Pharmacogenetics

Question 1

Define pharmacogenetics (3)

Answer 1

• The study of how an individual’s genetic make-up affects drug responses
• Pharmaco (relating to drugs)
• Genetics (study of all our genes)

Question 2

Define individualised medicine (5)

Answer 2

• Also called personalised or precision medicine
• Medical decisions and treatments tailored to an individual
• One component involves identification of disease ‘biomarkers’ that can be targeted e.g., HER2+ breast cancer, development of drugs that target HER2
• Also identifies specific disease targets, also need to consider how an individual responds to specific drug treatments
• Drug responses depend upon the genetic make-up of an individual

Question 3

What is pharmacokinetic variation? (1)

Answer 3

• Genetic variation affecting drug metabolism and transport

Question 4

Succinylcholine aka SCC (PK Variation) (4)

Answer 4

• Neuromuscular blocker used in surgery, fast acting but rapidly metabolised
• Metabolised by butyrylcholinesterase (BCHE)
• BCHE deficiency = prolonged SCC action, leads to paralysis and respiratory failure
• 4% Caucasians are heterozygous for BCHE allele, enzyme’s affinity and/or quantity is altered, prolonged SCC response

Question 5

Alcohol Metabolism ADH2 (PK Variation) (4)

Answer 5

• More active enzyme variant than ADH – contains a variant beta 2 subunit instead of usual beta 1 subunit
• Found more frequently among Japanese and Chinese populations than Caucasians
• Ethanol more quickly metabolised to toxic acetaldehyde
• Lower rates of alcoholism

Question 6

Nortriptyline TCA (PK Variation) (3)

Answer 6

• Inactivated by CYP2D6, metabolism varies widely with CYP2D6 genotype
• CYP2D6 Poor metabolisers have high plasma levels of nortriptyline, require much lower daily dose
• CYP2D6 Ultra metabolisers have low plasma levels of nortriptyline, require much higher daily dose

Question 7

What is pharmacodynamic variation? (1)

Answer 7

• Genetic variation in drug target or associated component of signalling pathway

Question 8

Warfarin Target - VKORC1 (PD Variation) (4)

Answer 8

• VKORC1 is a polymorphic gene, dose requirement might be 2-fold difference
• Two common Vit K Epoxide Reductase Haplotypes: A and B
• Haplotype A (Variants 1 and 2): Linked with Lower doses of Warfarin – present in 37% of Caucasians
• Haplotype B (Variants 7, 8 & 9): Linked with Higher doses of Warfarin – present in 58% of Caucasians

Question 9

Ryanodine Receptor (PD Variation) (4)

Answer 9

• Involved in the release of calcium ions and muscle contraction
• Defects in receptor are caused by halogenated anaesthetics and succinylcholine in those with RYR mutations, can cause malignant hyperthermia
• Mutations cause excessive release of calcium ions when given anaesthetics, permanent muscle contraction, also increased metabolic activity and increased generation of heat
• Defect is autosomal dominant – 1:12,000 incidence

Question 10

Why is it important to consider pharmacogenetics in drug design? (3)

Answer 10

• Offer the potential to target medicines more effectively, improving patient outcomes, reducing adverse drug reactions
• Polymorphisms in genes that code for drug-metabolising enzymes, drug transporters, drug receptors, and ion channels can affect an individual’s risk of having an adverse drug reaction or alter the efficacy of that drug
• These genetic polymorphisms of drug metabolism produce phenotypes of “poor metabolisers” or “ultra-rapid metabolisers” of numerous drugs