Transcript 510-08Pgenetics - dan

Pharmacogenetics
• Definitions
– Pharmacogenetics: single gene differences among
population groups and the effects on pharmacodynamics.
– Pharmacegenomics: genome-wide variations in DNA
sequences responsible for pharmacodynamic differences.
– In practice, these two terms are used interchangeably.
Pharmacogenetics
• Human genome comprised of approximately
30,000 genes from a total of 3 billion base
pairs.
• Different base-pair combinations result in
different proteins produced.
• Single base mutation can alter a produced
protein (enzyme) significantly.
• Result is that different population groups
have somewhat different proteins and
enzymes.
Pharmacogenetics
• Some population groups may metabolize
some compounds very rapidly, whereas
another group may metabolize the same
compound slowly. This can lead to overdose
or underdose situations.
• Understanding important pharmacogenetic
differences among populations allows better
drug and/or dosage choices for a particular
need.
Pharmacogenetics
• Examples:
– Multidrug Resistance Gene can cause differences in
absorption of some drugs (digoxin) by altering carrier
proteins or barrier compounds in the GI tract.
– 5-hydroxytryptamine transporter polymorphisms can
affect the neuronal reuptake of serotonin, an important
neurotransmitter.
– Plasma cholinesterase, which readily breaks down
succinylcholine, tetracaine, mivacurium, etc., is seen in
some individuals to have reduced activity, which can
cause increased duration of these compounds.
Pharmacogenetics
• Examples:
– Many different CYP genes identified. Results in
different metabolic rates of some drugs by individuals.
• CYP2D6 shows widest known differences, since it is responsible
for approximately 25% of all drug metabolism, including
analgesics, neuroleptics, antiarrhythmics, amide-type LA’s, beta
blockers, TCA’s, and antiemetics.
• CYP2C9 responsible for metabolism of warfarin, phenytoin,
NSAIDS
• NAT responsible for metabolism of Isoniazid (INH),
sulfonamides, procainamide
• NAT polymorphisms show fast (Asian) and slow (European)
types.
Pharmacogenetics
• Ethnicity
– While obvious phenotypic differences exist among
some ethnic groups, it is impossible to tell a persons
complete genetic background ‘on-sight’.
– Due to recent (last 100 years) world-wide population
mixing, different genes are mixing in the overall
population, making it almost impossible to be sure of any
ethnically-carried genetic differences.
Pharmacogenetics
• Sex
– Several differences in drug metabolism rates have been
identified between males and females:
• Females clear drugs oxidized by CYP3A4 40% faster than
males.
• Many conjugation (Phase II) metabolic reactions occur at a
faster rate in males than females.
• Females also demonstrated to have lower pain tolerance,
greater opioid sensitivity, and higher risk of Halothane toxicity than
males.
• Females awaken 50% faster from propofol/alfentanil/nitrous
oxide anesthesia than men, and may require greater doses to
reach proper anesthesia levels.
Pharmacogenetics
• Practical Considerations
– With so many defined differences, why has
pharmacogenetics not become more important in practice
of anesthesia?
• Requires genetic testing, which concerns people.
• Costs and time of screening.
– Many of the 3% of untoward outcomes of anesthesia
are believed to be attributed to pharmacogenetic
differences in the population, and could be alleviated.
– Changes are occuring, and will slowly be implemented.