pharmacogenetics Flashcards
pharmacogenetics
– ‘clinically important hereditary
variation in response to drugs’
Vogel 1959
– The study of how people respond
differently to medicines due to
their genetic inheritance
• 2.7 million Single Nucleotide
Polymorphisms (SNPs) identified
• 26000 - 39000 within coding regions
in man
• Several SNPs affect the metabolism
(and therefore the pharmacokinetics)
of Medicines
pharmacogenomics
The science of increasing the
effectiveness of drugs and
minimizing their side effects by
matching drugs to people
according to their genetic makeup
bespoke prescibing
Applying
general information on efficacy and
safety into specific action for an
individual patient
cyto and subtypes
cyp2c9
• Substrates include S-warfarin, phenytoin
diphenylhydantoin), and THC (cannabis)
• Induced by rifampicin and other inducers
• Inhibitors include the sulphonamides (e.g.
sulphinpyrazone and sulphaphenazole)
clopidogrel
metaolized to active drug by cyp2c19
Metabolism inhibited by omeprazole,
lansoprazole and rapebrazole
cyp2d6
• Defective N - oxidation of
Sparteine in man
• Polymorphic hydroxylation of
debrisoquine in man
cyp2d6 ad perhexilene
•Perhexilene very effective anti-anginal and
vasodilator agent (for heart failure)
• Detoxicated by oxidation via CYP 2D6
• Poor metaboliser phenotype prone to
peripheral neuropathy and ? hepatotoxicity
• Withdrawn from UK in 1985 but still available
on a named-patient basis in some countries,
and used in selected patients in Cardiff, with
close therapeutic drug monitoring
AZATHIOPRINE-INDUCED PANCYTOPENIA IN
A PATIENT WITH POMPHOLYX AND
DEFICIENCY OF ERYTHROCYTE THIOPURINE
METHYLTRANSFERASE
• 55 year-old man with itchy
blistering reaction on both
soles not responsive to
topical steroids
• Responded to
azathioprine
• Pancytopenia at 10 weeks
recovering after a further
3 months
• TPMT activity showed
marked deficiency
metabolism of azo
suxamethonium
• Suxamethonium metabolised in plasma by a non-specific esterase
pseudocholinesterase. Metabolism normally rapid and, the so tha
tneuromuscular blockade lasts only minutes
• Polymorphism of pseudocholinesterase means it does not metabolise
the drug as rapidly, resulting in prolonged neuromuscular blockade
• Numerous abnormalities of pseudocholinesterase, each inherited in
autosomal recessive fashion. Prevalence of the homozygous poor
metabolism phenotype is only 1 in 3000 (effects may last 8 hours)
• In some individuals there is a two- or threefold increase in the
concentration of pseudocholinesterase in the plasma (C5 variant), with
resistance to the effects of succinylcholine. The prevalence may be as
high as 1 in 1000, commoner than the deficiency state
drugs and met
med sand morph enzymes
hiv
• RESPONSE TO TREATMENT
– P-Glycoprotein
– CYP2D6
• TREATMENT TOXICITY
– SREBP-1C
• Hyperlipidaemia
– Haplotype HLA-B*5701, DR7, DQ3
• Hypersensitivity to abacavir (5% population)
pharmacogenetics
carbamazepine
May act by inhibiting calcium influx through the NMDA and
GABAB
receptors, and by producing sodium channel-mediated
membrane stabilization and potentiation of α2 adrenoceptors
Patients with ancestry from areas in which HLA-B*1502 is present should be screened for the HLAB*1502 allele before starting treatment with carbamazepine. If they test positive, carbamazepine should
not be started unless the expected benefit clearly outweighs the increased risk of serious skin
reactions
biomarkers
• Risk biomarker:
– identify predisposition to a particular disease
BRCA1 & BRCA2
• Prognostic biomarkers:
– Associated with disease outcome without treatment or with
standard (non-targeted) treatment
ER, HER2, PR & EGFR
• Predictive biomarkers:
– Prospectively identifies favourable clinical outcomes from using
a targeted treatment.
– Intermediate endpoint (surrogate) biomarkers: attempt to
replace clinical end-points to expedite regulatory drug approval
HER2 and trastuzumab R
