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Pathophysiology - Hematology > Hematology Pharmacology > Flashcards

Hematology Pharmacology Flashcards

1
Q

What is the goal INR range, and what level is considered unsafe for surgery?

A

2-3

> 1.7 is considered unsafe for surgery

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2
Q

Give two conditions which increase the INR in the absence of Warfarin.

A
  1. Liver disease - less clotting factor proteins made

2. Prolonged antibiotic use (less vitamin K uptake)

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3
Q

Why is Warfarin still commonly leaned on?

A

Big thing is there is no renal clearance -> can be used safely in renal failure

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4
Q

What are important drug interactions with Warfarin which decrease or increase INR?

A

Decrease (inducer): Rifampin

Increase (inhibitor): Amiodarone, quinolones / metronidazole (destroy microbiota), TMP-SMX - reduce warfarin albumin binding

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5
Q

How does acetaminophen react with Warfarin?

A

Pharmacodynamic interaction

  • > damage to liver naturally increases INR
  • > potentiates effects of warfarin due to necrosis if >2g of acetaminophen are taken over the course of 3+ days
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6
Q

How long must warfarin be held before surgery and why?

A

At least 5 days -> has a long halflife, and need at last two half-lives of thrombin to successfully replenish stores of it

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7
Q

What is the clinical standard for treatment of elevated INR in patients with no significant bleeding?

A

> 3, hold warfarin dosing
5, consider vitamin K, hold warfarin dosing
9, give vitamin K reversal, hold warfarin dosing

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8
Q

What is the clinical standard for treatment of elevated INR in patients with serious bleeding?

A

Hold warfarin, give vitamin K, supplement with prothrombin complex concentrate, factor 7, or FFP

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9
Q

What syndrome can be caused by usage of warfarin with protein C deficiency or usage of high warfarin loading dose?

A

Skin necrosis / purple toe syndrome

-> due to precipitous drop in protein C and subsequent thrombosis

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10
Q

What are the advantages of Dabigatran over warfarin? Include standard time window for stopping dabigatran before surgery.

A
  1. No INR monitoring is required (lab values often not elevated)
  2. Significantly shorter onset / offset action (can stop 1-2 days before surgery)
  3. Reduced risk for intracranial bleeding (tissue factor - 7 complex needed to control intracranial bleeds)
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11
Q

What are the disadvantages of dabigatran vs warfarin?

A
  1. Renally cleared -> may need more time to clear from system in chronic renal failure (up to 5 days)
  2. No antidote except a monoclonal antibody
  3. More GI bleeding and dyspepsia (acidic)
  4. No reliable way to measure anticoagulation state in the ACUTE setting (i.e. MI, stroke, PE)
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12
Q

What are the other two direct oral anticoagulants (other than dabigatran) and what is their main problem vs warfarin?

A

Apixaban / Rivaroxaban - Direct Xa inhibitors

  1. Increased GI bleeding (like dabigatran)
  2. Renally eliminated (like dabigatran)
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13
Q

Why are Heparin / LMWH so routinely used whenever we have DOACs?

A
  1. Very rapid onset and short half lives (UFH can be stopped 4-6 hours before surgey, enoxaparin/ LMWH can be stopped 12-24 hours before surgery)
  2. Protamine - easy reversal agent
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14
Q

A patient has heparin induced thrombocytopenia. Choose the best drug to fix their pro-thrombotic state:
1. Warfarin. 2. Bivalirudin. 3. Dalteparin

A

Bivalirudin is best -> a direct thrombin inhibitor (like argatroban)

Warfarin - halflife is too long, induces a pro-coagulant state immediately

Dalteparin - a low molecular weight heparin, will likely react with anti-PF4/heparin
-> LMWHs CANNOT be used in HIT

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15
Q

Which has a shorter halflife: fondaparinux or UFH? Why? Which responds to protamine better?

A

UFH - heparin is cleared by the reticuloendothelial system

Fondaparinux - pentasaccharide indirect Xa inhibitor - cleared renally. Longer half-life than midsize LMWH

UFH is larger and more easily reversed by protamine

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16
Q

Why might IV direct thrombin inhibitors be used vs PO (i.e. dabigatran)

A

IV agents i.e. bivalirudin have a much shorter halflife and are given in a hospital setting where there is close monitoring

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17
Q

What is viewed as the silver bullet in bleeding control, and works in hemophilia A and B as well as other acute bleeding scenarios? What is its drawback?

A

Recombinant Factor VII

-> super expensive

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18
Q

Give two anti-fibrinolytic agents and their mechanism of action.

A

Aminocaproic acid and tranexamic acid

Inhibit plasmin by preventing plasminogen from binding fibrin and cleaving the clot

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19
Q

What is the clinical indication of aminocaproic acid / tranexamic acid?

A

Used to control bleeding caused by different conditions

-> GI bleeding, heavy menstrual bleeding, dental procedure-associated, heavy trauma

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20
Q

What are two situations when antifibrinolytics would be contraindicated?

A
  1. Intracranial bleeds / cerebral hematomas -> can cause ischemic stroke
  2. Disseminated intravascular coagulation (presents with both bleeding and thrombosis, and drugs may worsen thrombosis)
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21
Q

Does aspirin cause a quantitative platelet defect?

A

No - it causes a qualitative platelet defect -> can’t make TXA2, so does not aggregate properly

-> prolongs bleeding time

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22
Q

How long should aspirin be held before surgery?

A

At least 5 days, since platelet halflife is 7-10 days and you need time to replenish platelets

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23
Q

How long should clopidogrel be held before surgery, and what are the adverse effects of concern?

A

At least 5 days as well

GI distress and bleeding may occur (especially if history of NSAID-induced ulcers)

Thrombotic thrombocytopenic purpura may be associated

24
Q

What are the other ADP receptor blockers other than clopidogrel and what is their claim to fame?

A

Clopidogrel needs to be activated by two CYP enzymes so there is a large % of non-responders to therapy

Prasugrel - better absorption, and only “one step” required for activation - quicker response and more potent

Ticagrelor - Only reversible inhibitor in class, shorter halflife which makes it theoretically requiring a shorter time to be withheld prior to surgery

25
Q

What are the adverse effects associated with ticagrelor and why?

A

Bleeding (obv)

Other two because it is an analog of adenosine / induces adenosine release:

  1. Ventricular pauses (AV node blockade)
  2. Dyspnea - causes bronchocontriction
26
Q

What is the treatment of choice for CML and gastrointestinal stromal tumors? Why?

A

Imatinib (think of the guy imitating in sketchy)

It is a TK inhibitor of the BCL-ABL gene product, and inhibits the expression of the philadelphia chromosome (9;22)

Also effective against c-kit tyrosine kinase in GI stromal tumors

27
Q

What is the primary side effect of concern with imatinib and next generation dasatinib?

A

Off-target effects

Imatinib - peripheral edema

Dasatinib (imatinib-refractory CML) - Central edema (i.e. pleural / pericardial)

28
Q

What are two hypomethylating agents and what is their mechanism? Why does it take a while for them to work?

A

Azacitidine, Decitabine

Inhibit DNA methyltransferase by incorporating into the DNA and inhibiting enzymatic function. Takes a couple cycles of semiconservative replication before an entire strand becomes demethylated and the effect is seen.

29
Q

What is the clinical use of the hypomethylating agents?

A

Improves survival in myelodysplastic syndromes

-> when no other treatment is available, it slows progression of cancer

30
Q

What side effects are shared by almost all chemotherapeutic agents?

A

Myelosuppression and gastrointestinal toxicity (damage to rapidly dividing cells)

Alopecia also common (rapidly dividing hair cells)

31
Q

What is the initial reaction of concern with Rituximab therapy?

A

Infusion reaction where binding of antibodies to CD20 markers on T cells causes a release of cytokines which may be fatal (fever, hypotension, rash, pruritis, dyspnea)

32
Q

What prophylactic treatment becomes far less effective while on Rituximab?

A

Vaccines - inhibition of proliferative B cell response

33
Q

What is the mechanism of action of methotrexate and its reversal agent? How does it work?

A

Inhibits dihydrofolate reductase - dihydrofolate accumulates and cells cannot make thymidine properly

Reversal agent: Folinic acid (leucovorin) - competes with MTX for transport into tissue cells and replenishes folate pools

34
Q

What are the side effects of methotrexate?

A

Myelosuppression
Hepatotoxicity - think of chef with liver on his apron
Mucositis
Pulmonary fibrosis - bonzai tree next to leukovorin cat

35
Q

What is the prodrug of 5-FU called and what is needed before it can work?

A

Capecitabine - 5-FU prodrug

Think of that saber-tooth tiger wearing a CAPE and you’ll remember CAPEcitabine is the prodrug of 5-FU.

All pyrimidine analogs need to be phosphorylated before they can be used to inhibit DNA/RNA enzymes

36
Q

What effect does folinic acid have on 5-FU?

A

It actually increases its activity
-> more folate is available to incorporate into the enzyme and form a stable tertiary complex to inhibit thymidylate synthase

37
Q

What side effects does bolus dose 5-FU cause vs continuous infusion dose?

A

Bolus dose - RNA effects more -> myelosuppression

Slow drip - DNA incorporation more -> hand-and-foot syndrome

“Schedule dependent toxicity”

38
Q

What is hand and foot syndrome?

A

Side effect caused by slow infusion or low dose 5-FU treatment
-> pain, redness, numbness, and desquamation of palms bilaterally

39
Q

Give two other pyrimidine analogs other than 5-fluorouracil. What is their mechanism?

A
  1. Cytarabine - Saber toothed tiger with hexagon spots
  2. Gemcitabine - bags of gems around the tiger

Rather than inhibiting thymidylate synthase (they are not uracil-like), they are incorporated into DNA and are unable to be removed by proofreading enzymes

40
Q

What is the first line treatment for hairy cell leukemia and its mechanism of action?

A

Cladribine - think of Hairy caveman “clad” in bearskins

  • > holding a purine stick
  • > purine analog
41
Q

What is the mechanism of action of 6-MP and what is the name of its prodrug? What must activate it?

A

Azathioprine - 6-mercaptopurine

Activated by HGPRT (think of HiGh PRiesT)

inhibits formation of IMP (think of azameralda kicking over the IMP imp) -> stops de novo purine synthesis

42
Q

What is the drug interaction of note with azathioprine?

A

Inhibitors of xanthine oxidase (i.e. febuxostat, allopurinol) will slow the degradation of 6-MP

  • > more 6-MP will go through the HGPRT pathway
  • > toxic accumulation and bone marrow suppresion
43
Q

What are the side effects of 6-MP?

A

Myelosuppression (nun holding birdseed marrow)
Liver toxicity (liver apron)
Pancreatitis (pancreas sponge)

44
Q

What is the mechanism of action of hydroxyurea outside of sickle cell disease?

A

Inhibition of ribonucleotide reductase -> mom running to hydropond knocking down waitress adding oxy’s to the UDP

45
Q

How does pentostatin work and when is it used?

A

Inhibitor of adenosine deaminase, which converts adenosine to inosine.

Accumulation of adenosine is toxic to B cells - used as treatment for hairy cell leukemia (in combination with cladribine)

46
Q

Is it okay to use fondaparinux for treatment of hypercoagulability in HIT?

A

Yes

-> small molecule not likely to trip heparin-PF4 complexes

47
Q

Are antiplatelet drugs better at stopping arterial or venous thrombosis and why? How about warfarin?

A

Antiplatelet drugs (i.e. clopidogrel / aspirin) - better for stopping arterial thrombosis in high pressure circulation, which requires good function of platelets to properly aggregate

Warfarin - works well on both, because it inhibitors thrombin synthesis which works in both platelet aggregation and the coagulation cascade

48
Q

How long does it take for the effects of UFH to wear off before surgery?

A

About 4 hours

Note: it has a 4-6 hour halflife

49
Q

How long does it take for the hypomethylating agents to take effect?

A

3-4 cycles of 28 days each = at least 3 months

50
Q

Why do we need to use high dose chemotherapy with methotrexate?

A

Better penetration into sanctuary sites like CNS and testes in males

51
Q

What tests can be used to measure the effectiveness of aspirin therapy?

A

Bleeding time

Light transmission aggregometry

-> used for all antiplatelet drugs

52
Q

What are the contraindications of prasugrel?

A

Prior TIA or stroke
>75 years of age (elderly)
Underweight patients <60kg

53
Q

Which DOAC is most associated with GI bleeding?

A

Dabigatran

54
Q

Which oral anticoagulant is best used for prophylaxis in patients with prosthetic valves?

A

Warfarin -> all of the DOACs have been shown to be risky

55
Q

What is the most common side effect of anti-fibrinolytic agents and why?

A

Dyspepsia -> acidic nature of the drugs (aminocaproic acid and tranexamic acid) makes for local irritation of the GI tract

Pathophysiology - Hematology (14 decks)

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