Pharmacogenomics in drug development - WIP

Question 1

Describe randomised controlled trials

Answer 1

Often carried out for a relatively short period of time, whereas in clinical practice the treatment will be used in a much greater variety of patients

There is a presumption that that in general what is shown in an RCT can be extrapolated to the wider population but this can be harmful due to what they miss

Question 2

What are some patient specific factors?

Answer 2

Drug interactions, age, behavior, stress, renal and liver function, immunological function, disease or infection, exercise, lactation or pregnancy, sex, physchological status

Question 3

Describe different common polymorphisms

Answer 3

Single nucleotide (SNPs) - only a single changed nucleotide in an allele, can occur in noncoding parts of the gene so would not affect the protein product

Short tandem repeat - short repeated DNA sequences in a line that involve repetitive units of 1-6 base pairs

gene deletion

copy number variant - large (thousands of base pairs) duplications or deletions

Question 4

Describe how Transport/carrier proteins are involved in drug action

Answer 4

Pharmacodynamics

Pharmacokinetics

Question 5

Describe how enzymes are involved in drug action

Answer 5

Pharmacodynamics

Pharmacokinetics

Question 6

Describe how receptors are involved in drug action

Answer 6

Pharmacodynamics

Question 7

Describe how ion channels are involved in drug action

Answer 7

Pharmacodynamics

Question 8

Describe how the HLA complex is involved in drug action

Question 9

Describe how disease pathogenesis is involved in drug action

Question 10

Describe Codeine and pharmacogenomics

Answer 10

An opioid analgesic, targeting opioid receptors in the CNS, however opioid receptors in the gastrointestinal system is also affected. Used for mild to moderate pain.

Is a schedule-II controlled substance with a risk of misuse and abuse

Codeine is a prodrug that only weakly binds to the mu opioid receptor, conversion to morphine increases the binding affinity by 200x.

Codeine is a prodrug metabolised in the liver into morphine (5-15%, most is converted into inactive metabolites) by CYP2D6. Most CYP2D6 alleles can produce either a non-functioning enzyme or an enzyme with decreased activity that can result in decreased pain relief. 1-2% of patients can carry multiple copies of CYP2D6 gene and can metabolize codeine more rapidly and completely, which may lead to morphine overdose or addiction