Antineoplastic Agents & Oral Complications

Front 1

Cell cycle specific

Back 1

-preferentially kill proliferating cells
-toxic to the proportion of cells in the part of cell cycle in which agent is active
-administer as a "continuous infusion"

Front 2

What are cell cycle specific drugs?

Back 2

Antimetabolites
antifolates (Methotrexate)
Pyrimidine antagonists (5-FU)
Purine analogs (6-mercaptopurine)
Plant derivatives
Vinca alkaloids (vincristine)
Epipodophyllotoxins (etoposide)
Camptothecins (irinotecan)
Taxanes (paclitaxel)

Front 3

Cell cycle NON-specific

Back 3

-kill BOTH normal & malignant cells to same extent
-exert their cytotoxic effect throughout cell cycle
-cell kill is proportional to dose

Front 4

What are cell cycle NON-specific drug?

Back 4

Alkylating agents
nitrogen mustards
cyclophosphamide
cisplatin
carboplatin
Antitumor antibiotics
doxorubicin
daunorubicin
bleomycin

Front 5

What are the principles of chemotherapy?

Back 5

-tumor must be susceptible to selected drugs
-no intolerable side effects that would inhibit completion of therapy
-dosage/schedule calculated to maximize drug contact w/ tumor cells
-chemo more effective when tumor is small
-chemo kills according to first-order kinetics
-combo chemo takes advantage of different MOA
-cells may develop resistance

Front 6

What are the alkylating agents?

Back 6

Cyclophosphamide

Front 7

What is the MOA of alkylating agents?

Back 7

Work by transferring alkyl group to cellular constituent

Front 8

How is Cyclophosphamide metabolized?

Back 8

-oxidized by CYP 450 3A4 -> 4-hydroxycyclophosphamide
-80% of dose is oxidized further to inactive metabolites
-4-hydroxycyclophosphamide spontaneously ring opens -> aldophosphamide
-aldophosphamide converted to phosphoramide Mustard & Acrolein (TOXIC metabolites)

Front 9

What are the ADE of cyclophosphamide?

Back 9

-Alopecia
-myelosuppression
-low WBC, RBC & platelet counts
-hemorrhagic cystitis
-acrolein metabolite irritates bladder lining
-prevention w/ hydration, mesna
-acute & delayed N/V

Front 10

What are the platinum analog drugs?

Back 10

cisplatin

Front 11

What is the MOA of cisplatin?

Back 11

-cell cycle NON-specific
-results in DNA cross-linking (similar to alkylating agents)
-requires hydration (equation) to be converted to active species

Front 12

What are the ADE of cisplatin?

Back 12

-N/V (all other chemos compared to cisplatin)
-renal toxicity
-myelosuppression
-hepatotoxicity
-anaphylaxis

Front 13

What are the antimetabolites?

Back 13

-antifolates (methotrexate)
-fluoropyrimidines (5-fluorouracil)
-purine antagonists (6-MP)

Front 14

What is the MOA of methotrexate (antifolate)?

Back 14

-irreversibly binds to DHFR (dihydrofolate reductase), which decreases pool of reduced floats to be incorporated into purine bases

Front 15

What are the ADE of methotrexate?

Back 15

-mucositis
-diarrhea
-myelosuppression
*use caution w/ renally eliminated drugs
Drug interactions: NSAIDS, PPIs, PCN, sulfa-methoxazole-trimethoprim

Front 16

What is the MOA of 5-fluorouracil (fluoropyrimidines)?

Back 16

"false" pyrimidine
-inhibits enzyme thymidylate synthase -> rate limiting step in formation of DNA base thymidine
-metabolites can also be incorporated into RNA & DNA adding to toxicity

Front 17

What are the major toxicities of 5-FU?

Back 17

-myelosuppression
-GI: mucositis (continuous infusion), diarrhea
-skin: hand-foot syndrome
-neurotoxicity

Front 18

What is the MOA of 6-MP (mercaptopurine)?
purine antagonist

Back 18

-used in pediatrics, immunosuppressant
-interferes w/ conversion of inosonic acid to adenine & guanine which inhibits DNA and RNA synthesis

Front 19

What are the ADE for 6-MP?

Back 19

-myelosuppression
-pulmonary fibrosis
-pancreatitis

Front 20

What are the Natural products?

Back 20

Taxanes (docetaxel, paclitaxel)

Front 21

What is the MOA of paclitaxel?

Back 21

promotes microtubule assembly -> results in inhibition of mitosis & cell division

Front 22

What are the ADE of paclitaxel?

Back 22

Acute:N/V, arrhythmias, hypersensitivity
pre-medicated w/ diphenhydramine (H1 blocker) + famotidine (H2 blocker) + dexamethasone (steroid) w/ each dose
Delayed: myelosuppression, peripheral neuropathy

Front 23

What are the ADE of Docetaxel?

Back 23

Acute: Hypersensitivity
pre-medicate w/ dexamethasone (steroid) to minimize fluid retention
Delayed: neurotoxicity, fluid retention, myelosuppression

Front 24

Antitumor antibiotics (anthracyclines - doxorubicin):

Back 24

bind w/ DNA to produce irreversible complexes that inhibit cell division

Front 25

Vinca alkaloids (vincristine):

Back 25

stop cell division by binding to tubulin (forms mitotic spindle)

Front 26

podophyllotoxins (etoposide):

Back 26

inhibits topoisomerase II

Front 27

camptothecins (topotecan):

Back 27

inhibits topoisomerase I

Front 28

tyrosine kinase inhibitors (imatinib):

Back 28

interrupt intracellular signaling pathways

Front 29

Monoclonal antibodies (rituximab):

Back 29

bind to extracellular receptors to interrupt cell signaling

Front 30

Drug interactions/contraindications

Back 30

-most chemotherapy agents have narrow therapeutic index & drug interactions can increase toxicity or decrease efficacy
-patients undergoing chemotherapy often have low platelets
-NSAIDs should be avoided!!!

Front 31

What are general ADE of chemotherapy?

Back 31

-N/V
-myelosuppression (neutropenia, anemia, thrombocytopenia)
vincristine, corticosteroids, bleomycin, interferons, l-asparaginase, hormones, methotrexate w/ leucovorin rescue DON'T

Front 32

What is the management of neutropenia?

Back 32

-consider giving CSF (filgrastim or pegfilgrastim) w/ each chemotherapy cycle
Primary prevention:
administer w/ first cycle if risk greater than 20%
Secondary prevention:
consider CSFs or dose reduction

Front 33

What is the management of anemia & thrombocytopenia?

Back 33

-typically managed w/ transfusions
Anemia: transfuse when hemoglobin < 8mg/dL
Thrombocytopenia: transfuse when platelets < 10,000 or if signs of bleeding at higher platelet counts