PharmacologyTier 1Medical Sciences concept

Chemotherapy drug mechanisms of action by class

Core concept

1. Alkylating agents - crosslink DNA

Cyclophosphamide, ifosfamide (nitrogen mustards), busulfan, melphalan, chlorambucil, temozolomide, dacarbazine, procarbazine, nitrosoureas (lomustine, carmustine)
Cell cycle non-specific -> kill resting cells -> highest gonadotoxicity and secondary AML/MDS

2. Platinums - form DNA adducts (alkylating-like)

3. Antimetabolites - S phase

4. Topoisomerase inhibitors

5. Antimicrotubule agents - M phase

Vinca alkaloids - inhibit polymerisation (vincristine, vinblastine, vinorelbine)
Taxanes - stabilise/hyperpolymerise (paclitaxel, docetaxel)

Plus: anthracyclines

Doxorubicin, daunorubicin, epirubicin, idarubicin - intercalate DNA, inhibit topo II, generate free radicals

Agent	Signature toxicity
Cyclophosphamide	Haemorrhagic cystitis (acrolein) - prevent with MESNA and hydration; SIADH; bladder cancer; infertility
Ifosfamide	Cystitis + encephalopathy (treat with methylene blue); Fanconi syndrome
Cisplatin	Nephrotoxicity, ototoxicity, peripheral neuropathy, dec Mg, highly emetogenic
Oxaliplatin	Cold-induced acute dysaesthesia, cumulative sensory neuropathy; minimal nephrotoxicity
Carboplatin	Myelosuppression (thrombocytopenia); dosed by AUC (Calvert formula)
Bleomycin	Pulmonary fibrosis (cumulative dose, inc O2, inc age, renal impairment); no myelosuppression
Anthracyclines	Dose-dependent, irreversible cardiomyopathy (doxorubicin lifetime ~450-550 mg/m2); vesicant; secondary AML
Vincristine	Peripheral neuropathy, no myelosuppression; fatal intrathecally; vesicant
Taxanes	Neuropathy, hypersensitivity (premedicate), alopecia, myalgia
5-FU / capecitabine	Mucositis, diarrhoea, hand-foot syndrome, coronary vasospasm; DPYD deficiency -> severe toxicity
Methotrexate	Mucositis, myelosuppression, crystal nephropathy, hepatic fibrosis, pneumonitis; folinic acid rescue
Irinotecan	Early cholinergic diarrhoea (atropine) and late diarrhoea (loperamide); *UGT1A128**
Cytarabine	Cerebellar toxicity at high dose, conjunctivitis
Busulfan	Pulmonary fibrosis, sinusoidal obstruction syndrome, seizures
Gemcitabine	TMA/HUS, flu-like syndrome

Match the toxicity to the drug - this is how the questions are asked
- Cardiomyopathy -> anthracycline or trastuzumab; echo before and during
- Pulmonary fibrosis -> bleomycin, busulfan, methotrexate; avoid high FiO2 in a bleomycin-exposed patient at anaesthesia and in diving
- Neuropathy without myelosuppression -> vincristine
- Haemorrhagic cystitis -> cyclophosphamide/ifosfamide
Pharmacogenomic pre-testing changes practice - DPYD before fluoropyrimidines, UGT1A1 before irinotecan, TPMT/NUDT15 before thiopurines
Non-specific agents are dose-dependent (bolus); cycle-specific agents are schedule-dependent (infusion)
Long-term survivorship - secondary malignancy (alkylators -> MDS/AML at 5-7 years; etoposide -> AML at 2-3 years), infertility, cardiac and pulmonary late effects

3 more sections, plus exam facts

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