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M2 Heme/Lymph > Thrombotic Drugs Study Guide (Bleeding Disorders Pre-Work) > Flashcards

Thrombotic Drugs Study Guide (Bleeding Disorders Pre-Work) Flashcards

1
Q

Broadly, what are main uses of antithrombotic agents?

A

Used as both prevention of thrombosis in high-risk patients as well as treatment of acute & symptomatic thrombotic events.

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2
Q

Compare the typical composition of venous thrombi with arterial thrombi.

A

Venous: RBCs enmeshed in fibrin (“red thrombi”)

Arterial: Platelets with little fibrin or white cells (“white thrombi”)

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3
Q

Is a DVT of the distal or proximal larger leg veins worse?

A

Proximal (at or above the knee) is worse, due to icnreased odds of PE

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4
Q

When does arterial thrombosis typically occur?

What are the most severe clinical manifestations of this?

A

When: After erosion or rupture of an atherosclerotic plaque

Cardiac ischemia & stroke are the severe possibilities

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5
Q

What are some shared risk factors for both venous and arterial thrombosis?

A
  • Advanced age
  • Obesity
  • Infection
  • Metabolic syndrome
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6
Q

What are some classic risk factors for **venous **but not arterial thrombosis?

A
  • Cancer
  • Surgery
  • Catheters
  • Immobilization
  • Fractures
  • Pregnancy
  • Estrogen Use
  • IBD
  • SLE autoantibodies
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7
Q

What are some classic risk factors for **arterial **but not **venous **thrombosis?

A
  • Smoking
  • Hypertension
  • Diabetes
  • Hyperlipidemia

NOTE: I think this is bullshit. The study guide later contradicts itself and lists these same things as venous thrombosis risk factors as well. I mean, it seems pretty obvious.

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8
Q

Common gain-of-function gene mutations, including Factor V Leiden and Prothrombin G20210A are mainly risks for (arterial/venous) thrombosis.

A

Venous

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9
Q

Name the function of the following platelet receptors:

  1. GP Ib/IX/V
  2. GP Ia/IIa
  3. GP IIb/IIIa
A
  1. Binds vWF
  2. Binds matrix collagen
  3. Allows platelet-to-platelet aggregation
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10
Q

Name two factors, released or produced by platelets, that serve to recruit additional platelets to a site of vascular injury?

A

ADP and thromboxane A2

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11
Q

Heparin

Mechanism of Action

A

Heparin

No instrinsic anticoagulant activity. Binds antithrombin (AT), making it up to 1000x more potent. Heparin must bind both AT and thrombin to be effective. Heparin chains must be at least 18 saccharide units long to accomplish this linking action.

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12
Q

Heparin

Pharmakokinetics

A

Heparin

Given by continuous IV or SubQ. Immediate onset when given IV, 1-2hr delay with SubQ. t1/2 varies with dose.

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13
Q

Heparin

Adverse Effects

A

Heparin

  • Bleeding
  • Heparin-induced thrombocytopenia
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14
Q

Enoxaparin & Dalteparin

Mechanism of Action

A

Enoxaparin & Dalteparin

Low Molecualr Weight Heparins (LMWH). More effective at inactivating Factor Xa than thrombin as compared to heparin. Otherwise, same mechanism as heparin.

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15
Q

Enoxaparin & Dalteparin

Pharmakokinetics

A

Enoxaparin & Dalteparin

Given parenterally. More uniform absorption with SubQ than heparin. Longer t1/2 than heparin. Cleared by kidneys.

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16
Q

Enoxaparin & Dalteparin

Adverse Effects

A

Enoxaparin & Dalteparin

  • Bleeding (less than heparin)
    • Kidney clears LMWHs
    • Mostly a concern in pts with renal impairment
  • Thrombocytopenia (less often than heparin) but still important to monitor
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17
Q

Lepirudin & Bivalirudin

Mechanism of action

A

Lepirudin & Bivalirudin

  • Direct thrombin inhibitors
  • Synthetic polypeptides that bind both the catalytic and extended recognition site (exosite I) of thrombin
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18
Q

Lepirudin & Bivalirudin

Pharmacokinetics

A

Lepirudin & Bivalirudin

  • Given IV
  • Excreted by kidneys
  • t1/2 is 1.3hrs for lepirudin & 25min for bivalirudin
  • Thrombin slowly cleaves the bond within the peptide drug that holds it’s catalytic site and regains activity
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19
Q

Lepirudin & Bivalirudin

Adverse Effects

A

Lepirudin & Bivalirudin

  • Use w/ caution in pts with renal failure - may accumulate and cause bleeding
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20
Q

Fondaparinux

Mechanism of Action

A

Fondaparinux

  • “Direct” Factor Xa inhbitor
    • Causes an AT-mediated selective inhibition of Xa
  • Synthetic pentasaccharide
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21
Q

Fondaparinux

Pharmacokinetics

A

Fondaparinux

  • SubQ
  • Reaches peak plasma levels in 2hrs
  • Excreted in urine, t1/2 ~17hrs
  • Do not use in pts w/ renal failure
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22
Q

Fondaparinux

Adverse Effects

A

Fondaparinux

  • Much less likely than heparin or LMWH to trigger the syndrome of heparin-induced thrombocytopenia

[Easy to remember considering it doesn’t have heparin in it’s name…]

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23
Q

Warfarin

Mechanism of Action

A

Warfarin

  • Inhibits hepatic vitamin K reductase (VKORC1), which is used to recycle the active form of vitamin K, vitamin K hydroxyquinone.
  • Without active vitamin K, clotting factors II, VII, IX, and X are not carboxylated and remain inactive
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24
Q

Warfarin

Pharmacokinetics

A

Warfarin

  • The S-enantiomer is most active
    • Metabolized by CYP2C9
      • Common genetic polymorphisms in 2C9 affect metabolism rate
  • Minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4
  • Polymorphisms in VKORC1 affect its susceptibility to warfarin
    • Affects dosing
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25
Q

Warfarin

Adverse Effects

A

Warfarin

  • Bleeding: Risk increases w/ intensity and duration of therapy & use of other hemostasis-affecting drugs
    • Serious cases arise when bleeding results in:
      • Compression of vital structures
        • e.g. PNS, CNS, Pericardium
      • Massive internal blood loss that is not rapidly diagnosed
        • e.g. GI, intra- & retroperitoneal
  • Rare: warfarin-induced skin necrosis
  • Purple toe syndrome
    • Reversible, sometimes painful, blue-tinged discoloration of plantar and side surfaces of toes. Blanches w/ pressure, fades w/ leg elevation. Develops 3-8 weeks into therapy.
26
Q

Warfarin

Contraindications

A

Warfarin

  • Pregnancy - causes birth defects & abortion
27
Q

Dabigatran etexilate

Mechanism of action

A

Dabigatran etexilate

  • Prodrug: converted in vivo to the active dabigatran
  • Specific, reversible direct thrombin inhibitor
    • Inhibits both free and fibrin-bound (clot-bound) thrombin
      • Heparin and LMWHs cannot inhibit fibrin-bound thrombin
28
Q

Dabigatran etexilate

Pharmacokinetics

A

Dabigatran etexilate

  • Orally available prodrug
    • Rapidly converted into active form by esterases
  • Peak plasma levels in 2hrs
  • t1/2: 14-17hrs
  • Eliminated mainly via kidneys
    • >80% of drug is excreted in the urine unchanged
29
Q

Dabigatran etexilate

Drug Interactions

A

Dabigatran etexilate

  • The prodrug but not the active form is a P-glycoproteins substrate in the gut and kidneys. Recall: Pgp pumps drugs out of cells. Thus:
    • Inducers of Pgp (e.g. rifampin) will decrease plasma concentration of dabigatran
    • Inhibitors of Pgp (e.g. ketoconazole, amiodarone, verapamil) will increase plasma concentration of dabigatran
30
Q

Dabigatran etexilate

Adverse Effects

A

Dabigatran etexilate

  • Comparable rates of serious bleeding vs. warfarin
  • Monitor renal function to prevent accumulation that can lead to bleeding events
    • Esp. important in elderly pts or those with renal impairment
31
Q

Rivaroxaban

Mechanism of Action

A

Rivaroxaban

  • Selective, direct-acting factor Xa inhibitor
    • Binds the S1 and S4 active site pockets
32
Q

Rivaroxaban

Pharmacokinetics

A

Rivaroxaban

  • Given orally (F > 80%)
  • Peak plasma levels at 2-4hrs
  • t1/2: 5-9 hours
  • Dual elimination
    • 1/3 eliminated unchanged by kidneys
    • 2/3 by liver
      • CYP3A4/5 and CYP2J2
33
Q

Rivaroxaban

Drug Interactions

A

Rivaroxaban

  • Like dabigatran, rivaroxaban is a Pgp substrate, so use with caution in pts receiving Pgp inducers or inhibitors
34
Q

Rivaroxaban

Adverse Effects

A

Rivaroxaban

  • Bleeding events possible, but lower than other anticoagulants
35
Q

Alteplase

Mechanism of Action

A

Alteplase

  • Thrombolytic
  • A naturally occuring plasminogen activator
  • Results in a ~50% reduction in circulating fibrinogen
  • Initiates local fibrinolysis by binding to thrombus-bound fibrin and converting entrapped plasminogen to plasmin
  • Thus, works on free and thrombus-bound fibrin
    • “Alteplase activates plasminogen in all-the-places”
36
Q

Alteplase

Pharmacokinetics

A

Alteplase

  • Given IV.
    • Administer a bolus dose over 1min, then follow with infusion.
  • t1/2: About five minutes. >80% cleared in 10min. Fast-acting, fast to be cleared.
37
Q

Alteplase

Adverse Effects

A

Alteplase

  • Major bleeding in up to 5% of pts
    • Most serious: intracranial hemorrhage
      • Risk factors:
        • >65yrs age
        • HTN, esp. when severe
        • Low body weight (<70kg)
38
Q

Aspirin

Mechanism of Action

A

Aspirin

  • Irreversible inhibition of COX via acetylation
    • Blocks thromboxane A2 production
      • Inhibits platelet aggregation
39
Q

Aspirin

Pharmacokinetics

A

Aspirin

  • Orally available. Effects seen within an hour.
  • Peak plasma levels in ~4hrs
  • t1/2 is only 20min, but the effect is irreversible so it doesn’t really matter
40
Q

Aspirin

  1. What is the life span of a platelet?
  2. What percentage of a person’s platelet population is normally turned over in a day?
  3. Knowing this, about how long would it take for a person’s functional platelet population to recover following a single dose of aspirin?
A

Aspirin

  1. 7-10 days
  2. 10%
  3. 10 days
41
Q

Aspirin

Adverse Effects

A

Aspirin

  • Bleeding
  • GI irritation
    • Inhibition of GI COX1
  • Dosing of 75-150mg appears to be as effective as higher doses
    • Side effects increase with dosage, so low doses are favored
42
Q

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor

Mechanism of Action

Which of the four is reversible?

A

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor

  • Inhibit binding of ADP to the platelet P2Y12 receptor
    • Inhibits platelet aggregation
  • All are irreversible, except for ticagrelor
    • Reversibility of ticagrelor is useful in some circumstances, e.g. pts about to undergo surgery
43
Q

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor

Pharmacokinetics

Which are prodrugs?

A

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor

  • Clopidogrel and ticlopidine are prodrugs
    • Activated primarily by CYP2C19
  • Prasugrel is also a prodrug
    • First metabolized to an inactive thiolactone intermediate
    • Then activated via CYP3A4 and 2B6
    • Despite the two-step activation, prasugrel shows more extensive activation and more consistent activity (between pts) than clopidogrel
44
Q

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor

Adverse Effects

A

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor

  • Bleeding risk
  • Ticagrelor: dyspnea
  • Ticlopidine: severe neutropenia
    • Ticlopidine has been largely replaced by the other 3 for this reason
45
Q

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor

Which of the four has a notable drug interaction concern? What is the interaction?

A

Clopidogrel

  • It’s activation by CYP2C19 can be inhibited by PPIs (e.g. omeprazole)
    • Less active clopidogrel means a great risk for CV events
    • Avoid concurrent use of moderate or strong PPIs
46
Q

Dipyridamole

Mechanism of Action

A

Dipyridamole

  • Inhibits adenosine deaminase & phosphodiesterase
    • Causes accumulation of adenosine, adenine nucleotides, & AMP
      • These inhibit platelet aggregation (opposite of ADP) and may cause vasodilation
    • May also stimulate release of prostacyclin or PGD2
    • coronary vasodilation
47
Q

Dipyridamole

Pharmacokinetics

A

Dipyridamole

  • Oral
  • Peak plasma levels in ~75min
  • t1/2: ~10hrs
  • Highly bound to plasma proteins
  • Metabolized in liver
    • Conjugated as a glucuronide, excreted w/ bile
48
Q

Dipyridamole

Adverse Effects

A

Dipyridamole

  • Usually minimal and transient
    • Headache
    • GI upset
    • Dizziness
49
Q

Abciximab & Eptifibatide

Mechanism of Action

A

Abciximab & Eptifibatide

  • Binds platelet GP IIb/IIIa receptors, preventing fibrinogen binding and platelet cross-linking
  • Abciximab is a chrimeric human-murine mAb
    • Does not bind GP IIb/IIIa at the ligand-binding site
      • Thus acts noncompetitively
  • Eptifibatide
    • Competitive, reversible inhibitor
    • A polypeptide derived from rattlesnake venom
      • Critical sequence: Lys-Gly-Asp (KGD)
50
Q

Abciximab & Eptifibatide

Pharmacokinetics

A

Abciximab & Eptifibatide

  • Both given IV
  • Abciximab:
    • Biological t1/2 is under 30min, but its slow clearance gives it a functional t1/2 of up to 7 days
  • Eptifibatide
    • Maximal inhibition by 15min
    • Reversible - platelet aggregation normalizes within 4-8hrs
    • Renal clearance
      • Use w/ caution in pts w/ renal dysfunction
51
Q

Abciximab & Eptifibatide

Adverse Effects

A

Abciximab & Eptifibatide

  • Bleeding
  • Thrombocytopenia
  • Hypotension
  • Bradycardia
52
Q

What drug(s) would you give for:

Acute venous thromboembolism

A

LMWH or fondaparinux

53
Q

What drug(s) would you give for:

Surgical prophylaxis for venous thromboembolism

A

Like acute VTE, LMWH or fondaparinux

54
Q

What drug(s) would you give for:

Long-term VTE prophylaxis

A

Warfarin or rivaroxaban

55
Q

What drug(s) would you give for:

PE

A

Heparin, fibrinolytic drug

56
Q

What drug(s) would you give for:

Unstable Angina and non-STE ACS

A

Aspirin + or - clopidogrel or prasugrel;

eptifibatide or tirofiban;

LMWH or fondaparinux

57
Q

What drug(s) would you give for:

STEMI

A

Fibrinolytic drug, aspirin, and LMWH

58
Q

What drug(s) would you give for:

Acute Thrombotic Stroke

A

Fibrinolytic drug or aspirin

59
Q

What drug(s) would you give for:

Thrombotic Stroke & TIA Prophylaxis

A

Aspirin + dipyridamole;

clopidogrel or prasugrel

60
Q

What drug(s) would you give for:

Afib

A

Heparin or LMWH, followed by warfarin, dabigatran, or rivaroxaban

61
Q

What drug(s) would you give for:

Prophylaxis in a pt with an atificial heart valve

A

Warfarin, aspirin

62
Q
A

M2 Heme/Lymph (32 decks)

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