Cytotoxic chemotherapy spans several mechanistic classes. Cyclophosphamide is an alkylating agent that crosslinks DNA, with signature toxicities of hemorrhagic cystitis (prevented with MESNA), SIADH, myelosuppression, and secondary malignancies including bladder cancer and leukemia. Methotrexate inhibits dihydrofolate reductase, reducing purine and thymidylate synthesis; leucovorin (folinic acid) rescue protects normal cells, with toxicities including hepatotoxicity, pulmonary fibrosis, mucositis, myelosuppression, and nephrotoxicity. 5-Fluorouracil is a pyrimidine analog that blocks thymidylate synthase to decrease dTMP, causing myelosuppression, mucositis, hand-foot syndrome, and photosensitivity. 6-Mercaptopurine and its prodrug azathioprine are purine analogs metabolized by xanthine oxidase, so concurrent allopurinol causes severe toxicity. Bleomycin generates free radicals to produce DNA strand breaks, with dose-limiting pulmonary fibrosis worsened by supplemental oxygen, used in Hodgkin lymphoma (ABVD) and testicular cancer. Doxorubicin inhibits topoisomerase II, causing dose-dependent dilated cardiomyopathy preventable with dexrazoxane, an iron chelator. Cisplatin crosslinks DNA but is severely nephrotoxic (requiring aggressive hydration or amifostine), ototoxic, emetogenic, and causes peripheral neuropathy; carboplatin shares the mechanism but is more myelosuppressive (especially thrombocytopenia) and less nephro- and ototoxic, dosed by the Calvert formula using GFR. Paclitaxel stabilizes microtubules against depolymerization, producing mitotic arrest with dose-limiting peripheral neuropathy and myelosuppression, plus hypersensitivity requiring premedication. Vincristine and vinblastine bind beta-tubulin to prevent microtubule polymerization; vincristine causes peripheral neuropathy as its dose-limiting toxicity while vinblastine is more myelosuppressive. Etoposide inhibits topoisomerase II with myelosuppression and risk of secondary AML.
Targeted therapies include imatinib, a BCR-ABL tyrosine kinase inhibitor for chronic myeloid leukemia and c-KIT-positive GIST. Rituximab is an anti-CD20 monoclonal antibody for B-cell lymphomas and CLL with risk of progressive multifocal leukoencephalopathy (PML) and HBV reactivation. Bevacizumab is an anti-VEGF antibody causing hypertension, proteinuria, poor wound healing, bleeding, thrombosis, and GI perforation. Trastuzumab is an anti-HER2 antibody for HER2-positive breast cancer that causes reversible (not dose-dependent) cardiomyopathy, requiring LVEF monitoring. Immunosuppressants cyclosporine and tacrolimus are calcineurin inhibitors that block IL-2 transcription in T cells, with shared toxicities of nephrotoxicity, hypertension, and neurotoxicity; cyclosporine additionally causes gum hyperplasia.
Hormonal therapies include leuprolide, a continuous GnRH analog that downregulates pituitary GnRH receptors and lowers LH/FSH for prostate cancer, endometriosis, precocious puberty, and fibroids. Finasteride is a 5α-reductase inhibitor that blocks conversion of testosterone to DHT, used for BPH and male-pattern baldness; pregnant women should not handle crushed tablets due to teratogenicity. Tamoxifen is a SERM that is an antagonist in breast tissue but an agonist in endometrium and bone, raising risks of endometrial cancer and thromboembolism. Raloxifene is a SERM that is an agonist in bone (osteoporosis) and antagonist in breast (chemoprevention) without endometrial stimulation, though DVT risk persists. Aromatase inhibitors (anastrozole, letrozole, exemestane) block peripheral conversion of androgens to estrogens as first-line therapy for postmenopausal ER-positive breast cancer, with osteoporosis and arthralgias as major adverse effects.
Specialty drugs include sildenafil, a PDE5 inhibitor that increases cGMP for smooth muscle relaxation in the corpus cavernosum, contraindicated with nitrates due to severe hypotension, with additional risks of blue-tinted vision and hearing loss. Latanoprost is a prostaglandin F2α analog that increases uveoscleral outflow in glaucoma with cosmetic side effects of iris hyperpigmentation, eyelash growth, and periorbital fat atrophy. Hydroxychloroquine, used in SLE and RA, has toxicities of retinopathy (bull's-eye maculopathy), QT prolongation, hemolysis in G6PD deficiency, and neuromyopathy. Many drugs across classes prolong the QT interval and risk torsades de pointes, including macrolides, fluoroquinolones, methadone, antipsychotics, ondansetron, and several antiarrhythmics, so avoiding stacking and obtaining a baseline ECG is prudent.