Pharmacogenomics Flashcards
people can have the same diagnosis and symptoms but
response to drugs differently
what are the 3 rights
need to provide the RIGHT treatment to the RIGHT patient at the RIGHT dose
pharmacogenomics
describes the interaction between drugs and the whole genome
pharmacogenetics (Vogel in 1959)
Study of genetically determined variations that are revealed solely by the effects of drugs
pharmacogenetics now
influence of genes on the efficacy and side effects of drugs
what does genetic variation effect
pharmacokinetics and pharmacodynamics and also cause idiosyncratic reactions
are introns or axons larger
introns (displayed as the same size in models - inaccurate)
what are the 3 types of structural variations?
copy number variation, inversion and translocation
what is copy number variation?
where there is an increase or decrease in the amount of DNA
•deletion: where an entire block of DNA is missing
• insertion: where a block of DNA is added in
• duplication: where there are additional copies of a section of DNA.
What is inversion?
when a chromosome breaks in two places and the resulting piece of DNA is reversed and reinserted back into the chromosome (the opposite way round).
what is translocation?
when genetic material is exchanged between two different chromosomes.
which is the most common type of genetic variation in the human genome
SNP
what is an SNP
change in a single nucleotide base
how often would an SNP occur
1/300 bases
what type of SNPs are there in non-coding regions?
spliced, promotor activity or and unknown/no change
what type of SNPs are there in coding regions?
synonymous - no change - same AA
non-synonomus - miscense and non-sense
what does HGVS stand for
human genome variation society
what do g, c and p stand for in HGVS stand for
g - genomic sequence
c - cDNA sequence (complementary DNA/RNA)
p - protein sequence (AA’s)
what do SNP cluster IDs do
all SNPs have a unique rs number - used be researchers to refer to them
what is the star allele nomenclature used in?
pharmacogenetics only
what star is used for the WT
1*
what do 2/3/4* represent
allele with altered fractionally which may lead to profiles of increased or reduced drug metabolism
one single star allele one can identify
not just a single variant, but even a group of variants.
consequences of genetic variation on proteins can be
No change
• No function
• Diminished function
• Altered/gain of function
estimated hospital patients that will have adverse drug reactions
15%
what helps to identify genetic profiles of patients who are more likely to suffer adverse events
PGx
Examples of drugs that can cause adverse events include
soniazid, Codeine Diclofenac, Statins, Warfarin, Carbamazepine
(anticonvulsant), Flucloxacillin etc
Adverse drug reactions can be
idosyncratic or caused by changes in the pharmacokinetics, pharmacodynamics of drug
what is abacavir and what is it used for?
a reverse transcriptase inhibitor which is used to treat HIV
% patients that show fatal hypersensitivity to abacavir?
5%
idiosyncratic reaction
Cannot relate to how it is metabolised in the body
does not occur in most patients at any dose and does not involve the known pharmacological properties of the drug
in 2002 which allele was found to have a strong association with abacavir hypersensitivity
HLA-B*57:01
where would you find whether you needed testing for a drug
on an information label
Pharmacokinetics
absorption, distribution, metabolism, excretion
what body does to the drug
pharmacodynamics
drug action and mechanism
what the drug does to the body
absorption
the process of a substance entering the blood circulation
distribution
the dispersion or dissemination of substances throughout the fluids and
tissues of the body
metabolism
the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites.
excretion
the removal of substances from the body
which part of pharmacokinetics is th focus for pharmacogenetics
metabolism
phase 1 metabolism
hydrolysis or most commonly oxidation. Oxidation by cytochrome P450 enzymes
phase 2 metabolism
conjugation - that is, the attachment of an ionised group to the drug - include glutathione, methyl, Sulfyl or acetyl groups.
CYP2D6 (Cytochrome P450 D6)
in phase 1 metabolism
Beta-blockers Tricyclic antidepressants Codeine metabolism
CYP2C9 (Cytochrome P450 D9)
oxidation i phase 1 metabolism of warfarin
NAT2 (N-acetyltransferase2)
acetylation in phase 2 of metabolism - isoniazid (Tuberculosis)
what are the types of metabolisers?
Ultra rapid metaboliser
• Extensive metaboliser
• Intermediate metaboliser
• Poor metaboliser
what are the 2 types of drugs?
Prodrugs– eg Codeine
• Active drugs – eg Warfarin
which enzyme metabolises codine
CYP2D6
CYP2D6 gene is
highly polymorphic, with more than 100 star (*) alleles described
why would pain relief in poor metabolisers of codine be inadequte
they don’t have the enzyme/enough to convert codine-morphine which is the active comound
what may ultra metabolisers of coding experience?
morphine overdose symptoms
what are thiopurine methyltransferases?
Cytoplasmic enzyme that methylates THIOPURINES to an inactive, non toxic form.
examples of thiopurine methyltransferases
- 6-mercaptopurine
– 6-thioguanine
– azothipurine
what are thiopurine methyltransferases used for?
treatment of inflammatory and autoimmune disease, leukaemia and to prevent rejection post organ transplant
what are the side effect of thiopurine methyltransferases?
- life threatening bone marrow suppression - neutropenia
- hepatotoxicity
- nausea and vomitting
- pancreatitis
what affect would you get if you ultrametaboliser of warfarin?
no effect - metabolise the active drug to quikcly
what % of the population has normal TPMT enzyme activity?
89%
what % of the population has low TPMT enzyme activity?
11%
what % of the population has undetectable TPMT enzyme activity?
0.3%
The TPMT*3A allele (low activity allele) is
bsent in the Chinese population, however its frequency in
Caucasians is approximately 4%. (Low activity)
genotype specific dosing can allow
similar (and non-toxic) levels to be achieved for a drug
what is recommended for dosing azothiopurine?
genotyping - DNA test
isn’t mandatory
when would you consider alternative medication to azothiopurine?
Homozygous for low activity variant – consider alternative medication or 10% of standard dose
what % of british people have low activity alleles for TPMT?
10%
Patients with undetectable TPMT activity are generally
not treated with these drugs
Those with low activity usually receive
a reduced dose
Normal enzyme levels have
standard dose
Genotyping in some circumstances…
Deficient TPMT activity
– Recent blood transfusion
– Previous severe reaction to thiopurine drugs
– Change in TPMT status on repeat testing
TMPT levels do not predict
all adverse reactions to thiopurines
Phenotype versus genotype - TPMT
Enzyme test (phenotype), can be affected by blood transfusions and other drugs – Genotype test – quick and easy but rare variants can be missed.
what do statins do?
reduce cholesterol levels
adverse affect to statin
1-5% of patients exposed experience skeletal muscle toxicity.
-Myalgias (pain)
• Myopathy (pain with evidence of muscle degradation)
• Rhabdomyolysis (severe muscle damage with acute kidney injury)
OATP1B1 transporter
facilitates the hepatic uptake of statins
encoded by the SLCO1B1 gene
what kind of genetic variation can effect drug targets?
enzymes, receptors and ion channels, and their associated pathways
what is malignant hyperthermia?
an autosomal dominant disorder of the skeletal muscle
Characterized by muscle rigidity and a hyper-metabolic state (high temperature)
• Can cause death if not treated promptly
what triggers malignant hyperthermia
volatile anaesthetics (e.g.halothane) and depolarizing muscle relaxants
what causes 50-70% of malignant hyperthermia?
mutation of the ryanodine receptor (type 1) (RYR1)
how would you test for malignant hyperthermia?
muscle biopsy
n-vitro contracture test (IVCT).
– Living muscle tissue is exposed to halothane and caffeine following a standard protocol
normal muscle v MH muscle
Normal muscle will relax when exposed to halothane whereas MH muscle will contract and this can be measured.
– MH muscle is more sensitive to caffeine and will contract at much lower concentrations than normal muscle.
MH genetic testing
available in leeds
Positive genetic test = no muscle biopsy • Safe anaesthesia
• No scar, no discomfort, cheaper test,
– Negative genetic test = muscle biopsy still required
what is neonatal diabetes
A form of diabetes that is diagnosed under the age of nine months (not an autoimmune condition)
• Some patients have neurological problems: – Developmental delay
– Epilepsy (<12 months)
how would you treat neonatal diabetes?
First line treatment is insulin, however in certain individuals sulphonylureas can be used
insulin is released through which receptor in response to
though the GLUT2 receptor in response to glucose
insulin secretnion
ATP generated causes KATP channel on the cell membrane to close
• Membrane depolarisation
• Ca2+ influx
• Insulin release through GLUT2 receptor
what causes neonatal diabetes?
a mutation in the Katp gene
what are the benefits of identifying Katp in NDM
95% of patients with Katp channel mutations can be treated with sulphonylureas
Glucose values fluctuate less as well as being lower
• Neurological function may improve
• Sulphonylureas = tablets
• Insulin =injection
what are the benefits of identifying Katp in NDM
95% of patients with Katp channel mutations can be treated with sulphonylureas
Glucose values fluctuate less as well as being lower
• Neurological function may improve
• Sulphonylureas = tablets
• Insulin =injection
what pedigree of disease is cystic fibrosis?
autosomal recessive
cystic fibrosis is fatal among
caucasian populations
CF is caused by a mutation in
CFTR gene on chromosome 7
what is the phenotype for CF?
malfunctioning epithelial ion channel - CF transmembrane conductance regulator protein
what does the CFTR usually do?
regulated the absorption and secretion of salt and water in various tissues
what do type 3 mutation in th CFTR gene/protein do? which drugs treat this?
impaired normal channel gating activity
vacaftor / Kalideco / VX-770 ameliorates the gating defect
Ivacaftor
Effective therapy for patients with type 3 CFTR mutations including the p.Gly551Asp mutation
In trials when compared with placebo:
– Ivacaftor significantly improved FEV1 by 10.6% over 48 weeks
– Subjects also were 55% less likely to have a pulmonary exacerbation
– gained more weight
what do Lumicaftor/Orkambi treat
cystic fibrosis
Effective therapies for patients bearing p.Phe508 mutation (type 2) would act to improve protein folding, channel gating and cell surface stability.
– Lumicaftor / VX-809 partially rescues processing defect
– Lumicaftor / Kalideco / VX-770 then can ameliorate the gating defec
