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.