SEM 2 EBL FLASHCARDS

Benefits of pegylated liposomal doxorubicin

• protects liposomes from detection by phagocytes.

• enhanced stability

• increased circulation time

• prevents opsionisation

how does pegylation prevent opsionisation

steric hinderance.

Peg chains create a steric barrier which prevents liposomes being coated with opsionins

what is opsionisation

the process by which pathogens are marked for destruction by the immune system through the binding of opsonins.

What is passive targeting

EPR mediated drug accumulation

what is the EPR effect

Preferential accumulation of nanoparticles in tumour tissue because of their leaky vasculature and insufficient lymphatic drainage.

things to consider when prescribing amongst various groups of people

communication

language barriers

education level

financial status if necessary

patient preference

examples of social prescribing

support groups

physical activity services

Role of cholesterol in liposomal formulation

integrates into liposomal membrane. Improves encapsulation, stability and rigidity

role of sucrose in liposomal formulation

prevents aggregation

role of ammonium sulfate in liposomal formulation

for active loading of drug into liposomes increases drug entrapment efficiency.

role of water for injections in liposomal formulation

solvent

what is the active ingredient in tumeric , what does it do, why is it unsuitable alongside some cancer treatment regimens?

• active ingredient is curcumin- anti oxidant properties.

• can interfere with efficacy of some cancer drugs as is a substrate for CYPa 3a4, therefore may increase the exposure of some chemotherapeutics, and increase adverse effects.

MOA- trastuzumab

binds to extracellular ligand binding domain of HER 2 receptor, blocking its activation and therefore stops downstream signalling of the PI3K and MAPK pathways.

Also affects immune cells through antibody dependent cellular cytotoxicity to destroy cancer cells.

What is the HER 2 receptor

Growth factor. Transmembrane tyrosine kinase receptor which is activated by the formation of dimers with other EGFR proteins- activates downstream signalling pathways such as MAPK, PI3K which promote cell growth and survival.

administration of trastuzumab

• IV over 90mins

• S/C over 2-5 mins

• need adequate contraception during and 7 months after treatment.

what is trastuzumab used in

HER 2 positive breast cancer

gastric cancer

Lapatanib MOA

inhibits tyrosine kinase HER 2 receptor through phosphorylation → decreased cell proliferation and survival.

Competes with ATP to block HER 2 signalling and disrupts downstream signalling pathways.

Why is being overweight a risk factor for breast cancer

• increased adipose tissue in overweight.

• Aromatase converts adipose tissue to oestrogen. Increased levels of oestrogen stimulates growth of ER+ breast cancers

SERMs

Selective oestrogen receptor modulatorsthat bind to estrogen receptors, acting as agonists in some tissues and antagonists in others.

SERDs

Selective osetrogen receptor degraders. Degrade ER alpha,

IM only

more side effects than SERMs

used after SERM or AI failure.

AIs

Aromatase inhibitors.

Inhibit aromatise enzymes (which convert androgens into oestrogen) and therefore stop oestrogen synthesis.

Preferred in post menopausal women

What is high dose methotrexate used in cancer therapy

>500mg/m2

What do you need to do when administering methotrexate for cancer therapy

methotrexate MOA

inhibits dihydrofolate reductase, so DNA synthesis can’t happen.

comon toxicities w high dose methotrexate

Blood disorders

immunosuppression

hepatotoxicity

renal toxicity

What is used to prevent methotrexate toxicity, and how do they do this

Folinic acid- dampens down the inhibition of DNA synthesis by methotrexate so there is not too much of this inhibiton. Helps nor,al cells to recover and reduce side effects. Also helps to eliminate methotrexate from the body

IV fluids - promote hydration and urine output to aid methotrexate elimination and prevent renal issues.

Sodium bicarbonare - alkalanises the urine. Methotrexate is less soluble in acidic urine. Sodium bicarb is used to increase methotrex solubility in the urine and aid elimination.

Why is it important to alkalinise the urine when taking high dose methotrexate

Acidic env’ts can cause crystallisation in renal tubules which can cause blockages and further damage to the kidneys.

common interactions with methotrexate.

• Some antibiotics

eg penicillins- they are weak acids and also renally excreted, so can slow methotrexate metabolism as too acidic.

ciprofloxacin- displaces methotrexate from plasma proteins.

• Theophylline

• epilepsy medications

• PPIs

• Diuretics

• NSAIDs (bc reduce renal blood flow)

• some HTN meds

• Alcohol

• other immunosuppressants

methotrexate and aciclovir

interaction- increased risk of nephrotoxicity

alternative to PPI when giving high dose methotrexate

H2 receptor antagonist eg famotidine

MOA rituximab

Monoclonal antibody that targets CD20 on B lymphocytes. This leads to the depletion of B cells, by acting on CD20, promotes cell lysis.

what is rituxumab used in

types of lymphomas, leukemia , other cancers and autoimmune diseases.

does rituximab penetrate the CNS

Not under normal conditions.

What is glucoparidase, when is it used.

Methotrexate reversal agent - rapidly hydrolyses methotrexate into inactive non cytotoxic metabolites which arent metabolised by the kidney.

Used on AKI or methotrexate induced renal dysfunction.

Very high cost.

Why is there an interaction between azole antifungals and vincristine? What antifungal can you give instead?

Azole antifungals inhibit CYP3a4 , which metabolises vincristine. Therefore, they inhibit the metabolism of vincristine, and increase exposure, which leads to enhanced toxicity. (myelosuppression, neurotoxicity, inc risk of seizures)

alternative antifungal - amphotericin B.

Safeguards for intrathecal administration

• clear labelling

• separate preparation and storage areas

• Administered only by trained professionals

• CHECK- correct medicine, dose , patient , route- these checks recorded on intrathecal drug chart

• collect from pharmacy ONLY when needed for administration

• intrathecal register.

What is meant by a ‘Never event’

serious preventable incidents that should not occur if proper safety procedures are followed.

Unsafe and avoidable in healthcare settings

examples of never events

• administration of intrathecal vincristine

• overdose of insulin - misunderstood abbreviations / incorrect device

• methotrexate overdose (prescribed as weekly dose).

What is TMPT? What does it do?

enzyme involved in metabolism of thiopurine drugs eg 6MP.

TPMT methylates 6MP into an inactive form- 6 methylmercaptopurine = less toxic and less active.

Why do you get variation in the activity of TPMT among different individuals

genetic polymorphism

Metabolism of 6MP

TPMT - methylates 6mp → 6 methylmercaptopurine = less toxic and less active.

HPRT- converts 6-MP into active metabolite= 6-TGN = gives drugs cytotoxic effects.

xanthine oxidase and other enzymes- inactivate 6mp further into other metabolites which are excreted.

consequences of low and intermediate TMPT activity.

Low= slow metabolism, higher levels of active metabolite 6TGN = increased risk of toxicity such as bone marrow suppression.

intermediate= moderate response , may need dose adjustments to avoid side effects.

What is meant by a heterozygous variant

has one normal allele and one mutated copy

Basic MOAs - immunotherapy, chemotherapy and targeted therapy

immunotherapy = modifies immune system to fight cancer

chemo- kills rapidly dividing cells

taergeted- targets specific molecules or pathways in cancer.

organs affected by immunotherapy

• immune system, skin, lungs, gut , liver, endocrine

organs affected by chemotherapy

Bone marrow, GIT, hair folicles, liver

organs affected by targeted therapy

skin, liver, heart, blood vessels

Management of QT prolongation in cancer treatment

monitoring electrolytes

drug interactions

review choice of cancer therapy.

What is the BCR-ABL fusion gene (philadelphia chromosome)?

arises from reciprocal translocation between chromosomes 9 and 22. encodes an active tyrosine kinase that continually sends growth and survival signals to the cell.

BCR-ABL fusion gene in CML

disrupts 1st exon of ABL leading to sustained activation of tyrosine kinase and resistance to deactivating mechanisms. leads to uncontrolled cell growth and proliferation.

imatinib MOA

• Tyrosine kinase inhibitor specifically targeting the BCR-ABL protein by competitively binding to the ATP binding site, blocking the ATP binding needed for kinase activity. This inhibits activation of PI3K, JAK/STAT and RAS/MAPK pathways to decrease proliferation, induce apoptosis, cause cell cycle arrest and slow disease progression.

Adverse effects of imatinib

• myelosuppression

• rashes/dry skin

• GI

• Oedema - report significant weight gain, monitor for swelling in ankles, face.

• musculoskeletal pain

• fatigue

Why can paracetamol sometimes cause issues in cancer treatment

• Can mask fever and temperature- may need additional monitoring.

Lab diagnostics of TLS

• uric acid inc

• potassium inc

• phosphorous inc

• calcium dec

Levels 25% increase from baseline

monitoring for TLS

uric acid

creatinine

renal function

urine output and pH

electrolytes

calcium

phosphate

ECG

seizures

Allopurinol in the treatment of TLS

Xanthine oxidase inhibitor- stops body from making uric acid.

consequence of high uric acid

renal failure

rasburicase in treatment of TLS.

breaks down uric acid by catalysing the enzymatic oxidation of uric acid to an inactive and soluble metabolite, making it easier for the kidneys to excrete.

victim drugs of allopurinol and what this means

• mercaptopurine

• azathioprine

• theophylline

are drugs that are metabolized by xanthine oxidase, thus their effectiveness may be increased or decreased when taken with allopurinol, requiring dosage adjustments.

management of TLS

• hydration -IV fluids, increase fluid intake

• consider diuretic eg furosemide if urine output is not adequate

• Initiate rasburicase

• monitor electrolytes

• do not give potassium fluids

When is rasburicase contraindicated? what to do instead in established TLS

• G6PD deficiency

• gove allopurinol instead.

pre screening requirements before starting treatment with 6mp

TPMT levels , may affect dosing.

monitoring with treatment of 6mp

• FBC weekly until stable dose, then every 2-4wks.

• LFTs

• renal function

• tpmt

• monitor for signs of infection

• GI sx

Monitor 2,4,8,12 weekly then once stable every year.

What does it mean if someone has a high level of 6TGN while on treatment with 6MP?

indicates increasef efficacy but also increased toxicity.

dose reduction needed if too toxic

what genetic factors may contribute to high levels of 6TGN in patient undergoing treatment with 6mp?

• Heterozygous mutant of TMPT- slower metabolism of 6MP leads to higher levels of 6-TGN. (tmpt normally inactivates 6mp, preventing int from conversion into cytotoxic metabolites such as tgn)

what can happen with too much TGN

bone marrow toxicity

blood disorders

What are non-synonymous mutations

alters the amino acid sequence of a protein

What are synonymous mutations?

Occur in DNA sequence, but do not alter the AA sequence because the changes in the sequence does not change the codon that specifies the amino acid

AKA silent mutation.

Nonsense mutation

change in DNA that causes a protein to terminate/ end its translation earlier than expected

= stop mutation

exon

a segment of DNA or RNA that codes for a protein. Exons are typically spliced together during the processing of the precursor mRNA.

intron

Non coding section within a gene that is removed during RNA splicing before translation to proteins.

intragenic single nucleotide polymorphism

genetic variation where a single nucleotide base changes within a gene that may or may not affect protein function.

can lead to expression of genes that are silent.

D538G mutation - why does it lead to resistance to endocrine therapy?

• mutation in the oestrogen receptor alpha gene.

  causes conformational change to an active shape even w/o oestrogen.

• when endocrine therapies are used, receptor continues to stimulate cell growth.

Why are tubulin pathways potential targets for cancer drug design

they are often overexpressed in various cancers. They are involved in several hallmarks of cancer and contribute to uncontrolled proliferation, inhibiting apoptosis, and immune evasion

their contribution to the progression of cancer makes them suitable targets for treatment.

the two types of mechanisms of resistance to immunotherapy

intrinsic and extrinisic mechanisms of resistance

Intrinsic- cancer cells alter processes relevant to immune recognition, signalling, expressiona dn DNA damage.

Extrinsic- external to tumour cells through immunological and non immunological interactions

Mechanisms of resistance to immunotherapy

impaired MHC presentation- can cause resistance to t cell mediated cytotoxicity

Poor DNA repair

epigenetic modifiers → changes to antigen processing , antigen presentation, immune evasion

Altered signalling pathways to impair anti tumour response

Persistent IFN- gamma can lead to therapy resistance

TREGS- regulatory Tcells in tumour micoenvironments - suppress effector T cells and APC, maintain immune status.

Tumour associated macrophages

Antigen masking and presentation -present inappropriate antigens for therapy.

contribution of tubulin genes and pathways involved in the immune escape of cancer cells

• tubulin interacts with actin - regulates cell shape, migration and invasion, so changes to tubulin could enhance migration and aid immune escape and thus metastasis

Who can prescribe cycle one of chemotherapy?

Consultant or appropriatelt credentialed clinician ONLY

Others can only prescribe chemo that has already been initiated.

vegan vitamin d supplement option

ergocalciferol

physiological changes associated with low testosterone

• weight gain

• night sweats

• sleep problems

• bone loss

• fatigue

psychological changes assoc w low testosterone

Mood changes

depression

anxiety

difficulty concentrating

low self esteem

What can help hot flushes caused by low testosterone and how does it do this

• sage. mimics oestrogen in the body.

side effects of goseralin treatment

myalgia- muscle and joint pain

myosiris- inflammation of muscle

fatighe

neuropathy that could impact muscle strength

increased risk of osteoporosis.

MOA - docetaxel

Disrupts microtubules in cells so they cannot grow and divide properly, leading to death of these cancer cells.

role of dexamethasone / steroids in cancer therapy

reduce inflammation

prevent fluid retention

reduce nausea

role of filgrastim in cancer therapy

boosts WBCs - encourages bone marrow to produce more WBCs.

protect from infection and help immune recovery from chemo.

role of metoclopramide in cancer therapy

anti emetic

speeds up digestion to empty stomach more quick;y

acts on brains nausea control centre- crosses BBB - careful parkinsons , schizo.

immediate management of neutropenic sepsis

blood cultures

IV Abx

Tazocin 4.5g QDS

Gentamicin IV - DO NOT USE NEPHROTIC ABX LIKE THIS IF PT ON NEPHROTOXIC CHEMO.

high flow oxygen if sats below 94

IV fluids

check serum lactate- assess tissue hypoperfusion/ early septic shock

monitor urine outpit

dailt FBC, U&E, LFT, renal function

Self monitoring of thrombocytopaenia

unusual bruising, bleeding

avoid injury

Management of chemo induced thrombocytopaenia

• platelet transfusion

• growth factors

• Changes in chemotherapy regimen

Key steps in metastatic spinal cord compression pathway

• Diagnosis - imaging

• Emergency care management - steroids, pain

• Surgerym radio, or systemic therapy 

• Rehab and supportive care

some of the key medicines used in metastatic spinal cord compression management

• corticosteroifs

• pain- opioids, NSAIDSm neuropathic pain agents eg gabapentin for nerve pain

• bone strengthening - bisphosphonares, denosumab

• PPIs, laxatives etc to manage symptoms.

risk factors for frailty

• age

• lower BMI

• Low excercise

• polypharmacy

• mental health issues- ie depression

• cognitive impairment - dementia etc

• poor nutrition

• chronic disease

• social isolation/ loneliness

Alternative therapies to manage pain/ anxiety/ depression

• st johns wort

• psilocybin

• cbd oil

• accupuncture

• massages

• taking therapy

• therapy animals

• etc

Dabrafenib MOA

ATP competitive inhibitor of mutant BRAF kinases which inhibits its kinase activity, therefore dec downstream MEK and ERK phosphorylation → inducing cell cycle arrest and apoptosis.

trametinib MOA

inhibitor of MEK1 and MEK 2. binds outside of ATP binding pocket - locks it into inactive conformation → prevents ERK phosphorylation.
Reduces proliferation , induces cell cycle arrest and triggers apoptotic pathways.

why are dabrafenib and trametinib good to use in combination therapy

Together they provide more complete pathway inhibition

They block two points in the MAPK pathway (BRAF and MEK), improving efficacy and reducing resistance compared to monotherapy.

side effect profile of trametinib

• skin reactions - regular monitoring - prevent secondary infection if necessary.

• GI - diarrhoea, ab pain, nausea

• fatiguem peripheral oedema , fever

• CV- reduced left vent ej fraction - baseline echocardiogram, then every 4-12wks

• HTN- regular monitoring

• Occular side effects- retinopathy , blurred vision - urgent referral if sx develop

• pulmonary - pneumonitis - rare - look out for new cough/ breathlessness - imaging / pulmonary referral if applicable

canabis oil and chemotherapeutics

• may mask sx/ side effects of medication

• no clinical evidence for efficacy

• can interfere with other chemotherapeutics