S7 Cancer Chemotherapy

Question 1

What is Chemotherapy ?

Answer 1

Chemotherapy is the administration of cytotoxic drugs and is one of the principal therapies used in cancer treatment.

Question 2

What is the DNA structure ?

Answer 2

Double helix of nucleotides

Question 3

Which Cells aren’t affected by chemotherapy agents ?

Answer 3

Cells in the G0 phase

Question 4

What is Fractional cell kill hypothesis ?

Answer 4

in chemo, tumour and bone marrow cells are destroyed. So chemo is given in stages, not continuously, however this can cause neutropenic sepsis (low neutrophils).

Question 5

What is Tumour chemo-sensitivity

Answer 5

In those with low sensitivity to chemo, chemo is used with adjuvant treatment e.g surgery.

Question 6

What is site of action of alkylating agents ?

Answer 6

• Platinum compounds allow covalent bonds to form between DNA strands (either interstrand or intrastrand adducts)
• This causes the strands to break
• Now DNA replication cannot occur preventing tumour growth
• However body has repair mechanisms for strand breaks hence why some cancers are resistant to chemo

Question 7

What is the site of action of antimetabolites ?

Answer 7

• E.g Methotrexate & 5-Fluorouracil, both inhibit DNA formation
• Methotrexate inhibits dihydrofolate reductase, which is necessary to form purines, thymine and aa, so cell is unable to form DNA.
• 5-FU is activated to 5-FdUMP which inhibits thymidylate synthase, thus preventing pyramidines to be incorporated in DNA.

Question 8

What is the site of action of spindle poisons ?

Answer 8

• Taxanes e.g Paclitaxel
• Vinca alkaloids e.g Vincristine
• During metaphase when chromosomes line up, spindle microtubules depolymerize, moving sister chromatids toward opposite poles
• SP affect microtubule dynamics by inhibiting polymerisation (Taxanes) or inhibiting microtubule assembly (VA)

Question 9

What is the mechanism of resistance for chemotherapy ?

Answer 9

1. Decreased entry or increased exit of the agent
2. Inactivation of the agent in the cell
3. Enhanced repair of DNA lesions produced by alkylation
   The overall result means that the cancer cells succumb less to the chemotherapy agents and the drugs are less effective in their action.

Question 10

What is the site of action on Intercalating agents/anthracycline antibiotics

Answer 10

• E.g Doxorubicin – prevents transcription

Bleomycin forms free radicals which cuts DNA strands

Question 11

What are the clinical indications of chemo ?

Answer 11

Used for cancer, but aim of treatment varies within different cancers.

Given based on: performance score (how the patient is functioning e.g living normally, so will give chemo, unlike to a patient who is close to death), clinical stage, prognostic factors, molecular markers (e.g HER-2).

An individual receiving palliative chemotherapy will have a lower dose to minimise side-effects compared to an individual where the aim is to cure them and so larger levels can be used despite increased side effects.

Question 12

What is the route of administration ?

Answer 12

IV (most common, e.g pump infusion), subcutaneous injection, PO, into a body cavity (e.g bladder).

Question 13

What are the adverse effects

Answer 13

Renal failure
• From hyperuricaemia caused by tumour lysis
GI perforation
Vomiting
• Due to action of chemotherapy drugs on the central chemoreceptor trigger zone.
Alopecia
• Hair thinning or complete loss. Especially high with vinca alkaloids and doxorubicin
Skin toxicity
• Phlebitis of veins (inflammation)
• Bleomycin can cause hyperkeratosis (thickening of outer layer) and ulcers
• Doxorubicin can cause hyperpigmentation
Mucositis
• Inflammation of mucous epithelia lining the GI tract esp oropharynx
• Presents as sore mouth or diarrhoea
Cardiotoxicity
• Caused by high dose doxorubicin or cyclophosphamide
Lung toxicity
• Bleomycin can cause pulmonary fibrosis: Lungs become scarred and breathing becomes difficult
Haematological Toxicity

Question 14

what are the issues of cytotoxic drugs ?

Answer 14

Chemo is difficult to prescribe due to the Narrow therapeutic indices and Significant side effect profile. Dosing is based on the patients BMI, wellbeing and how well they can handle drugs e.g renal function.
The frequency of administration (treatment phase) is based on growth fraction and bone marrow recovery.

Question 15

What causes variability in chemo ?

Answer 15

What causes variability?
Abnormalities in; absorption (causes gut problems), distribution (weight loss), elimination (liver and renal dysfunction), protein binding (low albumin).

Question 16

What the important drug interactions of chemo ?

Answer 16

Vincristine and itraconazole – more neuropathy. Capecitabine and warfarin - more bleeding. Have caution prescribing Methotrexate and penicillin.

Question 17

How should chemotherapy be monitored ?

Answer 17

radiological imaging, tumour marker blood tests, and bone marrow testing. Drug levels should constantly be monitored and organ damage should be checked for (esp creatinine clearance or echocardiography).

Question 18

What are anaesthetics ?

Answer 18

Anaesthetics reduce sensitivity to pain, they can be split into general, local or regional.

Question 19

What is conscious sedation ?

Answer 19

use of small amounts of anaesthetic or benzodiazepines to produce a ‘sleepy-like’ state.

Question 20

What are classes of anaesthetics ?

Answer 20

Gases (volatile): (delivered via lungs) e.g xenon, N2O

Intravenous: propofol, barbiturates, ketamine

Question 21

What are the Guedels signs ?

Answer 21

Stage 1: analgesia and consciousness
Stage 2: unconscious, breathing erratic
Stage 3: surgical anaesthesia given, with four levels describing decreasing breathing and muscle tone.
Stage 4: respiratory paralysis and death

Question 22

What is anaesthesia a combination of ?

Answer 22

• Analgesia
• Hypnosis (loss of consciousness)
• Depression of spinal reflexes
• Muscle relaxation (patient has insensibility and immobility)

When giving anaesthetics, End-Point Is Concentration Dependent. With increasing conc, memory is lost first, then consciousness, then movement, then CVS response.

Question 23

Define potency

Answer 23

Potency: conc dose range of a drug which produces a

Question 24

What is MAC and Volatile Anaesthetic Potency

Answer 24

Volatile anaesthetic potency is described by MAC or Minimum Alveolar Concentration: alveolar conc at which 50% of subjects fail to move to surgical stimulus.
Anatomical substrate for MAC is spinal cord.

Question 25

What Factors affect Induction and Recovery?

Answer 25

Partition coefficients. If blood:gas partition is low, shall have fast I & R
Oil:Gas partition (in fat) determines potency and slow accumulation due to partition into fat (obese patients take longer to wake up).

Question 26

What affects MAC?

Answer 26

Age (High in infants lower in elderly), Hyperthermia (high); hypo (low), Pregnancy and alcoholism (high), other anaesthetics and Opioids (low)

Question 27

Effects of N2O on MAC

Answer 27

When N2O added, less drug is needed to anaesthetise the patient.

Question 28

what is consciousness in the brain ?

Answer 28

In the brain, consciousness is a balance between excitation (Glutamate, awake) and inhibition (GABA, asleep). Anaesthetics modulate this balance.

Systems Target: Brain Circuitry

Question 29

How do anaesthetics work on GABA receptors ?

Answer 29

GABA receptors are critical targets, they are the major inhibitory transmitter. They have LGIC; Cl- enters hyperpolarising the cell stopping CNS activity.
With the exception of Xe, N2O and ketamine, all anaesthetics potentiate GABA mediated Cl-conductance to depress CNS activity. Also works on NMDA glutamate receptors.

Question 30

what are systems target and in relation to brain circuitry

Answer 30

Reticular formation depressed and connectivity lost (no communication within brain).
•Hippocampus depressed (memory lost).
•Brainstem depressed (respiratory and CVS reduced).
•Spinal cord depressed (analgesia; dorsal horn) and motor neuronal activity (MAC).

Question 31

What is intravenous aesthetic potency

Answer 31

Plasma conc to achieve a specific end point.

Question 32

What are the local anaesthetics and its characterisitcs

Answer 32

Lidocaine, Bupivacaine, Ropivacaine and Procaine. Characteristics:
• Made of aromatic ring, amine and either ester (short acting) or amide (long) link
• Higher Lipid solubility – higher potency
• Lower pKa – faster onset
• Chemical link – for metabolism
• Higher Protein binding – longer duration of action

Question 33

describe Bupivacaine Infiltration For Wound Analgesia.

Answer 33

BP is not charged so can pass through plasma memb, and depending on its pKa, it shall become charged and get sucked into the VG Na channel, blocking AP. The block is USE dependent; AP fires faster during pain so rate of sucking and blocking into Na channel is also faster. Adrenaline can increase the action of BP.

Compared to Procaine, Bupivacaine is more potent with a longer duration of action.

Question 34

Describe regional anaesthesia

Answer 34

• Selectively anaesthetising a part of the body.
• Blocks a nerve and hence the patient remains awake.
• Uses local anaesthetics and or an opioid
• Can use in e.g axillary or femoral nerve

Question 35

What are the aesthetic side effects ?

Answer 35

Anaesthetic Side Effects
General: nausea, hypotension, delirium
Local and regional: cardiovascular toxicity