Pharmacogenetics and Implications for Drug Action

Question 1

Define genes

Answer 1

Unit of information encoding a specific trait

Question 2

Define inheritance.

Answer 2

Transmission of traits from parent to offspring.

Question 3

Define traits.

Answer 3

Personal characteristics, e.g. eye colour

Question 4

Define phenotype.

Answer 4

Physical manifestation of genetic information, e.g. height, weight, drug target levels

Question 5

Define genotype

Answer 5

Actual gene expression or gene variant of individual

Question 6

Define pharmacogenetics

Answer 6

• 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

Question 7

Define pharmacogenomics.

Answer 7

• 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

Question 8

Describe genetic variation.

Answer 8

• Polymorphism; various types = SNPs (single nucleotide polymorphisms) + repetitive DNA sequences
• Must be functional - alter the expression levels or conformation of a drug-related protein

Question 9

What does the outcome of genetic variation depend on?

Answer 9

• Where in the genome the change occurs
• Exact nature of the change

Question 10

Describe SNPs in the coding region of a gene.

Answer 10

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.

Question 11

Why is pharmacogenetics important to pharmacy?

Answer 11

• 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.

Question 12

What are the different stages at which genetic variation can affect a patient’s response to a drug?

Answer 12

1. Metabolism - two phases of drug metabolism; phase 1 - e.g. cytochrome P450 enzymes and phase 2 - enzymes controlling drug excretion
2. Target response - process or pathway targeted responds differently
3. Catabolism and excretion - individuals differ in the rate at which they clear the active drug, can lead to adverse drug reactions e.g. TMPT

Question 13

Define pharmacokinetics.

Answer 13

Study of availability of therapeutic in body - absorption/excretion, metabolism and distribution

Question 14

Define pharmacodynamics.

Answer 14

Study of drug and target interactions - receptors, transporters/channels and enzymes

Question 15

Describe the link between codeine and cytochrome P450 CYP2D6.

Answer 15

• 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

Question 16

Describe the effect of metabolic rate on drug dose.

Answer 16

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

Question 17

Describe CYP 450 and metabolic of TCAs.

Answer 17

• Main rate limiting step in TCA metabolism is mediated by CYP2D6 isoenzyme
• CYP2D6 and CYP2C19 associated with increased side effects with several antidepressants

Question 18

Describe pharmocogenetics of warfarin

Answer 18

• 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

Question 19

What are the 2 common CYP2C9 polymorphisms associated with?

Answer 19

• Decreased CYP2C9 activity

Question 20

Describe thiopurine methyltransferase SNP

Answer 20

• 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.

Question 21

Describe azathioprine metabolism.

Answer 21

• 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.

Question 22

State the current impact of pharmacogenetics.

Answer 22

• 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

Question 23

State the ethical implications of pharmacogenetics.

Answer 23

• 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?