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
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
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
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.
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
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.
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
