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4q Pharm Test2 > Antineoplastics > Flashcards

Antineoplastics Flashcards

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1
Q

Resistance to antineoplastic drugs may occur b/c of:

A
  • changes in level/affinity of target enzymes
  • decreased drug activation
  • increased DNA repair
  • increased salvage pathways for purines & pyrimidines
  • decreased drug uptake
  • increased drug efflux
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2
Q

How do alkylating agents work? (4)

A
  • alkylate DNA
  • cause miscoding, breaking, crosslinking
  • not cell-cycle phase specific
  • most effect on rapidly proliferating cells (tumor cells, BUT: GI, hair, bone marrow too)
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3
Q

Alkylating agent toxicity

A

-vesicant: tissue damage at injection site
-rapidly proliferating cells: bone marrow, GI, sperm, hair
-Nausea/vomiting: CTZ & local
bone marrow depression
-immunosuppression
-teratogenesis, reproduction

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4
Q

Mechlorethamine (Mustargen):
CLASS
TOXICITIES

A

alkylating agent
phase nonspecific but M & G1 most sensitive
Toxicity: vesicant, hematologic, hyperuricemia, renal damage, nausea/vomiting, sterility, teratogenesis

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5
Q

Cyclophosphamide (Cytoxan): class, characteristics, use, SEs

A

Class: alkylating agent
NOT a vesicant
activated by cytochrome P-450
BROAD SPECTRUM OF USES

SEs: immunosuppressive, alopecia, hematologic toxicity, hemorrhagic cystitis (tx: MESNA), inappropriate ADH secresion

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6
Q

Major therapeutic approaches to cancer tx (3)

A
  1. surgery
  2. radiation
  3. chemotherapy
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7
Q

Goal of cancer chmotherapy

A

achieve SELECTIVE TOXICITY against malignant tumor cells & spare normal host cells

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8
Q

In general, antineoplastic agents do what?

A

suppress rapidly proliferating cells

so routine SE of CA chemo: toxicity to actively dividing normal cells (bone marrow, GI & germinal epithelia, hair follicles, lymphoid organs

SUCCESSFUL TX DEPENDS ON KILLING MALIGNANCY CELLS WITH DOSES THAT ALLOW RECOVERY OF NORMAL CELLS

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9
Q

When are cells most vulnerable to chemotherapy?

A

when in the actively dividing state

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10
Q

2 major classes of antineoplastic agents:
administered when?
effective in what?

A
  1. CELL CYCLE-SPECIFIC AGENTS: given continuously to hit cells as they go through dif. stages.
    - effective in HEMATOLOGIC MALIGNANCIES & other tumors w/large proportion of cells proliferating or in growth fraction
  2. CELL CYCLE-NONSPECIFIC AGENTS: affect cells regardless of where they are in the cell cycle, so long as they are proliferating
    - often administered in ONE LARGE DOSE
    - effective in low-growth solid tumors (e.g. ALKYLATING AGENTS, ANTIBIOTICS, CISPLATIN, NITROSOUREAS)
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11
Q

Susceptibility to chemotherapy:
rapidly growing tumors (4)
slower growing cancers (3)

A

RAPIDLY GROWING TUMORS (leukemias, lymphomas, choriocarcinoma, testicular CA)MORE SUSCEPTIBLE THAN
SLOWER GROWING TUMORS (non-small cell lung, colon, breast)

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12
Q

Growth fraction

A

percentage of viable cells actively dividing & potentially susceptible to chemotherapy

tumors with high growth fractions are easier to treat

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13
Q

Tumor size & response to chemo

A

small tumors have more cells in growth phase & are more sensitive to chemo

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14
Q

4 chemo difficulties a large tumor imposes

A
  1. PENETRATION: therapeutic concentrations of drug may not penetrate large tumors
  2. METASTASES: more likely to have occurred
  3. RESISTNANCE: increase potential for drug resistance
  4. MORE TUMOR CELLS to be killed
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15
Q

mechanisms of drug-resistance in chemotherapy

A
  1. decreased cellular uptake or enhanced efflux from cells (many drugs)
  2. increased or decreased levels of target enzyme (e.g. methotrexate)
  3. altered affinity for target enzyme (methotrexate)
  4. decreased activation/increased inactivation of the drug (6-mercaptupurine)
  5. increased DNA repair (alkylating agents)
  6. increased utilization of salvage pathways for purine & pyrimidine biosynthesis (antimetabolites)
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16
Q

P-glycoprotein

A

high molecular weight glycoprotein

  • present in elevated levels in the plasma membrane of resistant cells
  • functions as a drug efflux pump; can cause resistance to multiple drugs
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17
Q

How is drug resistance minimized in CA chemotherapy?

A

combinations of drugs w/different mechanosms of action against the specific tumor are employed and therapy is initiated when tumor burden is small

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18
Q

most drugs used in chemotherapy:
therapeutic index?
selective toxicity?

A

LOW THERAPEUTIC INDEX

LACK SELECTIVE TOXICITY

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19
Q

Chemotherapy toxicity is common in which 5 areas? what is the result of each?

A

BONE MARROW: decreases platelet & WBC count->HEMORRHAGE &/OR INFECTIONS

GI TRACT: stomatitis, dysphagia, diarrhea due to direct toxic effect on cells. N/V may result from stimulation of the chemoreceptor trigger zone, tx w/anti-emetics

HAIR FOLLICLES: alopecia

RENAL: destruction of tumor cells increases nucleic acids, increasing lvl of uric acid->precipitate in renal tubules->nephrotoxicity

REPRODUCTION & TERATOGENESIS: fetal abnormalities, impaired fertility, spermatogenesis & menstrual cycle

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20
Q

Alkylating agents: basics of how they work

A

-not cell-cycle specific

form highly reactive intermediate compounds, which covalently attach an alkyl group to DNA

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21
Q

Alkylation can result in (3)

A
  1. miscoding of DNA strands, leading to DNA strand breakage
  2. incomplete repair of alkylated segment leading to strand breaks
  3. excessive crosslinking of DNA & loss of strand separation at mitosis
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22
Q

Alkylation toxicity

A 
VESICANT
RAPIDLY DIVIDING CELLS
N/V
BONE MARROW DEPRESSION
REPRODUCTIVE SYSTEMS
TERATOGENESIS
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23
Q

resistance to alkylating agents occurs b/c

A
  • increased ability to REPAIR DNA
  • DECREASED PERMEABILITY to drug
  • increase in GLUTATHIONE
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24
Q

name the 2 Nitrogen Mustards

A

Mechlorethamine (Mustargen)

Cyclophosphamide (Cytoxan)

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25
Mechlorethamine (Mustargen): phases, indication
phase nonspecific but M and G1 most sensitive | WIDELY USED IN TREATMENT FOR HODGKIN'S DISEASE
26
Mechlorethamine (Mustargen): toxicity (8)
- strong VESICANT - HEMATOLOGIC toxicity - HYPERURICEMIA - acute RENAL failure - alkalinization of the urine & use of allopurinol can prevent nephropathy - nausea/vomiting - gonadal suppression - teratogenic
27
Cyclophosphamide (Cytoxan): describe, routes of admin, spectrum
nitrogen mustard prodrug, MUST BE ACTIVATED by CYP450 ***NOT A VESICANT IV (not a vesicant), ORAL BROAD SPECTRUM, widely used: breast, lung, ovarian, endometrial & cervical carcinoma, immunosuppression
28
Cyclophosphamide (Cytoxan) toxicity (4)
HEMATOLOGIC TOXICITY: less severe than other alkylating agents marked ALOPECIA HEMORRHAGIC CYSTITIS (5-10% of pts): build up of acrolein in bladder (prevent w/hydration, frequent voids, admin MESNA [provides syfahydryl groups to hind acrolein & red renal toxicity]) SIADH: pos. water intoxication anorexia & N/V
29
Cisplatin (Platinol)
alkylating agent, cell cycle nonspecific (but esp. S) TOXICITY: ACOUSTIC NERVE DAMAGE renal dysfunction electrolyte disturbances 2* to renal dysfunction
30
Hemorrhagic cystitis a/w which cancer med? how many pts get this? what causes it? how is it prevented?
cyclophosphamide (Cytoxan) 5-10% of pts get this build up of acrolein in the bladder preventative measures: hydration, frequent voiding, MESNA: provides sulfahydryl groups to bind acrolein & reduce renal toxicity
31
3 antimetabolites
Methotrexate (folic acid analogue) Mercaptopurine(purine/pyramidine analogue) 5-Flurouracil (purine/pyramidine analogue)
32
Methotrexate (Folex):basic activity
FOLIC ACID ANALOGUE antimetabolite inhibits DIHYDROFOLATE REDUCTASE, blocks conversion of folic acid to tetrahydrofolate (FH4) resistance develops through decreased uptake by tumor cell & INCREASED CONCENTRATION OF TARGET ENZYME
33
Leucovorin (folinic acid) does what?
1. bypasses metabolic block by methotrexate "leucovorin rescue" REDUCES TOXICITY of methotrexate 2. INCREASES response to 5-FU by providing folate
34
Methotrexate uses (the bolded ones) 3
leukemia choriocarcinoma immunosuppression: RA psoriasis
35
Methotrexate toxicity (bold ones)
HYDRATION is imp (methotrexate will precipitate in renal tubules) HEPATOTOXICITY PULMONARY INFILTRATES
36
Purine and pyramidine analoges do what?
interfere w/DNA & RNA | by substituting themselves for nat purines & pyramidines, stopping synthesis
37
6-Mercaptupurine (Purinethol): metabolism, interactions, use
- inhibits purine nucleotide synthesis & metabolism - must be converted by HGPRT to nucleotide, resistance develops through decreased HGPRT metabolized by XANTHINE OXIDASE to 6-thiouric acid breakdown blocked by ALLOPURINOL; REDUCED DOSE if allopurinol is used used for: LEUKEMIA, IMMUNSUPRESSANT
38
6 mercaptopurine toxicity
gradual BONE MARROW DEPRESSION CHOLESTATIC JAUNDICE HYPERURICEMIA MAY REQUIRE USE OF ALLOPURINOL (note metabolic interaction above)
39
5 Fluorouracil (5-FU, Adrucil): structure, mechanism
pyramidine analogue binds to THYMIDYLATE SYNTHASE & locks it in inhibited state (form of thymidylate is RATE-LIMITING STEP in DNA synth CELL CYCLE SPECIFIC-selectively toxic to cells in G1 & S phases LEUCOVORIN (folinic acid INCREASES responses to 5-FU)
40
5-FU uses
TOPICAL CREAM for premalignant keratosis of skin & BCCs combined w/LEUCOVORIN for COLORECTAL CA
41
5-FU toxicity
oral & GI ULCERATION BONE MARROW DEPRESSION anorexia & nausea, stomatitis & diarrhea
42
``` Doxorubicin hydrochloride (Adrianmycin): what is it what does it do use is limited by what when is max effort resistance is due to what ```
antibiotic that messes with DNA, inhibits RNA & DNA polymerases generates free radicals-exacerbated by IRON use limited by CARDIOTOXICITY max effort during S phase resistant due to diminished drug uptake by tumor cells or P GLYCOPROTEIN pumping drug out
43
Doxyrubicin hydrochloride toxicity
N/V/GI CARDIOMYOPATHY: may be acute & not very serious, or may develop into CHF unresponsive to digitalis, with mortality >50%, likelihood is decreased by giving IRON CHELATORS arrhythmias, bone-marrow depression, alopecia
44
Bleomycin sulfate (Blenoxane)
antibiotic - group of GLYCOPROTEINS - causes chain-breaks & FRAGMENTATION of DNA - CELL CYCLE SPECIFIC: most toxic in late G2 & early M phase
45
Bleomycin sulfate: uses
advanced TESTICULAR CANCER (abt. 75% remission rt when given w/vinblastine & cisplatin) OVARIAN CANCER [SCC & lymphomas,not bolded]
46
Bleomycin sulfate: toxicity
very LITTLE myelosupression PULMONARY FIBROSIS-may be fatal, occurs in 7-10% sxs sim to ANAPHYLAXIS, w/fever, hypotension, cardioresp. collpse
47
Vinblastine sulfate & Vincristine sulfate: class mechanism
plant alkaloids bind to TUBULIN, disrupts mitotic spindle apparatus CELL CYCLE SPECIFIC FOR M phase resistance due to increased levels of P-glycoprotein doesn't get into brain metabolized by liver, adjust dose in hepatic or biliary dz
48
Vicristine: use & toxicity
Wide use: Hodgkins-MOPP regimen LEUKEMIA IN KIDS (w/corticosteroids NONHODKINS LYMPHOMA toxicity: NEUROTOXICITY (limiting factor in use), PERIPHERAL NEUROPATHY constipation (use laxatives), alopecia, little myelosuprresion
49
Vinblastine: use & toxicity
TESTICULAR CA (combo w/bleomycin & cisplastin) less neurotoxicity than vincristine BONE MARROW DEPRESSION (limiting factor in use)
50
Paclitaxel (Taxol): mechanism, metabolized by, activity, toxicity
binds to TUBULIN & MICROTUBULIN-ARRESTS MITOSIS disrupts AXONAL TRANSPORT in nerve fibers resistence dvlps due to INCREASED TRANSPORT out of cells-P glycoprotein metabolized by liver one of MOST ACTIVE of all anticancer drugs, but quite TOXIC
51
Paclitaxel (Taxol) uses & toxicity
BREAST & OVARY CA myelosuppression (greatest effect on neutrophils) peripheral neuropathy myalgias severe hypersensitivity rxns
52
Imatinib (Gleevac): mechanism/type or drug, use, administration, metabolized by, what is used if pt is intolerant/resistant
inhibits Bcr-Abl tyrosine kinase, which underlies CML use: chronic myelogenouse leukemia can be given orally, metabolized by CYP3A4, drug interactions possible dasatanib & nilotibib are tyrosine kinase inhibitors used in pts who are intolerant or resistant to imatinib
53
``` Cetuximab (Erbitux): how does it work? how is it administered? for what? SEs? ```
binds to epidermal growth factor (EGFR), blocking signals for growth & survival -may have some direct toxicity against tumor cells IV for head/neck CA & EGFR positive colon CA SEs: rash, itching, HA,D, poss/ anphylactoid rxns (esp. Southern US)
54
Erlotinib (Tarceva): how does it work? what does it tx?
inhibits HER1/EGFR tyrosine kinase - 2nd line tx for non-small cell lung ca - w/gemcitabine for pancreatic CA
55
Bevacizumab (Avastatin): does what? | SEs
inhibits vascular endothelial growth factors->decrease antiogenesis & slow tumor growth rare SE: vessel injury & bleeding surgery should be delayed in pts on this drug due to excess bleeding & impaired would heeling incr. risk of thromboembolism (C) SEs include HTN & proteinuria
56
Prednisone (Deltasone)
suppresses mitosis in lymphocytes | used for managment of LEUKEMIA & LYMPHOMA in adults & for acute leukemia in kids
57
Dexamethasone use
to reduce radiation-treatment induced CNS edema
58
Prednisone (Deltasone) Dexamethasone (Decadron) toxicity (4)
- iatrogenic Cushing's syndrome - osteoporosis, infections - psych disturbances - HTN, edema
59
Tamoxifen: type of drug, use, toxicity
estrogen antagonist in the breast PREVENTION of breast CA in women w/previous hx hot flashes, nausea, uterine hyperplasia/CA
60
Trastuzumab (Herceptin)
antibody against HER2 protein, only used in pts w/ HER2 overexpression used for metastatic breast CA CARDIOMYOPATHY is most serious SE
61
Flutamide (Eulexin) Bicalutamide (Casodez) Nilutamide (Nilandron) what do they do? what are the used for?
block ANDROGEN RECEPTORS of androgen-sensitive tissues or tumors used for METASTATIC PROSTATE CARCINOMA

4q Pharm Test2 (7 decks)

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