Pharm Part 6

Front 1

pt. w/chemo for Hodgkins develops symptoms of schizophrenia; which drug is causing?

Back 1

-prednisone=CNS toxicity=psychosis

Front 2

Cancer cells lacking hypoxanthine-guanine phosphoribosyl transferase (HGPRTase)are resistant to ?

Back 2

-6-mercaptopurine and 6-thioguanine

-The enzyme HGPRTase converts 6-MP and 6-TG to a nucleotide form which inhibits purine synthesis and thus blocks
DNA/RNA synthesis

Front 3

Cyclophosphamide
-medical use?

Back 3

-Cyclophosphamide used to treat non-Hodgkins lymphoma, breast and ovarian carcinomas

Front 4

Cyclophosphamide
-MOA?

Back 4

-MOA = activated by CYP450 to a metabolite which covalently x-links
DNA strands at guanine N-7

Front 5

Cyclophosphamide
-S/E

Back 5

-S/E = causes sterile hemorrhagic cystitis; alkylating agents like cyclophosphamide can cause myelogenous (granulocytic) leukemia

Front 6

pt to be tx w/chem/cyclophosphamide. pt is also receiving tx for gout. which gout drug would inc the toxicity of cyclophosphamide?

Back 6

-allopurinol prolongs the half-life of cyclophosphamide

Front 7

Drug interactions with Allopurinol

Back 7

a.alluopurinol inhibits xanthine oxidase to prevent the formation of uric acid)

b.allopurinol often used after tx of hematologic cancers to prevent hyperuricemia after tumor cell lysis

c.allopurinol inhibits the metabolism of 6-mercaptopurine (6-MP) by xanthine oxidase,so need to reduce dose of 6-MP to 25% of normal dose in patients on allopurinol
d.Need to dec dose of immunosuppressive drug azathioprine by 25% of normal when given to a patient taking allopurinol because azathioprine is metabolized to 6-MP

Front 8

Drugs that interfere w/microtubule fxn?

Back 8

-vincristine:Vinblastine binds to tubulin and blocks the ability of tubulin to polymerize intomicrotubule = mitotic arrest in metaphase

-vinblastine
-placlitaxel (taxol)
-colchicine
-griseofulvin
-mebendazole

Front 9

Paclitaxel used to tx ovarian and breast cancer
-MOA?

Back 9

-MOA = binds to microtubules of mitotic spindle to hyperstabilize them so that they cannot break down in anaphase, get mitotic arrest

Front 10

dactinomycin (actinomycin D)
-MOA?

Back 10

-MOA of dactinomycin (actinomycin D)=binds tightly to double-stranded DNA between G-C pairs to inhibit all forms of DNA-dependent RNA synthesis, esp. mRNA synthesis

-used for the tx of Wilm’s tumor

Front 11

Doxorubicin and Danurubicin
= anthracycline antibiotics
-MOA?

Back 11

-MOA = intercalation into DNA - inhibits synthesis of DNA/RNA

Front 12

Doxorubicin and Danurubicin
= anthracycline antibiotics
-TOX?

Back 12

-toxicity = forms free radicals and oxygen radicals causing cardiac toxicity via
membrane damage

Front 13

Methotrexate
-uses?

Back 13

-used to tx leukemias and sarcomas
-forms a polyglutamate adduct which is important for its duration of action

Front 14

Methotrexate
-MOA

Back 14

-MOA = a folic acid antagonist which binds to DHF reductase, interferes w/ synthesis of thymidylate, purine nucleotides and the AA’s serine and methionine

=inhibition of synthesis of DNA, RNA and proteins

Front 15

Methotrexate
-causes of resistance?

Back 15

- decreased drug transport
- altered DHFR
- increased activity of DHFR
- decreased polyglutamate formation

Front 16

Methotrexate
-S/E

Back 16

-bone marrow depression

Front 17

pt tx w/methotrexate develops bone marrow dep. hot to tx?

Back 17

-“leucovorin rescue”
=tx w leucovorin (folinic acid) to reverse bone marrow
depression.

-Normal cells can take up leucovorin, but tumor cells cannot, so leucovorin rescues normal cells but not tumor cells

Front 18

5-flurouracil (5FU)
-uses?

Back 18

-used to tx colon cancer
-combined with levamisole

Front 19

5-flurouracil (5FU)
-MOA?

Back 19

-MOA: inhibition of DNA synthesis: 5-FU converted to FdUMP which inhibits thymidylate synthetase. No dTMP formed, so no thymidine nucleotides formed = “thymidineless death”

Front 20

5-flurouracil (5FU)
-what does it do?

Back 20

-inhibition of RNA processing

Front 21

5-flurouracil (5FU)
-leucovorin rescue?

Back 21

-no leuc rescue possible

Front 22

pt on chem has cough w/crackles. xr shows diffuse basilar infiltrates. DRUG?

Back 22

-bleomycin

Front 23

Bleomycin
-MOA?

Back 23

-MOA of bleomycin (a peptide antibiotic) = fragmentation of DNA via formation of activated oxygen species (free radicals),cells accumulate in G2 w/ chromatid breaks, gaps, fragments and translocations

Front 24

Bleomycin
-bone?

Back 24

-little bone marrow toxicity

Front 25

drug w/antiestrogenic effects for tx of breast cancer?

Back 25

-tamoxifen

Front 26

nitrosoureas

Back 26

-carmustine
-lomustine
-used to tx brain tumors
-(they can cross the BBB)

Front 27

nitrosoureas
-MOA?

Back 27

-MOA = cross link DNA via alkylation; requires bioactivation

Front 28

Which type of receptors must be present for the tx a breast cancer w/ the GnRH analogs leuprolide and goserelin?

Back 28

-estrogen receptors in the tumor tissue

Front 29

MOA of GnRH analogs?

Back 29

MOA of GnRH analogs = act on pituitary to inhibit the release of LH and FSH, decreased LH decreases estrogen synthesis by ovaries

Front 30

Cisplatin
-uses?

Back 30

-cisplatin used to tx testicular and lung carcinomas

Front 31

Cisplatin
-MOA?

Back 31

-MOA = forms intra- and interstrand cross links at N7 of guanine via hydroylsis of chloride groups = inhibits DNA replication and transcription; replacement of chloride with water forms the active drug

Front 32

Cisplatin
-S/E

Back 32

-S/E = nephrotoxic which is decreased by Cl- diuresis because Cl- stabilizes the
platin complex: renal toxicity causes loss of Mg++, Ca++, K+ and phosphate

Front 33

prednisone
-uses?

Back 33

-prednisone used to tx chronic lymphocytic leukemia, Hodgkin's

Front 34

prednisone
-MOA?

Back 34

-MOA=apoptosis in non-dividing cells

Front 35

radiation and alkylating agents

Back 35

-increase tumor cell death by increasing dose

Front 36

antimetabolites

Back 36

-inc tumor death by in exposure time, not the dose

Front 37

MAJOR TOXICITY

Back 37

-alkylating agents=moderate bone marrow depression, large doses cause severe
depression with leukopenia, thrombocytopenia and bleeding

-busulfan-skin pigmentation, pulmonary fibrosis, adrenal insufficiency

Front 38

MAJOR TOXICITY

Back 38

-cyclophosphamide-hemorrhagic cystitis

-cisplatin - renal damage, acoustic nerve dysfunction

-procarbazine -CNS depression

-glucorticoids=prednisone- immunosuppression, adrenal suppression, psychosis

Front 39

MAJOR TOXICITY

Back 39

-cytarabine - megaloblastosis

-5-fluorouracil - oral and GI ulceration

-mercaptopurine (6-MP) - toxicity potentiated by allopurinol

-methotrexate - oral and GI ulceration, bone marrow depression

Front 40

MAJOR TOXICITY

Back 40

-bleomycin - pulmonary fibrosis

-dactinomycin - bone marrow suppression

-doxorubicin - cardiac toxicity, bone marrow depression, red urine (not hematuria)

-etoposide - bone marrow depression

Front 41

MAJOR TOXICITY

Back 41

-vincristine - areflexia, peripheral neuritis, muscle weakness, paralytic ileus, alopecia

-vinblastine - loss of reflexes, bone marrow depression, alopecia

-paclitaxel (taxol) - bone marrow depression, peripheral neuropathy

Front 42

MAJOR TOXICITY

Back 42

-hydroxyurea - bone marrow depression

-tamoxifen - increased risk of endometrial cancer, menopausal symptoms

Front 43

what is the S-phase drug that inhibit DNA pol after metabolic activation?

Back 43

-cytarabine (cytosine arabinoside)

Front 44

cytarabine (cytosine arabinoside)
-MOA?

Back 44

-MOA: originally thought to inhibit DNA polymerase, but now know to inhibit DNA
synthesis by inhibiting chain elongation when AraCTP is incorporated into the growing DNA chain

Front 45

Cell Cycle Specific Drugs?

Back 45

-antimetabolites: cytarabine, 5FU, 6MP,6TP, methotrexate
-hydroxyurea
-bleomycin
-etoposide
-vincristine
-vinblastin
-paclitaxel )taxol)

Front 46

Cell Cycle Non-specific

Back 46

-alkylating agents:mechloethamine, melphalan,CYCLOPHOSPHAMIDE, chlorambucil, busulfan,cisplatin

-dacarbazine
-procarbazine
-nitrosureas
-glucocorticoids
-dactinomyin
-danurubicin
-doxorubicin
-plicamycin

Front 47

Cell cycle specific (phase specific)
-G1 phase

Back 47

-G1 phase = 40% of cell cycle = synthesis of compounds needed to synthsize DNA

Front 48

Cell cycle specific (phase specific)
-S phase

Back 48

-S phase=40% of cell cycle=DNA replication and repair=antimetabolites

hydroxurea - inhibits ribonucleotide reductase

5-fluorouracil - inhibits thymidylate synthetase

6-MP, 6-TP - inhibit purine synthesis
methotrexate - inhibits DHF reductase

cytarabine - inhibits DNA chain elongation

Front 49

Cell cycle specific (phase specific)
-G2 phase

Back 49

-G2phase=18% of cell cycle= synthesis of molecules needed for mitosis

-bleomycin – fragmentation of DNA, cells accumulate in G2

-etoposide=stabilizes the bond between Topo II and DNA; Topo II is inhibited so
double-stranded DNA breaks remain; DNA is degraded; blocks in late S-G2
(Topoisomerases cut 1- or 2-stranded DNA to allow the strand to unwind; TOP 1 and
TOP 2 are necessary for DNA replication and RNA transcription; TOP 2 is needed for the completion of mitosis)

Front 50

Cell cycle specific (phase specific)
-late G2 - early M phase

Back 50

-late G2 - early M phase

-vincristine and vinblastine bind to tubulin and prevent the assembly of microtubules;cells arrest in late G2 because mitotic filaments cannot form

-However,on the USMLE these vinca alkaloids act in the M phase

Front 51

Cell cycle specific (phase specific)
-M phase

Back 51

-M phase = 2% of cell cycle = mitosis

-paclitaxel(taxol)–enhances polymerization of tubulin, promotes microtubule
assembly and stabilizes microtubules against depolymerization;causes mitotic arrestbecause anaphase cannot occur

-vincristine and vinblastine

Front 52

Non-phase specific drugs

Back 52

-can work at any step in the cell cycle, including Go

-cells are more sensitive in late G1 and S because polynucleotides are more
susceptible to alkylation in the unpaired state than in the helical form

-toxicity usually expressed when cells enter S phase and progression through cell
cycle is blocked

-Example: doxorubicin - intercalates into DNA, DNA strand scission (single and
double strand breaks) via effect on Topo II, (cells die in G2)