Flashcards in Session 7 Deck (23):
1
What tumours have the highest chemosensitivity?
Lymphomas, germ cell, small cell lung, neuroblastoma, Wilm's tumour
2
What tumours have modest chemosensitivity?
Breast, colorectal, bladder, cervix, ovary
3
What are the categories of cytotoxic agents by their mechanism of action?
Anti metabolites - fluorouracil, methotrexate
Alkylating agents and platinum based - crosslink DNA
Intercalating agents
Mitotic inhibitors (spindle poisons)
4
Why doesn't chemotherapy target all cells in a tumour?
Not all of them are rapidly dividing - most are resting cells (compartment B) that are able to convert to diving cells (compartment A). Compartment C= cells no longer able to divide
Treated with surgery and radiation - however these can only be done for detected tumours
5
Describe the log kill ratio
A tumour needs to consist of about 10^9 cells before it is clinically detectable (small grape). If a given treatment kills 99.99% of cancer cells then there is a reduction to 10^5 cells (full stop size). This would be a four log kill ratio and further treatment of the same four log kill therapy would then result in only 10^1 cancer cells remaining. Not all cells are viable in reality.
6
What factors limit the oral route for chemotherapy?
Toxic agents, may have a low bioavailability and patients often have nausea and vomiting
7
What are mechanisms of drug resistance in chemotherapy?
Increased efflux, decreased influx, drug target enzymes expression can be upregulated to offset the decrease in production of metabolites, Increased rate of repair of drug induced lesions in DNA
8
What is done to counter the effects of resistance on chemotherapy?
Use of high dose, short term$intermittent repeated therapy with drugs given in optimal combination to treat
a specific tumour type
9
What are common side effects of chemotherapy?
Severe nausea, vomiting, diarrhoea mucositis, alopecia, myelosuppresion, impaired wound healing and skin toxicity. Renal failure from hyperuricaemia from rapid tumour lysis. More specific within groups include neurotoxicity, cardio, bladder and lung toxicity.
10
What is the most frequent dose limiting toxicity of chemotherapy?
Haematological toxicity
11
List some important drug interactions with chemotherapy agents
Vincristine (spindle inhibitor) and itraconazole (antifungal) leads to more neuropathy
Capectitabine (oral fluorouracil) and warfarin/st Johns Wort/grapefruit juice
Methotrexate and penicillin/NSAIDs
12
How can drug treatment be clinically monitored?
Response of the cancer - radiological imaging, tumour marker blood tests, bone marrow sampling
Drug levels -
Check for organ damage - creatinine clearance and echocardiogram, ECG, FEV1/FVC
13
What is the principle action and main therapeutic effects of NSAIDs?
Key enzymes in prostaglandin synthesis
Analgesia, anit-inflammatory and antipyretic
14
What enzymes synthesise prostaglandins from arachidonic acid and describe their interaction with NSAIDs
Cyclo-oxidase enzymes (COX): COX 1 and COX 2. NSAIDs inhibiting COX 1 produce most side effects as has a cytoprotective role. Main therapeutic effects via COX2 inhibition
15
Describe the actions of prostaglandins that are targeted by NSAIDs
Released post injury. Work with other autacoids (local, short half life mediators) - bradykinin/histamine
Vasodilators. Increase permeability via synergistic activity
Sensitise pain receptors to inflammatory mediators
Fever due to bacterial endotoxins triggering macrophage release of endogenous Il-1. This stimulates hypothalamic production of PG-E that elevates the set point on central ‘thermostat’.
16
What are the elimination kinetics of NSAIDs and how are they transported?
1st order (aspirin and paracetamol zero order above therapeutic range)
Heavily bound to plasma protein
Can be short half life (< 6hrs) eg, Ibuprofen or long half life (>10 hrs) eg, naproxen
17
What are the main indications for NSAIDs?
Anti inflammatories for MSK disorders - rheumatois/osteoarthritis
Mild to moderate pain - paracetamol 1st line unless pain is inflammatory condition
18
What are the side effects of NSAIDs?
GI in 30% users - abdominal pain, nausea, GORD, ulceration. Long term NSAIDs need PPI.
Heart failure, renal disease, hepatic cirrhosis, vascular problem, skin rashes, bronchial asthma
19
Name some NSAIDs
Ibuprofen, naproxen, diclofenac
20
Name 2 selective COX2 inhibitors and what disadvantage to they have over other NSAIDs?
Rofecoxib, celecoxib
Increased cardiovascular side effects (despite reduced GI side effects)
21
List some drug interactions with NSAIDs
Aspirin - compete for COX1 site - interferes with its cardioprotective mechanism
Highly protein bound drugs - sulphonylurea, warfarin, methotrexate
ACE inhibitors
22
What makes aspirin an unique NSAID?
Irreversibly inhibits COX enzymes
23