GEN: Genetics and therapeutic response Flashcards
what is the most common adverse drug reaction?
gastrointestinal bleeding
what are some drugs with possible severe reactions?
aspirin, diuretics, warfarin, non-steroidal anti-inflammatories
what is pharmacogenetics?
individual variation in the handling of drugs in the body according to genetically determined factors
what is the protocol for Butyrylcholinesterase BCHE warnings?
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
Butyrylcholinesterase BCHE variants
A (atypical), K (Kalow), J, S (silent)
what are the aims of pharmacogenetic testing?
- 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
what muscle relaxant is used for short term rapid skeletal muscle paralysis?
succinylcholine
why is pharmacogenetics important?
ensures maximum clinical benefit of any drug and least risk of toxicity
when is the normal genetic polymorphism revealed?
only when there is a drug challenge
what are some pharmacogenetic variation types?
- 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
is ibuprofen a cause of serious adverse reactions?
yes
do you see more patients with or without cytochrome p450 than without?
with than without
what can CYP2C9*3 genotyping do?
identify subgroups of persons who are at increased risk of gastroduodenal bleeding when treated with NSAIDs with 2C9 polymorphisms
what is warfarin?
anticoagulant used for thrombosis prevention
vitamin k epoxide reductase subunit 1 VKORC1 polymorphisms
what is allopurinol?
gout treatment
active metabolite = oxypurinol, potent xanthine oxidase inhibitor preventing uric acid formation
what is allopurinols toxicity mediated by
HLA-B*5801
what can be used instead of allopurinol?
febuxostat
what makes a good pharmacogenetic test?
- 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
what are inflammatory bowel diseases IBD?
ulcerative colitis and crohns disease
what is azathioprine?
thiopurine drug analogue for IBD
why is azathioprine called a “steroid sparing agent”?
has optimal Rx
what does TPMT explain?
subset of toxicities - carriers are highly likely to experience toxicity - variant have high penetrance
what is 5-fluorouracil?
fluoropyrimidine drug - first line solid tumour treatment (colorectal + breast cancers)
what is the cause of 5FU toxicity?
dihydropyrimidine dehydrogenase deficiency DPD
what percentage of 5FU is degraded by DPD?
80-90% ⇒ small tent in DPD activity causes large change in 5FU blood levels
what happens to nondegraded 5FU?
converted to fluorodeoxy UMP which is a potent inhibitor of thymidylate synthetase by folate binding
what type of disorder is complete DPD deficiency?
rare metabolic disorder
what is DPD deficiency characterised by?
increased thymine and uracil in urine
where does pharmacogenetic direct dosing advice come from?
clinical pharmacogenetics implementation consortium CPIC
what is an example of an alternative therapy?
thymidylate synthase raltitrexed
