WEEK 6 flashcards

why does chemotherapy cause side effects

targets rapidly dividing cells and is not specific

common chemo toxicity

n&v

mucositis

fatighe

neuropathy

alopecia

skin toxicity

loss of appetite

less common but serious chemo toxicities

anaphylaxis

TLS

secondary malignancies

fertility issues

electrolyte disturbances

grading scales used to assess chemo

• ECOG performance status

• Karnofsky score

• CTCAE

• WHO toxicity grading

Types of chemo induced N&V

• acute - within 24hr

• delayed

• anticipatory- anxiety driven before treatment

• breakthrough - despite treatment

• refractory- persists despite all meds

two pathways of N&V

Peripheral - GI

central - brain

Key antiemetic drug classes

• Dopamine antagonists - metoclopramide

• 5-HT3 antagonists- ondansetron

• Substance P antagonists

• cannabinoids

• antihistamines

• antimuscarinics

Mechanism of chemo induced diarrhoea

• epithelial damage

• inflammation

• microbiome disruption

Management of chemo induced diarrhoea

• Abx

• probiotics

• anti - inflammatories

• pain management

• nutritional support

what causes mucositis

DNA damage + immune mediated tissue breakdown after chemo

why is mmucositis dangerousj

can lead to systemic infection if mucosal barrier fails

why does platinum based chemotherapy cause neuropathy

disrupts neuron environment via DNA binding leading to inflammation and misfiring.

risk factors for chemo induced neuropathy

• age

• genetics

• alcohol

• comorbidities

treatment options for neuropathy

• pharmacological - selectove uptake inhibitors and non pharmacological- gentle exercise if possible.

mechanisms of doxorubicin cardiotoxicity

iron complex formation leading to lipid damage

mitochondrial dysfunction- highly concentrated in cardiac cells . reactive oxygen species produced .

topoisomerase targeting

disrupted calcium singalling in muscle cells

when can cardiotoxicity occur

up to 6 months post treatment

prevention/ treatment strategies for chemo induced cardiotoxicity

• cardioprotective meds

• iron regulation

• calcium pathway modulation

goal of immunotherapy

stimulate immune system to attack cancer cells

what is ICI induced colitis

overactive immune response in gut due to PD-L1 blockade

treatment of ICI induced colitis

• immunosuppressants eg infliximab

pt factors affecting immune related adverse events

• age

• sex

• genetics

• lifestyle

organs commonly affected bt immune related adverse events

• CNS

• Thyroid

• colon

• liver

• skin

• heart

management of immune related adverse events

monitor

sympromatic treatment eg with sterouds or infliximab

side effects of targeted therapy

skin issues

HTN

slow wound healing

liver tox

management of targeted therapy toxicity

• Sx management

• dose adjustment

what mutation do BRAF inhibitors target in melanoma

BRAF V600 - causes uncontrolled signalling

why do BRAF/MAK inhibs cause skin tox

overstimulation of IRF-1 which can cause inflammaiton

pt factors affecting response to BRAF/MEK inhibs

• mutation type

• age group

what causes bone marrow suppression in chemo

• cytotoxic effects on rapidly dividing marrow cells - leading to leukopenia, thrombocytopenia

example of a nephrotoxic chemotherapy drug

• cisplatin - need to hydrate and monitor renal function

what is constipation in chemo most commonly caused by

vinca alkaloids

what is therapeutic drug monitoring

• measuring drug concs in blood at intervals to maintain efficacy and minimise toxicity

Factors affecting therapeutic range

• physiology

• PK

• pharmacodynamics

how does TDM contribute to personalised dosing

accounts for genetic differences affecting metabolism.

eg 5fu dosing based on DPD enzyme activity

how can TDM help manage drug interactions

detects accumulation or subtehrapeutic levels due to interactions

what is the therapeutic window

range between minimim effective concentration and minimum toxic concentration

indications for tdm

• Narrow therapeutic window

• unpredictable response

• acute/chronic disease management

• drug interactions

• monitoring adverse reactions

common methods used to measure drug levels

• immunoassays

• HPLC

• Mass spectrometry

factors affecting drug concentration

hydration

food intake

timing of blood sampling

what should be done if drug levels are out of range

change dose

review interactions

check adherence and timing

how is monitoring schedule decided

• based on drug, pt condition , response and risk of toxicity

what causes variability in drug levels between patients

differences in ADME

genetics

age

disease state

what can affect TDM test accuracy

• lab errors

• poor sample handling

how is vancomycin cleared

• 90% renal

half life of vanco

6-8 hours

prolinged in renal impairment

key features of gentamicin PK

• poor GI absorption

• 70% plasma albumin bound

• excreted unchanged in urine

gentamycin toxicity

• ototoxicity

• nephrotoxicity

target serum levels gentamicin

peak- 5-10mg/L

trough- <2mg/l

Point of care testing in TDM

enables faster decision making by providing immediate drug level data

use of AI in TDM

• PK modelling for dose prediction

• simulating therapy scenarios

• predicting drug interactions and responses

dose concentration effect pathway

dose→ plasma conc → effect site conc→ effect→ clinical outcome

what does PK/PD integration allow

• links dose to effect and supports feedback for dose adjustment

why is conc more important than dose

effects are caused by drug concs at site of action, not just adminstered dose

what is Css min

minimum steady state plasma conc needed for efficacy

two main sources of variability in PK/PD

intrinsic- genetics, body weight, renal function

extrinsinc - diet, envt, other drugs)

role of polymorphism in drug metabolism

• polymorphisms in enzymes cause variability in drug clearance and response

types of PK/PD variability

• within subject

• predictable

• unpredictable

• between subject

what enzyme primarily metabolises 5FU

DPD - dihydropyrimidine dehydrogenase.

what gene encodes DPD

DPYD.

What happens in pt with DPYD polymorphism

• reduced or no DPD activity - leading to increased tisk of 5FU toxicity

DPYD normal metaboliser dosing

no dose adjustment

DPYD intermed metaboliser dosing

reduce dose by 50%

DPYD poor metaboliser dosing

avoid drug

what is the sex effect seen with 5FU

females have higher AUC (exposure) and therefore may require lower doses.

what is stratified dosing

• based on group-level predictors eg genotype, weight. this does not account for individual variability

what is precision dosing

Uses individual drug concentration data to tailor future doses.

steps in PK guided dosing for 5-fu

• administer standard dose

• measure plasma conc

• adjust next dose based on therapeutic window and variability

what is a limitation to RCTs

they cover a small portion of the popultion and cant capture all variability

what affects gentamicin dosing in morbidly obese

• body weight and renal function

why is gentamicin fosing complex in renal impairment

• is renally cleared

• toxocity risk increases with impaired clearance

what type of dosinf interval is used in renal dysfunction

extended interval to reduce nephrotoxicity

types of tools for individualised dosing

• software

• web platforms

what does precision dosing require

PK/PD models

pt specific data eg plasma conc

commercial tools or lab measurements

what type of drug is 6MP

thiopurine analogue - interferes with DNA/ RNA synthesis

6MP MOA

incorporates into DNA/RNA of rapidly dividing cells which impairs replication

what is 6MP commonly used in

leukaemia

why does 6mp require careful dosing

narrow TW and high PK variability

major toxicities of 6MP

bone marrow suppression

liver toxicity

pancreatitis

increased cancer risk

enzymes involved in 6mp metabolism

• TMPT

• HGPRT

• Xanthine oxidase

key metabolites of 6mp

6TGN

6- methylmercaptopurine

effect of allopurinol on 6MP

inhibits xanthine oxidase, increases 6mp and TGn - leading to both higher efficacy and toxicity

how is TPMT activity inherited

autosomal codominant trait- both alleles contribute to enzyme level.

how does methotrexate interact with 6mp

alters 6mp metabolism and may affect TGN levels in combination therapy

what are virtual twins in precision medicine

digital models simulating individual responses using patient data

why do you need to test levels of TPMT before starting 6mp

• lower levels of TPMT can lead to higher exposure of 6MP, which also increases the risk of toxicity