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Pharmacogenomics > Week 2 > Flashcards

Week 2 Flashcards

1
Q

What are the five different letter prefixes to indicate the reference sequence used?

A 
g - Genomic 
c - Coding 
n - Noncoding
r - RNA
p - protein
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2
Q

All variants should be described in relation to an accepted reference sequence from where?

A

NCBI/EBI

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3
Q

What is the 3’ rule?

A

For all the descriptions the most 3’ position possible of the reference sequence is arbitrarily assigned to have been changed.

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4
Q

What order should the full standard nomenclature follow?

A
  • HGNC Official Gene Symbol
  • Reference sequence
  • Single letter prefix
  • Position with the base change
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5
Q

If we are using genomic reference sequence; 1 would be what nucleotide?

A

The first nucleotide of the file

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6
Q

If we are using coding reference sequence; 1 would be of what nucleotide?

A

The A of the ATG start codon.

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7
Q

Why is the coding DNA preferred as a reference?

A

Because there is no need to deal with introns and the numbers don’t go so high so it is less complicated.

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8
Q

If there is repeated sequences and there is a change which one is recorded as changed?

A

Assume the most 3’ repeat has changed.

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9
Q

How are bases before ATG denoted in coding DNA?

A

They go into minus number, the first base before ATG would be -1 and the second would be -2 and so on…

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10
Q

How are bases after the stop codon denoted?

A

One after the stop codon would be 1* and the second 2* and so on…

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11
Q

How would you write a substitutions of a base from A to C at position 320

A

c.320A>C

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12
Q

How would you write a deletion a base A at position 210?

A

c.210delA

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13
Q

How would you write a duplication of T at position 25?

A

c.25dupT

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14
Q

How would you write an insertion between position 125 and 126 of a G?

A

c.125_126insG

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15
Q

What represents a stop codon?

A
  • at the end or Ter at the end
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16
Q

What is star allele nomenclature?

A

Alleles arnt identified by their cDNA or genomic position, rather through the means or numbers and letters, separated from the gene name by the star.

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17
Q

What are the advantages of star allele nomenclature?

A
  • One star allele can be used to identify a group of variants.
  • Faster and easier for non-specialised professional in identifying important phamacogenomic alleles.
    Could help transcription mistakes which may be more frequent using HGVS nomenclature.
18
Q

Problem with star allele nomenclature

A
  • A major obstacle is the complexity of nomenclature systems.
  • Genetic test interpretations should be uniform regardless of the lab.
19
Q

Rule 1 of star allele nomenclature

A

Prove an allele has pharmacogenomic relevance from an allele group, where it segregates together with other neutral alleles.

20
Q

Rule 2 or the star allele nomenclature

A

To identify groups of functional alleles, the number of the most powerful allele is always used, followed by a letter.
So the other variants will be for example *2A and *2B.

21
Q

What is Pharmacodynamics?

A

Is the drug action and mechanism

22
Q

What is Pharmacokinetics?

A

Is how the body metabolises the drugs.

23
Q

When drugs are metabolised what are the products?

A

Inactive Excretion products; urine and bile, and Toxic Intermediates.

24
Q

What are the possible results of phase 1 metabolism?

A
  • Drug becomes inactive.
  • One or more of the metabolites are pharmacologically active, but less than the original drug.
  • Original substance is not pharmacologically active. The original substance is called prodrug
25
Q

Why are the Cytochrome p450 enzymes important in phase 1 metabolism?

A
  • Responsible for degradation and elimination of drugs.
  • Superfamily of
    mono-oxygenases
  • use haem iron to oxidise molecules, often making them more water-soluble for clearance.
26
Q

Information on Cytochrome P450’s

A
  • There are aproximately 60 cytochrome P450 genes in humans.
  • 70-80% enzymes involved in drug metabolism are CP450.
  • Primarily found in liver cells
  • Located in endoplasmic reticulum and the mitochondria.
27
Q

Phase 2 metabolism

A

Involves reactions that chemically change the drug/P1 metabolites into soluble (adding polar group) compounds enough to be excreted in urine.
Metabolites are likely to be inactive.

28
Q

Differences in drug metabolism can account for differential response to drugs, How ?

A

Differences in drug metabolism can be caused by genetic variants…

29
Q

What can CYP2D6 (Cytochrome P450 D6) metabolising enzyme effect?

A

Beta-blockers
Tricyclic antidepressants
Codeine metabolism

30
Q

What are the types of metabolisers?

A
  • Ultra rapid metaboliser
  • Extensive metaboliser
  • Intermediate metaboliser
  • Poor metaboliser
31
Q

Types of drugs

A

Prodrugs
- Codeine
Active drug
- Warefarin

32
Q

Opioid drugs

A

Morphine is an effective analgesic for acute and chronic pain
Other effect:
euphoria, respiratory destress, depression of cough reflex, Nausea and vomiting.
Opioids are any substance that produce morphine like effects - Synthetic and endogenous.

33
Q

What is the mechanism of action of opioids?

A
  • Bind to the opiate receptors in the CNS.
  • pain relief through mu.
  • Decreases activity of adenylyl cyclase, decreasing cAMP.
  • Increase in the efflux of K+ and cellular hyper-polarisation and a decrease in the influx of Ca++ and lower intracellular concentrations of free Ca++
34
Q

What are the four subtypes of opiate receptors?

A

mu, delta, epsilon and kappa

35
Q

Codine

A
  • Prodrug, weakly binds to the mu opioid receptor.
  • Undergo o-demethylation by CYP2D6 to morphine to exert opioid activity
  • Only 5-10% of coding is metabolised to morphine
36
Q

CYP2D6 and codeine metabolism

A
  • CYP2D6 gene is highly polymorphic, with more than 100 star (*) alleles described
  • Inadequate pain relief in poor metabolisers because of reduced morphine levels.
37
Q

Who shouldn’t take prescriptions Codeine or Tramadol?

A
  • Children younger than age 12
  • Mother who are breastfeeding
  • Children younger than age 18 following surgery to remove tonsils and/or adenoids.
38
Q

Tramadol

A

Synthetic opioid, related to codeine

  • Post-operative pain, and pain caused by cancer.
  • Some activity at mu-opioid AND it also inhibits the synaptic reuptake of serotonin and norepinephrine which inhibits pain transmission at the spinal cord
39
Q

Tramadol metabolism

A
  • O-desmethyltramadol, known as M1
  • Tramadol and M1 contribute to the analgesic effect.
  • M1 has significantly higher affinity for opioid receptors than tramadol.
  • CYP2D6 catalyses the production of M1.
  • CYP2B6 and CYP3A4 catalyse the production of M2, an inactive metabolite.
40
Q

Thiopurines

A
  • Used for treatment of inflammatory and autoimmune disease, leukaemia.
  • Prevent rejection post organ transplant.
41
Q

Side effects of thiopurines

A
  • Life threatening bone marrow suppression
  • Hepatotoxicity
  • Nausea and vomiting pancreatitis
42
Q

What turns thiopurines in to their inactive form?

A

TPMT- turns into non-toxic forms, Phase II

Pharmacogenomics (11 decks)

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