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Neuroscience > Pharmacogenomics > Flashcards

Pharmacogenomics Flashcards

1
Q

What is a haplotype?

A

An inheritable, proximal block of SNPs on the same chromosomes

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2
Q

Example of SNP variation

A

TAS2R38 gene variation and PTC taste

  • Mendelian Inheritance pattern
  • 3 Phenotypes; Super-taster, taster, non-taster
  • As an inheritance pattern, has been inherited after species divergence
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3
Q

TD50

A

Dose at which toxicity occurs in 50% of cases

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4
Q

ED50

A

Dose at which the drug is effective in 50% cases

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5
Q

G6PD Deficiency: what it is

A
  • Glucose 6 Phosphate Dehydrogenase- enzyme that metabolises glycosides
  • G6PD deficiency is an X-linked recessive disorder with 140 single-base changes
  • 5 classes of enzymatic variation
  • 400 million affected worldwide, most common Sub-Saharan africa
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6
Q

How is G6PD deficiency diagnosed

A

Quantitative spectrophotometric analysis

Flow cytometric assay (assesses RBC G6PD activity)

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7
Q

Classes of enzymatic variation in G6PD deficiency

A

Classes 1-5
Class I- severe, deficient haemolytic anaemia
Class IV- normal activity
Class V- increased activity

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8
Q

G6PD deficiency in Malaria

A

G6PD creates NADPH which removes oxidants, such as those generated by antimalarials

  • Primaquine (antimalarial treatment) produces excess oxidants, which can’t be removed by NADPH supply
  • Destroys RBC membranes and causes haemolytic anaemia
  • Sx: Acute haemolysis, jaundice, tiredness, SOB, dark urine
  • CI in pregnancy
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9
Q

Other drugs CI in G6PD deficiency

A

Sulfasalazine

Nitrofurantoin

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10
Q

Isoniazid- what for, features etc.

A

Nicotinic acid derivative used in TB treatment

  • Blocks mycolic acid synthesis (component of the mycobacterial cell wall)
  • Metabolised to its active form by N-Acetyltransferase 2
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11
Q

NAT-2 Variation

A

3 SNPs in NAT2 gene; two are synonymous

  • Species and geographical variation
  • Rapid, intermediate and slow acetylators
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12
Q

Symptoms of slow acetylators with Isoniazid

A

Peripheral neuropathy, hepatotoxicity, neuritis

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13
Q

Meta-analysis of acetylator studies:

A
  • NAT2 variation accounts for 88% variability of isoniazid metabolism
  • Rapid acetylators have higher rates of microbiological failure, particularly for combination therapy
  • ADRs also more common
  • Genotype/phenotype disconcordancy in 5% patients
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14
Q

Further PK issues with TB treatment

A

Isoniazid and Rifampicin both first-line

Variation in Rifampicin activity may also be associated with SNPs of SLCO1B1

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15
Q

How was CYP2D6 variation established

A

Variation in Sparteine activity with increased effects in 7% mothers (induces uterine contractions)
- Sparteine is metabolised by CYP450 into Sparteine-N1-Oxide, then into 2 inactive metabolites

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16
Q

CYP2D6 variation

A

CYP2D6 metabolises 25% of clinically-used drugs, importantly Theophylline, COCP, Warfarin, Carbamazepine, and Phenytoin

  • Phenotypes: Ultrarapid (UM), Extensive (EM), Intermediate (IM), Poor (PM)
  • EM most common in caucasians
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17
Q

Effects of codeine and CYP2D6 status

A

O-methylation of codeine to morphine is essential for its analgesic activity, but only 10% metabolism

-ADRs are more common in UMs e.g. respiratory depression, with standard PO 25mg TDS in one patient

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18
Q

Clinical study of variation of Codeine and CYP2D6

A

EMs vs PMs (single PO 75mg codeine dose)

  • Increased pain thresholds to nociceptive laser stimuli
  • Reduced urine codeine concentration
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19
Q

Clinical study of variation of Tramadol and CYP2D6

A

AUC (blood-drug concentration) is lower for both enantiomers of Tramadol in PMs vs EMs

  • Pain Pressure
  • Nociceptive reflex
  • Cold pressor reflexes

Have different responses in PMs and EMs
-PMs only had significant response to pressure-pain tolerance and nociceptive reflex

SEs: nausea, dizziness, tiredness

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20
Q

Opioid toxicity in neonates/mothers

A

-Neonates breastfeeding from UM mother died (concentration in breastmilk was too high; neonates have impaired morphine mwtabolising/eliminating capacity)

  • Opioid exposed newborns may have greater methylation of the CYP2D6 gene and related genes- reduced expression, lower metabolism
  • In a methadone maintained model of opioid dependent mothers
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21
Q

Epidemiology of Bipolar Disorder

A

Significant cause of global morbidity (QALYs)
Increased mortality vs. non-bipolar patients
-Suicide increased (but lower than unipolar depression)
-Medical deaths increased

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22
Q

Bipolar I

A

Manic and depressive episodes

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23
Q

Bipolar II

A

Hypomaniac and depressive episodes

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24
Q

Cyclothymic disorder

A

2 years of hypomaniac periods

Bipolar NOS- other medical conditions causing a mood disorder

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25
Q

Symptomatic features of Bipolar

A

Mania
Hypomania
Depression
Subsyndromal Depression

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26
Q

Features of Mania

A

Extreme happiness w/euphoria, grandiosity, impulsivity, libido, social intrusiveness

  • Psychotic Sx (delusions, hallucinations, formal though disorders)
  • Cognitive Sx (racing thoughts, distractibility, disorganisation, in-attentiveness)
27
Q

Treatments for Bipolar

A

Mania

  • Antipsychotics (Haloperidol, Risperidone, Olanzapine)
  • Lithium +/ Sodium valproate if first line ineffective

Long Term management
-APs OR Lithium +/ Sodium Valproate

28
Q

Lithium treatment in Bipolar

A

The most-prescribed drug
Requires monitoring
Exerts clinical effects by inhibition of Inositol Monophosphatase, Glycogen Synthase Kinase 3B, and Adenylyl Cyclase
Response to lithium may be a familial trait which clusters in families
- Twin studies have shown lithium prophylaxis is better in twins whose co-twin also has BPD

29
Q

Purpose of Genome wide association studies

A

Identifying loci that increase disease risk and predict treatment response

30
Q

GWAS of Chinese individuals and lithium response

Chen 2014

A

High specificity/sensitivity (linkage disequilibrium) for 2 SNPs in Glutamic Acid Decarboxylase Like 1 Enzyme (GADL1) on Chr3

  • Inclusion criteria: clinical course, adherence, minimising the influence of other medications
  • Patients with SNPs and rapid disease cycling had a better treatment response

-GADL1 similar to GAD65/67, underexpressed in bipolar patients

31
Q

Follow up Chen 2016 study (bipolar)

A

Carriers of T allele have lower frequencies of recurrent affective episodes than non-T carriers during period adherence
-One GADL1 SNP and medication adherence contribute to treatment response

32
Q

Additional GWAS study for lithium response

Squassina 2011:

A

GWAS of 200+ Sardinian patients

  • GWAS and Quantitative trait analysis
  • SNP in intron 1 of the ACCN1 gene
  • Encodes a cation channel with high lithium permeability and Na+ affinity
33
Q

Genetic variants and lithium response GWAS

A

4 SNPs on Chr21 on long non-coding RNA genes

  • Strong linkage disequilibrium to lithium response
  • lncRNAs are important regulators of gene expression in the CNS and may decrease during manic episodes
34
Q

Evidence against GADL1 involvement in lithium variation

Birnbaum 2014

A

Microarray/ RNA sequencing identified minimal GADL1 expression throughout the brain

Autopsies identified minimal GADL1 protein expression

Western blot of mouse brain lysates shows that this reduces with age

35
Q

Role of GADL1 in the Kidney

A

Is abundantly expressed and involved in PLP-dependent taurine synthesis

Taurine may cross the BBB to interact with glutamate NMDA receptors
-Relation to GADL1 in bipolar

36
Q

Switching in Bipolar

A

The sudden transition from one mood polarity to the other

PM CYP2D6 patients likely to experience switching more frequently after introducing a new drug

Pharmacogenetic testing relevant e.g. Amplichip CYP450 test

37
Q

Features of lung cancer

A

Non-Small Cell most common (75%)
50% cases inoperable so cytotoxic chemotherapy is first line treatment
- SEs of chemo: Nausea, vomiting, myelosuppression, alopecia, impotence, teratogenicity, carcinogenicity
-17% 5 year survival

38
Q

EGFR pathway in NSCLC

A

15% of the 55% of NSCLC patients with mutations have an EGFR mutation
Increase protein expression/phosphorylation in EGFR-dependent pathways which increase Ras/Raf, PI3K/AKT pathway activation
- Induce proliferation and angiogenesis

39
Q

EGFR mutations

A

Normally in the kinase domain
Increase sensitivity to TK inhibitors (Gefitinib, Erlotinib)

L858R mutation: increases Gefitinib sensitivity
T790M mutation acquired resistance to TK inhibitors

40
Q

Benefits of Gefinitib treatment in L858R/ Exon 19 NSCLC patients

A

Improved clinical outcomes

In vitro: 50x sensitivity to Gefitinib treatment

41
Q

HER2 and breast cancer

A

HER2 o/e in 20% breast adenocarcinomas

Mutation is associated with worse untreated prognosis

42
Q

Phase 2 RCT of Trastuzumab with HER o/e breast cancer

Vogel 2002

Phase 3 RCT

A

114 women with o/e identified by IHC, FISH
Trastuzumab administered at 2 doses

Clinical benefit demonstrated showing no disease progression at 12 months vs. controls

P3 RCT: effectively enhanced first-line chemotherapy

43
Q

EGFR in Gastric/GOJ cancers

Bang 2010 P3 RCT

A

Multi-centre P3 RCT to account for ethnic differences
Inclusion based upon IHC/FISH

Improved overall and progression-free survival when used adjunctively to chemotherapy
- No effect upon number/magnitude of ADRs

44
Q

Effects of BCHE mutations on Succinylcholine/ Mivacurium activity

Gatke 2007

A

Mutations responsible for variation in BChE prolong drug activity
BCHEFS126- produces a truncated protein lacking an active site
BCHE328D- produces an inactive protein due to a radical AA change

Have extensively prolonged succinylcholine activity- prolonging respiratory depression and apnoeas

May also have sever reactions to Donepezil etc.

45
Q

Jensen 1995- determining genetic variation in Succinylcholine activity

A

Used differential inhibitors of BCHE

  • There were no age/sex differences under 10 years
  • Activity decreased with age
46
Q

ALOX5 status and Asthma

A

ALOX5 encodes 5-Lipooxygenase (5LPO)- involved in leukotreine/ Arachidonic acid synthesis

5LPO encoded by ALOX5 gene; has a variable number of tandem repeats (VNTRs) in promoter region
-Only fully expressed with 5VNTRs

Cells with more/less VNTRs less active in vitro

Patients with mutant ALOX5 have a poorer response to Zileuton (5-LPO inhibitor used in asthma) by FEV1 score

47
Q

What does the clinical pharmacogenetics implementation consortium (CPIC) do?

A

Create gene/drug practice guidelines for implementation of certain drugs

48
Q

Variation in TMPT activity and Thiopurine drugs

What are the alleles- and effects?

A

Thiopurines e.g. 6-MP are purine analogues, prevent DNA formation
Have a narrow TI, increased risk of myelosuppression

3 alleles of activity:

  • TPMT1: 90%, high activity
  • TPMT*3A: 10%, intermediate activity
  • TPMT*3C: 0.3%, low activity- increased risk of myelosuppression (6MP levels remain higher for longer)
49
Q

Why are the effects seen in 3A/3C allele patients

A

The protein encoded by 3A/3C is degraded rapidly by a ubiquitin-proteasome mediated process

Naturally higher in neonatal RBCs vs age-matched adults

50
Q

ALL and TPMT activity

A

Children with ALL have better outcomes if they also have low TPMT activity

  • Higher concentrations of TGN metabolites can form from lower doses
  • Allows dose lowering in deficient patients, so chemo can be delivered at maximum doses
  • Reduced rates of mercaptopurine-induced neutropenias
51
Q

Clinical implementations of thiopurine dosing

A

Genotyping, phenotyping (radiochemical, chromatographic techniques)

  • Concordance of ~86%
  • Can be influenced by RBC transfusion

3A individuals need to be treated with 1/10 of standard dose
High activity may need elevated dose

Genotyping is worth it- the cost of 400 genotyping tests is the same as 1 treatment of a TPMT associated ADR

52
Q

Warfarin administration

A

Inhibits Vitamin K Epoxide Reductase (VKOR) to reduce clotting cascade activation
Is administered as R-Warfarin but the more potent S-Warfarin is inactivated by CYP2C9

53
Q

Variation in warfarin activity- CYP2C9 and VKORC1

A

CYP2C9- 9% of variability

  • *1 allele is highest activity
  • *2 allele reduced activity
  • *3 allele is minimal/no activity

VKORC1- 25% variability

  • G allele- high liver expression
  • A allele- low liver expression

May also have complete loss of function mutations

54
Q

Warfarin Dosing Refinement Collaboration

A

Genotype-specific warfarin dosing

-2014 meta analysis suggests this does not reduce dosing-related ADRs

55
Q

Other clinical considerations in warfarin dosing

A

Maintain an INR of 2-3
May be affected by other AC use
Interactions with other CYP450 drugs may occur

56
Q

Inhibitors of CYP450

A

Grapefruit/Cranberry juice, valproate, miconazole, Erythromycin, Ciprofloxacin

57
Q

Inducers of CYP450

A

Carbamazepine, Phenytoin, Rifampicin, Alcohol, BBQ meat, St Johns Wort

58
Q

Indications of Carbamazepine

A

Focused/ Generalised Tonic/Clonic Seizures

Trigeminal Neuralgia

59
Q

Side effects of CBZ

A

Anaemias and blood disorders
Ataxia
Dizziness, blurred vision, Nausea

60
Q

Mechanism of action of CBZ, and how metabolised

A

Blocks voltage-gated Na channels in neurons

Metabolised by CYP3A4

61
Q

What effects might CBZ have on CYP3A4

A

Induces it- may affect transcription/+ expression of CYP3A4/5 via the Pregnane X receptor

62
Q

Effects of CYP3A4 genotype of CBZ

Korean epileptics study

A

35 Korean epileptic patients
Investigate CYP3A5*3 expression effects
CYP3A4 activity may vary 20x in vivo

Positive correlation between dose-requirement and serum level of CBZ in expressors and non-expressors
Oral clearance of CBZ in non-expressors was significantly lower and therefore serum levels were significantly higher

63
Q

Carbamazepine and SCN1A

A

SCN1A- encodes VG Sodium channels in neurons

SNP7 of the SCN1A gene highly associated with maximum dose
Less of an issue with CBZ than with phenytoin
Starting doses are normally less than the final req.d dose
400mg OD vs 800-1200mg OD

Neuroscience (17 decks)

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