Exam I - Chemotherapy Flashcards
Drug List
- Methotrexate
- 5-FU
- Cyclophosphamide
- Hydroxyurea
Chemotherapy
Purpose
- Toxicity with a purpose
- remove target
- ideally selectively toxic for target (bug/cancer)
Logarithmic Chemotx
- successive treatments
- each treatment kills a PERCENTAGE
Normal cell populations
that actively replicate
- hair
- skin
- blood
- GI mucosa
- pregancy
- immune processes
Cell proliferation processes
- DNA synthesis
- cell division
Chemotherapy
Toxicities
- targets normal actively replication cells
- skin, hair, blood, GI mucosa
Cell-cycle specific
Examples
- DNA synthesis inhibitors
- mitotic inhibitors
Cell cycle non-specific
Exampl
-alkylating agents
Drug Resistance
3 ways
- therapy failure
- acquired or innate
- mutation or gene expression changes
Resistance Mechanisms
- altered target
- detoxifying enzymes inactivate drugs
- decrease uptake/decrease permeability/increased efflux
- increased target enzyme
- increased levels of competitive substrate
Methotrexate
Mechanism
-inhibits DNA synthesis:
inhibs thymidine synth (by blocking DHFR
and depleting tetrahydrofolate)
Methotrexate
Indications
- arthritis
- autoimmune dz
- cancer (at higher dose)
Methotrexate
ADME
- oral or parenteral
- absorbed better at low dose
- renal elim
Methotrxate
Adverse
- hepatotoxicity
- bone marrow/GI/urine crystals
Fluorouracil
Mechanism
- inhibits DNA and RNA synth
- analog of thymidine (FdUMP DNA, FdUTP RNA)
- inhibits thymidine synth
- inhibits thymidylate synthetase
Fluorouracil
ADME
- topical or IV
- metab’d extensively
- secreted renally
Fluorouracil
Adverse
- Nausea, vomit
- myelosuppression
- Oral/GI ulceration
Fluorouracil
indications
-topical for actinic keratoses, skin cancer
Hydroxyurea
Mechanism
-inhibits DNA synthesis:
-inhibits ribonucleotide reductase
(which converts ribonucs to dexoxyribonucs)
-induces fetal Hgb (use with sickle cell)
(suppresses erythrocyte precursors)
Hydroxyurea
ADME
-oral
Hydroxyurea
Adverse
- myelosuppression (pancytopenia)
- GI disturbance
- dermatologic rxns
- potent teratogen
- does NOT increase risk of leukemia in sickle cell
- monitor neutrophil count in sickle cell tx
Cyclophosphamide
Mechanism
- alkylating agent
- inhibits DNA synth
- primary: cross-links DNA
- also damages bases
- also makes DNA-protein cross-links
Cyclophosphamide
Indications
- rheumatoid d/o
- immunosuppression
- autoimmune nephritis
- bone marrow transplant
Cyclophosphamide
ADME
- Oral or IV
- pro-drug; metab’d in liver (P450)
- active metabolite: phosphoramide mustard
- toxic metabolite: acrolein
Cyclophosphamide
Adverse
- alopecia
- nause/vomit
- myelosuppression
- hemmorhagic cystitis (acrolein)
Cyclophosphamide
How to combat hemorrhagic cystitis
- drink lots of fluid
- MESNA-sulfhydryl reagent deactivate acrolein
