L71: Pharmacogenetics And Adverse Drug Reactions

Question 1

Adverse drugs reactions

Answer 1

Harmful reactions at a normal dose
- Type A: due to pharmacological activity of drug
- Type B: drug-induced hypersensitivity (unrelated to action of drug)
—> lack of dose-dependency
—> delay onset
—> unpredictability
—> host sensitivity
- Idiosyncratic

Question 2

Pharmacogenetics vs Pharmacogenomics

Answer 2

Pharmacogenetics: inherited difference in drug metabolism and response
Pharmacogenomics: general study of all genes that determine drug behaviour

Question 3

Mutation vs Genetic polymorphism

Answer 3

Mutation:
- difference in DNA code in < 1% of population
- associated with rare diseases

Genetic polymorphism:
- Genetic variations occurred at a frequency of >= 1% in a population
- less likely to be main cause of disease

Question 4

Consequence of genetic polymorphism

Answer 4

1. Different amino acid / stop codon
2. Change in protein function / quantity
3. Change in mRNA stability
4. No consequence

Question 5

Haplotype

Answer 5

A set of closely-linked SNP (genetic markers) on one chromosome
—> not separable by recombination / inherit together

Question 6

Candidate gene studies vs Genome-wide studies (rapidly scanning marker across complete set of DNA to find variations associated with a disease)

Answer 6

Increases biological plausibility, but cannot identify novel gene
Identification of genes not known before

Reduces possibility of false discovery
More significant risk of false discovery

Reduced expense if candidate gene found to be relevant to outcome
Increased expense following up on large amounts of positive findings

Moderate sample size is enough
Large sample size is needed as need to make large number of comparisons

Question 7

Polymorphism in CYP450

Answer 7

Affect inactivation of drugs (safety) / activation of prodrug (efficacy)

Ultrarapid metaboliser: more than 2 active genes on same allele / increased expression of single gene
Extensive metaboliser: 2 functional gene
Intermediate metaboliser: 1 defective gene / 2 partially defective gene
Poor metaboliser: 2 defective genes

Question 8

CYP450 2D6 polymorphism: Codeine

Answer 8

Metabolise 25% of drugs
UM: multiple copies of 2D6 gene
PM: autosomal recessive: decreased 2D6 activity / no activity

Phenotype using debrisoquin (probe drug) —> measure urine level / plasma level
PM: high plasma / low urine level of debrisoquin

Codeine (prodrug): PM: resistant to analgesic effect

Question 9

2C19: PPI

Answer 9

PPI metabolism:
RM: cure rates of stomach ulcer very low

Question 10

2C9: Warfarin

Answer 10

Warfarin metabolism
* 1 (wild type): normal metabolism
* 2: reduce metabolism by 30% —> need lower dose
* 3: reduce metabolism by 90% —> need lower dose

Question 11

Vitamin K epoxide reductase complex subunit 1 (VKORC1): Warfarin

Answer 11

Vitamin K cycle:
- Vitamin K quinol (Hydroquinone) is oxidised —> Vitamin K epoxide, in the oxidation process activate clotting factors
- Vitamin K epoxide is reduced —> Vitamin K quinone —> Vitamin K quinol

Warfarin inhibit vitamin K epoxide reductase (VKORC1) —> prevent Vitamin K epoxide back to quinol —> decrease availability of Vitamin K quinol (Reduced vitamin K)

• 1639 SNP: G allele replace by A allele (less VKORC1) —> lower dose needed

Question 12

Thiopurine methyltransferase (TPMT)

Answer 12

Metabolise thiopurines (Azathioprine, 6-mercaptopurine)

Decreased TPMT activity —> myelosuppression

Homozygous TPMT*3A —> great increased risk of myelosuppression —> reduce dose by 10-15 fold

Question 13

Hepatitis C

Answer 13

Hep C virus have different mutations exist
—> different response to Interferon-alpha-2b + ribavirin

Question 14

Succinylcholine

Answer 14

Genetic polymorphism of butyrylcholinesterase will affect metabolism of succinylcholine