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oncology > alkylating agents > Flashcards

alkylating agents Flashcards

1
Q

what are the three MOAs of alkylating agents

A
  1. monofunctional alkyl lesions on DNA block replication machinery (DNA polymerase)
  2. bifunctional (interstrand crosslinks) alkyl lesions on DNA prevent DNA strands from unwinding during DNA replication
  3. monofunctional alkyl lesions lead to mutations
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2
Q

what are the different classes of alkylating agents

A

nitrogen mustards
alkyl sulfonate
triazenes
platinum coordination complexes

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3
Q

which drugs are the nitrogen mustards

A

mechlorethamine
cyclophosphamide
ifosfamide
chlorambucil
melphalan

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4
Q

what’s in a name for mechlorethamine

A

R group is methyl
Amine= nitrogen
Bis-chloroethyl groups

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5
Q

what does the methyl R group do for mechlorethamine

A

adds nucleophilicity to mustard nitrogen, enhancing reactivity

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6
Q

what’s in a name for cyclophosphamide

A

cyclic structure, and phosphoramide group

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7
Q

what’s in a name for ifosfamide

A

isomer of cyclophosphamide

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8
Q

what’s in a name for chlorambucil

A

bis-chloroethyl groups
R group is phenylbutyric acid

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9
Q

what does the phenylbutyric acid R group do for chlorambucil

A

aromatic ring withdraws electron density from mustard nitrogen, reducing reactivity

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10
Q

what’s in a name for melphalan

A

R group is L-phenylalaline

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11
Q

which drug is an alkyl sulfonate

A

busulfan

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12
Q

which drugs are triazenes

A

dacarbazine, temozolomide

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13
Q

what’s in a name for dacarbazine

A

di-methyl groups
carboxamide
triazene

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14
Q

which drugs are platinum coordination complexes

A

cisplatin, carboplatin, oxaliplatin

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15
Q

what’s in a name for cisplatin

A

platinum agent
cis (same side) arrangement

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16
Q

what are the side effects of mechlorethamine

A

IV: myelosuppression, very high emetogenicity, infertility, potent vesicant, secondary malignancies

topical: dermatitis, pruritis, bacterial skin infection, skin ulceration, skin hyperpigmentation

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17
Q

what are the toxicities of cyclophosphamide

A

HEMORRHAGIC CYSTITIS: MESNA recommended to prevent hemorrhagic cystitis with high dose therapy

other side effects are myelosuppression, alopecia, infertility, n/v, mucositis

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18
Q

what are the toxicities of ifosfamide

A

acrolein: hemorrhagic cystitis (MESNA MANDATORY)
chloracetaldehyde: encephalopathy

other side effects are myelosuppression, n/v, infertility

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19
Q

what are the toxicities of melphalan

A

mucositis with IV high dose therapy: oral cryotherapy prevents

other side effects are myelosuppression, infertility, n/v, secondary cancers

20
Q

toxicities for chlorambucil?

A

weekly CBC required (platelets, ANC)
infertility, secondary malignancies, myelosuppression

21
Q

which drugs have a potential for dispensing error and why

A

Melphalan (Alkeran) and chlorambucil (Leukeran) because of similar sounding brand names, same drug class, similar indications, similar storage, both 2 mg tablets

22
Q

what are the toxicities of busulfan

A

seizures, pulmonary fibrosis (busulfan lung), SOS/VOD, myelosuppression, secondary malignancies

IV is pref over PO because it decreases risk of hepatic veno-occlusive disease (VOD) also known as sinusoidal obstruction syndrome (SOS)

23
Q

toxicities of dacarbazine

A

myelosuppression, hepatotoxicity, anaphylaxis, secondary malignancies, n/v, infusion site pain, alopecia, flu-like symptoms, photosensitivity

24
Q

toxicities of temozolomide

A

myelosuppression, lymphopenia, opportunistic infections (PJP), n/v (dose dependent), alopecia, headache, secondary malignancies

Pearl: PJP prophylaxis required during concomitant radiation phase

25
Q

what does MESNA stand for

A

2-mercaptoethanesulfonic acid

26
Q

what is MESNA indicated for

A

urinary tract protectant mandatory for ifosfamide; recommended for high dose cyclophosphamide

27
Q

what is the MOA of MESNA

A

circulates in the blood in inactive, oxidized form (dimesna)- dimerization enhanced by Cu ions in plasma. dimesna is excreted into urine where it is partially reduced back to mesna. free sulfhydryl group inactivates acrolein (exposure to acrolein is responsible for causing hemorrhagic cystitis)

28
Q

which alkylating agents are prodrugs

A

cyclophosphamide
ifosfamide
dacarbazine
temozolomide

29
Q

why is cyclophosphamide not suitable for topical administration

A

it is a prodrug and first requires bioactivation in the liver by CYP450 system

30
Q

what is the mechanism of activation of cyclophosphamide

A

phosphoramide linkage reduces the nucleophilicity of the mustard nitrogen, thus the prodrug is very stable & inactive until it undergoes CYP450-mediated 4-hydroxylation:
aldophosphamide spontaneously decomposes to acrolein & phosphoramide mustard, the latter forming the active cross-linking alkylating aziridinium ion
(bladder exposure to acrolein is responsible for causing hemorrhagic cystitis)

31
Q

what is the mechanism of activation of ifosfamide

A

prodrug activated by CYP450 mediated metabolism: slower metabolism, so chloroethyl side chain oxidation plays a greater role in metabolism- resulting in more chloracetaldehyde produced (encephalopathy)

32
Q

ifosfamide has a ___ bioavailability

A

high
but IV only form

33
Q

why is ifosfamide not available PO

A

1st pass liver metabolism leads to excessive side chain oxidation, producing toxic levels of chloracetaldehyde, leading to excessive neurotoxicity

34
Q

which agent is MESNA mandatory for

A

ifosfamide

35
Q

dacarbazine and temozolomide are prodrugs metabolized to _______

A

active methylating species

36
Q

how is dacarbazine activated

A

N-demethylation (CYP450 mediated) in the liver, followed by spontaneous decomposition to MTIC, the active methylating species (MTIC leads to methylation of DNA at O6 and N7 positions of guanine)

37
Q

how is temozolomide activated

A

it is also rapidly converted to the active alkylating species MTIC

unlike dacarbazine, the conversion is spontaneous, nonenzymatic, and occurs under physiologic conditions in all tissues to which the drug distributes

38
Q

cisplatin toxicities

A

NEPHROTOXICITY!!!!!!

hypokalemia & hypomagnesemia
tinnitus, hearing loss
hypersensitivity
neuropathy
infertility

39
Q

what is cisplatin used for

A

it is highly versatile

40
Q

administer _____ before the platinum agents for less neutropenia

A

taxanes

41
Q

supportive care for cisplatin

A

adequate pre and post hydration (IV) with NS +/- K/Mg to protect kidneys
aggressive antiemetic regimen required

dilute in at least 0.3% saline and always call prescriber for dose>100 mg/m2

42
Q

carboplatin toxicities

A

less nephrotoxicity, n/v, neuropathy, & ototoxicity than cisplatin

MORE myelosuppression (especially thrombocytopenia) than cisplatin & oxaliplatin

also causing hypokalemia and hypomagnesemia

43
Q

carboplatin dosing considerations

A

dose is based on CrCL to target a desired AUC (Calvert formula)
total dose = target AUC x (GFR + 25)

44
Q

oxaliplatin toxicities

A

MORE NEUROTOXICITY THAN CISPLATIN!!!!

less nephrotoxic and ototoxic than cisplatin

45
Q

peripheral sensory neuropathy with oxaliplatin

A

dose-limiting and occurs in two patterns:
1. acute (within 2 days): reversible, cold-induced; may cause pharyngolaryngeal spasms upon drinking a cold beverage
2. chronic: persistent, stocking/glove pattern neuropathy, improvement may take several months-years, dose reduction/interruptions often required

46
Q

drug interactions with busulfan

A

APAP (glutathione depletion)
metronidazole

oncology (19 decks)

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