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Pharm 7 > Antiplatelet, Anticoag, and Thrombolytic > Flashcards

Antiplatelet, Anticoag, and Thrombolytic Flashcards

0
Q

Glycoprotein IIb/IIIa receptor antagonist

A

Abciximab- Antiplatelet

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1
Q

ADP receptor antagonist

A

Clopidogrel- antiplatelet

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2
Q

Indirect thrombin/factor Xa inhibitors

A

Heparin, enoxaparin, fondaparinux (anticoagulants)

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3
Q

Vitamin K antagonists

A

Warfarin- antocoagulant

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4
Q

Antidote to heparin

A

Protamine

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5
Q

Antidote to warfarin

A

Vitamin K

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6
Q

Direct thrombin/factor Xa inhibitors

A

Lepirudin, dabigatran

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7
Q

Plasminogen activators

A

Tissue plasminogen activator (t-PA)

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8
Q

T/F: Platelet activation is normally suppressed by Gs/cAMP- mediated activation of PKA.

A

True

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9
Q

How does ADP increase platelet activation?

A

ADP triggers aggregation by stimulating two GPCRs-P2Y1 and P2y12 is coupled to Gi, which inhibits adenyl cyclase–> decrease production of cAMP–> decrease activation of PKA; decreased PKA activity–> increase platelet activation

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10
Q

MOA of Clopidogrel (plavix)

A
  • Blocks platelet aggregation
    1) Prodrug metabolized in LIVER to active thiol metabolite by CYP2C19.
    2) Bind irreversibly to platelet P2Y12 ADP receptor subtype; ultimately prevents activation of platelet surface GPIIb/IIIa receptors that bind fibrinogen and cross-link platelets.
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11
Q

Pharmacokinetics of Clopidogrel

A

Orally effective and extensively metabolized; maximal antiplatelet efficacy occurs 8-11 days after starting therapy; a loading dose can be used to a more rapid antiplatelet effect.

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12
Q

Therapeutic use for Clopidogrel

A
  • Alternative to low-dose aspirin.
  • Reduces rate of stroke, MI and death in atherosclerotic patients with recent stroke, MI, acute coronary syndrome(ACS) or PAD.
  • Somewhat better efficacy than aspirin but higher cost.
  • In combo with aspirin for prevention of coronary stent thrombosis and ACS
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13
Q

T/F: Clopidogrel has wide variability in drug response; therapeutic failure in patients with loss of function CYP3A4 allele

A

False- Loss of function CYP2C19*2 allele (boxed warning)

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14
Q

Adverse effects of Clopidogrel include…

A
  • 2nd gen drug with less bone marrow toxicity; most common are N/V, diarrhea and rash.
  • Bleeding- less than aspirin but prolonged
  • Thrombotic thrombocytopenic purpura (TTP)- rare but life threatening
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15
Q

Drug interactions and contraindication of Clopidogrel?

A

A) Use with caution in patients with bleeding disorders; avoid use with NSAIDs.
B) CYP2C19 inhibitors (omeprazole)

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16
Q

MOA of Abciximab

A
  • Blocks platelet aggregation

1) A Fab fragment of a monoclonal antibody against GPIIb/IIIa receptors; blocks fibrinogen binding

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17
Q

Pharmacokinetics of Abciximab

A

Given IV; plasma half-life= 10 min but DOA is much longer (48 hrs) due to irreversible binding of the antagonist

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18
Q

Therapeutic use of Abciximab

A

1) Most effective antiplatelet drugs (“super aspirins”) but very expensive.
2) Short term in combo with aspirin and low dose heparin to prevent ischemic events in patients with acute coronary syndromes or undergoing PCI.

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19
Q

Adverse effects of Abciximab

A
  • Bleeding, esp. GI and intracerebral reversed with donor platelets.
  • Thrombocytopenia- due to antibodies developing against chimeric protein
20
Q

What is a heterogenous mixture of sulfated mucopolysaccharides that is highly (-) charged; extracted from porcine intestinal mucosa (mast cells)

A

Heparin

21
Q

What is prepared (fractionated) from heparin by gel filtration chromotography? Low MW heparins?

A

Enoxaparin

22
Q

What is a synthetic pentasaccharide that contains the minimum number of heparin SO4- groups to bind antithrombin

A

Fondaparinux

23
Q

T/F: Heparin inactivates both thrombin and factor Xa equally?

A

True

24
Q

T/F: Low MW heparin (Enoxaparin) inactivates Xa and thrombin equally?

A

False- Inactivates Xa well but thrombin poorly

25
Q

T/F: Fondaparinux inactivates Xa but thrombin poorly?

A

False: No effect on thrombin

26
Q

T/F: Heparins have no intrinsic activity? They serve as a catalytic surface for antithrombin and target proteases and makes the catalytic site for antithrombin more accessible?

A

True- this is the MOA of heparins.

27
Q

T/F: Heparins anticoagulant effects occurs within 30 minutes of IV administration?

A

False- occurs rapidly

28
Q

1) How is heparin administered?
2) How is it cleared?
3) Why must patients on heparin be monitored?

A

1) IV, can be SC
2) Cleared by reticuloendothelial system
3) Binds to plasma proteins, mononuclear and endothelial cells, so free drug concentrations vary widely.
* LMWH /Fondaparinux given SC and no monitoring; both longer half-lives and cleared by kidney.

29
Q

Therapeutic uses of heparins:

A
  • Initial treatment for DVT/PE- rapid and short DOA. Used during outpatient transition to oral anticoagulants.
  • During different procedure to prevent thrombosis.
  • LMWH/Fondaparinux: replaced heparin in many cases because f convenience and no need for monitoring.
  • In combo with antiplatelets
  • Can be used safely in pregnancy (does not cross placenta).
30
Q

An adverse effect of heparin is bleeding. What is a polycationic protein antidote for severe hemorrhage?

A

Protamine sulfate- partial effect on LMWH but inactive against fodaparinux

31
Q

Besides bleeding, what is another major side effect of heparin? What can you use to during withdrawal of heparin and what is contraindicated?

A
  • Heparin-induced thrombocytopenia: occurs during first 5-14 days of treatment if IgG antibodies develop to an antigen created when heparin binds to a cytokine called platelet factor 4. This forms a complex, IgG tails binds FcyIIa receptors on platelets causing aggregationPlatelet numbers fall and patient predisposed to thrombosis.
  • Can use bivalirudin/lepirudin while patient is withdrawn. Warfarin is contraindicated.
32
Q

MOA of Vit K antagonists (warfarin)

A
  • Decrease formation of fibrin.
    1) Depletes vit K-dependent clotting factors (II,VII,IX,X) by inhibiting vit K epoxide reductase (VKORC1). This blocks regeneration of the reduced (active) form of vitamin k; an essential cofactor for y-glutamyl carboxylase (prevents carboxylation in the last step of coagulation).
  • Also depletes “anticoag” factors protein c and protein s.
33
Q

T/F: Warfarin onset of action is rapid.

A

False- delayed. Depends on the half-life of preexisting biological active clotting factors in circulation. VII has shortest half life (6hr) so response is not evident for 18-24 hr. Full effect not for several days.
-Reduce clotting factor levels by 30-50%.

34
Q

T/F: Warfarin is 99% bound to albumin and is the “oral” anticoagulant; half life ranges from 26-40 hr. Metabolized by CYP2C19. Activity and dose a adjustment must be monitored by measuring Pt/INR; INR target 2-3 for most patients.

A

False- Metabolized by CYP2C9 (CYP2C19 metabolizes clopidogrel). The rest of the statement is true.

35
Q

therapeutic uses of warfarin include:

A

Prevent DVT or PE following an initial course of heparin.

  • Prevention of thromboembolism in patients with prosthetic heart valves or a fib.
  • Not useful in emergency anticoag
36
Q

Why is there a wide variability in drug response due to polymorphisms what 2 genes in warfarin use?

A

-CYP2C9 (reduced clearance) and VKORC1 (achieve target INR more rapid)

37
Q

A boxed warning for warfarin is bleeding. What should you do if this happens?

A
  • Antidote Vitamin K- within hours if INR >5

- Life threatening hemorrhage requires transfusion of fresh frozen plasma containing active clotting factors.

38
Q

Besides bleeding, what other side effects/interactions does warfarrin have?

A
  • Teratogen (crosses placenta)
  • Lots of drug interactions: CYP 2C9, 3A4 inhibitors. Displacement from plasma albumin. Broad spectrum antibiotics. Anything that promotes bleeding (aspirin, etc.).
  • Drugs that reduce effect: Inducers of CYP, excessive vit. K intake
39
Q

Direct inhibitors of Thrombin (or factor Xa)- name the parenteral drug

A

Lepirudin

40
Q

What is a recombinant peptide derivatives of hirudin?

A

Lepirudin

41
Q

MOA of lepirudin?

A

Binds tightly to the catalytic and substrate recognition sites of thrombin; prevents thrombin from activating fibrinogen.

42
Q

Direct inhibitor of thrombin (or factor Xa) the oral prototype? And what is the MOA

A
  • Dabigatran etexilate (pradaxa)

- MOA: prodrug that is metabolized to a competitive inhibitor of thrombin (binds only to active site).

43
Q

What is given to lyse existing clots and restore obstructed vessel patency. To be effective they must be given within first 3 hr.

A

Thrombolytic agents: t-PA (atelpase)

44
Q

What is a human recombinant serine protease? MOA is converts inactive plasminogen to plasmin that digest fibrin to degradation products; most effective in the presence of fibrin?

A

t-PA (altepase)

45
Q

Describe pharmacokinetics of dabigatran etexilate?

A

-Etexilate substituent renders drug orally active; hydrolysis yields active form

46
Q

Therapeutic use of dabigatran etexilate

A
  • Considered a potential “warfarin eplacement”
    1) Currently approved only for prevention of stroke in patients with non-valvular atrial fibrilation.
    2) Main advantage over warfarin is its predictable coagulation response; monitoring INR is unnecessary.
47
Q

Adverse effects with dabigatran etexilate?

A

-Most common is GI upset; most serious is bleeding. No antidote.

Pharm 7 (10 decks)

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