I have a pharamcology test tomorrow.on chemotherapy
Asking for Preferences
Reading File
Finding Sources
Finding Sources
Finding Sources
Reading File
Reading File
Finding Sources
Reading File
Finding Sources
Finding Sources
Reading File
Reading File
Reading File
I now have comprehensive data. Let me compile the full study guide from all the information gathered.
🧬 Chemotherapy Pharmacology - Complete Medical School Study Guide
Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics (2024), Lippincott Illustrated Reviews: Pharmacology, Sabiston Textbook of Surgery
CORE CONCEPTS TO KNOW FIRST
Cell Cycle Specificity
- Cell cycle-SPECIFIC drugs: Only kill cells in a particular phase (most antimetabolites, plant alkaloids). They obey a plateau effect - increasing dose beyond a threshold doesn't increase kill.
- Cell cycle-NONSPECIFIC drugs: Kill cells regardless of cycle phase (alkylating agents, antitumor antibiotics, nitrosoureas). Show a linear dose-response - more dose = more kill.
Log Kill Hypothesis
- Chemotherapy follows first-order kinetics - a given dose kills a constant fraction (not a fixed number) of cells.
- Diagnosis of leukemia typically made at ~10⁹ cells. A 5-log kill (99.999%) leaves 10⁴ cells - patient enters remission but is NOT cured.
- This is why combination therapy and multiple cycles are required.
Why Combination Chemotherapy?
- Each drug attacks a different target - less overlap in toxicity
- Reduces development of drug resistance
- Broader coverage of heterogeneous tumor cell populations
Pharmacologic Sanctuaries
- The CNS is a sanctuary site where many drugs cannot penetrate (blood-brain barrier).
- Requires intrathecal (IT) drug administration or craniospinal irradiation (e.g., in ALL).
Drug Resistance
- Intrinsic resistance: Some tumors (e.g., melanoma) are inherently resistant.
- Acquired resistance: Mutations after prolonged suboptimal dosing.
- Multidrug resistance (MDR): Overexpression of P-glycoprotein (encoded by MDR1 gene) - an ATP-dependent efflux pump that pushes drugs out of cells. Affects vinca alkaloids, anthracyclines, dactinomycin. Verapamil can inhibit this pump.
CLASS 1: ALKYLATING AGENTS
Mechanism: Form covalent bonds with DNA - cross-link DNA strands or alkylate guanine residues → prevent DNA replication → cell death. Cell cycle NONSPECIFIC.
Common Toxicities (ALL alkylating agents):
- Myelosuppression + immunosuppression
- Oral mucositis, alopecia (toxicity to dividing cells)
- Pulmonary fibrosis (delayed)
- Gonadal toxicity (premature menopause, sterility)
- Leukemogenesis (secondary AML, up to 5%) - highest risk with mechlorethamine, procarbazine, thiotepa
Subclasses & Key Drugs:
| Subclass | Drug | Key Use | Special Toxicity |
|---|---|---|---|
| Nitrogen mustards | Cyclophosphamide | Lymphoma, breast, ovary, nephrotic syndrome, autoimmune | Hemorrhagic cystitis (acrolein metabolite) - prevent with MESNA + hydration |
| Nitrogen mustard | Ifosfamide | Germ cell testicular, sarcoma | Hemorrhagic cystitis; CNS toxicity (encephalopathy) |
| Nitrogen mustard | Melphalan | Multiple myeloma, high-dose with BMT | Standard alkylator effects |
| Nitrogen mustard | Chlorambucil | CLL, lymphoma | Can cause CNS seizures |
| Nitrogen mustard | Bendamustine | CLL, non-Hodgkin lymphoma | Lacks cross-resistance with classical alkylators |
| Alkyl sulfonate | Busulfan | CML, pre-BMT conditioning | Prolonged pancytopenia; pulmonary fibrosis; seizures |
| Nitrosourea | Carmustine (BCNU) | Malignant gliomas (crosses BBB!) | Profound + delayed myelosuppression (4-6 weeks!) |
| Nitrosourea | Lomustine (CCNU) | Gliomas, Hodgkin lymphoma | Same as BCNU |
| Nitrosourea | Streptozocin | Pancreatic islet cell tumors | Nephrotoxicity (dose-limiting), diabetogenic |
| Platinum complexes | Cisplatin | Testicular, ovarian, bladder, head & neck, lung | Nephrotoxicity (dose-limiting) - prevent with IV hydration; Ototoxicity (irreversible); peripheral neuropathy; severe N/V |
| Platinum | Carboplatin | Ovarian, lung | Myelosuppression (dose-limiting); less nephro/neuro/ototoxic than cisplatin |
| Platinum | Oxaliplatin | Colorectal cancer (FOLFOX) | Peripheral neuropathy (dose-limiting, cold-induced acutely) |
High-yield tip: Cisplatin = nephro + oto + neuro toxic. Carboplatin = bone marrow toxic. BCNU/CCNU = delayed myelosuppression (4-6 wks vs 10-14 days for others).
CLASS 2: ANTIMETABOLITES
Mechanism: Structural analogs of normal metabolites that interfere with DNA/RNA synthesis. Cell cycle SPECIFIC (S-phase).
Folate Antagonists
| Drug | Mechanism | Uses | Key Toxicities | Notes |
|---|---|---|---|---|
| Methotrexate (MTX) | Inhibits dihydrofolate reductase (DHFR) → blocks THF synthesis → no purines/thymidylate | ALL, osteosarcoma, breast, head & neck; Non-cancer: psoriasis, RA | Myelosuppression, mucositis/stomatitis, nephrotoxicity (high-dose), hepatotoxicity, teratogenic | Leucovorin rescue reverses toxicity; dose-adjust in renal impairment; intrathecal for CNS disease |
| Pemetrexed | Multi-enzyme folate inhibitor (DHFR + TS + GARFT) | Mesothelioma, NSCLC | Similar to MTX | Give folic acid + B12 supplementation to reduce toxicity |
Pyrimidine Analogues
| Drug | Mechanism | Uses | Key Toxicities | Notes |
|---|---|---|---|---|
| 5-Fluorouracil (5-FU) | Inhibits thymidylate synthase (TS) → no dTMP; also incorporated into RNA | Colorectal (FOLFOX/FOLFIRI), breast, gastric, head & neck | Mucositis (bolus dosing), hand-foot syndrome (continuous infusion), myelosuppression, coronary vasospasm | IV only; leucovorin enhances 5-FU efficacy |
| Capecitabine | Oral prodrug of 5-FU; converted in tumor by thymidine phosphorylase | Breast, colorectal cancer | Hand-foot syndrome (palmar-plantar erythrodysesthesia), mucositis, diarrhea | Take within 30 min of a meal |
| Cytarabine (Ara-C) | Inhibits DNA polymerase; incorporated into DNA → strand termination | AML, ALL, non-Hodgkin lymphoma | Severe myelosuppression, hepatotoxicity; conjunctivitis (high-dose) | Use steroid eye drops at high doses; given IV or IT |
| Gemcitabine | Inhibits DNA polymerase; causes strand termination | Pancreatic, ovarian, lung, bladder cancer | Myelosuppression, flu-like syndrome, hepatotoxicity | IV administration |
| Azacitidine | Inhibits DNA methyltransferase (hypomethylating agent) | Myelodysplastic syndrome (MDS) | Myelosuppression (neutropenia, thrombocytopenia), N/V | Also decitabine - same mechanism |
Purine Analogues
| Drug | Mechanism | Uses | Key Toxicities | Notes |
|---|---|---|---|---|
| 6-Mercaptopurine (6-MP) | Incorporated into DNA/RNA as false purine; inhibits purine synthesis | ALL, Crohn disease | Myelosuppression, hepatotoxicity (jaundice), N/V | Reduce dose 50-75% with allopurinol (allopurinol blocks xanthine oxidase which metabolizes 6-MP) |
| 6-Thioguanine (6-TG) | Same as 6-MP | AML | Myelosuppression, hepatotoxicity | |
| Fludarabine | Inhibits DNA polymerase; DNA strand termination | CLL, non-Hodgkin lymphoma | Myelosuppression, severe immunosuppression (CD4 depletion) → opportunistic infections | Dose-adjust in renal impairment |
| Cladribine | Resistant to adenosine deaminase; accumulates → apoptosis | Hairy cell leukemia | Neutropenia, severe immunosuppression, fever | First-line for hairy cell leukemia |
High-yield tip: 6-MP + allopurinol = dangerous interaction (xanthine oxidase inhibition). MTX toxicity is reversed by leucovorin. 5-FU's efficacy is enhanced by leucovorin (different mechanism).
CLASS 3: ANTITUMOR ANTIBIOTICS
Mechanism: Mostly intercalate into DNA or inhibit topoisomerase II. Cell cycle NONSPECIFIC (except bleomycin = G2/M-specific).
| Drug | Mechanism | Uses | Key Toxicity | Notes |
|---|---|---|---|---|
| Doxorubicin (Adriamycin) | Intercalates DNA + inhibits topo II + generates free radicals | Breast, lymphoma, leukemia, sarcoma ("broad spectrum") | Cardiotoxicity (dilated cardiomyopathy, cumulative dose-dependent) + alopecia + myelosuppression | Cardiotoxicity prevented by dexrazoxane (iron chelator); Red/orange urine |
| Daunorubicin | Same as doxorubicin | AML, ALL | Cardiotoxicity | Anthracycline like doxorubicin |
| Idarubicin | Same class | AML | Cardiotoxicity | Less cardiotoxic than doxorubicin |
| Bleomycin | Generates free radicals → DNA strand breaks | Testicular cancer, Hodgkin lymphoma (ABVD) | Pulmonary fibrosis (dose-limiting, cumulative); skin hyperpigmentation; minimal myelosuppression! | G2/M-phase specific; monitor pulmonary function; no myelosuppression (unique!) |
| Mitomycin C | Alkylates DNA (acts like alkylating agent) | Gastric, bladder, cervical cancer | Myelosuppression, hemolytic uremic syndrome (HUS) | |
| Dactinomycin (actinomycin D) | Intercalates between G-C base pairs; inhibits RNA synthesis | Wilms tumor, Ewing sarcoma, gestational trophoblastic disease | Myelosuppression, GI toxicity, alopecia | Used in pediatric cancers |
High-yield tip: Anthracyclines (doxorubicin/daunorubicin) → cardiomyopathy. Bleomycin → pulmonary fibrosis. Bleomycin is the only antibiotic with no significant myelosuppression.
CLASS 4: PLANT ALKALOIDS
Topoisomerase Inhibitors
| Drug | Mechanism | Uses | Key Toxicity | Notes |
|---|---|---|---|---|
| Etoposide (VP-16) | Inhibits Topo II (stabilizes cleavable complex) | Testicular, lung (SCLC), lymphoma | Myelosuppression, secondary AML | S and G2-phase specific |
| Irinotecan (CPT-11) | Inhibits Topo I | Colorectal cancer | Severe diarrhea (early: cholinergic; late: treat with loperamide), myelosuppression | Late diarrhea is dose-limiting |
| Topotecan | Inhibits Topo I | Ovarian, SCLC | Myelosuppression |
Vinca Alkaloids (Tubulin Binders)
Mechanism: Bind β-tubulin → prevent microtubule polymerization → M-phase arrest (mitotic spindle cannot form)
| Drug | Uses | Key Toxicity |
|---|---|---|
| Vincristine | ALL, lymphoma, Wilms tumor, neuroblastoma | Peripheral neuropathy (dose-limiting), constipation; minimal myelosuppression |
| Vinblastine | Hodgkin lymphoma (ABVD), testicular cancer | Myelosuppression (dose-limiting); less neurotoxic than vincristine |
| Vinorelbine | NSCLC, breast cancer | Myelosuppression, neuropathy |
High-yield tip: Vincristine vs Vinblastine - "Vincristine = Constipation/Neurotoxicity (no bone marrow); Vinblastine = Bone marrow toxicity"
Taxanes (Tubulin Binders)
Mechanism: Bind β-tubulin → prevent microtubule DEpolymerization → cells cannot exit mitosis → M-phase arrest. (Opposite of vinca alkaloids!)
| Drug | Uses | Key Toxicity |
|---|---|---|
| Paclitaxel | Breast, ovarian, NSCLC, Kaposi sarcoma | Peripheral neuropathy, myelosuppression, hypersensitivity (premedicate with dexamethasone + antihistamine), bradycardia/arrhythmias |
| Docetaxel | Breast, NSCLC, prostate | Peripheral neuropathy, myelosuppression, fluid retention/edema |
High-yield tip: Both taxanes and vinca alkaloids target tubulin - but in opposite ways. Taxanes FREEZE microtubules assembled; vincas PREVENT assembly.
CLASS 5: TARGETED THERAPY
Tyrosine Kinase Inhibitors (TKIs)
| Drug | Target | Use | Key Toxicity |
|---|---|---|---|
| Imatinib (Gleevec) | BCR-ABL kinase | CML (Philadelphia chromosome +), GIST | GI upset, edema, hepatotoxicity |
| Erlotinib / Gefitinib | EGFR kinase | NSCLC (EGFR-mutant) | Rash (acneiform), diarrhea |
| Trastuzumab (Herceptin) | HER2 receptor | HER2+ breast cancer, gastric cancer | Cardiotoxicity (do NOT combine with anthracyclines) |
| Rituximab | CD20 (B-cells) | B-cell NHL, CLL, RA | Infusion reactions, reactivation of hepatitis B |
| Bevacizumab | VEGF (anti-angiogenic) | Colorectal, lung, ovarian cancer | Hypertension, impaired wound healing, thromboembolism |
| Cetuximab / Panitumumab | EGFR receptor | Colorectal, head & neck cancer | Rash, hypomagnesemia; only effective if KRAS wild-type |
Hormone Therapy
| Drug | Mechanism | Use |
|---|---|---|
| Tamoxifen | Selective estrogen receptor modulator (SERM) | ER+ breast cancer |
| Leuprolide | GnRH agonist → LH/FSH suppression → castration | Prostate cancer, breast cancer |
| Flutamide / Bicalutamide | Androgen receptor antagonist | Prostate cancer |
| Anastrozole / Letrozole | Aromatase inhibitor | Post-menopausal ER+ breast cancer |
CLASS 6: MISCELLANEOUS IMPORTANT DRUGS
| Drug | Mechanism | Use | Toxicity |
|---|---|---|---|
| Hydroxyurea | Inhibits ribonucleotide reductase → blocks DNA synthesis (S-phase) | CML, sickle cell disease (↑HbF), polycythemia vera | Myelosuppression, skin ulcers |
| Asparaginase | Hydrolyzes asparagine → deprives tumor cells | ALL (lymphoblasts lack asparagine synthetase) | Hypersensitivity/anaphylaxis, pancreatitis, coagulopathy, hepatotoxicity; no myelosuppression |
| Procarbazine | Alkylating (methylates DNA); also MAO inhibitor | Hodgkin lymphoma (MOPP) | Myelosuppression, leukemogenesis, tyramine reaction (MAO inhibitor!) |
| Arsenic Trioxide (ATO) | Induces ROS, apoptosis, degrades PML-RARα fusion protein | Acute promyelocytic leukemia (APL) | QT prolongation (monitor ECG and K+), hyperglycemia |
| All-trans Retinoic Acid (ATRA) | Promotes differentiation of APL blasts | APL | Retinoic acid syndrome (pulmonary distress, effusions) |
KEY COMBINATION REGIMENS TO KNOW
| Regimen | Drugs | Used For |
|---|---|---|
| ABVD | Adriamycin + Bleomycin + Vinblastine + Dacarbazine | Hodgkin lymphoma |
| CHOP | Cyclophosphamide + Hydroxydaunorubicin (doxorubicin) + Oncovin (vincristine) + Prednisone | Non-Hodgkin lymphoma |
| R-CHOP | Rituximab + CHOP | CD20+ NHL |
| FOLFOX | Folinic acid + Oxaliplatin + 5-Fluorouracil | Colorectal cancer |
| BEP | Bleomycin + Etoposide + Platinum (cisplatin) | Testicular cancer |
| MOPP | Mechlorethamine + Oncovin + Procarbazine + Prednisone | Hodgkin lymphoma (historical) |
TOXICITY QUICK-REFERENCE TABLE
| Toxicity | Drug(s) | Management |
|---|---|---|
| Cardiotoxicity (cardiomyopathy) | Doxorubicin, daunorubicin, trastuzumab | Dexrazoxane for anthracyclines; cumulative dose limit |
| Pulmonary fibrosis | Bleomycin, busulfan, carmustine | Monitor PFTs; lifetime dose limit |
| Nephrotoxicity | Cisplatin, streptozocin, methotrexate (high-dose) | IV hydration; amifostine for cisplatin |
| Hemorrhagic cystitis | Cyclophosphamide, ifosfamide | MESNA + aggressive hydration |
| Peripheral neuropathy | Vincristine, cisplatin, oxaliplatin, paclitaxel | Dose reduction |
| Ototoxicity | Cisplatin | Audiometry monitoring |
| Hand-foot syndrome | 5-FU (continuous), capecitabine | Dose reduction; skin moisturizing |
| Secondary leukemia (AML) | Alkylating agents (especially procarbazine, mechlorethamine), etoposide | Monitor CBC long-term |
| Mucositis/stomatitis | Methotrexate, 5-FU, doxorubicin | Leucovorin (MTX rescue); oral hygiene |
| Severe diarrhea | Irinotecan | Loperamide (late diarrhea); atropine (early/cholinergic) |
| QT prolongation | Arsenic trioxide | ECG + electrolyte monitoring |
| Hypersensitivity | Paclitaxel, asparaginase | Premedicate with steroids + antihistamines |
| Myelosuppression | Nearly all | G-CSF (filgrastim), dose delays |
HIGH-YIELD EXAM MNEMONICS
- "Bleomycin has No Bone Marrow toxicity" - it destroys lungs, not marrow
- "Vincristine = Nerves; Vinblastine = Bone marrow" - Cs stands for CNS/Constipation, Bs for Blood
- "Cisplatin = CIA" - Cardio... no wait: Cisplatin = Ototox, Isotonic saline hydration, Amifostine protection
- "MESNA prevents cystitis" from Cyclophosphamide/Ifosfamide (gives it a mercapto group that neutralizes acrolein in urine)
- "6-MP + Allopurinol = Toxic" - allopurinol blocks XO, so 6-MP cannot be metabolized → reduce dose 50-75%
- Leucovorin: Rescues from MTX toxicity; Enhances 5-FU activity
- Taxanes vs Vincas: Taxanes STABILIZE microtubules (hyperstabilize); Vincas DESTABILIZE (prevent polymerization)
CELL CYCLE PHASE SUMMARY
| Phase | Drugs Active Here |
|---|---|
| S-phase | Antimetabolites (MTX, 5-FU, cytarabine, gemcitabine, hydroxyurea), etoposide |
| M-phase | Vinca alkaloids, taxanes |
| G2/M | Bleomycin, etoposide |
| Cell cycle NONSPECIFIC | Alkylating agents, antitumor antibiotics (most), nitrosoureas, cisplatin |
Good luck on your test tomorrow! The highest-yield areas based on frequency in medical school pharmacology exams are:
- Alkylating agent toxicities (especially cyclophosphamide/hemorrhagic cystitis, cisplatin triad)
- Antimetabolite mechanisms and interactions (MTX/leucovorin, 6-MP/allopurinol)
- Anthracycline cardiotoxicity vs bleomycin pulmonary toxicity
- Vincristine vs vinblastine dose-limiting toxicities
- Targeted therapies (imatinib for CML, trastuzumab for HER2+, rituximab for CD20+)
Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics 14e, Lippincott Illustrated Reviews: Pharmacology, Sabiston Textbook of Surgery
This is a shared conversation. Sign in to Orris to start your own chat.