Hematology/Oncology Rx – Flashcards

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Enoxaparin Dalteparin Tinzaparin
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*Antithrombotics: Anticoagulants* Low-molecular weight heparins (LMWHs) *Mechanism* (1) LMWH-AT complex inhibits Factor Xa >> other factors (2) Blocks action of von Willebrand factor *Indications*: DVT prophylaxis s/p hip, knee or abdominal surgery; DVT +/- PE; mgmt acute coronary syndromes *Side effects* (1) Bleeding--LMWHs don't respond well to protamine sulfate! (2) Dose-dependent osteoporosis (3) Heparin-induced thrombocytopenia (HIT) Type 1: direct heparin-induced platelet aggregation, typically ASx & self-limited w/in days; generally does not require cessation of heparin tx (4) HIT Type 2: immune-mediated Ab formation against heparin-platelet complexes → platelet activation, aggregation & clot production; may cause life-threatening bleeding & thrombosis, requiring immediate cessation of heparin & administration of direct thrombin inhibitor (e.g. lepirudin, bivalirudin, argatroban) Note: HIT is less likely w/ LMWHs but still a possibility
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Lepirudin Hirudin Bivalirudin Argatroban
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*Antithrombotics: Anticoagulants* Direct Thrombin Inhibitors *Mechanism* Inhibition of thrombin independent of antithrombin *Indications* *(1)* Maintenance of anticoagulation & thrombus prevention in setting of HIT *(2)* Preoperative UA ptt undergoing PCI (bivalirudin) *Side effects* Bleeding
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Heparin
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*Antithrombotics: Anticoagulants* *MOA* *(1)* Cofactor acivation of antithrombin → inhibition of factor Xa & thrombin *(2)* ↓vWF *Indications*: UA/NSTEMI; AMI s/p fibrinolytic Tx or extensive wall motion abnormality; PE; DVT *Toxicities* *(1)* Bleeding--reversible w/ protamine sulfate! *(2)* Dose-dependent osteoporosis *(3)* Heparin-induced thrombocytopenia (HIT) Type 1: direct heparin-induced platelet aggregation, typically ASx & self-limited w/in days; generally does not require cessation of heparin tx *(4)* HIT Type 2: immune-mediated Ab formation against heparin-platelet complexes → platelet activation, aggregation & clot production; may cause life-threatening bleeding & thrombosis, requiring *immediate cessation* of heparin & administration of direct thrombin inhibitor (e.g. lepirudin, bivalirudin, argatroban)
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Warfarin
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*Antithrombotic anticoagulant* *Mechanism* Vit K epoxide reductase antagonist → ↓Vit K metabolism → ↓γ-carboxylation (activation) of factors II, VII, IX & X (primarily affects *extrinsic* pathway) *Indications* Chronic anticoagulation & stroke prophylaxis in A fib ptt *Side effects* Bleeding (esp. w/ aspirin--relative contraindication), teratogenic (crosses placenta!, skin/tissue necrosis, other drug-drug interactions (hepatic enzymes) *Pharmacology* Extremely delayed onset (2-7 days) w/ 37-hr half-life; CYP450 metabolism *To reverse*: Vitamin K; rapid reversal of effects w/ *FFP*
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Alteplase (tPA) Reteplase (rPA) Tenecteplase (TNK-tPA)
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*Thrombolytics* *MOA*: aid conversion of plasminogen to plasmin → thrombin & fibrin cleavage *Indications*: early intervention of STEMI *when PCI/CABG is not available w/in 90 min*, early ischemic stroke, direct thrombolysis of severe PE *Toxicities*: bleeding *To reverse*: give *aminocaproic acid*
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Aspirin
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*COX 1/2 inhibitor* *Mechanism* Blocks TXA₂ synthesis from arachidonic acid → ↓platelet activation & aggregation; platelets lack nuclei so COX1 inhibition is irreversible. *Indications* *(1)* Reduce risk of recurrence/other vascular event (MI/CVA) in ptt w/ known vascular dz. *(2)* Lower incidence of graft occlusion in s/p CABG ptt. *(3)* Kawasaki's dz *Side effects* *(1)* GI irritation: bleeding, dyspepsia, N *(2)* Bleeding *(3)* Nephropathy (precipitation of ARF/AIN) *(4)* Reyes syndrome (contraindicated in children w/ suspected viral illness) *(5)* Hypersensitivity *(6)* Asthma exacerbation *(7)* Gout *(8)* Salicylism: tinnitus, vertigo, decreased hearing *OD mgmt*: activated charcoal lavage, IV glucose + isonormal saline + NaHCO₃ (alkalinize urine), dialysis
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Clopidogrel Ticlopidine Prasugrel Ticagrelor
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*Antithrombotics: Anti-platelet* Thienopyridines *Mechanism* Block extracellular ADP binding to the P2Y₁₂ receptor → ↑cAMP formation (P2Y₁₂ & P2Y₁ Rs bind inhibitory G protein that acts on AC to decrease cAMP production; cAMP inhibits Ca²⁺ release, part of cascade of platelet activation leading to activation of glycoprotein IIb/IIIa receptor) *Indications* *(1)* Anti-platelet alt. to aspirin in pt w/ aspirin ALLG *(2)* Prevention of thrombotic complications s/p PCI stenting *(3)* Aspirin adjunct in Tx UA/NSTEMI/STEMI *Side effects* *(1)* Bleeding, dyspepsia, D *(2)* Neutropenia & TTP (ticlopidine) *Pharmacokinetics* Clopidogrel requires hepatic CYP2C19 met to active form (contraindicated to PPI tx); prasugrel *does not* require CYP2C19 met!
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Abciximab Eptifibatide Tirofiban
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*Antithrombotics: Anti-platelet* Glycoprotein IIb/IIIa Receptor Antagonists *Mechanism* Inhibits binding of activated platelet GP IIb/IIIa receptors to fibrinogen & von Willebrand factor → ↓aggregation *Indications* PCI & high-risk acute coronary syndromes *Side effects* Bleeding, thrombocytopenia (more common w/ abciximab) *Pharmacokinetics* Abciximab has a short plasma half-life
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Dipyridamole
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*Mechanism* (1) PDE3 inhibitor → ↑[cAMP] → ↓Ca²⁺-induced platelet activation (2) Inhibits thromboxane synthase → ↓TXA₂ & inhibits the TXA₂ receptor (3) Inhibits adenosine deaminase (ADA) *Indications* (1) CVA/TIA as aspirin adjunct (2) Adjunct Tx for prevention of heart valve embolic complications (3) Aspirin adjunct for PAD Tx (4) Pharmacological coronary vasodilation ITSO radionuclide stress testing *Toxicities*: N/HA/AP, facial flushing, hypotension, GI bleeding
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Methotrexate
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*Antimetabolite* *MOA*: folic acid analogue → inhibition of dihydrofolate reductase → ↓dTMP → ↓DNA synthesis & ↓protein synthesis--*S-phase specific* *Indications*: leukemias (*ALL*: POMP, maintenance w/ *6-MP*); lymphomas (*Burkitt*: CODOX-M/IVAC); choriocarcinoma; sarcomas; abortion/ectopic preggars; RA (first choice!); psoriasis *Toxicities*: myelosuppression (mitigated by leucovorin (folinic acid) rescue), macrovesicular fatty change (liver), mucositis, teratogenic (d'obviously)
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5-fluorouracil
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*Antimetabolite* *MOA*: pyrimidine analogue, bioactivated to 5F-dUMP → covalent linkage to folic acid → inhibition of thymidylate synthase → ↓dTMP → ↓DNA synthesis & ↓protein synthesis--*S-phase specific* *Indications*: colon cancer, basal cell CA (topical) *Toxicities*: myelosuppression (does *NOT* respond to leucovorin--'rescue' w/ thymidine!!), photosensitivity
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Cytarabine (arabinofuranosyl cytidine)
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*Antimetabolite* *MOA*: pyrimidine analogue → inhibition of DNA polymerase--*S-phase specific* *Indications*: leukemias (*AML*: 7 & 3 +/- *6-TG*; *CML*: w/ *IFN-α-2a*) & lymphomas (*Burkitt*: CODOX-M/IVAC) *Toxicities*: leukopenia, thrombocytopenia, megaloblastic anemia *Note*: this MOA is identical to that of the antivirals in mgmt herpesviridae infections!
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Azathioprine 6-MP 6-TG
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*Antimetabolites* *MOA*: purine analogues → *activation by HGPRT* → ↓de novo purine synthesis--*S-phase specific* *Indications*: leukemias (*ALL*: POMP, maintenance w/ *MTX*; *AML*: *6-TG* sometimes in addition to 7 & 3) *Toxicities*: bone marrow suppression, GI irritation, hepatotoxicity; *metabolized by XO* → relative CONTRAINDICATION to allopurinol
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Dactinomycin
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*Antitumor Antibiotic* *MOA*: intercalating agent → ds breaks *Indications*: many pediatric malignancies--Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma *Toxicities*: Myelosuppression
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Doxorubicin (Adriamycin) Daunorubicin
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*Antitumor Antibiotics* *MOA*: free radical generation, noncovalent intercalation → ds breaks *Indications*: solid tumors, leukemias (*ALL*: induction w/ *asparaginase* + *prednisone* + *vincristine*; *CLL*: CHOP; *AML*: 7 &3) & lymphomas (*Burkitt*: CODOX-M/IVAC; *Hodgkin*: ABVD; *follicular variant NHL*: R-CHOP) *Toxicities*: cardiotoxicity (DCM), myelosuppression, alopecia; give *dexrazoxane* (Fe-chelator) to combat DCM
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Bleomycin
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*Antitumor Antibiotic* *MOA*: induces free radical formation → strand breakdown--*G₂-phase sepcific* *Indications*: testicular cancer, Hodgkin's lymphoma (ABVD); chemical pleurodesis ITSO recurrent pleural effusion *Toxicities*: pulmonary fibrosis (esp. pleural), skin changes; minimal myelosuppression
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Cyclophosphamide Ifosfamide
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*Alkylating Agents* *MOA*: Covalently crosslinks DNA at guanine N-7; requires hepatic activation *Indications*: solid tumors, some brain cancers, leukemias (*CLL*: CHOP), lymphomas (*Burkitt*: CODOX-M/IVAC; *follicular variant NHL*: R-CHOP); Wegener's granulomatosis; polyarteritis nodosa; lupus nephritis; nephrotic syndrome recalcitrant to steroid Tx; severe refractory RA *Toxicities*: myelosuppression, hemorrhagic cystitis w/ ↑risk transitional uroepithelial CA of the bladder; give *MESNA* to combat hemorrhagic cystitis (thiol group binds toxic metabolites)
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Carmustine Lomustine Semustine Streptozocin
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*Alkalating Agents: nitrosoureas* *MOA*: highly CNS penetrant *Indications*: brain tumors (including glioblastoma multiforme) *Toxicities*: CNS... =-O
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Busulfan
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*Alkylating Agent* *MOA*: alkylates DNA *Indications*: CML; marrow ablation ITSO transplant *Toxicities*: pulmonary fibrosis, hyperpigmentation
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Vincristine (Oncovin) Vinblastine
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*Vinca Alkyloids* *MOA*: bind tubulin → inhibition of the mitotic spindle polymerization--*M-phase specific* *Indications*: solid tumors, leukemias (*ALL*: POMP, induction w/ *asparaginase* + *prednisone* + *daunorubicin*; *CLL*: CHOP) & lymphomas (*Burkitt*: CODOX-M/IVAC; *Hodgkin*: ABVD; *follicular-variant NHL*: R-CHOP) *Toxicities* *Vincristine*: neurotoxicity (areflexia, peripheral neuritis), paralytic ileus *Vinblastine*: marrow suppression
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Paclitaxel
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*Taxols* *MOA*: hyperstabilize microtubules → inhibition of anaphase--*M-phase specific* *Indications*: ovarian & breast cancers *Toxicities*: myelosuppression & HSRs
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Cisplatin Carboplatin
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*MOA*: cross-link DNA *Indications*: testicular, bladder, ovarian & lung CAs *Toxicities*: nephrotoxicity & acoustic nerve damage; give *amifostine* (free radical scavenger) & chloride diuresis to mitigate nephrotoxicity
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Etoposide Teniposide
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*MOA*: inhibits topoisomerase II → ↑DNA degredation → G₂ arrest--*S- & G₂ specific* *Indications*: solid tumors, leukemias, lymphomas (*Burkitt*: CODOX-M/IVAC) *Toxicities*: myelosuppression, GI irritation, alopecia
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Hydroxyurea
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*MOA*: inhibits RR (ribonucleotide reductase) → ↓DNA synthesis--*S-phase specific*; ↑RBC H₂O content → ↓sickling; *note* that this is the pathophysiology behind ADA-deficiency SCID! *Indications*: melanoma, CML; sickle cell dz (↑HbF); polycythemia vera, essential thrombocythemia *Toxicities*: marrow suppression, GI irritation
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Tamoxifen
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*Selective Estrogen Receptor Modulator (SERM)* *MOA*: antagonistic action on estrogen receptors in breast tissue *Indication*: recurrence of ER-positive breast cancer *Toxicities*: partial agonist in endometrium → ↑risk endometrial cancer; hot flashes
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Raloxifene
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*Selective Estrogen Receptor Modulator (SERM)* *MOA*: partial agonist action on estrogen receptors in bone → ↓resorption *Indication*: osteoporosis mgmt in *postmenopausal FF*--note that since it is only a *partial* agonist it will have the opposite effect in premenopausal FF (i.e. favors osteoporosis)
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Trastuzumab (Herceptin)
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*MOA*: monoclonal anti-HER-2 (RTK) Ab → Type II HSR against breast tissue over-expressing HER-2 *Indications*: HER-2-positive breast cancer *Toxicity*: cardiotoxicity
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Imatinib (Gleevec) Nilotinib Dasatinib
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*MOA*: inhibits BCR-Abl non-receptor TK gene product *Indications*: CML, GI stromal tumors (GIST--malignancies of the interstitial cells of Cajal) *Toxicity*: fluid retention
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Rituximab
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*MOA*: anti-CD20 Ab *Indications*: B-cell malignancies (or any malignancy expressing CD20; RA (w/ *MTX*) *Untoward effects*: pneumonia, septic arthritis & reactivation HBV & PML (JCV)
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Vemurafenib
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*MOA*: small molecule inhibitor of V600E B-Raf kinase mutant *Indications*: malignant melanoma
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Bevacizumab
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*MOA*: monoclonal anti-VEGF Ab → ↓angiogenesis *Indications*: solid tumors
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Brentuximab
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*MOA*: anti-CD30 Ab conjugated to MMAE (MT-disrupting agent) w/ protease-cleavable peptide linker--binds CD30 → uptake & cleavage by cellular protease → activation *Indications*: Hodgkin lymphoma & anaplastic large cell lymphoma
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Eculizumab
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*MOA*: monoclonal anti-C5 Ab *Indications*: PNH, thrombosis *Untoward effects*: ↑risk Neisseria spp. infections
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S-phase specific Rx
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MTX Azathioprine/6-MP/6-TG 5-FU Fludarabine Azacytidine Cladribine Pentostatin Cytarabine Hydroxyurea
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M-phase specific Rx
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Griseofulvin Paclitaxel/taxols Vinca alkaloids Colchicine
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G₂-phase specific Rx
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Etoposide/teniposide Bleomycin
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MESNA
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*MOA*: thiol group binds toxic metabolites of *cyclophosphamide* *Indication*: hemorrhagic cystitis prophylaxis ITSO *cyclophosphamide* Tx
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Amifostene
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*MOA*: free radical scavenger *Indication*: nephrotoxicity prophylaxis ITSO *cisplatin* Tx
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Dexrazoxane
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*MOA*: Fe chelator *Indications*: DCM prophylaxis ITSO *doxorubicin* Tx
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Leucovorin
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*MOA*: folinic acid *Indication*: 'rescue' ITSO *MTX* Tx
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Thymidine
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*Indication*: 'rescue' ITSO *5-FU* Tx
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DDAVP
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*ADH/desmopressin* *Indications*: cDI, von Willibrand dz, hemophilia A w/ FVII levels > 5%, nocturnal enuresis
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Anti-thymocyte Globulin (ATG)
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*MOA*: removal of circulating CD8⁺ T lymphocytes → allows marrow regrowth *Indication*: aplastic anemia (when marrow transplant is not an option; use w/ *cyclosporine*), GVHD & renal transplant rejection prophylaxis *Toxicities*: serum sickness, rash, anaphylaxis, thrombocytopenia, myalgias
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Azacytidine
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*MOA*: incorporation into DNA → inhibition of DNA methylation → direct cytotoxicity to abnormal marrow hematopoietic cells--*S-phase specific* *Indications*: myelodysplastic syndromes *Toxicities*: myelosuppression, severe N/V
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Thalidomide Lenalidomide
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*MOA*: inhibition of TNFα → anti-inflammatory effects, inhibition of angiogenesis *Indications*: multiple myeloma, myelodysplasia, myelofibrosis, lepromatous skin infections, aphthous ulcers, Bechet's disease *Toxicities*: highly teratogenic; sedation, thrombosis (especially w/ *dexamethasone*)
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Cladribine Pentostatin
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*MOA*: purine analogues → direct lymphocyte cytotoxicity--accumulates in cells *Indications*: hairy-cell leukemia *Toxicity*: myelosuppression
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Fludarabine
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*Antimetabolite* *MOA*: inhibits DNA polymerase--*S-phase specific* *Indications*: advanced-stage CLL
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Fondaparinux
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*Antithrombotics: Anticoagulants* Direct Factor Xa inhibibitor *Mechanism*: complexes AT & inhibits Factor Xa exclusively w/ NO effect on other factors *Indications*: DVT prophylaxis s/p hip, knee or abdominal surgery; DVT +/- PE; mgmt acute coronary syndromes *Side effects* (1) Bleeding--not reversible by protamine sulfate! (2) Dose-dependent osteoporosis
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Cilostazol
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*Mechanism* (1) PDE3 inhibitor → ↑[cAMP] → ↓Ca²⁺-induced platelet activation (2) Reversible inhibition of thrombin, ADP, collagen & epinephrine effects on platelet aggregation (3) Direct vasodilator w/ highest action in femoral bed *Indication*: intermittent claudication ITSO PAD (single best Tx--used in combination w/ aspirin, dipyridamole & exercise) *Toxicities*: edema, dizziness, vertigo, worsening of CHF
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