alkylating agents Flashcards
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
what are the different classes of alkylating agents
nitrogen mustards
alkyl sulfonate
triazenes
platinum coordination complexes
which drugs are the nitrogen mustards
mechlorethamine
cyclophosphamide
ifosfamide
chlorambucil
melphalan
what’s in a name for mechlorethamine
R group is methyl
Amine= nitrogen
Bis-chloroethyl groups
what does the methyl R group do for mechlorethamine
adds nucleophilicity to mustard nitrogen, enhancing reactivity
what’s in a name for cyclophosphamide
cyclic structure, and phosphoramide group
what’s in a name for ifosfamide
isomer of cyclophosphamide
what’s in a name for chlorambucil
bis-chloroethyl groups
R group is phenylbutyric acid
what does the phenylbutyric acid R group do for chlorambucil
aromatic ring withdraws electron density from mustard nitrogen, reducing reactivity
what’s in a name for melphalan
R group is L-phenylalaline
which drug is an alkyl sulfonate
busulfan
which drugs are triazenes
dacarbazine, temozolomide
what’s in a name for dacarbazine
di-methyl groups
carboxamide
triazene
which drugs are platinum coordination complexes
cisplatin, carboplatin, oxaliplatin
what’s in a name for cisplatin
platinum agent
cis (same side) arrangement
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
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
what are the toxicities of ifosfamide
acrolein: hemorrhagic cystitis (MESNA MANDATORY)
chloracetaldehyde: encephalopathy
other side effects are myelosuppression, n/v, infertility
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
