GEN: Genetics and therapeutic response

Question 1

what is the most common adverse drug reaction?

Answer 1

gastrointestinal bleeding

Question 2

what are some drugs with possible severe reactions?

Answer 2

aspirin, diuretics, warfarin, non-steroidal anti-inflammatories

Question 3

what is pharmacogenetics?

Answer 3

individual variation in the handling of drugs in the body according to genetically determined factors

Question 4

what is the protocol for Butyrylcholinesterase BCHE warnings?

Answer 4

phenotype/genotype characterises patients ⇒ warning cards issued when BCHE activity is low ⇒ familial cascade testing done in at risk family members but testing is done AFTER toxicity has occurred

Question 5

Butyrylcholinesterase BCHE variants

Answer 5

A (atypical), K (Kalow), J, S (silent)

Question 6

what are the aims of pharmacogenetic testing?

Answer 6

• patient benefit - reduced morbidity + mortality
• optimised use of proven first line therapies
• cost saving to NHS by reducing adverse drug reactions and hence hospital admissions

Question 6

what muscle relaxant is used for short term rapid skeletal muscle paralysis?

Answer 6

succinylcholine

Question 7

why is pharmacogenetics important?

Answer 7

ensures maximum clinical benefit of any drug and least risk of toxicity

Question 8

when is the normal genetic polymorphism revealed?

Answer 8

only when there is a drug challenge

Question 9

what are some pharmacogenetic variation types?

Answer 9

• genetic polymorphisms
• coding region SNPs and indels changing aa sequence
• variants affecting splicing - exon skipping/new exons
• repeat variation in regulatory elements
• gene duplications + deletions
• multiple rare variants within a single gene
• marks in disequilibrium with causative variant

Question 10

is ibuprofen a cause of serious adverse reactions?

Answer 10

yes

Question 11

do you see more patients with or without cytochrome p450 than without?

Answer 11

with than without

Question 12

what can CYP2C9*3 genotyping do?

Answer 12

identify subgroups of persons who are at increased risk of gastroduodenal bleeding when treated with NSAIDs with 2C9 polymorphisms

Question 13

what is warfarin?

Answer 13

anticoagulant used for thrombosis prevention

vitamin k epoxide reductase subunit 1 VKORC1 polymorphisms

Question 14

what is allopurinol?

Answer 14

gout treatment

active metabolite = oxypurinol, potent xanthine oxidase inhibitor preventing uric acid formation

Question 15

what is allopurinols toxicity mediated by

Answer 15

HLA-B*5801

Question 16

what can be used instead of allopurinol?

Answer 16

febuxostat

Question 17

what makes a good pharmacogenetic test?

Answer 17

• replication
• marker has large effect/high penetrance but not explain all toxicity
• clear patient benefit by reducing toxicity or improving efficacy
• testing should not delay therapy
• testing must be cost effective
• predictive not prognostic: alternate therapies or therapeutic strategies must be available

Question 18

what are inflammatory bowel diseases IBD?

Answer 18

ulcerative colitis and crohns disease

Question 19

what is azathioprine?

Answer 19

thiopurine drug analogue for IBD

Question 20

why is azathioprine called a “steroid sparing agent”?

Answer 20

has optimal Rx

Question 21

what does TPMT explain?

Answer 21

subset of toxicities - carriers are highly likely to experience toxicity - variant have high penetrance

Question 22

what is 5-fluorouracil?

Answer 22

fluoropyrimidine drug - first line solid tumour treatment (colorectal + breast cancers)

Question 23

what is the cause of 5FU toxicity?

Answer 23

dihydropyrimidine dehydrogenase deficiency DPD

Question 24

what percentage of 5FU is degraded by DPD?

Answer 24

80-90% ⇒ small tent in DPD activity causes large change in 5FU blood levels

Question 25

what happens to nondegraded 5FU?

Answer 25

converted to fluorodeoxy UMP which is a potent inhibitor of thymidylate synthetase by folate binding

Question 26

what type of disorder is complete DPD deficiency?

Answer 26

rare metabolic disorder

Question 27

what is DPD deficiency characterised by?

Answer 27

increased thymine and uracil in urine

Question 28

where does pharmacogenetic direct dosing advice come from?

Answer 28

clinical pharmacogenetics implementation consortium CPIC

Question 29

what is an example of an alternative therapy?

Answer 29

thymidylate synthase raltitrexed