Hematology and Oncology Drugs Flashcards
What is the MOA of heparin? Does heparin have a short or long half-life?
Heparin is an activator of anti-thrombin (thrombin is what cleaves fibrinogen to fibrin to form clot), which will decrease thrombin and decrease factor Xa.
Heparin has a short half-life
When do you use heparin? How do you monitor heparin?
immediate anticoagulation for pulmonary embolism, acute coronary syndrome, MI, DVT. Unlike warfarin, it is not teratogenic so used during pregnancy. You monitor heparin by looking at partial thromboplastin time (PTT: normal: 25-35 secs)
List some side effects associated with heparin use
- bleeding b/c it’s an anticoagulant
- heparin-induced thrombocytopenia -develop IgG Abs against heparin-bound platelet factor 4 (PF4). Ab-heparin PF4 complex will activate platelets leading to thrombosis and since you’re using up platelets, you will get thrombocytopenia.
- osteoporosis
- drug-drug interactions
Explain how heparin can cause heparin-induced thrombocytopenia
heparin use can cause production of autoantibodies against heparin bound platelet factor 4. Antibody+heparin-bound platelet factor 4 complex can activate platelets leading to thrombosis. Since platelets are being used up, can lead to thrombocytopenia.
How to treat a heparin toxicity? what’s the charge on the molecule?
Use protamine sulfate (a positively charged molecule) that will bind heparin which is negatively charged
List 2 LMW heparin and the synthetic heparin. How do they compare to regular heparin?
- LMW heparin: enoxaparin, dalteparin
- synthetic heparin: fondaparinux
- act more on factor Xa than thrombin
- better bioavailability
- 2-4x higher half-live
- can be administered subcutaneously (heparin is iv and sc)
- no need to monitor labs
- **but no antidote if there’s toxicity so not easily reversible
People who need immediate anticoagulation with heparin, but get heparin induced thrombocytopenia have what other alternatives?
-argatroban, bivalirudin, dabigatran are DIRECT thrombin inhibitor that can be used as alternatives to heparin in cases of HIT.
List the 3 direct thrombin inhibitors that can be used for immediate anticoagulation if heparin is contraindicated like in cases of HIT. Which one is related to hirudin, an anticoagulant used by leeches
- argatroban
- bivalirudin -related to hirudin, an anticoagulant used by leeches
- dabigatran
What’s the mech of action of warfarin aka coumadin? How is warfarin use monitored?
Warfarin interferes with y-carboxylation of vitamin K-dependent clotting factors II, VII, IX and X, and proteins C and S.
Warfarin use is monitored by prothrombin time/INR, affecting the extrinsic coagulation cascade.
How’s the half-life of warfarin?
long half-life
Warfarin metabolism can be affected by polymorphisms in the gene for?
Vitamin K epoxide reductase complex (VKORC1)
What are the clinical uses of warfarin?
-chronic anticoagulation (venous thromboembolism ppx, and prevention of stroke in atrial fibrillation)
AF is assoc with increased clotting b/c of disturbed blood flow so to prevent clots, warfarin is used ppx.
Warfarin or heparin cannot be used in pregnant ppl b/c of its teratogenicity?
Warfarin cannot be used in pregnancy b/c can cause dandy-walker malformation (cerebellar hypoplasia), blindess and intellectual disability.
What are some side effects assoc with warfarin?
- bleeding b/c it’s an anticoagulant
- teratogenic
- skin/tissue necrosis due to small vessel microthromboses
- “warfarin skin necrosis” -due to already shorter half-lives of proteins C and S (anti-coagulants) than factors II, VII, IX, X so in the beginning of warfarin treatment can be hypercoagulable
- drug-drug interactions
How to reverse Warfarin toxicity (too much bleeding)?
- give Vitamin K
- but for rapid reversal, give fresh frozen plasma.
Explain the need for “heparin bridging” during anticoagulation with warfarin.
- heparin is freq used when starting warfarin
- heparin activates anti-thrombin which decreases thrombin and factor Xa –> anti-coagulable state
- early warfarin use is assoc with hypercoagulability b/c proteins C, S (anticoaguants) < factors II, VII, IX, X = transient hypercoagulable state
*this reduces risk of recurrent venous thromboembolism and skin/tissue necrosis
Compare structure of heparin and warfarin.
heparin is large and negatively charged polymer (which is why its antidote protamine sulfate is + charged)
warfarin is small, amphipathic molecule.
Compare route of administration of heparin and warfarin
heparin is parenteral (IV, SC)
warfarin is oral (po)
Compare site of action of heparin and warfarin.
heparin = blood by activating antithrombin warfarin = liver by inactivating vit K epoxide reductase (enzyme in the liver)
Compare onset of action of heparin and warfarin.
heparin = rapid (secs) warfarin = slow, limited by half-lives of clotting factors that are already formed
Compare duration of action of heparin and warfarin.
heparin = acute (hrs) -short t1/2 (t1/2 = .7Vd/Cl) warfarin = chronic (days)
Compare if heparin and warfarin can inhibit coagulation in vivo
heparin = yes b/c works on the blood to activate anti-thrombin III warfarin = no b/c works on the LIVER
Direct thrombin (IIa) inhibitors = argatroban, bivalirudin, dabigatran. What are the 2 direct factor Xa inhibitors? What do you use them clinically for? Toxicity?
direct factor Xa inhibitors = Apixaban, rivaroxaban so they bind to and directly inhibitor factor Xa used as treatment and PPX for DVT and PE (rivaroxaban); stroke PPX in pts with AF (like warfarin)
given orally; and do not usu require coagulation monitoring. There’s a risk of bleeding and there’s no reversal agent.
List the 5 thrombolytics.
- tPA/tissue plasminogen activato (alteplase)
- rPA (reteplase)
- streptokinase
- TNK-tPA (tenecteplase)
What’s the mech of action of thrombolytics? What is the drug’s effect on PTT, PT, and platelet count?
- directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots
- clot buster –> increase bleeding –> increase PTT and increase PT; no effect on platelet count
What’s the clinical use for thrombolytics (clot busters)?
- Early MI (used within 3 - 4.5 hrs of onset of symptoms)
- early ischemic stroke (used w/in 3 - 4.5 hrs of onset of symptoms)
- direct thrombolysis of SEVERE PE
Thrombolytics are clot busters assoc with risk of bleeding. Thrombolytics (tPA, reteplase, streptokinase, tenectplase) are contraindicated in?
- pts with active bleeding
- h/o of intracranial bleeding
- h/o of stroke or head trauma within past 3 months
- known bleeding diastheses
- severe HTN (syst > 185, diastolic > 110)
- PLT count < 100,000
- age < 18
How to treat toxicity with thrombolytics? ALso, what can be used to correct factor deficiencies.
antidote for toxicity with thrombolytics = aminocaproic acid (inhibitor of fibrinolysis = prevent fibrin breakdown = preserve clot)
to restore factor deficiencies, you can give FFP and cryoprecipitate (source of fibrinogen)
Aspirin is an NSAID that irreversibly inhibits COX-1 and COX-2 via covalent acetylation. How long will the effect of aspirin last?
The plts cannot synthesize new COX until new platelets are made and then they can synthesize COX.
What are changes to PT, PTT, bleeding time, TXA2, prostaglandings, and leukotrienes when someone is on aspirin?
aspirin inhibits COX-1 and COX-2 which are enzymes responsible for making prostaglandins and thromboxanes. So a person will have lower levels of TXA2 and prostaglandins. No effect on leukotriene levels b/c those are produced by lipooxygenase.
PT, PTT are unaffected b/c aspirin doesn’t affect extrinsic or intrinsic coagulation pathway. Bleeding time will increase b/c TXA2 is impt in plt aggregation so lower TXA2 = lower plt aggregation = increase bleeding time
Platelets have ADP receptors that when ADP (released by platelets) bind will induce expression of GPIIb/IIIa on plt surface which will interact with fibrinogen to start platelet aggregation. List the 4 ADP receptor inhibitors. 3 of them inhibit plt aggregation by irreversibly blocking ADP receptors while 1 reversibly blocks ADP receptor.
-clopidogrel, prasugrel, ticagrelor, ticlopidine
- *clopidogrel, prasugrel, ticlopidine = irreversible blocker
- *ticagrelor = reversible
ADP receptor blockers are used in which 3 clinical settings?
-clopidogrel, prasugrel, ticagrelor, ticlopidine
used in acute coronary syndrome, coronary stenting, decrease incidence or recurrence of thrombotic stroke
Which condition may be seen in patients on ADP receptor blockers (clopidogrel, prasugrel, ticagrelor, ticlopidine)? Which one of the 4 ADP receptor blockers is assoc with neutropenia?
all may cause thrombocytic thrombocytopenic purpura (TTP) -due to decreased enzyme (ADAMTS13) that normally cleaves vWF multimers into small monomers for degradation; no degradation –> abnormal platelet adhesion –> microthrombi (microangiopathic hemolytic anemia)
*only ticlopidine is assoc w/ neutropenia
List the 2 phosphodiesterase (PDE) III inhibitors that increase cAMP in platelets –> inhibition of platelet aggregation; vasodilators. What are they used for? Toxicities?
-Cilostazol and dypyridamole are phosphodiesterase III inhibitors that increase cAMP in platelets –> inhibition of plt aggregation; they are also vasodilators
used for: intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (when used with aspirin), angina ppx
toxicities: N/V, headache, facial flushing, hypotension, abdominal pain
List the 3 GPIIb/IIIa inhibitors (GPIIb/IIIa impt in interacting with fibrinogen to aid in plt aggregation) Which one is the monoclonal antibody Fab fragment?
- Abciximab = monoclonal ab against GPIIb/IIIa inhibitor
- eptifibatide
- tirofiban
these inhibitors bind to the glycoprotein receptor IIb/IIIa on activated platelets to prevent aggregation by preventing its interaction with fibrinogen
What are the clinical uses and side effects of GPIIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban)
clinical uses: unstable angina, percutaneous transluminal coronary angioplasty
toxicity: bleeding, thrombocytopenia
Azathioprine (prodrug of 6-mercaptopurine), 6-mercaptopurine, 6-thioguanine (6-TG) are antimetabolites. What’s their mech of action?
-they are purine (thiol) analogs that will be metabolized to 6-thioinosinic acid (TIMP) by HGPRT (enzyme responsible for purine salvage) which inhibits DE NOVO purine synthesis.
List the clinical uses of the antimetabolites: azathioprine (prodrug of 6-mercaptopurine), 6-mercaptopurine, 6-thioguanine
- tx rejection ppx
- RA
- IBD (chrohn’s, UC)
- SLE
- used to wean patients off steroids in chronic disease and to treat steroid refractory chronic disease
Which antimetabolites can be used to wean pts off steroids in chronic disease and to treat steroid refractory chronic disease?
azathioprine, 6-mercaptopurine, 6-thioguanine
Azathioprine and 6-mercaptopurine are degraded by xanthine oxidase. Which 2 drugs are contraindicated b/c they inhibit xanthine oxidase and thus will cause toxic accumulations of azathioprine/6-MP?
allopurinol
febuxostat
What are 3 side effects of azathioprine, 6-mercaptopurine, 6-thioguanine?
myelosuppresion
GI side effects
liver side effects
The anti-metabolite Cladribine (2-CDA) has multiple mechanisms. Explain. What is it used for?
Cladribine is a purine analog that has multiple mech (can inhibit DNA polymerase, can cause DNA strand breaks). It is an adenosine deaminase inhibitor causing build-up of toxic levels of adenosine in neoplastic B cells.
can treat hairy cell leukemia, a neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes that stain + for tartrate-resistant acid phosphatase (TRAP)
Cladribine, an antimetabolite, used for treatment of hairy cell leukemia has which 3 toxicities
- myelosuppresion
- nephrotoxicity
- neurotoxicity
The anti-metabolite Cytarabine (arabinofuranosyl cytidine) is used for AML, lymphomas. What is its mech of action and toxicities?
Mech of action: pyrimidine analog that will cause inhibition of DNA polymerase
Side effects: thrombocytopenia, leukopenia, megaloblastic anemia –> pancytopenia
5-fluorouracil, is an antimetabolite, used to treat colon cancer, pancreatic cancer, basal cell carcinoma (topical) What is its mech of action? Toxcities? Can the toxicities be reversed with leucovorin (folinic acid)?
5-FU is a pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex will inhibit thymidylate synthase –> decrease dTMP –> decrease DNA synthesis
myelosuppresion, which is NOT REVERSIBLE with leucovorin (folinic acid) while myelosuppression with methotrexate (also involves folic acid) is prevented with leucovorin.
Methotrexate is an antimetabolite. It is a folic acid analog that competitively inhibits which enzyme?
MTX is a folic acid analog that competitively inhibits dihydrofolate reductase –> decrease dTMP –> decrease DNA synthesis.
Which 2 antimetabolites work similiarly by involving folic acid? Which one causes myelosuppression that can be rescued with leucovorin (folinic acid aka 5-formyl-THF)?
5-fluorouracil is a pyrmidine analog that is bioactivated to 5F-dUMP that can complex folic acid; this complex will inhibit thymidylate synthase –> decrease dTMP –> decrease DNA synthesis
Methotrexate is a folic acid analog that competitively inhibits dihydrofolate reductase (dihydrofolic acid –> THF (impt in making purines –> DNA, RNA, thymidine –> DNA, methionine –> proteins)
Both can cause myelosuppression. 5-FU cannot be rescued with leucovorin while methotrexate can.
Methotrexate is a folic analog that competitively inhibits dihydrofolate reductase impt in making THF which is impt in making DNA, RNA and proteins. MTX can be used for?
Cancers: leukemias (ALL), lymphomas, choriocarcinoma (high hcG), sarcomas
non-cancers: ectopic pregnancy, medical abortion (w/ misoprostal/prostaglandin E1 analog), rheumatoid arthritis, psoriasis, IBD (chrohn’s, UC), vasculitis.
List 4 side effects of methotrexate. Which one could be reversed by leucovorin?
- myelosuppression reversible with leucovorin
- hepatotoxicity
- mucositis (.e.g mouth ulcers)
- pulmonary fibrosis
All the cancer antimetabolites (azathioprine/6-MP/6-TG, cladribine, cytarabine, 5-FU, MTX) work in which phase of cell cycle?
S-phase (DNA synthesis) specific
Bleomycin is an antitumor antibiotic. What is its mechanism of action? Clinical use? Toxicity?
Bleomycin induces free radical formation leading to breaks in DNA strands.
Clinical uses: Testicular cancer, Hodgkin Lymphoma
Toxicity: Pulmonary fibrosis (dose-dependent), skin hyperpigmentation, mucositis, minimal myelosuppression
Dactinomycin (actinomycin D) is an antitumor antibiotic used how and for? Toxicity?
Dactinomycin intercalates in DNA used for Wilms tumor, Ewing sarcoma, rhabdomyocarcoma (“children act out”). Toxicity includes myelosuppression.
Doxorubicin, daunorubicin are antitumor abx work by? used to treat? Side effects?
Doxorubicin, daunorubicin generate free radical, intercalate DNA to cause breaks in DNA leading to decreased DNA replication. They’re used for solid tumors, leukemias, lymphomas.
Side effects: Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. Toxic to tissues following extravassation.
Doxorubicin and daunorubicin are antitumor abx that work by generating free radicals and intercalating DNA causing breaks that will prevent DNA replication. A side effect is cardiotoxicity (dilated cardiomyopathy). What is used to prevent cardiotoxicity?
Dexrazoxane (iron chelating agent) used to prevent cardiotoxicity associated with using doxorubicin, daunorubicin.
What is busulfan? what is it used for? Any side effects?
Busulfan is an alkylatin agent that cross-links DNA used for CML. Also used to ablate patient’s bone marrow before transplantation.
Side effects: severe myelosuppression, pulmonary fibrosis, hyperpigmentation.
What agent can be used to ablate the patient’s bone marrow before bone marrow transplantation? State its mech of action and side effects.
Busulfan is an alklating agent that cross-links DNA that can be used to ablate pt’s bone marrow before bone marrow transplantation. Toxicity includes severe myelosuppression (in all cases), pulmonary fibrosis, hyperpigmentation.
Which 2 anti-cancer drugs can both cause hyperpigmentation and pulmonary fibrosis? State them and state their mech of action.
Bleomycin -antitumor abx that induces free radical formation to cause breaks in DNA strands to treat testicular cancer, Hodgkin lymphoma.
Busulfan -alkating agent that cross-links DNA, used in CML and ablate bone marrow before bone marrow transplantation.
Cyclophosphamide, ifosfamide are 2 alkylating agents that are used for solid tumors, leukemia, and lymphomas. What’s their mech of action, and toxicity?
- cross-link DNA at guanine N-7. Require bioactivation by liver
toxicity: myelosuppression, hemorrhagic cystitis (partially prevented by co-administering MESNA that will neutralize metabolites)
Nitrosoureas are alkylating agents. List the 4 nitrosoureas. How do they work? What are they used for? What are side effects?
Nitrosoureas like carmustine, lomustine, semustine, streptozocin) are alkylating agents that require bioactivation and can cross BBB to cross-link DNA.
They’re used for brain tumors including glioblastoma multiforme.
Side effects: CNS toxicity (convulsions, dizziness, ataxia) and acute, chronic pulmonary fibrosis.
Microtubule inhibitors: Paclitaxels + other taxols and vincristine/vinblastine (vinca alkaloids). Explain the mech of paclitaxels + other taxols and what they can be used to treat. What about side effects?
Paclitaxels and other taxols can hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur).
Treat ovarian and breast carcinomas
toxicity: myelosuppression, alopecia, hypersensitivity
Microtubule inhibitors: Paclitaxels + other taxols and vincristine/vinblastine (vinca alkaloids). Explain the mech of action of vinca alkaloids. What can they be used to treat? What about specific toxicites assoc with vincristine, vinblastine.
Vincristine and vinblastine bind to b-tubulin and inhibit its polymerization into microtubules –> prevent mitotic spindle formation (M-phase arrest).
They’re used in solid tumors, leukemias, lymphomas, wilm’s tumor
- Hodgkin (vinblastine)
- non-hodgkin (vincristine)
vincristine: neurotoxicity (areflexia, peripheral neuritis), paralytic ileus.
vinblastine: blasts bone = bone marrow suppression
Cisplatin and carboplatin can cross-link DNA used in testicular, bladder, ovary and lung carcinomas. What are 2 of their toxicities. How can one be prevented?
Cisplatin and carboplatin cross-link DNA used in testicular, ovary, bladder and lung carcinomas. Side effects are nephrotoxicity and ototoxicity.
Can prevent nephrotoxicity with AMIFOSTINE (free radical scavenger) and chloride (saline) diuresis.
What is amifostine used to prevent?
Amifostine is a free radical scavenger that can be given with cisplatin, carboplatin (cross-link DNA to treat testicular, ovary, bladder, lung cancer) to prevent NEPHROTOXICITY
What is the MOA of etoposide, teniposide? What do they treat? And What are side effects?
Etoposide and teniposide are topoisomerase II inhibitors that will increase DNA degradation use in treating solid tumors (particularly testicular and small cell lung cancer), leukemias and lymphomas
toxicity: myelosuppression and GI upset, alopecia.
What is the MOA of irinotecan, topotecan? What can they treat? Side effects?
Irinotecan and topotecan inhibit topoisomerase I and prevent DNA unwinding and replication.
treat: colon cancer (irinotecan); ovarianand small cell lung cancers (topotecan)
Side effects: severe myelosuppression, diarrhea
What is the MOA of hydroxyurea? What can it treat? Side effects?
Hydroxyurea inhibits ribonucleotide reductase which decreases DNA synthesis (S-phase specific).
Can be used to treat melanoma, CML, sickle cell disease (by increasing HbF).
Can cause myelosuppression and GI upset.
List the 2 most commonly used glucocorticoids in cancer chemotherapy.
Prednisone, prednisolone.
Prednisone (prodrug) that can be activated into prednisolone via 11b-hydroxysteroid dehydrogenase
What are some side effects of glucocorticoid use?
Cushing-like symptoms, weight gain, central obesity, muscle breakdown, cataracts, acne, osteoporosis, HTN, peptic ulcers, hyperglycemia, psychosis (profound mood changes -“steroid psychosis”
What is Bevacizumab? Side effects?
Monoclonal ab that targets VEGF which can be used to treat colon cancer, RCC, and macular degeneration.
Side effects: hemorrhage, blood clots, impaired would healing.
What is Erlotinib? What is it used for? Side effect?
Ertolinib is a EGFR tyrosine kinase inhibitor that can be used for non-small cell lung cancer (squamous cell, adenocarcinoma, large cell, brochioalveolar, carcinoid)
What is Imatinib? What is imatinib used for? Side effects?
It is a tyrosine kinase inhibitor of BCR-ABL (philadelphia chromosome fusion gene in CML) and c-kit (comon in GI stromal tumors)
So imatinib is used for CML and GI stromal tumors (GISTs)
Toxicity: Fluid retention
What is Rituximab? Increase risk of?
Rituximab is a monoclonal antibody against CD20, which is found on most B-cell neoplasms used to treat non-hodgkin, CLL, IBD, RA.
Side effect: increase risk of PML (JC virus)
What are tamoxifen and raloxifene? What are they used for?
Tamoxifen, raloxifene are selective estrogen receptor modulators (SERMs)-receptor antagonists in breast and agonists in bone. Block the binding of estrogen to ER+ cells.
Tamoxifen is used for breast cancer treatment. Both tamoxifen and raloxifene can be used for breast cancer prevention. Raloxifene can also be used to prevent osteoporosis.
How come both tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs) that are antagonists at breasts and agonists in bones, but only raloxifene is used for osteoporosis?
b/c tamoxifen is also a partial agonist in endometrium which can cause endometrial hyperplasia and increase risk of endometrial cancer. Tamoxifen use is assoc with hot flashes.
Raloxifene does not have increase risk of endocmetrial carcinoma b/c it’s an antagonist in endometrial tissues which is why it can be used in osteoporosis to prevent bone loss (estrogen stimulates bone growth).
What is the mechanism of action of trastuzumab (herceptin)? Clinical use? Side effects?
Trastuzumab (herceptin) is a monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor. Helps kill cancer cells that overexpress HER-2, through inhibition of HER2-initiated cellular signaling and antibody-dependent cytotoxicity.
Side effects: cardiotoxicity
What is vemurafenib? Mech of action and clinical use?
Vemurafenib is a small molecule inhibitor of BRAF oncogene positive melanoma used in the treatment of metastatic melanoma.
