USMLE (Fach) / Pharmacology - Hematology and Oncology (Lektion)

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• Heparin Mechanism: Activates antithrombin, which ↓ the activity of IIa (thrombin) and factor Xa.- Short half-life. Clinical use:- Immediate anticoagulation for pulmonary embolism (PE)- Acute coronary syndrome, MI- Deep venous thrombosis (DVT)- Used during pregnancy (does not cross placenta)- Follow PTT Adverse effects: bleeding, thrombocytopenia (HIT), osteoporosis- For rapid reversal (antidote), use protamine sulfate (positively charged molecule that binds negatively charged heparin). Low-molecular-weight heparins (eg, enoxaparin, dalteparin) and fondaparinux act more on factor Xa, have better bioavailability, and 2-4x longer half-life; can be administered subcutaneously and without laboratory monitoring. Not easily reversible. Heparin-induced thromobcytopenia (HIT) – development of IgG antibodies against heparin-bound platelet factor 4 (PF4). Antibody-heparin-PF4-complex activates platelets → thrombosis and thrombocytopenia.
• Bivalirudin Mechanism: Direct thrombin inhibitor Clinical use: - Venous thromboembolism- Atrial fibrillation- can be used in HIT Adverse effects: Bleeding; no specific reversal agent.
• Warfarin Interferes with γ-carboxylation of vitamin K-dependent clotting factors II, VII, IX, and X, and proteins C and S. Metabolism affected by polymorphisms in the gene for vitamin K epoxide reductase complex (VKORC1).  Clinical use:- Chronic anticoagulation (eg, venous thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation)- Not used in pregnant women (crosses placenta)- Follow PT/INR Adverse effects: bleeding, teratogenic, skin/tissue necrosis, drug-drug interactions- Initial risk of hypercoagulation: protein C has a shorter half-life than factors II and X. Existing protein C depletes before existing factors II and X deplete → hypercoagulation. Skin/tissue necrosis within first few days of large doses believed to be due to small vessel microthrombosis.- For reversal, give vitamin K- For rapid reversal, give fresh frozen plasma or PCC. Heparin "bridging": heparin frequently used when starting warfarin. Heparin's activation of antithrombin enables anticoagulation during initial, transient hypercoaguable state. Reduces risk of recurrent venous thromboembolism and skin/tissue necrosis. Cytochrome P-450 inhibitors increase warfarin effect.
• Apixaban Mechanism: Direct factor Xa inhibitor Clinical use:- Treatment and prophylaxis for DVT and PE- Stroke prophylaxis in patients with atrial fibrillation - Oral agents do not usually require coagulation monitoring
• Rivaroxaban Mechanism: Direct factor Xa inhibitor Clinical use:- Treatment and prophylaxis for DVT and PE- Stroke prophylaxis in patients with atrial fibrillation - Oral agents do not usually require coagulation monitoring
• Thrombolytics Alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA) Mechanism: Aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots.↑ PT, ↑ PTT, no change in platelet count. Clinical use:- Early MI- Early ischemic stroke- Direct thrombolysis of severe PE - Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diathesis, severe hypertension.- Nonspecific reversal with antifibrinolytics (eg, aminocaproic acid, tranexamic acid), platelet transfusions, and factor corrections (eg, FFP, cryoprecipitate)
• ADP receptor inhibitors Clopidogrel, prasugrel, ticagrelor (reversible), ticlopidine Mechanism: Inhibit platelet aggregation by irreversibly blocking ADP (P2Y12) receptors. Prevent expression of glycoproteins IIb/IIIa on platelet surface. Clinical use:- Acute coronary syndrome; coronary stenting- ↓ incidence or reccurence of thrombotic stroke Adverse effects: Neutropenia (ticlopidine). TTP may be seen.
• Cilostazol Mechanism: Phosphodiesterase III inhibitor; ↑ cAMP in platelets, resulting in inhibition of platelet aggregation; vasodilator. Clinical use: - Intermittent claudication- Coronary vasodilation- Prevention of stroke or TIAs (combined with aspirin) Adverse effect: Nausea, headache, facial flushing, hypotension, abdominal pain
• Glycoprotein IIb/IIIa inhibitors Abciximab, eptifibatide, tirofiban Mechanism: Bind to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. - Abciximab is made from monoclonal antibody Fab fragments. Clinical use:- Unstable angina- Percutaneous coronary intervention Adverse effects: Bleeding, thrombocytopenia
• Vemurafenib Small molecule inhibitor of BRAF oncogene ⊕ melanoma V600E-mutated BRAF inhibition Clinical use: Metastatic melanoma
• Trastuzumab (Herceptin) Monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor. Helps kill cancer cells that overexpress HER-2 through inhibition of HER-2 initiated cellular signaling and antibody-dependent cytotoxicity. Clinical use: HER-2 ⊕ breast cancer and gastric cancer (tras2zumab) Adverse effects: Cardiotoxicity
• Tamoxifen, raloxifene Selective estrogen receptor modulators (SERMs) – receptor antagonists in breast and agonist in bone. Block the binding of estrogen to ER ⊕ cells. Clinical use: Breat cancer treatment (tamoxifen only) and prevention. Raloxifene also useful to prevent osteoporosis. Adverse effects:- Tamoxifen – partial agonst in endometrium, which ↑ the risk of endometrial cancer; "hot flashes."- Raloxifene – no ↑ in endometrial carcinoma because it is an estrogen receptor antagonist in endometrial tissue.- Both ↑ risk of thromboembolic events (eg, DVT, PE).
• Rituximab Monoclonal antibody against CD20, which is found on most B-cell neoplasms Clinical use: Non-Hodgkin lymphoma, CLL, ITP, rheumatoid arthritis Adverse effects: ↑ risk of progressive multifocal leukoencephalopathy
• Imatinib Tyrosine kinase inhibitor of BCR-ABL (Philadelphia chromosome fusion gene in CML) and c-kit (common in GI stromal tumors) Clinical use: CML, GI stromal tumors Adverse effects: Fluid retention
• Cetuximab Monoclonal antibody against EGFR. Clinical use: Stage IV colorectal cancer (wild-type KRAS), head and neck cancer Adverse effects:- Rash- Elevated LFTs- Diarrhea
• Erlotinib EGFR tyrosine kinase inhibitor Clinical use: Non-small cell lung carcinoma Adverse effects: Rash
• Bevacizumab Monoclonal antibody against VEGF. Inhibits angiogenesis. Clinical use: Solid tumors (colorectal cancer, renal cell carcinoma), wet age-related macular degeneration. Adverse effects:- Hemorrhage- Blood clots- Impaired wound healing
• Prednisone, prednisolone Clinical use:- most commonly used glucocorticoids in cancer chemotherapy- used in CLL, non-Hodgkin lymphoma- also used as immunosuppressants Adverse symptoms: Cushing-like symptoms, weight gain, central obesity, muscle breakdown, cataracts, acne, osteoporosis, hypertension, peptic ulcers, hyperglycemia, psychosis
• Hydroxyurea Inhibits ribonucleotide reductase → ↓ DNA synthesis Clinical use: Myeloproliferative disorders (eg, CML, polycythemia vera), sickle cell disease (HbF ↑) Adverse effects: Myelosuppression
• Irinotecan, topotecan Inhibit topoisomerase I and prevent DNA unwinding and replication. Clinical use: - Colon cancer (irinotecan)- Ovarian and small cell lung caners (topotecan) Adverse effects: Severe myelosuppression, diarrhea
• Etoposide, teniposide Inhibit topoisomerase II → ↑ DNA degradation Clinical use: Solid tumors (particularly testicular and small cell cancer), leukemias, lymphomas Adverse effects: Myelosuppression, alopecia
• Cisplatin, carboplatin Cross-link DNA Clinical use: Testicular, bladder, ovary, and lung carcinomas Adverse effects: Nephrotoxicity, peripheral neuropathy, ototoxicity.- Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride (saline) diuresis.
• Paclitaxel, other taxols Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur). Clinical use: Ovarian and breast carcinomas Adverse effects:- Myelosuppression- Neuropathy- Hypersensitivity
• Vincristine, vinblastine Vinca alkaloids that bind β-tubulin and inhibit its polymerization into microtubules → prevent mitotic spindle formation (M-phase arrest). Clinical use:- Solid tumors- Leukemias- Hodgkin (vinblastine) and non-Hodgkin lymphomas Adverse effects:- Vincristine: neurotoxicity (areflexia, peripheral neuritis), constipation (including paralytic ileus)- Vinblastine: bone marrow suppression
• Bleomycin Antitumor antibiotic. Induces free radical formation → breaks DNA strands Clinical use: Testicular cancer, Hodgkin lymphoma Adverse effects: - Pulmonary fibrosis- Skin hyperpigmentation- Minimal myelosuppression (vs busulfan)
• Dactinomycin (actinomycin D) Antitumor antibiotic. Intercalates in DNA, preventing RNA synthesis. Clinical use: Used for childhood tumors.- Wilms tumor- Ewing sarcoma- Rhabdomyosarcoma Adverse effects: Myelosuppression
• Busulfan Alkylating agent. Cross-links DNA. Clinical use: Used to ablate patient's bone marrow before bone marrow transplantation. Adverse effects: Severe myelosuppression (vs bleomycin), pulmonary fibrosis, hyperpigmentation.
• Cyclophosphamide, ifosfamide Alkylating agent. Cross-link DNA at guanine. Require bioactivation by liver. A nitrogen mustard. Clinical use: Solid tumors, leukemia, lymphomas Adverse effects:- Myelosuppression- SIADH- Metabolized to acrolein, which is toxic to uroepithelial cells → Hemorrhagic cystitis, prevented with mesna (thiol group of mesna binds toxic metabolites) or adequate hydration.
• Nitrosoureas Carmustine, lomustine, semustine, streptozocin. Alkylating agent.Require bioactivation. Cross blood-brain barrier → CNS. Cross-link DNA. Clinical use: Brain tumors (including glioblastoma multiforme) Adverse effects: CNS toxicity (convulsions, dizziness, ataxia)
• Azathioprine, 6-mercaptopurine Purine (thiol) analogs → ↓ de novo purine synthesis. Activated by HGPRT. Azothioprine is metabolized into 6-MP. Clinical use:- Preventing organ rejection- Rheumatoid arthritis, IBD, SLE- Used to wean patients off steroids and to treat steroid-refractory chronic disease Adverse effects: Myelosuppression, GI, liver toxicity.- Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have ↑ toxicity with allopurinol or febuxostat.
• Cladribine Purine analog → inhibition of DNA polymerase, DNA strand breaks Clinical use: Hairy cell leukemia Adverse effects:- Myelosuppression- Nephrotoxicity- Neurotoxicity
• 5-fluorouracil Pyramidine analog bioactivated to 5-FdUMP, which covalently complexes with thymidylate synthase and folic acid. This complex inhibits thymidylate synthase → ↓ dTMP → ↓ DNA synthesis.- Capecitabine is a prodrug with similar activity. Clinical use: Colon cancer, pancreatic cancer, actinic keratosis, basal cell carcinoma Adverse effects: - Myelosuppression – worsened with the addition of leucovorin (folinic acid)- Palmar-plantar erythrodysesthesia (hand-foot syndrome)
• Methotrexate Folic acid analog that competitively inhibits dihydrofolate reductase → ↓ dTMP → ↓ DNA synthesis. Clinical use:- Cancers: leukemias (ALL), lymphomas, choriocarcinoma, sarcomas- Non-neoplastic: ectopic pregnancy, medical abortion (with misoprostol), rheumatoid arthritis, psoriasis, IBD, vasculitis Adverse effects: - Myelosuppression, which is reversible with leucovorin "rescue"- Hepatotoxicity- Mucositis (eg, mouth ulcers)- Pulmonary fibrosis- Folate deficiency, which may be teratogenic (neural tube defects) without supplementation
• Ticagrelor ADP receptor inhibitor (reversible)
• Ticlopidine ADP receptor inhibitor Adverse effect: Neutropenia
• Clopidogrel ADP receptor inhibitor
• Dipyridamole Mechanism: Phosphodiesterase III inhibitor; ↑ cAMP in platelets, resulting in inhibition of platelet aggregation; vasodilator. Clinical use: - Intermittent claudication- Coronary vasodilation- Prevention of stroke or TIAs (combined with aspirin). Adverse effects: Nausea, headache, facial flushing, hypotension, abdominal pain
• Abciximab Glycoprotein IIb/IIIa inhibitor - Made from monoclonal antibody Fab fragments Clinical use: - Unstable angina- Percutaneous transluminal coronary angioplasty Adverse effects:- Bleeding- Thrombocytopenia
• Eptifibatide Glycoprotein IIb/IIIa inhibitor Clinical use: - Unstable angina- Percutaneous transluminal coronary angioplasty Adverse effects:- Bleeding- Thrombocytopenia
• Tirofiban Glycoprotein IIb/IIIa inhibitor Clinical use: - Unstable angina- Percutaneous transluminal coronary angioplasty Adverse effects:- Bleeding- Thrombocytopenia
• Doxorubicin, daunorubicin Antitumor antibiotic.Generate free radicals. Intercalate in DNA → breaks DNA → ↓ replication. Interferes with topoisomerase II. Clinical use: Solid tumors, leukemias, lymphomas Adverse effects:- Cardiotoxicity (dilated cardiomyopathy)- Myelosuppression- Alopecia- Dexrazoxane (iron chelating agent) used to prevent cardiotoxicity.
• Argatroban Direct thrombin inhibitor Clinical use:- Venous thromboembolism- Atrial fibrillation- Can be used in HIT Does not require lab monitoring. 
• Dabigatran Direct thrombin inhibitor Clinical use:- Venous thromboembolism- Atrial fibrillation- Can be used in HIT Does not require lab monitoring.  Can be reversed with idarucizumab.
• Bortezomib Proteasome inhibitor, induce arrest at G2-M phase and apoptosis. Clinical use: - Multiple myeloma- Mantle cell lymphoma Adverse effects:- Peripheral neuropathy- Herpes zoster reactivation
• Carfilzomib Proteasome inhibitor, induce arrest at G2-M phase and apoptosis. Clinical use: - Multiple myeloma- Mantle cell lymphoma Adverse effects:- Peripheral neuropathy- Herpes zoster reactivation
• Rasburicase Recombinant uricase that catalyzes metabolism of uric acid to allantoin. Clinical use: Prevention and treatment of tumor lysis syndrome.
• Drugs that affect warfarin metabolism CYP-450 Inhibitors (↑ warfarin effect):- Antibiotics/antifungals- Acetaminophen, NSAIDs- Amiodarone- Cimetidine- Cranberry juice, vitamin E- Omeprazole- Thyroid hormone- SSRIs (eg, fluoxetine) CYP-450 Inducers (↓ warfarin effect)- Rifampin- Carbamazepine, phenytoin- Phenobarbital- Oral contraceptives- Ginseng, St. John's wort
• Direct thrombin inhibitors Bivalirudin (related to hirudin, the anticoagulant used by leeches), argatroban, dabigatran (only oral agent in class). Directly inhibits activity of free and clot-associated thrombin. Clinical use:- Venous thromboembolism- Atrial fibrillation- Can be used in HIT, when heparin is BAD for the patient.- Does not require lab monitoring. Adverse effects: Bleeding- Can reverse dabigatran with idarucizumab.- Consider PCC and/or antifibrinolytics (eg, tranexamic acid) if no reversal agent available.
• Cytarabine (arabinofuranosyl cytidine) Pyrimidine analog → DNA chain termination. At higher concentrations, inhibits DNA polymerase. Use: Leukemias (AML), lymphomas Adverse effect: Myelosuppression with megloblastic anemia
• Procarbazine Cell cycle phase-nonspecific alkylating agent. Mechanism not yet defined. Mechanism: Hodgkin lymphoma, brain tumors. Adverse effects:- Bone marrow suppression- Pulmonary toxicity- Leukemia

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