alkylating agents Flashcards by Keri Courtnage

what are the three MOAs of alkylating agents

monofunctional alkyl lesions on DNA block replication machinery (DNA polymerase)
bifunctional (interstrand crosslinks) alkyl lesions on DNA prevent DNA strands from unwinding during DNA replication
monofunctional alkyl lesions lead to mutations

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what are the different classes of alkylating agents

nitrogen mustards
alkyl sulfonate
triazenes
platinum coordination complexes

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which drugs are the nitrogen mustards

mechlorethamine
cyclophosphamide
ifosfamide
chlorambucil
melphalan

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what’s in a name for mechlorethamine

R group is methyl
Amine= nitrogen
Bis-chloroethyl groups

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what does the methyl R group do for mechlorethamine

adds nucleophilicity to mustard nitrogen, enhancing reactivity

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what’s in a name for cyclophosphamide

cyclic structure, and phosphoramide group

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what’s in a name for ifosfamide

isomer of cyclophosphamide

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what’s in a name for chlorambucil

bis-chloroethyl groups
R group is phenylbutyric acid

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what does the phenylbutyric acid R group do for chlorambucil

aromatic ring withdraws electron density from mustard nitrogen, reducing reactivity

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what’s in a name for melphalan

R group is L-phenylalaline

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which drug is an alkyl sulfonate

busulfan

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which drugs are triazenes

dacarbazine, temozolomide

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what’s in a name for dacarbazine

di-methyl groups
carboxamide
triazene

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which drugs are platinum coordination complexes

cisplatin, carboplatin, oxaliplatin

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what’s in a name for cisplatin

platinum agent
cis (same side) arrangement

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what are the side effects of mechlorethamine

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

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

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what are the toxicities of cyclophosphamide

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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what are the toxicities of ifosfamide

acrolein: hemorrhagic cystitis (MESNA MANDATORY)
chloracetaldehyde: encephalopathy

other side effects are myelosuppression, n/v, infertility

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what are the toxicities of melphalan

mucositis with IV high dose therapy: oral cryotherapy prevents

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

toxicities for chlorambucil?

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

which drugs have a potential for dispensing error and why

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

what are the toxicities of busulfan

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)

toxicities of dacarbazine

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

toxicities of temozolomide

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

Pearl: PJP prophylaxis required during concomitant radiation phase

what does MESNA stand for

2-mercaptoethanesulfonic acid

what is MESNA indicated for

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

what is the MOA of MESNA

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)

which alkylating agents are prodrugs

cyclophosphamide ifosfamide dacarbazine temozolomide

why is cyclophosphamide not suitable for topical administration

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

what is the mechanism of activation of cyclophosphamide

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)

what is the mechanism of activation of ifosfamide

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)

ifosfamide has a ___ bioavailability

high but IV only form

why is ifosfamide not available PO

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

which agent is MESNA mandatory for

ifosfamide

dacarbazine and temozolomide are prodrugs metabolized to _______

active methylating species

how is dacarbazine activated

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)

how is temozolomide activated

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

cisplatin toxicities

NEPHROTOXICITY!!!!!! hypokalemia & hypomagnesemia tinnitus, hearing loss hypersensitivity neuropathy infertility

what is cisplatin used for

it is highly versatile

administer _____ before the platinum agents for less neutropenia

taxanes

supportive care for cisplatin

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

carboplatin toxicities

less nephrotoxicity, n/v, neuropathy, & ototoxicity than cisplatin MORE myelosuppression (especially thrombocytopenia) than cisplatin & oxaliplatin also causing hypokalemia and hypomagnesemia

carboplatin dosing considerations

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

oxaliplatin toxicities

MORE NEUROTOXICITY THAN CISPLATIN!!!! less nephrotoxic and ototoxic than cisplatin

peripheral sensory neuropathy with oxaliplatin

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

drug interactions with busulfan

APAP (glutathione depletion) metronidazole