Pharmacology of cancer agents Flashcards
mechanism of action of alkylating agents:
Alkylates DNA, major cytotoxic effect results from formation of positively charged carbonium ion which binds to electron-rich nucleophilic sites on biological molecules
MoA of cyclophosphamide (nitrogen mustard)
Activated in liver to active metabolites
Stop cell division by alkylating DNA
Formation of positively charged carbonium ion which binds to electron-rich nucleophilic sites on biological molecules
Also binds to reactive molecules on DNA
inhibits DNA replication and transcription
Mispairing of DNA
Strand breakage
Tissues most susceptible to cancer treatment:
tissues with fast renewal cell populations (bone marrow, GI mucosal cells, skin and hair)
examples of delayed toxicities in cancer treatment:
anthracycline-induced cardiac toxicities
methotrexate-induced pneumonitis
what is cyclophosphamide metabolised by:
CYP450
Dose-limiting toxicity for alkylating agents:
myelosuppression
- usually neutropenia with nadir at 6-10 days and recovery in 14-21 days
- demonstrates delayed nadir and recovery for nitrosoureas
Common toxicities for alkylating agents:
- mucocitis, chemo-induced N/V or CI NA, neurotoxicity alopecia, stomatitis
important counselling points when cyclophosphamide is given:
patients need to drink more water
active metabolites of cyclophosphamide:
4-hydroxycyclophosphamide, aldophosphamide, phosphramide mustard, acrolein
Inactive metabolites of cyclophosphamide:
4-keto-cyclophosphamide, carboxyphospamide, nornitrogen mustard
MoA of alkylators:
analogue of cyclophosphamide activated in liver by CYP 3A4
Cytotoxic action primarily through DNA crosslinks caused by alkylation of isophosphoramide mustard at guanine N-7 positions
Formation of inter and intra strand cross links in DNA –> cell death
what is ifosfamide (IV) used for:
Testicular cancer, diffuse B-cell lymphoma
What is usually given with ifosfamide:
MESNA, to prevent dose-limiting hemorrhagic cystitis as it acts as a scavenger to remove excess cytotoxic material
examples of platinum analogues:
cisplatin, carboplatin, oxaliplatin
Important counselling point for cisplatin:
drink more water – nephrotoxic
How to prevent nephrotoxicity in cisplatin users:
Avoid use in renal dysfunction
hydration with ≥1-2 L 0.9% NaCL IV pre and concurrent with cisplatin, with K+ and Mg2+ supplementation
maintain urine output > 100mL/h
provide mannitol or furosemide to protect patient
prolong infusion time but may reduce efficacy of the drug
things that need to be done if cisplatin is used
Replenish K+ and Mg2+ in patients
Why is ototoxicity and peripheral neuropathy less of a concern compared to nephropathy in Cisplatin use?
they may be reversible and is related to high peak doses (ototoxicity) and cumulative doses (peripheral neuropathy)
what is usually done in peripheral neuropathy in Cisplatin use?
- limit cumulative doses
- Decrease dose/discontinue treatment
- Substitute with carboplatin
- Use of medications to reduce neuropathic pain
General MoA of platinum analogues:
form reactive electrophile that covalently binds to DNA
what is oxaliplatin commonly used for:
colorectal cancer
important adverse event to take note of in the use of oxaliplatin:
cumulative peripheral neuropathy
- acute: usually within the first 2 days, reversible and primarily peripheral symptoms after exacerbated by cold air
- Persistent: often interferes with daily activities
- symptoms may improve upon treatment discontinuation
MoA of enzyme inhibitors (topoisomerase inhibitors):
prevention of religation of DNA, causing strand break during replication and replication cannot proceed.
Examples of topoisomerase I inhibitors:
irinotecan (CPT-11)
Example of topoisomerase II inhibitors:
etoposide
Active metabolite of irinotecan:
SN-38
metabolism of irinotecan:
primarily hepatic, rapidly converted to SN-38 by hepatic carboxylesterase enzymes
what is irinotecan usually used for?
metastatic colorectal cancer
Symptoms of toxicity in irinotecan used:
dose-limiting diarrhea
Cholinergic syndrome: salivation, sweating, lacrimation, urination, diarrhea
How to prevent cholinergic syndrome in patients on irinotecan?
Pre-medicate with IV or SC atropine
Genetic considerations in the use of irinotecan:
UGT1A1 deficiency: decrease starting dose by at least one dose level for homozgosity for UGT 1A1*28 allele
- because these patients cannot inactivate SN-38
Available forms of etoposide:
IV (100mg injection)
oral(50mg caplet)
instructions for the administration of etoposide:
- IV infusion should be infused ≥1hr to avoid hypotension
- IV solution diluted to concentration of <0.4mg/mL
- use non-PVC tubing
- PO dose is x2 of IV for same effect
Symptoms of toxicity in etoposide use:
- Dose-limiting myelosuppression and hypotension (if infuse too quickly)
symptoms of toxicity in cisplatin use:
Dose-limiting acute and delayed CINV, nephrotoxicity, ototoxicity, peripheral neuropathy, irritation to veins
symptoms of toxicity in carboplatin use:
- dose limiting myelosuppression (esp thrombocytopenia)
- nephrotoxicity, ototoxicity, delayed N/v
- Hypersensitivity –> after 6-7 doses
why is carboplatin preferred over cisplatin use:
much lower incidence of nephrotoxicity, ototoxicity and delayed N/V
wha can be used to treat dose-limiting diarrhea in irinotecan use:
loperamide (4mg at earliest sign, followed by 2mg PO q2h until diarrhea free for 12 hours)