Hematology Pharmacology Flashcards
What is the goal INR range, and what level is considered unsafe for surgery?
2-3
> 1.7 is considered unsafe for surgery
Give two conditions which increase the INR in the absence of Warfarin.
- Liver disease - less clotting factor proteins made
2. Prolonged antibiotic use (less vitamin K uptake)
Why is Warfarin still commonly leaned on?
Big thing is there is no renal clearance -> can be used safely in renal failure
What are important drug interactions with Warfarin which decrease or increase INR?
Decrease (inducer): Rifampin
Increase (inhibitor): Amiodarone, quinolones / metronidazole (destroy microbiota), TMP-SMX - reduce warfarin albumin binding
How does acetaminophen react with Warfarin?
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
How long must warfarin be held before surgery and why?
At least 5 days -> has a long halflife, and need at last two half-lives of thrombin to successfully replenish stores of it
What is the clinical standard for treatment of elevated INR in patients with no significant bleeding?
> 3, hold warfarin dosing
5, consider vitamin K, hold warfarin dosing
9, give vitamin K reversal, hold warfarin dosing
What is the clinical standard for treatment of elevated INR in patients with serious bleeding?
Hold warfarin, give vitamin K, supplement with prothrombin complex concentrate, factor 7, or FFP
What syndrome can be caused by usage of warfarin with protein C deficiency or usage of high warfarin loading dose?
Skin necrosis / purple toe syndrome
-> due to precipitous drop in protein C and subsequent thrombosis
What are the advantages of Dabigatran over warfarin? Include standard time window for stopping dabigatran before surgery.
- No INR monitoring is required (lab values often not elevated)
- Significantly shorter onset / offset action (can stop 1-2 days before surgery)
- Reduced risk for intracranial bleeding (tissue factor - 7 complex needed to control intracranial bleeds)
What are the disadvantages of dabigatran vs warfarin?
- Renally cleared -> may need more time to clear from system in chronic renal failure (up to 5 days)
- No antidote except a monoclonal antibody
- More GI bleeding and dyspepsia (acidic)
- No reliable way to measure anticoagulation state in the ACUTE setting (i.e. MI, stroke, PE)
What are the other two direct oral anticoagulants (other than dabigatran) and what is their main problem vs warfarin?
Apixaban / Rivaroxaban - Direct Xa inhibitors
- Increased GI bleeding (like dabigatran)
- Renally eliminated (like dabigatran)
Why are Heparin / LMWH so routinely used whenever we have DOACs?
- 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)
- Protamine - easy reversal agent
A patient has heparin induced thrombocytopenia. Choose the best drug to fix their pro-thrombotic state:
1. Warfarin. 2. Bivalirudin. 3. Dalteparin
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
Which has a shorter halflife: fondaparinux or UFH? Why? Which responds to protamine better?
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
Why might IV direct thrombin inhibitors be used vs PO (i.e. dabigatran)
IV agents i.e. bivalirudin have a much shorter halflife and are given in a hospital setting where there is close monitoring
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?
Recombinant Factor VII
-> super expensive
Give two anti-fibrinolytic agents and their mechanism of action.
Aminocaproic acid and tranexamic acid
Inhibit plasmin by preventing plasminogen from binding fibrin and cleaving the clot
What is the clinical indication of aminocaproic acid / tranexamic acid?
Used to control bleeding caused by different conditions
-> GI bleeding, heavy menstrual bleeding, dental procedure-associated, heavy trauma
What are two situations when antifibrinolytics would be contraindicated?
- Intracranial bleeds / cerebral hematomas -> can cause ischemic stroke
- Disseminated intravascular coagulation (presents with both bleeding and thrombosis, and drugs may worsen thrombosis)
Does aspirin cause a quantitative platelet defect?
No - it causes a qualitative platelet defect -> can’t make TXA2, so does not aggregate properly
-> prolongs bleeding time
How long should aspirin be held before surgery?
At least 5 days, since platelet halflife is 7-10 days and you need time to replenish platelets
How long should clopidogrel be held before surgery, and what are the adverse effects of concern?
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
What are the other ADP receptor blockers other than clopidogrel and what is their claim to fame?
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
What are the adverse effects associated with ticagrelor and why?
Bleeding (obv)
Other two because it is an analog of adenosine / induces adenosine release:
- Ventricular pauses (AV node blockade)
- Dyspnea - causes bronchocontriction
What is the treatment of choice for CML and gastrointestinal stromal tumors? Why?
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
What is the primary side effect of concern with imatinib and next generation dasatinib?
Off-target effects
Imatinib - peripheral edema
Dasatinib (imatinib-refractory CML) - Central edema (i.e. pleural / pericardial)
What are two hypomethylating agents and what is their mechanism? Why does it take a while for them to work?
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.
What is the clinical use of the hypomethylating agents?
Improves survival in myelodysplastic syndromes
-> when no other treatment is available, it slows progression of cancer
What side effects are shared by almost all chemotherapeutic agents?
Myelosuppression and gastrointestinal toxicity (damage to rapidly dividing cells)
Alopecia also common (rapidly dividing hair cells)
What is the initial reaction of concern with Rituximab therapy?
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)
What prophylactic treatment becomes far less effective while on Rituximab?
Vaccines - inhibition of proliferative B cell response
What is the mechanism of action of methotrexate and its reversal agent? How does it work?
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
What are the side effects of methotrexate?
Myelosuppression
Hepatotoxicity - think of chef with liver on his apron
Mucositis
Pulmonary fibrosis - bonzai tree next to leukovorin cat
What is the prodrug of 5-FU called and what is needed before it can work?
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
What effect does folinic acid have on 5-FU?
It actually increases its activity
-> more folate is available to incorporate into the enzyme and form a stable tertiary complex to inhibit thymidylate synthase
What side effects does bolus dose 5-FU cause vs continuous infusion dose?
Bolus dose - RNA effects more -> myelosuppression
Slow drip - DNA incorporation more -> hand-and-foot syndrome
“Schedule dependent toxicity”
What is hand and foot syndrome?
Side effect caused by slow infusion or low dose 5-FU treatment
-> pain, redness, numbness, and desquamation of palms bilaterally
Give two other pyrimidine analogs other than 5-fluorouracil. What is their mechanism?
- Cytarabine - Saber toothed tiger with hexagon spots
- 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
What is the first line treatment for hairy cell leukemia and its mechanism of action?
Cladribine - think of Hairy caveman “clad” in bearskins
- > holding a purine stick
- > purine analog
What is the mechanism of action of 6-MP and what is the name of its prodrug? What must activate it?
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
What is the drug interaction of note with azathioprine?
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
What are the side effects of 6-MP?
Myelosuppression (nun holding birdseed marrow)
Liver toxicity (liver apron)
Pancreatitis (pancreas sponge)
What is the mechanism of action of hydroxyurea outside of sickle cell disease?
Inhibition of ribonucleotide reductase -> mom running to hydropond knocking down waitress adding oxy’s to the UDP
How does pentostatin work and when is it used?
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)
Is it okay to use fondaparinux for treatment of hypercoagulability in HIT?
Yes
-> small molecule not likely to trip heparin-PF4 complexes
Are antiplatelet drugs better at stopping arterial or venous thrombosis and why? How about warfarin?
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
How long does it take for the effects of UFH to wear off before surgery?
About 4 hours
Note: it has a 4-6 hour halflife
How long does it take for the hypomethylating agents to take effect?
3-4 cycles of 28 days each = at least 3 months
Why do we need to use high dose chemotherapy with methotrexate?
Better penetration into sanctuary sites like CNS and testes in males
What tests can be used to measure the effectiveness of aspirin therapy?
Bleeding time
Light transmission aggregometry
-> used for all antiplatelet drugs
What are the contraindications of prasugrel?
Prior TIA or stroke
>75 years of age (elderly)
Underweight patients <60kg
Which DOAC is most associated with GI bleeding?
Dabigatran
Which oral anticoagulant is best used for prophylaxis in patients with prosthetic valves?
Warfarin -> all of the DOACs have been shown to be risky
What is the most common side effect of anti-fibrinolytic agents and why?
Dyspepsia -> acidic nature of the drugs (aminocaproic acid and tranexamic acid) makes for local irritation of the GI tract
