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Cardiopulm Exam 1 > Drugs for Thromboembolic Disorders > Flashcards

Drugs for Thromboembolic Disorders Flashcards

1
Q

Heparin: Mechanism of Action

A
  • Prepared from lungs of cattle and intestines of pugs, units/mL can vary widely
  • Long polysaccharide chains
  • Pentasaccharide sequence found randomly that binds to/activates ANTITHROMBIN III to inhibit factor Xa, and, via formation of a ternary complex, THROMBIN
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2
Q

Heparin: Effects

A
  • Blocks the generation of thrombin and inactivates thrombin
  • Prevents formation of RED CLOTS
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3
Q

Heparin: Clinical Applications

A
  • Used when there is a need for RAPID ONSET anticoagulant effects including PULMONARY EMBOLISM, evolving STROKE, massive DEEP VEIN THROMBOSIS, treatment of DISSEMINATED INTRAVASCULAR COAGULATION and as adjunct to thrombolytic therapy for ACUTE MI
  • used in PREGNANCY since it doesn’t cross the placenta
  • Used to prevent coagulation in extracorporeal circuits
  • Antidote: Protamine (protein with many positive charges)
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4
Q

Heparin: Pharmacokinetics

A
  • Given parenterally (IV or SC) since highly negatively charged and cannot readily cross membranes
  • Binds nonspecifically. Gives highly variable plasma levels which requires intensive monitoring via aPTT assay
  • Half-life of ~1.5 hours but value can vary widely
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5
Q

Heparin: Toxicities

A
  • Contraindicated for patients with THROMBOCYTOPENIA and uncontrollable bleeding, and avoid use during any surgery or procedure involving brain, eye, or spinal cord
  • Bleeding is a big concern and develops in 10% of patients; must be used with extreme caution in all patients with a high likelihood of bleeding
  • Bleeding can occur at any site and can be fatal so need to monitor
  • Pose a risk of spinal or epidural hematoma that can cause paralysis
  • Heparin- induced thrombocytopenia ***
    • Potentially fatal immune-mediated disorder characterized by reduced platelet counts with a paradoxical increase in thrombotic events
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6
Q

Low molecular weight Heparin: Enoxaparin

MOA?

A
  • Heparin molecules of shorter length
  • Because of short length, they cannot form the ternary complex with antithrombin III and thrombin that is needed to inactivate this enzyme… but, factor Xa is inhibited
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7
Q

Low molecular weight Heparin: Enoxaparin

Effects?

A
  • Selectively blocks factor Xa

- Prevents formation of RED CLOTS

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8
Q

Low molecular weight Heparin: Enoxaparin

Clinical Applications?

A
  • prevention of deep venous thrombosis after abdominal surgery or hip/knee replacement surgery
  • treatment of established DVT without/with pulmonary embolism
  • prevention of ISCHEMIC COMPLICATIONS in unstable angina, non-Q-wave MI, STEMI
  • Safe in pregnancy
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9
Q

Low molecular weight Heparin: Enoxaparin

Pharmacokinetics

A
  • Easier to use because dosing is predictable, can be used at home
  • First choice for treatment and prevention of DVT **
  • Much longer half-lives
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10
Q

Low molecular weight Heparin: Enoxaparin

Toxicities?

A
  • Bleeding is major. Antidote: Protamine
  • can cause heparin-induced thrombocytepenia
  • Like heparin, can cause severe neurologic injury in spinal puncture or spinal or epidural anesthesia
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11
Q

Fondaparinux: MOA

A
  • synthetic pentasaccharide identical to antithrombin-binding structure of heparin
  • selectively inhibits factor Xa without affecting thrombin
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12
Q

Fondaparinux: Effects

A
  • Blocks coagulation but preventing conversion of prothrombin to thrombin
  • Slightly more effective than enoxaparin, but also has increased risk of bleeding
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13
Q

Fondaparinux: Clinical Applications

A
  • preventing deep venous thrombosis
  • treatment of acute pulmonary embolism in conjunction with warfarin
  • treatment of acute deep venous thrombosis in conjunction with warfarin
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14
Q

Fondaparinux: Pharmacokinetics

A
  • administered subQ as a fixed daily dose
  • predictable pharmacokinetics
  • half-life of 17-21 hrs, longer if renal impairment… too long?
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15
Q

Fondaparinux: Toxicities

A
  • bleeding is biggest concern. NOT reversible with protamine
  • does NOT cause heparin-induced thrombocytopenia
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16
Q

Hirudin analogs: Bivalirudin

MOA?

A

synthetic 20 aa peptide similar to hirudin (anticoagulant of leeches), directly blocks thrombin

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17
Q

Hirudin analogs: Bivalirudin

Effects?

A

reversibly inhibits thrombin

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18
Q

Hirudin analogs: Bivalirudin

Clinical Applications?

A

can be given in combination with ASPIRIN to patients undergoing coronary ANGIOPLASTY

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19
Q

Hirudin analogs: Bivalirudin

Pharmacokinetics?

A
  • Must be given by IV

- Expensive

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20
Q

Hirudin analogs: Bivalirudin

Toxicities

A
  • doesn’t require antithrombin and causes less bleeding

- NO antidote

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21
Q

Argatroban: MOA

A

directly binds to CATALYTIC SITE OF thrombin (like hirudin analog but doesn’t bind to substrate binding site of thrombin like them)

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22
Q

Argatroban: Effects

none emphasized

A
  • reduces development of new thrombosis

- permits restoration of platelet counts in those with HIT

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23
Q

Argatroban: Clinical Applications

A
  • prophylaxis and treatment of thrombosis in patients with heparin-induced thrombocytopenia
  • efficacy of treatment is monitored by aPTT
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24
Q

Argatroban: Pharmacokinetics

A
  • given IV

- Short half-life

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25
Q

Argatroban: Toxicities

none emphasized

A
  • Risk for hemorrhage

- 12% develop hematuria

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26
Q

Warfarin: MOA

A
  • vitamin K antagonist

- ORAL

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27
Q

Warfarin: Effects

A
  • Decreases production of biologically active forms of calcium-dependent clotting factors II, VII, IX and X, as well as Protein C and Protein S
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28
Q

Warfarin: Clinical Applications

A

• Drug most widely used for long-term prophylaxis of thrombosis… especially for:

  • prevention of venous thrombosis
  • prevention of thromboembolism in patients with mechanical heart valves
  • prevention of thrombosis in patients with atrial fibrillation
  • not useful in emergencies since effects are delayed
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29
Q

Warfarin: Pharmacokinetics

A
  • Orally active, 100% bioavailability
  • eliminated by liver in bile
  • slow onset
  • slow offset
  • monitored with prothrombin time ratio, patients value to control value… now normalized (INR), must be monitored frequently, aim for INR = 2-3
  • monitor more frequently whenever a drug is added or subtracted
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30
Q

Warfarin: Toxicities

A

• bleeding is major complication

  • If bleeding occurs, discontinue warfarin immediately:
    • warfarin effects can be reversed by administering vitamin K
    • can quickly raise clotting factors levels with fresh whole blood, plasma or plasma concen
    • liver disease increases risk
  • crosses the placenta
  • has many drug interactions:
  • drugs that INCREASE effects of warfarin
  • drugs that PROMOTE BLEEDING
  • drugs that DECREASE effects of warfarin
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31
Q

Rivaroxaban: MOA

A

direct inhibitor of activated factor X

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32
Q

Rivaroxaban: Effects

A
  • directly inhibits the production of thrombin
  • advantages over warfarin:
  • rapid onset
  • fixed dosage
  • lower bleeding risk
  • fewer drug interactions
  • no need for INR monitoring
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33
Q

Rivaroxaban: Clinical Applications

A

• Has 2 approved uses:
1. Prevention of deep venous thrombosis and pulmonary embolism after hip or knee replacement

  1. prevention of STROKE in patients with NONVALVULAR ATRIAL FIBRILLATION

• But..

  • Dosing on time is important
  • no antidote for overdose (but andexanet alfa recently approved)
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34
Q

Rivaroxaban: Pharmacokinetics

A
  • administered ORALLY and has a high bioavailability
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35
Q

Rivaroxaban: Toxicities

A

• Bleeding is the major concern and has caused:

  • epidural hematoma
  • major intracranial/retinal bleeds
  • adrenal bleeding
  • GI bleeding
  • should be avoided in patients with significant renal or hepatic impairment
  • unsafe in pregnancy
  • should not be combined with other anticoagulants
  • interacts with CYP3A4
36
Q

What is a recombinant form of hirudin, no longer available in US?

A

desirudin

37
Q

What drugs are similar to Enoxaparin with similar indications?

A

delteparin, tinazeparin

38
Q

Other drugs besides Rivaroxaban?

A

others include apixaban and edoxaban

39
Q

Dabigatran: MOA

A

Reversible direct thrombin inhibitor

40
Q

Dabigatran: Effects

A
  • Directly blocks thrombin
  • Has 5 advantages over Warfarin:
  1. rapid onset
  2. no need to monitor
  3. few drug or food interactions
  4. lower risk of bleeding
  5. same dose is used for all patients
41
Q

Dabigatran: Clinical Applications

A
  • approved for use in prevention of STROKE and SYSTEMIC EMBOLISM IN patients with NONVALVULAR ATRIAL FIBRILLATION
  • recently given a contraindication for therapy of those with mechanical heart valves
42
Q

Dabigatran: Pharmacokinetics

A
  • Pills are unstable
43
Q

Dabigatran: Toxicities

A
  • Bleeding is the major concern

- antidote recently approved: idarucizumab

44
Q

Aspirin: MOA

A
  • irreversibly inhibits cyclooxygenase (thereby blocks synthesis of TXA2)
  • see benefits since low dose aspirin (≤325 mg/day) preferentially blocks COX-1
45
Q

Aspirin: Effects

A
  • blocks formation of TXA2

- Because platelets have no ability to synthesize new COX-1, this blockade persists for the LIFETIME of the platelet

46
Q

Aspirin: Clinical Applications

A
  • transient ischemic attacks
  • ischemic stroke
  • chronic stable angina
  • unstable angina
  • Acute MI
  • Previous MI
  • Primary prevention of MI
  • coronary stenting
47
Q

Aspirin: Pharmacokinetics

none emphasized

A
  • ORAL

- Doses need to be low

48
Q

Aspirin: Toxicities

none emphasized

A 
• Even at low doses, increases risk of: 
- peptic ulcer
- GI bleeding 
- hemorrhagic stroke
… so benefits must be weighed against risks
49
Q

Clopidogrel: MOA

A
  • irreversible blockade of P2Y12 receptors on platelets

- blocking the P2Y12 receptor prevents its Gi-protein driven decreases in platelet cAMP

50
Q

Clopidogrel: Effects

A
  • inhibits platelet aggregation

- like aspirin, has effects of platelet for its lifetime

51
Q

Clopidogrel: Clinical Applications

A

• Used to:
- prevent stenosis of coronary stents

  • secondary prevention of MI and ischemic stroke
52
Q

Clopidogrel: Pharmacokinetics

A
  • PRODRUG must be converted to active form by CYP2C19…

* some people have CYP2C19 variant enzyme that cannot activate clopidogrel (certain races)

53
Q

Clopidogrel: Toxicities

A
  • generally well-tolerated

- carries a risk of bleeding, but risk is lower for GI bleeding and intracranial hemorrhage than for aspirin

54
Q

another prodrug that is a close relative of clopidogrel, more effective with fewer drug interactions, but also causes more major bleeding

A

prasugrel

55
Q

reversible P2Y12 blocker that is not a prodrug, more effective than clopidogrel but increased risk of hemorrhagic stroke

A

ticagrelor

56
Q

Dipyridamole: MOA

none emphasized

A

Uncertain

57
Q

Dipyridamole: Effects

A

somehow suppresses platelet aggregation

58
Q

Dipyridamole: Clinical Applications

A

Used in a fixed-dose combination with aspirin to prevent recurrent ischemic stroke

59
Q

Dipyridamole: Pharmacokinetics

none emphasized

A

ORAL

60
Q

Dipyridamole: Toxicities

A
  • BLEEDING is a concern
  • most common adverse effects are:
  • headache
  • dizziness
  • nausea
  • vomiting
  • dyspepsia
  • diarrhea
61
Q

Cilostazol: MOA

A

type 3 phosphodiesterase inhibitor … i.e., prolongs life of cAMP in platelets and cells

62
Q

Cilostazol: Effects

A
  • platelet aggregation inhibitor

- vasodilator

63
Q

Cilostazol: Clinical Applications

A

claudication

64
Q

Cilostazol: Pharmacokinetics

none emphasized

A
  • ORAL tablet

- Metabolized by CYP3A4

65
Q

Cilostazol: Toxicities

none emphasized

A
  • headache (~34%)
  • diarrhea/abnormal stools
  • palpitations
  • dizziness
  • peripheral edema
66
Q

Abciximab: MOA

A

purified Fab fragment of monoclonal antibody

67
Q

Abciximab: Effects

A

• Blocks the final common pathway of platelet aggregation

  • Thus inhibits aggregation caused by all factors

•most effective of antiplatelet drugs

68
Q

Abciximab: Clinical Applications

A

• used short-term to prevent ischemic events in:
- acute coronary syndromes

  • percutaneous coronary intervention
69
Q

Abciximab: Pharmacokinetics

A

Administered IV

70
Q

Abciximab: Toxicities

none emphasized

A
  • doubles risk of major bleeding

* also may cause GI, urogenital and retroperitoneal bleeds

71
Q

SMALL PEPTIDE INHIBITOR of GP IIb/IIIa, also approved for ACS and PCI; Integrilin(TM), recently available as generic

A

eptifibatide

72
Q

NON-PEPTIDE INHIBITOR of GP IIb/IIIa modeled from venom of saw-scaled viper, also used for ACS and off-label for PCI, patent expired Jan 2019 but no generics yet

A

tirofiban

73
Q

alteplase (tPA): MOA

A

• purified glycoprotein of 527 amino acids

  • AA sequence is identical to HUMAN TISSUE PLASMINOGEN ACTIVATOR
  • generated in Chinese hamster ovary cells by recombinant DNA technology
74
Q

alteplase (tPA): Effects

A

catalyzes the conversion of clot-bound plasminogen to plasmin, the major enzyme responsible for clot breakdown

75
Q

alteplase (tPA): Clinical Applications

A

3 main indications:

  1. acute myocardial infarction
  2. acute ischemic stroke
  3. acute massive pulmonary embolism
76
Q

alteplase (tPA): Pharmacokinetics

A
  • large molecule that must be administered parenterally, almost always IV
  • very short half-life
77
Q

alteplase (tPA): Toxicities

A

bleeding is the major complication
- INTRACRANIAL HEMORRHAGE is the most serious concern

Occurs for 2 reasons:
1. DESTROYING PREEXISTING CLOTS CAN promote re-occurrence of bleeding at that site

  1. By degrading clotting factors, interferes with clot formation
78
Q

tPA variant (3 aa) with longer half-life (20-24 min), can be given as IV bolus, approved only for MI; recent data –> 2X more effective than alteplase for stroke

A

tenectaplase

79
Q

355 aa tPA derivative, has half-life of 13-16 min, approved only for MI

A

reteplase

80
Q

alteplase (tPA): Absolute contraindications

A
  • any prior intracranial hemorrhage
  • know structural cerebral vascular lesion
  • ischemic stroke with past months, unless has occurred within past 4.5 hrs*
  • active internal bleeding (other than menses)
  • suspected aortic dissection
81
Q

alteplase (tPA): Relative Contraindication

A
  • severe uncontrolled hypertension on presentation (BP > 180/110 mm Hg)
  • history of prior ischemic stroke, dementia or known intracerebral pathology not covered in absolute contraindications
  • traumatic or prolonged CPR (> 10 min) or major surgery (< 3 weeks ago)
  • noncompressible vascular punctures
  • active peptic ulcer
  • history of chronic, severe, poorly-controlled hypertension
  • current use of anticoagulants in therapeutic doses (INR 2-3 or greater); known bleeding diathesis
  • recent internal bleeding (< 4 weeks ago)
  • pregnancy
82
Q

urokinase (uPA): MOA

A

second physiologic plasminogen activator, present in high concentration in the URINE

83
Q

urokinase (uPA): Effects

A

the major activator of fibrinolysis in the fluid phase / extravascular compartment

84
Q

urokinase (uPA): Clinical Applications

A

pulmonary embolism

85
Q

urokinase (uPA): Pharmacokinetics

A

injected IV slowly

86
Q

urokinase (uPA): Toxicities

A
  • potentially fatal hemorrhage

- anaphylactic shock

87
Q

similar/classic systemic non-proteolytic activator of plasminogen purified from bacteria, appears to no longer be available in the US

A

streptokinase

Cardiopulm Exam 1 (13 decks)

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