Pharmacology of Anti-Cancer Agents Flashcards
Which chemotherapy agents are cell cycle phase specific to the M phase?
- docetaxel
- paclitaxel
- vinblastine
- vincristine
Which chemotherapy agents are cell cycle phase specific to the S phase?
- 5 FU
- Irinotecan
- Methotrexate
What cells do chemotherapy agents preferentially kill?
Proliferating cells
What cells do non specific agents eg radiation kill?
Both normal and malignant cells to the same extent.
What does each transition in the cell cycle require?
Activation of cyclin-dependent kinases
How do we allow more exposure for cell cycle phase specific agents?
Continuous infusion
What are some characteristics of cell cycle phase non specific agents?
- exert cytotoxic effect throughout the cell cycle, including resting phase
- cell kill is proportional to dose
- examples: alkylating agents
What are some acute toxicities of anti cancer drugs?
- due to inhibition of cell division
- tissue with fast renewal affected: bone marrow, GI mucosa cells, skin/hair
What are some delayed toxicities of anti cancer drugs?
- infertility
- secondary malignancies
- anthracyclines can cause cardiac toxicity
- methotrexate can cause pneumonitis
What are the two groups of alkylating agents?
- Nitrogen mustards e.g. cyclophosphamide, ifosfamide
- Platinum analogues e.g. cisplatin, carboplatin and oxaliplatin
What is cyclophosphamide?
A prodrug -> must be activated in the liver to active metabolites
What are the indications of cyclophosphamide?
- lymphoma
- breast cancer
- bone marrow transplants
What are some toxicities of cyclophosphamide?
- myelosuppression
- cardiac dysfunction in high doses
- N&V
- hemorrhagic cystitis (esp with high dose/long term therapy)
What is ifosfamide?
Analogue of cyclophosphamide, activated in the liver by CYP3A4
What is the MOA of ifosfamide?
inter- and intra-strand cross links in DNA causes cell death
Is ifosfamide cell cycle phase specific?
No. Cell cycle phase non specific.
What are the indications for ifosfamide?
- testicular cancer
- diffuse large B-cell lymphoma
What is an administration instruction for ifosfamide?
- must administer with mesna
- vigorous hydration with normal saline pre and post administration
- encourage pts to increase oral fluid intake
What are the toxicities of ifosfamide?
- dose limiting toxicity is hemorrhagic cystitis
- neurotoxicity (hallucinations, confusion etc)
- N&V
- nephrotoxicity
How to manage neurotoxicity of ifosfamide?
- caution in elderly
- caution in renal dysfunction
- increase infusion time
- avoid concurrent CNS drugs
- decrease dose or discontinue with onset of symptoms
- methylene blue as antidote
What is the indication of cisplatin?
- solid tumours
What are the 5 toxicities of cisplatin?
- Acute and delayed N&V (one of the most emetogenic drugs) (DOSE LIMITING)
- cisplatin nephrotoxicity
- ototoxicity (cannot hear high pitch sounds)
- peripheral neuropathy
- irritant to veins (phlebitis)
What is cisplatin induced nephrotoxicity?
- deterioration of renal function and electrolyte wasting
How to manage cisplatin induced nephrotoxicity?
- avoid in renal dysfunction
- hydration with saline pre and concurrent with cisplatin, with potassium and magnesium supplementation
- maintain urine output >100ml/h
- provide mannitol and or furosemide for diuresis
- prolong infusion time
- amifostine as scavenger
What is carboplatin indicated for?
Solid tumours
What are the toxicities of carboplatin?
- Myelosuppression (dose-limiting)
- Hypersensitivity
Advantages of carboplatin over cisplatin?
- much lower incidence of nephrotoxicity, ototoxicity and delayed N&V than cisplatin
What is oxaliplatin indicated for?
Colorectal cancer
How do we administer oxaliplatin?
Stable only in D5W (dextrose)
What are the toxicities of oxaliplatin?
- cumulative peripheral neuropathy
- myelosuppression
- nephrotoxicity (much less than cisplatin)
- hypersensitivity
What are the enzyme inhibitors?
Topoisomerase I inhibitor: Irinotecan -> causes single stranded break
Topoisomerase II inhibitor: Etoposide, Anthracyclines (doxorubicin) -> causes double stranded break
What is the active metabolite of irinotecan?
SN-38 is an active metabolite
Is irinotecan cell cycle phase specific?
It is S phase specific.
What is irinotecan indicated for?
Metastatic colorectal cancer
What are the toxicities of irinotecan?
- diarrhoea (dose-limiting) - both early and late diarrhoea -> treat with loperamide
- cholinergic syndrome can occur (salivation, sweating, lacrimation, urination and diarrhoea) -> routinely premedicate with IV or SC atropine
What is problematic about irinotecan?
UGT1A1 deficiency can cause SN-38 to accumulate
Hence, dose adjust.
What is etoposide indicated for?
Solid tumours
What are the toxicities of etoposide?
- myelosuppression (primarily neutropenia)
- hypotension if infused too quickly
What are the toxicities of anthracyclines?
- dose limiting myelosuppression (primarily neutropenia)
- cardiotoxicity (need baseline MUGA/ECHO)
- alopecia
- acute N&V
- vesicant -> extravasation
- red discolouration of urine
How to prevent anthracycline-induced cardiotoxicity?
- limit cumulative dose
- fractionate doses
- prolonged infusion
What are the agents under the “antimetabolites” class?
- methotrexate
- pyrimidine analogues
MOA of antimetabolites?
- structurally similar to naturally occurring compounds
What are the toxicities of methotrexate?
- dose limiting myelosuppression
- mucositis, diarrhoea
- pulmonary pneumonitis
What drugs should be avoided when taking methotrexate?
Drugs that interfere with methotrexate excretion (renal excretion) eg NSAIDs, penicillin
MOA of methotrexate?
Inhibits dihydrofolate reductase -> inhibits conversion of folic acid to tetrahydrofolate (active form of folic acid required for purine and thymidylate synthesis)
What does high dose methotrexate require?
Therapeutic drug monitoring and folinic acid rescue
Does methotrexate escape into third spaces?
Yes. Those w/ ascites or pleural effusions are at high risk for methotrexate toxicity.
What are the pyrimidine analogues?
5FU and capecitabine
MOA of 5FU?
Analog of pyrimidine uracil -> acts as pyrimidine antagonist
What happens to 5FU in DPD deficiency?
5FU is degraded in the liver by DPD.
Hence, DPD deficiency -> toxicity
What is the toxicity of 5FU?
Bolus - dose limiting myelosuppression
Continuous infusion - dose limiting hand-foot syndrome and diarrhoea
What are the indications of capecitabine?
Colorectal and breast cancer
MOA of capecitabine?
Orally active prodrug of FU, selectively activated by tumour cells
How to administer capecitabine?
Give within 30 mins after a meal
Toxicities of capecitabine?
- hand-foot syndrome
- mucositis and diarrhoea
What are the two groups of anti microtubules?
- taxanes
- vinca alkaloids
MOA of vinca alkaloids?
binds to tubulin and inhibits its polymerization
What are examples of vinca alkaloids?
- vincristine
- vinblastine
- vinorelbine
In which phase of the cell cycle does vinca alkaloids act at?
Mitosis (metaphase)
What are some toxicities of vincristine?
- peripheral neuropathy
- ileus, constipation
What are some toxicities of vinblastine and vinorelbine?
- dose limiting neutropenia and thrombocytopenia
- neurologic toxicity and constipation can also occur but much less than vincristine
MOA of taxanes?
Stabilize against depolymerization -> cannot recycle materials
What are the pre-medications required for paclitaxel?
To prevent hypersensitivity,
- H1 blocker
- H2 blocker
- corticosteroids
What are the premeds required for docetaxel?
To prevent edema,
dexamethasone starting on the day before chemo
What is tamoxifen?
- selective estrogen receptor modulator
- blocks estrogen from stimulating breast cancer cells
- treatment of estrogen receptor positive breast cancer in premenopausal and post menopausal women
- increases the risk of endometrial cancer and thromboembolic events in women treated with this drug
What is letrozole (aromatase inhibitor)?
- indicated for treatment of estrogen receptor positive breast cancer in post-menopausal women
- reversible competitive inhibitor of enzyme aromatase
- causes bone-related adverse effects eg bone pain, fractures and new onset osteoporosis -> supplement with calcium and vit D
What are targeted cancer therapies?
- drugs that interfere with specific molecules involved in cancer growth and survival
- often cytostatic, whereas standard chemo drugs are cytotoxic
- not necessarily have lesser side effects/drug interactions than standard chemo drugs
What are examples of targeted cancer therapies?
- tyrosine kinase inhibitors (TKI)
- VEGFR inhibitors
What are examples of epidermal growth factor receptor TKI?
erlotinib, gefitinib, afatinib
What are some toxicities of EGFR TKI?
- dermatological toxicities
- diarrhoea
What is the toxicity of rituximab?
- infusion related reactions -> premedicate with paracetamol and diphenhydramine, start infusion slow and increase rate over time
What is bevacizumab?
- vascular endothelial growth factor inhibitor
- used in colorectal cancer, lung cancer and kidney cancer
- no premedications required
- avoid in pts at high risk of bleeds or CNS metastasis
- causes proteinuria: monitor urine protein, discontinue in nephrotic syndrome
What is trastuzumab?
HER2 receptor antagonist
- used in breast and gastric cancer
- can cause cardiotoxicity
What is the difference between passive and active immunotherapy?
Passive - Act on the tumour
Active - Act on immune system
What is PD-1 and PD-L1?
PD-1 is the receptor found on T cells
PD-L1 is the ligand for the receptor.
What is pembrolizumab and nivolumab?
PD-1 inhibitor
What are the adverse effects of immunotherapies?
Immune-related adverse events - inflammation. Over-stimulated immune response. Can affect any tissue or organ in the body.
Manage using immunosuppresants like steroids.
