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The toxic life savers > Chemotherapy side effects, metabolism, etc > Flashcards

Chemotherapy side effects, metabolism, etc Flashcards

1
Q

Which drugs are vesicants?

A
  1. Doxorubicin, Dactinomycin
  2. Vincristine, Vinblastine
  3. Mechlorethamine
  4. Dacarbazine (DTIC)
  5. Rabacfosadine (some people call it an irritant, but Thamm stated in his lecture it should be considered like a vinca alkaloid)
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2
Q

Which drugs cause cardiotoxicity?

A

Doxorubicin (dogs), HDAC inhibitors, Cyclophosphamide (high dose), 5-FU, cytarabine (high dose)

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3
Q

Which drugs cause pancreatitis?

A

Elspar, cytarabine

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4
Q

Which drug causes ototoxicity?

A

Cisplatin

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5
Q

Which drugs cause nail abnormalities?

A

Hydroxyurea, docetaxel, 5-FU, mitoxantrone, bleomycin

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6
Q

Which drugs cause SIADH?

A

Cyclophosphamide, vincristine, cisplatin

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7
Q

Which drugs cause dermatologic changes?

A

Tanovea, Topotecan

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8
Q

Which drugs cause palmar-plantar erythrodysesthesia?

A

Doxil, 5-FU, capecitabine, sunitinib, sorafenib

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9
Q

Which drugs cause mucosal ulceration?

A

methotrexate (GI mucositis), 5-FU, bleomycin, cytosar, , topotecan, sunitinib, sorafenib

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10
Q

Which drugs cause hypersensitivity reactions?

A

Etoposide, Doxorubicin, L-aspar, Paclitaxel, Methotrexate, cytarabine (high dose)

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11
Q

Which drugs cause pulmonary fibrosis?

A

bleomycin, busulfan, hydroxyurea, Tanovea

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12
Q

Which drugs cause pneumonitis?

A

Methotrexate, Fludarabine, gemcitabine

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13
Q

Which drugs cause acute emesis?

A

Cisplatin, Doxorubicin, Dacarbazine

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14
Q

Which drugs cause pulmonary edema?

A

Cisplatin, ifosfamide (cats), cytarabine (high dose)

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15
Q

Which drugs cause peripheral neuropathy?

A

Vincristine

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16
Q

Which drugs cause CNS/Neuro toxicity?

A

5 FU (cats; dogs at high dose), Ifosfamide, Cisplatin, Oxaliplatin, Methotrexate, cyatarbine (high dose)

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17
Q

Which drugs cause sterile hemorrhagic cystitis?

A

Cyclophosphamide, Ifosfamide

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18
Q

Which drugs cause renal toxicity?

A

Cisplatin, Carboplatin, Doxorubicin (cats), Streptozotocin, methotrexate (high dose), hydroxyurea, procarbazine, dacarbazine (DTIC)

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19
Q

Which drugs cause hepatotoxicity?

A

Lomustine (dogs), Methotrexate (fibrosis w/ long term use), topotecan

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20
Q

Which drugs cross the BBB?

A
  1. Lomustine, Carmustine
  2. Cytosine Arabinoside
  3. Hydroxyurea
  4. Procarbazine
  5. Temozolomide
  6. High dose methotrexate
  7. 5-FU
  8. Steroids
  9. Busulfan?
  10. Etoposide?
  11. Topotecan?
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21
Q

Which drugs are excreted unchanged in the urine?

A
  1. Carboplatin
  2. Methotrexate
  3. Hydroxyurea
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22
Q

Drugs that undergo CYP450 metabolism?

A
  1. Chlorambucil
  2. Cyclophosphamide and ifosfamide
  3. Procarbazine, DTIC
  4. Imatinib
  5. Palitaxel
  6. Vinca alkaloids
  7. Valproic acid
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23
Q

Which drugs can be found in urine 7 days after administration?

A
  1. CTX: below limit of detection on days 1-3
  2. VCR: still detected at day 3
  3. VBL: detected for 7 days after treatment
  4. Doxo and carbo: detected for up to 21 days after tx
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24
Q

Which drugs are ABCB1 substrates?

A

Mnemonic: “two vets went to lunch – DVM DVM ATE”

Doxorubicin, VCR, Mito, Daunorubicin, VBL, Mitomycin C, Actinomycin D, Taxanes, Etoposide

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25
Q

Which drugs go through primary hepatobiliary metabolism?

A
  1. vinca alkaloids

2. alkylators

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26
Q

Which drugs are radiosensitizers?

Name which ones cause radiation recall.

A
  1. Doxorubicin (can cause radiation recall)
  2. Gemcitabine
  3. Hydroxyurea (can cause radiation recall)
  4. 5-FU
  5. Mitomycin-C
  6. Fludarabine
  7. Taxanes
  8. Carboplatin/Cisplatin
  9. Vinca alkaloids (block cell cycle in G2/M)
  10. Mitoxatrone
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27
Q

Which drugs require dose modification for hepatic dysfunction?

A

doxo, taxanes, vinca alkaloids, mitoxantrone, etoposide, irinotecan, procarbazine, DTIC

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28
Q

Which drugs require dose modification for renal insufficiency?

A

Methotrexate, Cisplatin, Carboplatin, Streptozotocin, Hydroxyurea, Cytoxan, ifosfamide, procarbazine, dacarbazine, fludarabine, topotecan

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29
Q

What are the general mechanisms associated with resistance (Dr. Childress review)
Give the drugs with each:
1. Decreased uptake?
2. Increased Efflux?
3. Decreased Rx Activation/Increased RX Metabolism?
4. Increased/Decreased levels of target enzyme?
5. Alterations in Target Enzyme?
6. Inactivation by binding to sulfhydryls, increased DNA repair, decreased apoptosis?

A
  1. Decreased uptake: Methotrexate, Cisplatin, nitrogen mustards
  2. Increased Efflux: Anthracyclines
  3. Decreased Rx Activation/Increased RX Metabolism: Antimetabolites
  4. Increased/Decreased levels of target enzyme: Methotrexate
  5. Alterations in Target Enzyme: Methotrexate
  6. Inactivation by binding to sulfhydryls, increased DNA repair, decreased apoptosis: Cisplatin, Alkylators (in the form of glutathione), Anthracyclines
30
Q

In case you want to challenge yourself, Chabner’s list is much more exhaustive :)
Give the drugs with each:
1. Decreased uptake?
2. Increased efflux?
3. Decrease in drug activation?
4. Increase in drug catabolism?
5. Increase or decrease in target enzyme levels?
6. Alterations in target protein?
7. Inactivation by binding to sulfhydryls?
8. Increased DNA repair?
9. Decreased ability to undergo apoptosis?

A
  1. Decreased uptake: methotrexate, other antimetabolites, cisplatin, nitrogen mustard
  2. Increased efflux: anthracyclines, vinca alkaloids, etoposide, taxanes, methotrexate, 5-FU, TKIs
  3. Decrease in drug activation: many antimetabolites (5-FU, ara-C)
  4. Increase in drug catabolism: many antimetabolites (5-FU, ara-C)
  5. Increase or decrease in target enzyme levels: methotrexate, topoisomerase inhibitors, 5-FU, TKIs
  6. Alterations in target protein: methotrexate, other antimetabolites, topoisomerase inhibitors, TKIs
  7. Inactivation by binding to sulfhydryls: alkylating agents, cisplatin
  8. Increased DNA repair: alkylating agents, cisplatin, anthracyclines
  9. Decreased ability to undergo apoptosis: alkylating agents, cisplatin, anthracyclines, etoposide
31
Q

What are the cell cycle specific drugs and where do they best have effect?

A
  1. Antimetabolites: S phase specific
  2. Antimicrotubule Agents: m phase specific
  3. Topoisomerase I: Camptothecins, Topotecan, Irinotecan- S phase specific
  4. L-Asparaginase: maximal effect in G1
32
Q

Drugs that have require metabolic activation or are considered prodrugs?

A
  1. cyclophosphamide, ifosfamide
  2. procarbazine, dacarbazine
  3. Fluorinated pyrimidines: 5-Fluorouracil
  4. Cytosine arabinoside (gemcitabine)
  5. irinotecan

Cyclophosphamide –> phosphoramide mustard
Procarbazine –> azoprocarbazine –> benzylazoxyprocarbazine, methylazoxyprocarbazine
5-FU –> FdUMP (thymidine synthase), FdUTP (DNA), and FUTP (RNA)
Cytosar –> ara-CTP
Irinotecan🡪 active metabolite SN-38

33
Q

Which drug can cause thrombotic microangiopathy leading to hemolytic uremic syndrome?

A

gemcitabine

34
Q

Which drugs go through extensive hepatic/billiary excretion?

A 
vincas
taxanes
cyclophosphamide
irinotecan
anthracyclines
mitoxantrone
5-FU
cytosar
gemcitabine
6-MP and azathioprine, 6-TG
hydroxyurea (maybe, unknown)
  • Just memorize what is renal elimination and then you will know the rest are liver
35
Q

Which drugs are inactivated in the blood stream by conjugation to sulfhydryl groups and are 90% eliminated in the urine?

A

Platinums

36
Q

Which drugs go through extensive renal excretion?

A

platiunums
topotecan
epipodophyllotoxins (etoposide, tenoposide)
methotrexate

37
Q

Which drug is a level X teratogen?

A

Methotrexate

38
Q

Which breeds are at highest risk for MDR mutation?

A

Collie > Long-haired whippet > Aussie > Sheltie

39
Q

Which breed has the highest % mut/mut PGP?

a. Border collie
b. Aussie
c. Sheltie
d. OES
e. GSD

A

Aussie

40
Q

Which drugs have glutathione mechanism of resistanc?

A

Alkylators, Anthracyclines (doxo), platiunums

41
Q

What is the difference in MOA of leucovorin with MTX and 5-FU?

A

leucovorin is given with MTX to decrease toxicity; in contrast, it increases 5-FU toxicity

42
Q

Which chemotherapeutics have a drug interaction with heparin?

A

doxorubicin and mitoxantrone

43
Q

Which cancer has shown a decreased response to epirubicin?

A

T cell lymphoma

• Included in multi-drug protocol as doxorubicin substitute for LSA (n=97) (Elliott et al, VCO, 2013)
o Only 16% were neutropenic; overall hospitalization for entire protocol was only 9% (comparable to CHOP)
o 100% ORR (96% CR)
o Median TTR 216 days, MST 342 days – compares favorably to CHOP
o Negative prognostic indicators on univariate analysis: T-cell immunophenotype, hypercalcemia, substage b

44
Q

A large Vd (a value larger than the total volume of the body water is possible) represents what type of drug binding?

A

extensive binding of drug in tissue (eg, vincas)

45
Q

T/F: Drugs with extensive high protein-tissue binding or with high lipid solubility exhibit prolonged elimination phases because the release of bound drug from tissues is slow?

A

True

46
Q

Fill in the blank with increases or decreases:

High plasma protein binding ___a___ Vd?

High tissue binding ___b___ Vd?

A

a. decreases

b. increases

47
Q

In regards to 1st order kinetics what happens to the AUC if the drug clearance is constant?

A

If clearance remains constant, AUC will increase in proportion to drug dose

48
Q

Answer the following questions about Phase I drug metabolizing enzymes:

  1. Modifies the target via which process?

2 Reactions via which superfamily?

  1. T/F: Leads to inactivation, activation, or no change in toxicity?
  2. Produces what type of metabolites (active or inactive)?
A
  1. oxidation, reduction, hydrolysis
  2. superfamily of cytochrome P450
    o Also includes NADPH, quinone oxidoreductase, aldo-keto reductase, peroxidases
  3. True
  4. produces metabolites that retain therapeutic activity or convert an inactive prodrug to an active moiety
49
Q

Answer the following questions about Phase II drug metabolizing enzymes:

  1. Metabolites are conjugated with?
  2. Produces what type of metabolites (active or inactive)?
  3. Eliminated by the body how?
A
  1. a charged species such as glutathione, sulfate, glycine, or glucuronic acid
  2. generally, produce inactive metabolites
  3. eliminated from the body by biliary or renal excretion
    UDP-glucuronosyltransferase, sulfotransferase, arylamine N-acetyltransferase, glutathione S-transferases
50
Q

Fill in the blank for the Goldie-Coldman hypothesis:
The probability of at least one drug resistant cell in a tumor population is dependent on size. The likelihood of acquiring such a mutation increases with cell # and these events are likely to begin at sizes between _______ and _______?

A

10^3 and 10^6 cells (clinical detection = 10^9)

51
Q

What is the MOR of docetaxel?

A
  1. Upregulation of Pgp (ABCB1) or MRP1 (ABCC1)
  2. Alterations in tubulin binding sites or microtubule dynamics
  3. Decreased apoptosis due to altered cell signaling
52
Q

The AUC is most important for which drugs?

A

cisplatin, carboplatin, doxorubicin, alkalaytors

53
Q

Which are the most common drugs to cause sepsis?

A

Dogs: doxo (OR 12.5) followed by VCR (9.0); Sorenmo et al, JAVMA, 2010

Cats: CCNU followed by vinca alkaloids; Pierro et al, VCO, 2017

54
Q
  1. Which drugs block serotonin receptors (5-HT3 receptor antagonists)?
  2. Where do these drugs act?
  3. Which drug blocks NK1 receptors (substance P antagonists)?
  4. Where does this drug act?
  5. Which drug blocks dopamine receptors (D2 antagonist)?
  6. Where does this drug act?
  7. Which drug blocks H1 receptors?
  8. Where does this drug act?
A
  1. ondansetron, dolasetron
  2. Vomiting center, CRTZ, GI tract
  3. Cerenia
  4. Vomiting center, CRTZ, GI tract
  5. Metoclopramide
  6. CRTZ +/- GI tract
  7. Benadryl
  8. Vomiting center, Vestibular nuclei
55
Q

MTD of vinorelbine in cats?

A

11.5mg/m2 IV once weekly

56
Q

Sodium Thiosulfate for which drug extravasation

A

mechlorethamine

57
Q

Which drug would actively compete with melphalan for active transport and can block its uptake?

A

leucine

58
Q

Do cats experience clinically significant hepatotoxicity from CCNU?

A

Clinically significant hepatotoxicity appears rare in cats (Musser et al, JFMS, 2012)
6.8% (n=2) developed elevated ALT after 4 weeks, 1 of which had assoc. clinical signs

59
Q

What occurs to liver enzymes in dogs when CCNU administered with Denamarin?

A

Increased LE occurs in 84% of dogs with CCNU and 68% receiving concurrent Denamarin

60
Q

Which cancer has the highest response rate to CCNU?

A

Epitheliotropic LSA: 78-83%

61
Q

Discuss % of CCNU canine fatal hepatotoxicity?

A

Most articles report 1-2% fatal hepatotoxicity; a single article (Hosoya JAAHA 2009) reports up to 16.6%
Clinically significant hepatotoxicity reported in 3-6%.

62
Q

Mechanism of nephrotoxicity of ifosfamide?

A

• In the liver, ifosfamide undergoes N-chloroethylation (catalyzed by P450) to form chloroacetaldehyde  this metabolite is neurotoxic
o Renal tubules also possess CYP450  form chloroacetaldehyde  nephrotoxicity
• Damages proximal tubule, resulting in Fanconi-like syndrome (loss of glucose, Phos, bicarb, AA and protein into the urine)

63
Q

Fatal toxicity of ifosfamide in cats?

A

fatal nephrotoxicity and 1 developed fatal pulmonary edema

64
Q

Carboplatin nadir for neutropenia and thrombocytopenia?

A

Double nadir – neutrophil and platelet nadirs common at day 14 and 21

65
Q

What is the DLT or unique AE that occurs with Doxil?

A

cutaneous toxicity resembling palmar-plantar erythrodysesthesia (PPES)

66
Q

What is the efficacy of cisplatin and piroxicam when given together for TCC?

A

One study (dogs with TCC) had to reduce cisplatin to 40mg/m2 to give along with piroxicam; little anti-tumor activity and a high frequency of nephrotoxicity (86%) and GI toxicity were noted. Another study found MTD of cisplatin was 50mg/m2 when given with piroxicam, and the addition of an NSAID did not affect drug clearance.

67
Q

A histone deacetylase inhibitor or DNA demethylator could impact impact p53 expression in an experiment on cell culture in what way?

A

P53 is a tumor suppressor gene. So treatment with an HDAC inhibitor would cause re-expression of p53 and inhibit cell growth

68
Q

What is the difference in side effects between Palladia dosing of 2.5 vs 3.25 mg/kg?

A

Biologic activity is similar to 3.25mg/kg dose, but there were NO grade 3 or 4 GI toxicities in 2.5mg/kg group

69
Q

What is the MTD of vinblastine when administered with Palladia for the tx of TCC?

A

MTD of VBL = 1.6mg/m2 q 14 days when given with Palladia; no increased response seen with TCC

70
Q

Most common AE of Palladia in cats (different than dogs?)

A

Merrick et al, VCO, 2017
• GI upset (21.8%), thrombocytopenia (16%), neutropenia (9%), azotemia (14.5%), elevated ALT (7.2%)
o GI toxicity is improved compared to dogs (40-59%)
o Hematologic toxicity was mild and thrombocytopenia was more common than neutropenia; this is also different than dogs (neutropenia more common)
 Dogs: one study reported 45% neutropenia, 28% thrombocytopenia, though another said 11% neutropenia and no episodes of thrombocytopenia
o Cats with lower body weights were less likely to develop CBC changes

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