Pharmacogenetics Flashcards

1
Q

What is the definition of Pharmacogenetics?

A
  • Refers to the study of inherited differences in drug metabolism and response
  • Single gene/phenotype
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2
Q

What does Pharmacogenetics aim to do?

A

Links differences in gene structure (polymorphisms) to drug metabolism and response. Genetic Variation (genotype) has interaction with drug metabolism and response (phenotype)

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3
Q

What are pharmacogenetic consequences on pharmacokinetics?

A

Decreased first-pass effect

  • Greater bioavailability
  • Higher peak concentration

Reduced parent drug elimination

  • Longer half-life
  • More/fewer active metabolites

Altered concentration-effect relationship between poor and good metabolisers

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4
Q

How can Pharmacogenetics be applied?

A
  • Drug development: More targeted, more powerful drugs
  • Individualisation of therapy: The right drug and the right dose for every patient
  • Predicting ADRs (& reducing mortality)
  • Defining susceptibility
  • Identifying potential addiction
  • Reducing cost of health care
  • Don’t treat non-responders (stratification)
  • Don’t treat those most susceptible to toxicity (stratification)
  • Adjust dose to maximise efficacy while avoiding toxicity
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5
Q

What are clinical applications of Pharmacogenetics?

A
  • Anti-coagulation: Warfarin
  • Psychiatry: Tricyclic anti-depressants, Atomoxetine
  • Oncology: Thiopurines (TPMT), 5-fluorouracil, Herceptin (Her-2/neu), Tamoxifen (CYP2D6/ABCC2), Cetuximab (KRAS)
  • Cardiovascular: Statins, Clopidogrel
  • Pain control: Codeine, methadone
  • Epilepsy: Phenytoin, Carbamazepine
  • Infection: Abacavir
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6
Q

What s the effect of Pharmacognetics on Cholinesterase?

A

Enzyme required to breakdown short acting muscle relaxant suxamethonium or mivacurium

Genetic variants result in prolonged paralysis requiring ventilation support

Determine patient’s phenotype, Family studies

  • UU phenotype is usual/normal activity
  • UA and UF may have increased risk
  • FF, FS and AF intermediate sensitivity
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7
Q

What are feature of Thiopurine Drugs?

A
  • Used in the routine treatment of inflammatory and autoimmune diseases
  • Highly efficacious but ADRs are common
  • TPMT testing used routinely to tailor individual drug dose
  • Steroid sparing reagent
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8
Q

What are the TPMT genetics?

A
  • TPMT coded by 27 kb gene, 10 exons, located on 6p22.3
  • Wild-type is TPMT*1
  • Very low activity associated with ~41 variants, most common = TPMT*3 (80-90%)
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9
Q

How is TPMT tested?

A

Phenotype testing is first-line test

Genotype testing appropriate in some patient groups

  • Children with acute lymphocytic leukaemia

Recommended in NICE guidelines for Crohn’s disease, Recommended in BNF

TPMT phenotype/genotype can prospectively identify

  • Deficient patients at risk of life-threatening toxicity
  • Heterozygotes who will respond well to low-dose aza therapy
  • Patients with high TPMT activity who will need high doses from the start
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10
Q

What is the epidemiolgy of Thiopurine drugs?

A

In caucasians:

  • 1 in 300 - Very low TPMT activity
  • 6 – 11% - Intermediate TPMT activity
  • 2% - Ultra high TPMT activity

Very low TPMT activity can lead to potentially fatal myelosuppression when treated with standard drug doses

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11
Q

Describe how dosing of Azathioprine and 6-MP is affected by Pharmacognenetics?

A

Phenotype

AZA Dosing

6-MP Dosing

Normal/High Activity

Start with normal starting dose (2-3 mg/kg/d) then disease specific guidelines

Start with normal starting dose (1.5 mg/kg/d)

Intermediate Activity

Start at 30-80% of target dose (e.g. 1-1.5 mg/kg/d) and titrate to tolerance

Start at 30 – 80% of target dose (e.g. 0.75 mg/kg/d)

Deficient Activity

Consider Alternative agents. If using AZA drastically reduce dose to 10% of target and only give thrice weekly

For non-malignant conditions consider alternative non-thiopurine immunosuppressant therapy

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12
Q

What are enzymes of Drug metabolism?

A

Phase 1 (oxidative) – SER

  • CYP 1A2, CYP2B, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4,NADPH-quinone oxidoreductase

Phase 2 (conjugative) - cytosol

  • Glutathione S-transferase, N-acetyltransferase, UDP-glucuronosyltransferase, Sulphotransferases
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13
Q

What are cytochrome P450 enzymes?

A
  • Superfamily of enzymes that catalyze the metabolism of drugs and other substances
  • Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters
  • Genetic polymorphisms of CYPs may affect the enzyme catalytic activity
  • Association with both disease states and ADRs
  • 57 CYP genes and 58 pseudogenes arranged into 18 families and 43 subfamilies in man
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14
Q

What are types of Cytochrome P450 enzymes?

A

CYP2D6

  • Debrisoquine, Tricyclics, Antipsychotics, SSRI’s, Anti-arrhythmics, Anti-hypertensives, Morphine derivs

CYP2C19

  • Sedatives, Barbiturates, Tricyclics

CYP3A4

  • Tricyclics, Antipsychotics, SSRI’s, Sedatives

CYP1A2

  • Tricyclics, Antipsychotics, SSRI’s, Sedatives

CYP2C9

  • Antiepileptics, Anticoagulants
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15
Q

What are features ofWarfarin?

A
  • Narrow therapeutic window requires careful monitoring and strict compliance
  • Multiple clinically important drug interactions and erratic safety profile
  • 10-fold variability around dose, target INR and side-effects
  • Polymorphisms account for 30-50% of the variability in dosing
  • Very commonly prescribed for prophylaxis and treatment of thromboembolic disorders, atrial fibrillation and systemic embolism after MI
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16
Q
A
17
Q

What are is involved in Warfarin paharmacogenetic testing?

A
  • CYP2C9
  • Target of warfarin inhibition
  • Converts vit K epoxide to quinone (vit K recycling)
  • Deficiency (1639 G>A) means less warfarin target and smaller dose requirement
  • Reduction in hospitalisations when starting doses are informed by the patient genotypes VKORC1/CYP2CP (demonstrated in 2010)
18
Q

What are features of CYP2D6?

A

Most extensively characterised polymorphic drug-metabolising enzyme (20-25% of all clinically used drugs)

  • more than 75 allelic variants described
  • more than 15 encode an inactive enzyme or no enzyme at all
  • other alleles encode enzyme with reduced, normal or increased enzyme activity
19
Q

What are categories for phenotyping of metabolism of psychoactive drugs?

A
  • Poor metabolizers (PM)
  • Intermediate metabolizers (IM)
  • Extensive metabolizers (EM)
  • Ultrarapid metabolizers (UM)
20
Q

What is the KRAS Gene?

A
  • Important role in cell growth and tumour development
  • Gene can be mutated or normal in colorectal ca cells
  • If KRAS is mutated, then anti-EGFR therapies such as cetuximab are not effective and should not be used
  • KRAS gene mutations occur in about 40% of colorectal ca. patients
  • Patients diagnosed with metastatic colon ca. should be tested for KRAS mutation status to determine eligibility for anti-EGFR Rx
21
Q

What is Hercptin?

A
  • HER2 gene associated with 25-30% of early-stage breast cancers
  • Overexpression of HER2 is associated with enhanced tumour aggressiveness
  • Herceptin (Trastuzumab) is a monoclonal antibody against HER2
  • Only effective in patients with tumours that overexpress HER2
22
Q

What is the reason for slow uptake of Pharmacogenetics?

A
  • Lack of good phenotypic data or access to appropriate patient samples
  • Lack of participation by pharma
  • Lack of technological and methodological tools for PGx discovery
  • Lack of good evidence base for clinical use
  • Lack of interest/competence on part of clinicians to use information
  • Lack of timeliness of results
23
Q

What is Genome wide association studies?

A
  • Possible due to technology advances
  • GWAS are hypothesis-free
  • Many genetic variants associated with various drug responses and adverse effects e.g. Genetic risk variant for myopathy in patients treated with simvastatin