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Yr 2 - EMS > Pharmacogenetics > Flashcards

Pharmacogenetics Flashcards

1
Q

Define genomics

A

Relating to the genome i.e. total DNA/RNA

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2
Q

Define pharmacokinetics

A

What the body does the drug

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3
Q

Define pharmacodynamics

A

What the drug does to the body

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4
Q

Define stratified medicine

A

Selecting therapies for groups of patients with shared biological characteristics

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5
Q

Define personalised medicine

A

Therapies tailored to the individual

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6
Q

Are somatic mutations inherited?

A

No

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7
Q

Define pharmacogenetics

A

The study of inherited genetic differences in drug metabolic pathways which can affect an individuals response to drugs.

e.g. may result in a positive response to a drug therapy or an adverse drug reaction.

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8
Q

What type of genetic variations can lead to an altered outcome to treatment?

A
  • SNPs (most common)
  • Deletions, insertions
  • Translocations
  • Promoter polymorphisms
  • Gene amplification

These all lead to change in protein (e.g. enzyme, transporter, target) structure/activity

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9
Q

What is a SNP?

A

Single nucleotide polymorphism

A single nucleotide adenine (A), thymine (T), cytosine (C), or guanine (G) is replaced

May change protein structure/activity e.g. missense changes

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10
Q

What is a missense change?

A

A point mutation in which a single nucleotide change results in a codon that codes for a DIFFERENT amino acid.

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11
Q

What is mitochondrial inheritance?

A

Always inherited maternally

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12
Q

How can genetic variants affect the metabolism of drugs?

A
  • Absorption
  • Activation
  • Altered target
  • Catabolism (breakdown)
  • Excretion

N.B. Drugs may have complex metabolic pathways and single genes are unlikely to explain all variability

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13
Q

What % of UK hospital admissions are related to adverse drug reactions (ADRs)? How much does this cost the NHS?

A
  1. 5%
  2. 3% of those admitted with ADRs died as a result

Costs the NHS approximately £1 Billion/year

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14
Q

What altered outcomes can pharmacogenetics lead to?

A
  • Inactive drug

- Overactive drug (toxic)

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15
Q

How is pharmacogenetics implicated in cancer drugs?

A

Most cancer drugs have response-rates of ~20% due to genetic variation in the tumour or patient.

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16
Q

How can genetics help this problem?

A
  • Identify genetic variations that lead to altered outcomes
  • Change dose of drug where appropriate
  • Use a different drug that works better and/or has reduced toxicity
  • Guide new targeted drug development
  • Reintroduce effective drugs which have ADR in few patients
  • Stratified/personalised medicine
  • Reduce financial costs of inappropriate treatment
17
Q

Cancers contain genetic variations that are not present in germline DNA (i.e. somatic). How can these variations be used in treatment?

A

These variations are potential targets (i.e. as drug would have an effect on cancer cells but not normal cells)

18
Q

What is Trastuzumab? What is its brand name? What is it used to treat? Mechanism of action?

A

Brand name: Herceptin

Used to treat: Breast cancer

Mechanism: a monoclonal antibody to the HER2 receptor

19
Q

How is HER2 (human epidermal growth factor receptor 2) and cancer related?

A

20% of breast cancers have over-expression of HER2 (human epidermal growth factor receptor 2)

20
Q

What are BRAF inhibitors? What is an example of one? What are they used to treat?

A

What: BRAF inhibitors are drugs that can shrink or slow the growth of metastatic melanoma in people whose tumours have a BRAF mutation

Example: Vemurafenib

Used to treat: Melanoma

21
Q

How is the BRAF mutation and cancer related?

A

~50% of melanomas have a somatic mutation in the BRAF gene

22
Q

Why is chemo not used for melanoma?

A

Melanoma is notoriously resistant to chemotherapy treatment

A new targeted therapy Vemurafenib recently showed a 48% response rate compared with 5% for standard chemotherapy

23
Q

What is Thiopurine methyltransferase (TPMT)?

A

An enzyme that inactivates certain drugs

E.g. Azathioprine (immunosuppressant used in organ transplantation and autoimmune disease)

24
Q

What is Ivacaftor? What is it used to treat?

A

CF drug

Used to treat: cystic fibrosis in people with certain mutations in the CFTR gene

25
Q

What is Succinylcholine?

A

Muscle relaxant used in anaesthesia (to stop breathing and facilitate tracheal intubation)

26
Q

What are Aminoglycosides?

A

Aminoglycosides are a class of antibiotics used mainly in the treatment of aerobic gram-negative bacilli infections.

27
Q

What condition can Aminoglycosides lead to?

A

Aminoglycoside induced hearing loss (mutation in MT-RNR1 gene)

28
Q

How can Aminoglycoside induced hearing loss occur?

A

Strongly linked to genetic variations within one particular mitochondrial gene, MT-RNR1

Aminoglycosides appear to generate free radicals within the inner ear, with subsequent permanent damage to sensory cells and neurons, resulting in permanent hearing loss.

29
Q

What gene variants is warfarin affected by?

A

Associated with an increased sensitivity to warfarin and lower dose requirements

30
Q

In 2020, the NHS Genomic Medicine Service becomes fully operational. What will this mean?

A

Genomic screening and personalised treatments will be the “new normal” in the NHS.

This will enable a better understanding of the links between genes and drug response.

31
Q

What issues will arise with the NHS Genomic Medicine Service?

A

a) Genetic data will need to be linked to patient records.

b) Further guidance for patients whose ideal dose, as predicted by their genetics, falls outside the NICE guidelines.

32
Q

What is the most common type of genetic variant that can affect drug metabolism?

A

SNPs

33
Q

What can TPMT gene polymorphisms affect TPMT activity? What can this lead to?

A

Reduce TPMT protein activity –> can lead to severe toxicity if BOTH copies of the gene have the variant

34
Q

What proportion of the Caucasian population carry inactivating polymorphisms in TPMT?

A

10%

35
Q

What does the TPMT enzyme play a critical role in breaking down?

A

Thiopurine drugs

36
Q

How is the mutation in MT-RNR1 gene inherited?

A

Maternal inheritance (as mitochondrial MT-RNR1 gene)

Yr 2 - EMS (60 decks)

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