Pharmacology of anti-neoplatics Flashcards
What is anti neoplastic pharmacology?
Drugs used to treat cancer, also called:
anticancer, chemotherapy,
cytotoxic, or hazardous drugs
When is medical therapy indicated for cancer?
- Neoadjuvant therapy
- Eradication of micro-metastasis
- Medical treatment sensitive tumour
- Palliation
What is Neoadjuvant therapy:
o Admin of therapeutic agents before a main treatment.
Examples of neoadjuvant therapy include chemo, radiation therapy and hormone therapy BEFORE main surgery
What are:
Micrometastasis?
And what is Palliationtherapy?
EMM= refers to presence of clinically undetectable tumour cells at diagnosis or cells that remain present after treatment to eradicate the primary tumour
Palliation = Making patient feel more comfortable, not curing disease
When does chemo work best?
What are the responses in large tumours typically?
When tumour/metastasis is small
Responses in large tumours typically limited and transient
Generally a bigger tumour = higher chance of resistant cells within:(
What do we need to consider before chemotherapy?
o Tumour growth kinetics
o Naturally resistant populations (tumour heterogeneity)
o Factors influencing drug penetration of tumour
o Patient factors (signalment, pharmacogenetics)
What are ways in which we can overcome resistance in tumours?
o Reduce tumour burden before medical therapy
o Multidrug chemotherapy
o High dose intensity
Why use multidrug chemotherapy?
- Broaden range of tumour cells which are sensitive to treatment
- Slow development of resistant population
- Maintain acceptable toxicity and allows increase dose intensity
What is dose intensity?
What does a high dose intensity mean?
Intensity = drug dose per unit time
Keeping high dose intensity reduces the number of resistant cells
How can we achieve a high dose intensity?
- Use drugs known to have single agent efficacy
- Avoid drug combination with overlapping toxicities
- Administer drugs as close to maximum tolerated dose as possible
What are the factors affecting response and side effects chemo?
EDAM
- Administration
- Distribution
- Metabolism
- Excretion
Talk about Administration and Distribution in factors affecting response and side effects of chemo
Administration: Dose, ability to get into blood stream if oral (can be quite variable)
Distribution:
- Ability of molecule to get to target site
- Size of drug, vasculature, necrosis, environment
- Blood barriers e.g. blood brain barrier - Cellular uptake / efflux pumps e.g ABCB1
Talk about Metabolism and Excretion in factors affecting response and side effects of chemo
Metabolism
- Drug activation / deactivation e.g. CYP450, glutathione s-transferase
- (Anti-apoptotic mechanism, DNA damage repair)
- Cell cycle
Excretion
- Clearance – hepatobiliary system, kidney, (lung)
- For kidney excreted GFR correlates with adverse effects of some drugs
How does chemotherapy work?
There are 2 broad categories:
- damages DNA
- Inhibits DNA replication
What is a problem with chemo untargeted therapy
- will affect all tissues, especially rapidly dividing tissue
- General side effects:
o Bone marrow – lowest white count typically 7 – 10 days
o Alopecia – uncommon in dogs /cats except a few breeds
o Gastrointestinal – usually lasts longer than the first 4 days
Which agents come under “conventional chemotherapy”
- Alkylators
- Vinca-alkaloids
- Anti-tumour antibiotics
- Platinating agents
- Anti-metabolites
MOA alkylators
MOA: add an alkyl group to the guanine base of the DNA molecule, preventing the strands of the double helix from linking as they should. This causes breakage of the DNA strands, affecting the ability of the cancer cell to multiply.
o Bind DNA, insert an alkyl group leading to a change in structure.
Transcription and replication are thus inhibited.
If the lesion is not repaired the cell undergoes apoptosis
How are alkylators metabolised and excreted?
o Metabolism to active forms in the liver
o Excretion via the kidney
Side effects alkylators
- Myelosuppression (low white blood cells) > GI problems
- Cyclophosphamide – sterile haemorrhagic cystitis
• Caused by metabolite acrolein
• To protect: Monitor urine for blood, increase water intake and urination frequency, take Diuretics - furosemide - Lomustine – hepatic toxicity
• Vinca-alkaloids MOA
o Either binds to or inhibits formation of microtubules thus preventing the formation mitotic spindle.
o Cell cycle specific (cells die in M phase but most sensitive in S phase)
Where are Vinca-alkaloids metabolised and excreted?
o Metabolism in the liver
o Excretion in bile
Side effects Vinca-alkaloids
GI – vincristine > vinblastine
Myelosuppression – vinblastine > vincristine
Perivascular irritation if drug extravasation
Antitumour antibiotics OA
- Topoisomerase inhibition DNA strand breaks
- Intercalation with DNA Prevents transcription
- Free radical formation DNA damage
Greatest effect in S phase, but not specific to cell cycle
Whereare anti-tumour antibiotics excreted and metabolsied?
o Metabolised by hydrolysis in the liver
o Excreted in bile
Side effects anti-tumour antibiotics
GI
Myelosuppression
Severe perivascular irritation in case of extravasation
Cumulative cardiotoxicity (systolic dysfunction) (dogs)
Arrhythmia if administered too quickly (VPCs)
Anaphylaxis (skin in dogs/lung in cats)
Kidney damage (cats)
