How does imatinib work as a chemotherapy drug?
BCR-ABL tyrosine kinase inhibitor
What factors contribute to tumour growth?
- Short window to get in with treatments before death!
- Chemotherapy can only work on cells in the cell cycle as there is variations of 9 to 43 hours with cancer cells making it hard to target them
What is the fractional cell kill hypothesis?
A defined chemotherapy concentration, applied for a defined time period, will kill a constant fraction of the cells in a population, independent of the absolute number of cells so…
- Fraction of cells killed not number of cells killed
- Given in doses to allow bone marrow to recover (this recovers faster than cancer cells)
How are tumours classfied based on their chemo-sensitivity and give some examples of tumours in each category?
- High will only need chemo
- Low may not respond to chemo at all so need surgery
What are the different groups of chemotherapy drugs based on their mechanisms of action?
- Antimetabolites
- Antibiotics
- Alkylating/Platinating agents
- Mitotic spindle inhibitors
What is the mechanism of action of alkylating agents/platinating agents and what are some examples of these drugs?
- Target DNA synthesis in G1/S phase
- Forms covalent bonds with DNA nucleosides disrupting structure and preventing replication
- Stops DNA replication
What are some specific ADRs of alkylating/platinating agents?
- Peripheral, sensory and motor neuropathy
- High frequency ototoxicity
What are some possible mechanisms of resistance to alkylating agents?
- Decreased entry or increased exit of agent
- Inactivation of agent in cell
- Enhanced repair of DNA lesions produced by alkylation
What are some examples of antimetabolites and what are their mechanism of action?
- Methotrexate: in malignancy works as dihydrofolate reductase inhibitor stopping DNA synthesis
- 5-Fluorouracil: Inhibits thymidylate synthase which is needed to make pyrimidines for DNA synthesis
What are some examples of microtubule/spindle poisons and what is their mechanism of action?
- Vinca Alkaloids: Vincristine which is a microtubule assembly inhibitor
- Taxanes: Paclitaxel which is a microtubule depolymerisation inhibitor
- Cells cannot undergo prometaphase and anaphase as tubulin proteins affected. Cell cannot divide properly so cell undergoes apoptosis
What is an adverse drug reaction associated with spindle poisons?
Neurotoxicity: glove and stocking peripheral neuropathy
When is chemotherapy used and why is there different responses with the same chemotherapy on the same cancer?
CANCER: different schedules used to balance side effects and best anticipated outcome
Predicted response depends on each patients:
- performance score
- clinical score
- prognostic factors
- molecular or cytogenetic markers
What are the different routes of administration for chemotherapy?
What are the two different types of IV pump that can be used in chemotherapy?
- With Hickman it goes into SVC and patient can wear a pump of chemo
- Both methods the patient can go home
What are the common side effects of chemotherapy?
Why can acute renal failure occur during chemotherapy?
Hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules so need to monitor for this
What are some other serious acute side effects with chemotherapy apart from acute renal failure that can cause a patient to die?
- GI perforation: at site of tumour such as a lymphoma in the stomach that melts away with chemo. Can cause peritonitis. If at risk then artificially feed in hospital
- DIC: onset a few hours after starting treament for acute myeloid leukaemia
Why do people vomit after chemotherapy and what are the different patterns of emesis?
Multifactorial but direct action of chemotherapy drugs on central chemoreceptor trigger zone
Acute phase: 4-12 hours
Delayed onset: 2-5 days later
Chronic phase: persistance up to 14 days
Give anti-emetics
What happens to body hair when undergoing chemotherapy treatment and how can we minimise the effects of this?
- Hair thins after 2-3 weeks and often total body
- Can regrow during therapy and be marked with chemo drugs like doxorubicin but warn patient this doesn’t mean tumour is coming back
- Minimal hair loss with platinums
What are some toxic skin effects that can occur when a patient is undergoing chemotherapy?
- Thrombophlebitis of veins and extravasation
- Hyperkeratosis, hyperpigmentation and ulcerated pressure sores when using bleomycin
- Hyperpigmentation when using doxorubicin and cyclophosphamide
- Boe lines
Mucositis is a side effect of chemotherapy, how does this present?
- Can involve whole tract but worse in oropharynx
- Secondary infections can occur e.g thrush
- Presents as sore throat, GI bleed and diarrhoea
What are the cardiotoxic and lung toxic effects of chemotherapy?
Cardio: cardiomyopathy (bleomycin) and arrhythmias (cyclophosphamide)
Lung: pulmonary fibrosis (bleomycin and lots of others). Need to be careful giving concurrent radiotherapy and oxygen as they can make the fibrosis worse even after treatment years later, carry card!!
What is the most common cause of cancer therapy death?
Haematological toxicity!! e.g neutropenia and low platelets
Prescribing chemotherapy is a highly specialised field, why is this and what factors are taken into consideration when prescribing?
- Narrow TI and large side effect profile
- Dose depends on patient surface area/BMI, drug handling ability (e.g liver function) and general wellbeing (e.g performance status and comorbities)
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1 - Safe Prescribing6
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2 - Clinical Trials36
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3 - Pharmacokinetics and Pharmacodynamics44
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4 - Hypertension and Heart Failure Drugs42
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6 - Pharmacovigilence and Pharmacogenetics23
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