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EMS - GiM > (15) Pharmacogenetics > Flashcards

(15) Pharmacogenetics Flashcards

1
Q

Define genomics

A

Relating the genome i.e. total DNA/RNA

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2
Q

What is pharmacokinetics vs. pharmacodynamics?

A

Pharmacokinetics = what the body does to the drug

Pharmacodynamics = what the drug does to the body

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3
Q

What is stratified medicine?

A

Selecting therapies for groups of patients with shared biological characteristics

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4
Q

What is personalised medicine?

A

Therapies tailored to the individual

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5
Q

What is germline vs somatic?

A

Germline = hereditary

Somatic = acquired, in non-germline, not hereditary

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6
Q

Give some examples of genetic variations

A
  • gene amplification
  • promoter polymorphisms
  • translocations
  • deletions, insertions
  • single nucleotide polymorphisms (SNPs)
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7
Q

Genetic variations lead to what?

A

Change in protein (eg. enzyme, transporter, target) structure/activity

This leads to altered outcome to treatment

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8
Q

What is a single nucleotide polymorphism (SNP)?

A

A variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population - the most common type of genetic variation

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9
Q

What effect may SNPs cause?

A

May change protein structure/activity eg. missense changes

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10
Q

Give 4 different types of inheritance pattern

A
  • autosomal recessive
  • autosomal dominant
  • X-linked recessive
  • mitochondrial inheritance
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11
Q

In autosomal recessive genetic variations that affect drugs, who are the most severe side effects seen in?

A

In those homozygous for the variant

Heterozygote = less affected or unaffected

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12
Q

Which gender is at risk in X-linked recessive variants?

A

Males

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13
Q

Who does mitochondrial genetic information come from?

A

From mother only

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14
Q

Genetic variations can cause effects in what? (concerning drugs/pharmacology)

A
  • absorption
  • activation
  • altered target
  • catabolism (breakdown)
  • excretion

NB. drugs may have complex metabolic pathways and single genes are unlikely to explain all variability

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15
Q

What are the consequences of getting in wrong? (genetic variation and drugs)

A
  • inactive drug (poor response/ no response)
  • over-active drug (excess toxicities)
  • financial costs to health services
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16
Q

How big a problem is ADRs (adverse drug reactions)?

A
  • 6.5% of UK hospital admissions related to ARDs
  • median hospital stay = 8 days
  • 4% of hospital bed occupancy
  • 2.3% of those with ARDs died as a result
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17
Q

Why do most cancer drugs have response rates of around 20%?

A

Due to genetic variation in the tumour or in the patient

Many patients receive toxic treatments without benefit

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18
Q

How can genetics help in pharmacology?

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
  • stratified/personalised medicine
  • reduce financial costs of inappropriate treatment
19
Q

What is TPMT?

A

Thiopurine methyltransferase

20
Q

What does TPMT do?

A

Inactivates certain drugs

21
Q

What drugs does TPMT inactive?

A
  • 6-mercaptopurine and 6-thioguanine (chemotherapies)

- azathioprine (immunosuppressant)

22
Q

What do TPMT gene polymorphisms do?

A

Reduce TPMT protein activity

23
Q

What is the consequence if a patient has variants in both copies of the TPMT gene?

A

Severe toxicity

24
Q

What are N-acetyltransferases?

A

Group of liver enzymes inactivating drugs by acetylation

Different distributions in different ethnic populations

25
Q

There can be “fast” and “slow” acetylators due to what?

A

Due to SNP variations in genes eg. NAT2

26
Q

In the use of isoniazid for TB, slow acetylators are at what risk?

A

Increased risk of side effects including neuritis and liver toxicity

27
Q

Which other drugs are affected by N-acetyltransferase activity?

A
  • sulfasalzine (Crohn’s disease)

- hydralazine (hypertension)

28
Q

What is succinylcholine?

A

Muscle relaxant used in anaesthesia (to stop breathing)

  • related to the poison curare
  • usually wears off after a few minutes
29
Q

What increases the length of activity of succinylcholine?

A
  • rare BCHE gene variant homozygotes have reduced butyrylcholinesterase activity
  • effects may last for an hour or more and risk of death if artificial ventilation is not continued
30
Q

What does mitochondrial MT-RNR1 gene encode?

A

Mitochondrial 12s rRNA

31
Q

G to A mutation in MT-RNR1 at nucleotide position 1555 causes what?

A

Non-syndromic hearing loss (at later ages)

  • mutation changes structure of the rRNA to resemble E. coli 16s rRNA
  • aminoglycosides more likely to bind to patient’s rRNA = increased risk of hearing loss at younger age
32
Q

What is the inheritance pattern of aminoglycoside induced hearing loss?

A

Maternal inheritance

Accounts for 30% of tendency to aminoglycoside ototoxicity

33
Q

What is warfarin?

A
  • widely used oral anticoagulant to reduce embolism/thrombosis
  • decreases the availability of vitamin K by blocking VKOR
34
Q

Which enzyme activates certain clotting factors while oxidising vitamin K into vitamin K epoxide?

A

y-glutamyl carboxylase

35
Q

What does incorrect dose of warfarin lead to?

A

Dose too low = patient remains at risk

Dose too high = risk of haemorrhage

36
Q

How does the optimum warfarin dosage vary?

A

Varies 20x between individuals

37
Q

Which genes explain 50% of genetic variability of warfarin activity?

A

CYP2C9 (one of the cytochrome p450 family)

and VKORC1 (vitamin K oxidoreductase complex-1)

38
Q

Testing for genes CYP2CP and VKO6C1 may lead to what?

A

More correct dosing of warfarin and therefore may reduce hospital admissions by 30%

39
Q

How are new cancer drugs increasing overall response rates and survival while reducing treatment failure an toxicities?

A

By targeting specific genetic variations that the cancer contains but that are not present in germline DNA

40
Q

20% of breast cancer have over-expression of what?

A

HER2 (human epidermal growth factor 2)

41
Q

HER2 breast cancer patients benefit from which drug?

A

Trastuzumab (herceptin) - a monoclonal antibody to the HER2 receptor

42
Q

50% of melanomas have a somatic mutation in which gene?

A

BRAF gene

43
Q

Which targeted therapy against melanoma showed a 48% response rate compared with 5% for standard chemotherapy?

A

Vemurafenib (BRAF inhibitor)

EMS - GiM (14 decks)

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