Hematology Flashcards
Cromolyn sodium
Prevents mast cell degranulation
Used for asthma prophylaxis
Heparin
Cofactor for the activation of antithrombin III
Decreases thrombin and factor Xa
SHORT half-life
Heparin antidote
Protamine sulfate
Positively charged molecule that binds negatively charged heparin
Low molecular weight heparins (2)
Enoxaparin
Dalteparin
Act more on factor Xa Better bioavailability 2-4x longer half-life Administered subcutaneously No lab monitoring
Is heparin used in pregnancy?
YES
Does not cross placenta
Test used to monitor heparin?
PTT
Intrinsic pathway
Protamine sulfate
Antidote for heparin
Direct thrombin inhibitors (2)
Argatroban
Bivalirudin
Derivatives of hirudin
Inhibit thrombin directly
Used instead of heparin for anticoagulating patients with HIT
Warfarin
Inhibits Vitamin K epoxide reductase
Interferes with normal synthesis and gamma-carboxylation of vitamin K-dependent clotting factors
Metabolized by cytochrome P450 pathway
LONG half-life
What are the vitamin K dependent clotting factors?
II, VII, IX, X
Proteins C and S
Test used to monitor warfarin?
PT/INR
Extrinsic pathway
Is warfarin used in pregnancy?
NO = teratogenic
Can cross the placenta
Warfarin antidote?
Vitamin K
Fresh frozen plasma (rapid reversal)
Serious complication of warfarin toxicity?
Warfarin skin/tissue necrosis
Direct factor Xa inhibitors (2)
Apixaban Rivaroxaban (oral)
Bind and directly inhibit activity of factor Xa
Oral agents = no coagulation monitoring
Direct factor Xa inhibitor antidote?
NONE!!!
Heparin uses
Immediate anticoagulation for PE, ACS, MI, DVT
Pregnancy
Warfarin uses
Chronic anticoagulation after STEMI, venous thromboembolism prophylaxis, prevention of stroke in a fib
NOT used in pregnancy
Apixaban and rivaroxaban uses
Tx and prophylaxis DVT and PE (rivaroxaban)
Stroke prophylaxis in patients with a fib
Thrombolytics (3)
Alteplase (tPA)
Reteplase (rPA)
Tenecteplase (TNK-tPA)
Directly or indirectly aid conversion plasminogen to plasmin, which cleaves thrombin and fibrin clots
PT/PTT and platelet count with thrombolytics?
Increased PT/PTT
Normal platelet count
Thrombolytic antidote?
Aminocaproic acid
Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies
Thrombolytic uses
Early MI or ischemic stroke
Direct thrombolysis of severe PE
Aspirin MOA
Irreversibly inhibits cyclooxygenase (covalent acetylation)
Platelets cannot synthesize new enzyme = effect lasts until new platelets are produced
How does ASA irreversibly inhibit COX?
Covalent acetylation
Aspirin labs
Increased bleeding time
Decreased TXA2 and prostaglandins
NORMAL PT/PTT
Affects primary hemostasis
Aspirin overdose acid/base
Respiratory ALKALOSIS initially
superimposed metabolic ACIDOSIS later
Aspirin toxicity
Gastric ulceration
Tinnitus
Chronic use = acute renal failure, interstitial nephritis, upper GI bleed
Should you give ASA to a child?
NO = can cause Reye syndrome!
ADP (P2Y12) receptor inhibitors (5)
Clopidogrel (Plavix) Ticlopidine Prasugrel Ticagrelor Cangrelor = reversible
Inhibit platelet aggregation by irreversibly blocking ADP receptors
Inhibit fibrinogen by preventing GPIIb/IIIa from binding fibrinogen
P2Y12 inhibitor toxicity
Neutropenia (ticlopidine)
TTP/HUS may be seen
Cilostazol, dipyridamole
MOA?
Toxicity?
Phosphodiesterase III inhibitors
Block cAMP –> AMP = increased cAMP in platelets, which inhibits platelet aggregation
Vasodilators
Toxicity = nausea, headache, facial flushing, hypotension, abdominal pain
GPIIb/IIIa inhibitors (3)
Toxicity?
Abciximab (“six”)
Eptifibatide
Tirofiban
Bind to GPIIb/IIIa on activated platelets and prevent aggregation = prevent fibrinogen cross linking
Toxicity = bleeding, thrombocytopenia
Antimetabolites
Methotrexate (MTX)
5-fluorouracil (5-FU)
Cytarabine (arabinofuranosyl cytidine) = ara-C
Azathioprine, 6-mercaptopurine (6-MP), 6-thioguanine (6-TG)
All are S-PHASE specific
Methotrexate
Folic acid analog
Inhibits dihydrofolate reductase (decrease dTMP, DNA, protein synthesis)
Toxicity: Myelosuppression (reversible with LEUCOVORIN [folinic acid] "rescue") Macrovesicular fatty change in liver Mucositis Teratogenic
Methotrexate “rescue”
Leucovorin (folinic acid)
5-FU
Pyrimidine analog bioactivated to 5F-dUMP = covalently complexes folic acid
Inhibits thymidylate synthase (decrease dTMP, DNA, protein synthesis)
Toxicity:
Myelosuppression
“Rescue” with URIDINE
Photosensitivity
5-FU “rescue”
Uridine
Cytarabine
Pyrimidine analog
Inhibition of DNA polymerase
Toxicity: Leukopenia Thrombocytopenia Megaloblastic anemia (folate deficiency) (CYTarabine = panCYTopenia)
Azathioprine, 6-MP, 6-TG
Purine (thiol) analogs = decrease de novo purine synthesis
Activated by HGPRT
Toxicity:
bone marrow, GI, liver
Increased toxicity with allopurinol (azathioprine and 6-MP metabolized by xanthine oxidase)
Antitumor antibiotics
Dactinomycin (actinomycin D)
Doxorubicin (Adriamycin), daunorubicin
Bleomycin
Dactinomycin
Intercalates in DNA
Used for childhood tumors
Toxicity = myelosuppression
Doxorubicin, daunorubicin
Generate free radicals
Intercalate in DNA = breaks = decreased replication
Toxicity = CARDIOTOXICITY (dilated cardiomyopathy), myelosuppression, alopecia
Agent used to reduce cardiotoxicity from doxorubicin and daunorubicin
Dexrazoxane = iron chelating agent
Bleomycin
Induces free radical formation = breaks in DNA
Toxicity = PULMONARY FIBROSIS, skin changes, mucositis; minimal myelosuppression
Alkylating agents
Cyclophosphamide, ifosfamide
Nitrosoureas (carmustine, lomustine, semustine, streptozocin)
Busulfan
Enzymes inhibited by lead
ALA dehydratase
Ferrochelatase
Lead poisoning treatment
Dimercaprol and EDTA
Succimer used for chelation for kids
Sideroblastic anemia treatment
Pyridoxine (B6, cofactor for delta-ALA synthase)
Cyclophosphamide, isofosfamide
Covalent cross-links DNA at guanine N7
Bioactivation by liver
Toxicity:
Myelosuppression
Hemorrhagic cystitis (prevent with mesna)
Agent used to prevent hemorrhagic cystitis due to cyclophosphamide
Mesna
Thiol group binds toxic metabolites
Nitrosoureas
Carmustine, lomustine, semustine, streptozocin
Cross BBB to CNS, cross links DNA
Treatment for brain tumors
Toxicity = CNS; convulsions, dizziness, ataxia
Busulfan
Cross-links DNA
CML; ablates bone marrow before transplant
Toxicity = myelosuppression, pulmonary fibrosis, hyperpigmentation
Vincristine, vinblastine
Vinca alkaloids, bind B-tubulin
INHIBITS POLYMERIZATION
Prevents mitotic spindle formation (M phase arrest)
Toxicity:
Vincristine = neurotoxicity (areflexia, peripheral neuritis), paralytic ileus
Vinblastine = bone marrow suppression
Paclitaxel and other taxols
Hyperstabilize polymerized microtubules in M phase so spindle cannot break down (prevent anaphase)
INHIBITS DEPOLARIZATION
“Taxing to stay polymerized”
Toxicity = myelosuppression, alopecia, hypersensitivity
Cisplatin, carboplatin
Non-classical alkylating agents
Cross-link DNA
Nephrotoxicity and acoustic nerve damage
Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride diuresis
Etoposide, tenoposide
Topoisomerase II inhibitors = increase DNA degradation
Myelosuppression, GI irritation, alopecia
Irinotecan, topotecan
Topoisomerase I inhibitors = prevent DNA unwinding and replication
Severe myelosuppression, diarrhea
Hydroxyurea
Inhibits ribonucleotide reductase = decreases DNA synthesis (S-phase specific)
Bone marrow suppression, GI upset
Prednisone, prednisolone, dexamethasone
Used to decrease adverse effects of chemotherapeutics
May trigger apoptosis = inhibits lymphocyte proliferation
Immunosuppressive
Toxicity = Cushing syndrome sx (WG, central obesity, muscle breakdown, cataracts, acne, osteoporosis, HTN, peptic ulcers, hyperglycemia, psychosis)
Tamoxifen, Raloxifene
Selective estrogen receptor modulators (SERMs) = antagonists in breast and agonists in bone
Block binding of estrogen to ER + cells
Tamoxifen = breast cancer; toxicity = partial agonist in endometrium (increased risk cancer), hot flashes
Raloxifene = osteoporosis; not an endometrial antagonist
Trastuzumab
Herceptin
Monoclonal AB against HER-2 (c-erbB2) = tyrosine kinase receptor = kills breast cancer cells that overexpress HER-2
Cardiotoxicity = damages the heart
Imatinib
Gleevec
Tyrosine kinase inhibitor of bcl-abl (CML) and c-kit (GI stromal tumors)
Toxicity = fluid retention
Rituximab
Monoclonal antibody against CD20 (B cell neoplasms)
Toxicity = increased risk of progressive multifocal leukoencephalopathy
Vemurafenib
“VemuRAFenib”
Small molecule inhibitor of forms of B-Raf kinase with V600E mutation
Tx metastatic melanoma
Bevacizumab
Monoclonal AB against VEGF = inhibits angiogenesis
Toxicity = hemorrhage and impaired wound healing
