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Pharm Block 2 > 5 - Anticoagulants > Flashcards

5 - Anticoagulants Flashcards

1
Q

What is hemostasis?

A

Process that prevents blood loss from damaged blood vessels via vasoconstriction, adhesion and activation of platelets (platelet plug), and formation of fibrin.

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2
Q

What is Thrombosis?

A

Pathological formation of a “hemostatic” plug within the vasculature in the absence of bleeding.

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3
Q

Where do venous thrombi typically occur? When is this most serious?

A

In the superficial or deep veins of the leg.

DVT in the larger leg veins (above knee) is more serious because thrombi often embolize to the lungs and cause pulm infarction.

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4
Q

When does arterial thrombosis occur? What are the clinical manifestations of this?

A

ADD CLINICAL INDICATIONS

After erosion or rupture of an atherosclerotic plaque.

Cardiac ischemia and stroke are the most severe clinical manifestations of artherothrombosis.

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5
Q

What drug is an antagonist of heparin?

A

Protamine sulfate

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6
Q

What drug is an antagonist of dabigatran?

A

Idarucizumab

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7
Q

What drug is an antagnoist of thrombolytics?

A

Aminocaproic acid

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8
Q

Briefly describe the coagulation cascade? What is this synthesis dependent on?

A
  1. Activagtion of Factor X to Xa
  2. Conversion of prothrombin (II) to thrombin (IIa)
  3. Thrombin-mediated transformation of fibrinogen to fibrin ( the glue)

Synthesis dependent on Vitamin K: factors II, IX, X, and VII

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9
Q

What is heparin (unfractioned)?

A

Highly negative heterogenous mixture with a high molecular weight.

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10
Q

What is the mechanism of action of unfractionated heparin?

A

Antithrombin (AT) traps and inactivates coag factors, esp thrombin and Xa.

Heparin binds AT causing a conformational change in the reactive site, causing a 1000-fold increase in the rxn rate.

Serves as a catalytic template to which AT and activated coag factors can bind.

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11
Q

How effective are low molecular weight heparins?

A

They poorly catalyze the inhibition of thrombin by antithrombin (AT).

Can’t inhibit thrombin well because it doesn’t wrap around it like high MW heparin does.

Longer half life than heparin.

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12
Q

What does heparin do and not do?

A

Does NOT affect synthesis of clotting factors or lyse the existing clot.

DOES prevent further clot formation and prevents further extension of the clot.

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13
Q

What is the absorption and metabolism of heparin?

A

Not absorbed orally because it’s large and - charged, given by IV for immediate onset of action.

Half-life dose dependent.

Does not cross placenta and can be used in pregnancy.

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14
Q

How do you know if heparin is working?

A

Get an activated partial thromboplastin time (aPTT).

Heparin is therapeutic when the aPTT is 1.5 to 2.5 times the normal mean.

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15
Q

What adverse reactions are associated with heparin? How is this treated?

A

Bleeding/hemorrhage is a major adverse rxn.

Controlled with antagonist, protamine sulfate.

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16
Q

Other than bleeding, what is another adverse effect of heparin? What is the mechanism by which this occurs?

A

Heparin-induced thrombocytopenia: small number of pts but greater incidence in women.

  1. IgG Ab form against heparin-platelet factor 3.
  2. Copmlex activated platelets by binding FcgammaIIa receptors on platelet
  3. Causes plately aggregation and a fall in platement #

Discontinue heparin immediately

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17
Q

What are contraindications for heparin use?

A

Active bleeding
Severe uncontrolled HTN
Recent surgery of the eye, brain, or spinal cord

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18
Q

What are the therapeutic uses of heparin?

A

DVT or pulm embolism.

Initial management or acute MI

Drug choice for anticoagulation during pregnancy.

Low dose for prevention in surgical pts

NOT used chronically

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19
Q

What drug has a longer half life than heparin, is advantageous in a hospital setting, and has renal elimination? What are the benefits to using this? What are the contraindictions? What are therapeutic uses?

A

Enoxaparin (low molecular weight heparin).

Less risk of bleeding, lower risk of thrombocytopenia.

Used for ACUTE DVT and acute angina/MI.

Contraindications same as heparin + renal impairment

Poor inhibitor of thrombin due to it’s size.

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20
Q

What parenterally administered anticoagulant is used as a selective factor Xa inhibitor? Does it require AT?

A

Fondaparinux

Requires antithrombin (AT);
Has no effect on AT-thrombin.

Given SubQ.

Adverse effect: hemorrhage

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21
Q

What parenterally administered anticoagulant is used as a direct thrombin inhibitor? Does it require antithrombin (AT)? How is it given? Who is it given to?

A

Bivalirudin: synthetic polypeptide that directly inhibits thrombin by blocking substrate binding.

Does NOT require AT

Given by IV.

For pts who’ve had heparin-induced thrombocytopenia.

22
Q

What are important notes about free thrombin vs. fibrin-bound thrombin?

A

Thrombin bound to fibrin within a thrombus remains enzymatically active and protected from inactivation by AT; it can locally activate platelets and trigger coag.

This is why you need a drug that can act on free thrombin AND fibrin-bound thrombin to inactivate it.

23
Q

What heparin antagonist has a low MW, is positively charged, and is therapeutically used for heparin overdose? What is a second use of this drug?

A

Protamine sulfate.

Also reverses heparin following cardiopulmonary bypass.

24
Q

What is Warfarin? How is it given and what is the more active form?

A

A structural analog of vitamin K. VitK synthesized by gut bacteria and from dietary sources.

Given as a racemic mixture; S-warfarin more active form.

25
Q

What is the mechanism of action of warfarin?

A

Prevents gamma-carboxylation of several glu residues, resulting in incomplete coag factor molecules that are biologically inactive.

Rxn coupled to oxidation of VitK.

S-warfarin prevents recycling of oxidized VitK epoxide back to its reduced/active hydroquinone form.

26
Q

Why is warfarin a competitive inhibitor of VitK?

A

Because admin of VitK will displace warfarin.

27
Q

How do you know if warfarin is working? How long does it take to get your desired INR for warfarin?

A

Prothrombin time (PT)

Warfarin is therapeutic when PT is between 15 and 26 seconds (normal 12-14) and INR is 2-3 (normal 0.8-1.2).

Takes anywhere from 36-60 hours to get desired plasma concentration.

28
Q

When will you see the full therapeutic effect of warfarin? Why is this? What does this time depend on?

A

Not until several hours to days.

B/c circulating factors already synthesized are NOT inhibited by warfarin, so some active factors are still around while you can no longer synthesize more factors.

Depends on half-life of the particular clotting factor.

29
Q

How is warfarin administered? How is it metabolized? What are adverse reactions?

A

Oral.

Inactivated by liver microsome, primarily via CYP2C9- S-warfarin.

Hemorrhage.

30
Q

What are contraindications for warfarin?

A

Similar to heparin but also include:

  • CYP2C9 polymorphisms
  • Genetic variation in Vit K epoxide reductase complex protein 1
  • Pregnancy (teratogenic)
  • Liver, kidney disease, VitK deficiency
31
Q

What would you give to reverse warfarin? When would you need to do this?

A

If the pts INR is >5, VitK administered; but there’s a time delay for effectiveness due to time it takes to make more clotting factors

For immediate reversal: transfuse with fresh frozen plasma

32
Q

Why is it important to monitor INR in patients taking warfarin?

A

Increased INR means an increased risk of bleeding.

Decreased INR means risk of thrombosis.

33
Q

How common are drug interactions with warfarin? What else can interfere with warfarin?

A

Very common.

Decrease in INR with increased intake of green vegetables (decrease INR means risk of thrombis)

Cranberries, alcohol, vitE increase INR (risk of bleeding).

34
Q

Name four oral anticoagulants?

A

Warfarin

Dabigatran

Rivaroxaban

Apixaban

35
Q

What are therapeutic uses for warfarin?

A

Long-term treatment of venous thromboembolic disease, prophylaxis for thromboembolism in pts with Afib and in pts with prosthetic <3 valve.

36
Q

What is the bridging effect? Why is it needed?

A

It takes time for warfarin to work, so if you need immediate anticoagulation give heparin followed by warfarin to bridge the time it takes for warfarin to work.

37
Q

What does LMWH do poorly compared to HMWH?

A

LMWH poorly inactivates antithrombin.

38
Q

What newer oral anticoagulant is a pro-drug that’s metabolized in vivo to an active drug? What monitoring is required for pts on this drug?

A

Dabigatran

Usuallly none (unlike warfarin which requires monitoring); little effect on PT or INR.

Only requires monitoring in pts with renal insuff., hepatic impairment, low body weight, or extreme obesity.

39
Q

What is the mechanism of action of dabigitran?

A

Reversible competitive direct thrombin inhibitor.

Inhibits both fibrin-bound and free thrombin.

40
Q

How is dabigatran given? How long does it take to work?

A

Oral; rapid onset.

Excreted by the kidney; be careful when pts have problems with renal function

41
Q

What are adverse effects of dabigatran? Describe the reversal of it?

A

Bleeding.

Stop administration: reversal depends on 1/2 life ~14 hrs.

Give Idarucizumab neutralizes dabigatran within minutes.

42
Q

When is Dabigatran contraindicated? What is the therapeutic use?

A

Can cause renal impairment.
Pts with prosthetic <3 valves.

Used in pts with non-valvular atrial fibrillation at risk for stroke or systemic embolism.

43
Q

What is Dabigatran a substrate for? How can this impact metabolism?

A

Substrate of P-glycoprotein (P-gp) efflux transporter.

Use with P-gp inducer can reduce plasma concentrations of dabigatran.

Use with P-gp inhibitors can increase plasma concentrations.

44
Q

What is the function of P-glycoprotein efflux transporters?

A

Limit oral absorption of drugs by transporting them back into GI.

45
Q

Which drugs are direct factor Xa inhibitors? What do these do?

A

RivaroXAban

ApiXAban

Decrease amplified generation of thrombin without affecting existing thrombin levels. (Remaining thrombin sufficient to ensure primary hemostasis for safety).

46
Q

What is the mechanism of action of rivaroxaban?

A

Inhibits free factor Xa and clotbound factor Xa.

Prevents extension of thrombus by blocking further generation of thrombin within the clot.

47
Q

What is the administration and metabolism of rivaroxaban? What is the elimination.

A

Oral, rapid onset. Hepatic metabolism by CYPs (3A4) and CYP-independent metabolism.

Dual elim: from liver and kidneys

Substrate for P-glycoprotein.

48
Q

Shat are adverse effects of rivaroxaban?

A

Bleeding

Drug interactions with CYP3A4 inhibitors/inducers and P-glycoprotein inhibitors/inducers.

49
Q

What is the therapeutic use of rivaroxaban?

A

Similar to dabigatran

Pts nonvalvular atrial fibrillation at risk of stroke or systemic embolism.

50
Q

How does apixaban differ from rivaroxaban?

A

Apixaban has reduced bioavailability compared.

Both inhibit Xa, cleared by the kidney, and have same concerns.

51
Q

What are the benefits of new oral anticoagulants (NOAC) compared to older ones?

A

NOAC’s have a quicker onset and offset.

No food interactions. Fewer drug interactions.

Wider therapeutic window.

Lower risk of bleeding.

52
Q

What are disadvantages of new oral anticoagulants compared to warfarin?

A

Severe chronic kidney disease.

More expensive.

No specific antidote (except new antidote for dabigatran).

Pharm Block 2 (12 decks)

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