:

Answer 52

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

Question 53

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

Answer 53

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 (t_1/2 = 1 to 4 minutes)
   
   • requires continuous intravenous administration
6. Nonantigenic

Question 54

Complications of thrombolytic therapy:

Answer 54

• 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

Question 55

Indications for Thrombolytic Therapy:

Answer 55

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

Question 56

Contraindications to Thrombolytic Therapy:

Answer 56

• 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

Question 57

PROCOAGULANT DRUGS:

Answer 57

Aminocaproic acid [trade name: Amicar®]

• potent inhibitor of fibrinolysis

Question 58

Aminocaproic acid:

Answer 58

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

Question 59

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

Answer 59

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

Question 60

What causes platelets to adhere to the subendothelium?

Answer 60

• 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

Question 61

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

Answer 61

1. Protease activated: PAR1/PAR4
2. Purinergic: P2Y1/P2Y12
3. Fibrinogen-binding: GPIIb/IIIa and COX-1

Question 62

What does fibrinogen binding result in?

Answer 62

cross-linking of adjacent platelets

Question 63

1. ____ is major product of COX-1
2. ____ is synthesized by endothelial cells to inhibit platelet activation

Answer 63

1. TXA₂
2. PGI₂

Question 64

Aspirin [trade name: Bayer®]

Mechanism of action

Answer 64

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

Question 65

Aspirin:

Pharmacokinetics

Answer 65

• 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

Question 66

Asprin:

Adverse Effects

Therapeutic Uses

Answer 66

• 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

Question 67

Dipyridamole [trade name: Persantine®]:

Answer 67

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

Question 68

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

Answer 68

1. Clopidogrel
2. Ticlopidine
3. Prasugrel
4. Ticagrelor

Question 69

What is the overall effect of platelet ADP receptor binding?

Answer 69

a further increase in platelet activation and aggregation

Question 70

All platelet ADP blockers are irreversible antagonists except:

Answer 70

Ticagrelor

Question 71

When would it be advantageous to use ticagrelor?

Answer 71

in patients about to undergo surgery

Question 72

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

Answer 72

• 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

Question 73

Compare the pharmacokinetics of prasugrel vs. clopidogrel:

Answer 73

• 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

Question 74

All ADP blockers increase the risk of ________.

Answer 74

bleeding

Question 75

Other Adverse Effects of ADP blockers:

Answer 75

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

Question 76

ADP Blockers:

Therapeutic Use

Answer 76

• 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

Question 77

Glycoprotein IIb/IIIa receptor blockers (2):

Answer 77

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

Question 78

Glycoprotein IIb/IIIa receptor blockers:
Mechanism of action

Answer 78

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

Question 79

Glycoprotein IIb/IIIa receptor blockers:
Pharmacokinetics

Answer 79

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

Question 80

Glycoprotein IIb/IIIa receptor blockers:

• Adverse Effects
• Clincal Uses

Answer 80

• 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