Pharmacogenetics and Implications for Drug Action Flashcards
Define genes
Unit of information encoding a specific trait
Define inheritance.
Transmission of traits from parent to offspring.
Define traits.
Personal characteristics, e.g. eye colour
Define phenotype.
Physical manifestation of genetic information, e.g. height, weight, drug target levels
Define genotype
Actual gene expression or gene variant of individual
Define pharmacogenetics
- The study of the genetic basis for the difference between individuals in
response to drugs - The study of candidate genes that may influence drug effects and metabolism
Define pharmacogenomics.
- Study of all genes (and their expression) in the genome that may influence drug effects and metabolism [Non-hypothesis based]
- Use of population genetic information for drug research, design and development
- Clinical management of drug therapy (drug dosing and drug choice)
- May be used to predict how a patient may respond to a drug, with the aid of a genetic test
Describe genetic variation.
- Polymorphism; various types = SNPs (single nucleotide polymorphisms) + repetitive DNA sequences
- Must be functional - alter the expression levels or conformation of a drug-related protein
What does the outcome of genetic variation depend on?
- Where in the genome the change occurs
- Exact nature of the change
Describe SNPs in the coding region of a gene.
SNP results in alteration of the amino acid sequence of protein
* arginine (Arg) substituted for glycine (Gly)
* Distinct protein structures could result in phenotypic differences between the subjects, such as variation in response to medication.
Why is pharmacogenetics important to pharmacy?
- Most commonly used drugs will only be fully effective in around 45% of patients with the same disease.
- Proportion of patients will suffer adverse effects due to genetics
- Adverse drug reactions major cause of death worldwide
- Severe adverse effects have lead to the withdrawal of blockbuster drugs
- Bringing a new drug to market is estimated to cost as much as £800M.
Being able to predict a population’s response to a drug would be
invaluable to the pharmaceutical industry.
What are the different stages at which genetic variation can affect a patient’s response to a drug?
- Metabolism - two phases of drug metabolism; phase 1 - e.g. cytochrome P450 enzymes and phase 2 - enzymes controlling drug excretion
- Target response - process or pathway targeted responds differently
- Catabolism and excretion - individuals differ in the rate at which they clear the active drug, can lead to adverse drug reactions e.g. TMPT
Define pharmacokinetics.
Study of availability of therapeutic in body - absorption/excretion, metabolism and distribution
Define pharmacodynamics.
Study of drug and target interactions - receptors, transporters/channels and enzymes
Describe the link between codeine and cytochrome P450 CYP2D6.
- Codeine commonly used
opioid - Codeine is a prodrug
- Must be metabolised into
morphine for activity - Cytochrome P450 2D6 is
metabolising enzyme in liver - 7% of Caucasians are missing
one copy of the Cytochrome
P450 CYP2D6 gene - codeine doesn’t work
effectively in these people
Describe the effect of metabolic rate on drug dose.
POOR METABOLISER PHENOTYPE
Prodrug - needs metabolism to work - poor efficacy so possible accumulation of prodrug
Active drug - inactivated by metabolism - good efficacy - accumulation of active drug can produce adverse reactions - may need lower dose
ULTRA-RAPID METABOLISER PHENOTYPE
Prodrug - good efficacy, rapid effect
Active drug - poor efficacy - need greater dose or slow release formulation
Describe CYP 450 and metabolic of TCAs.
- Main rate limiting step in TCA metabolism is mediated by CYP2D6 isoenzyme
- CYP2D6 and CYP2C19 associated with increased side effects with several antidepressants
Describe pharmocogenetics of warfarin
- Most widely prescribed oral anticoagulant drug worldwide
- Activity is monitored by a coagulation test to ensure an adequate yet safe dose is taken
- Serious adverse reactions still occur:
- levels are too high – haemorrhage
- levels are too low - thromobosis or embolism
- Warfarin is mix of S - and R-warfarin – both isoforms are active
- S form (3-5 x more potent) – catalysed by mainly CYP2C9
- R form - catalysed by mainly by CYP1A2 and CYP3A4
What are the 2 common CYP2C9 polymorphisms associated with?
- Decreased CYP2C9 activity
Describe thiopurine methyltransferase SNP
- TPMT catalyses the S-methylation of thiopurine drugs - Immunosuppressants used to treat leukaemia, IBS and organ transplantation
- Thiopurines have ‘narrow therapeutic index‘; Individuals deficient in TPMT activity, thiopurine metabolism proceeds producing active thiopurine which is myelotoxic.
Describe azathioprine metabolism.
- Azathioprine converted into its biologically active form, 6-mercaptopurine,
- 6-mercaptopurine converted into its inactive forms, by xanthine oxidase and
TPMT. - The primary mechanism of action of azathioprine and 6-
mercatopurine is through 6-thioguanine nucleotides, which are incorporated
into nucleic acids and are cytotoxic.
State the current impact of pharmacogenetics.
- Seen as future of current medicine – Personalised Medicine
- Adopted widely by pharmaceutical industry in drug discovery and
development – new drugs and old - Significant investment by public and private funding, both in therapeutic
implications and diagnostic methodology - Pharmacogenetics testing is not routinely used currently in clinical practice
- done “as needed” preventing usefulness for initial dosing
- Many drugs, many genes, many studies result in information overload for
the provider
State the ethical implications of pharmacogenetics.
- Do people want to know? ”When will I develop diabetes?”
- Will treatment be appropriate? Over-/Under- dosing?
- How informed does pharmacist need to be?
- Use of genetic information by insurers, employers…
- Who should have access to personal genetic information?
- Privacy and confidentiality.
Who owns and controls genetic information? - Stigmatisation.
How does personal genetic information affect an individual and
society’s perceptions of that individual?
