2006 Annual Scientific Meeting - CLICK FOR PROGRAMME

Pharmacogenetics for Infusionists

Dr Sue Hill MA PhD FRCA, Consultant Neuroanaesthetist, Southampton General Hospital

The new science of pharmacogenomics describes how the entire genome determines drug response, whereas pharmacogenetics describes the influence of a single gene. With the advent of the human genome project’s successful sequencing of DNA there has been an exponential growth in research into predicting individual response to drug therapy with a view to personal prescribing. Several reviews have appeared summarizing potential implications for anaesthetists in general. For those who use TIVA, pharmacogenetic differences are potentially of greater importance than for volatile techniques since metabolism plays a far greater role in drug elimination. This presentation will describe pharmacokinetic and gender influences on drug action that are of interest to anaesthetists and intensivists who use drugs by infusion, with an emphasis on opioids.

Pharmacokinetics & genetics:

Phase I metabolism

Activation: Codeine is metabolised by CYP2D6 to morphine, its major active analgesic component. CYP 2D6 demonstrates both polymorphism and gene duplication. There are three phenotypically distinct groups of patients: those homozygous for the wild type are normal metabolisers; some people carry multiple copies of the CYP2D6 gene and are ultrafast metabolisers; others are homo-or heterozygous for abnormal alleles, those homozygous for CYP2D6*3 phenotypically fail to respond to codeine.

Metabolism: Fentanyl is commonly (ab)used by infusion in the ICU. It is metabolised by CYP3A4 & 5 isoforms to norfentanyl. Post-mortem identification of homozygotes for CYP3A5*3 show these to be associated with higher fentanyl concentrations in cases of toxicity.

Phase II metabolism

Glucuronidation: UDP-glucoronosyltransferase involved in morphine glucuronidation to M-3-G and the active M-6-G also demonstrate polymorphism that influences both rate of metabolism and susceptibility of the enzyme to induction by barbiturates.

Pharmacodynamics & genetics: gender and receptor differences for opioids

There is little evidence that metabolism of morphine differs between men and women. However there is clear evidence for differences between analgesic effects of morphine in the different sexes. The efficacy of morphine is greater in women than in men, despite equivalent plasma levels, although onset/offset times are slower. Promoter polymorphisms of the m-opioid receptor appear to be associated with greater severity of side effects, but not with differences in analgesic potency. There is also a suggestion from MOR-knockout mice that analgesia induced by M-6-G and fentanyl occurs at a different receptor from that for morphine itself. If this translates into human analgesic response then genetic variation in the proportion of the different receptor-types may influence our choice of opioid.

Many steps govern the final response to a drug: pharmacokinetic factors determine access to and removal from the active site and pharmacodynamic factors determine the observed response. At each stage genetic products, such as transport proteins, receptor proteins and metabolic enzymes - each with potential inter-individual variation - contribute to the overall response to drug administration. With our increasing knowledge, the area of pharmaocogenomics is moving the advent of the implanted chip containing individual genetic information ever closer and the day of tailor-made drug prescription may well be dawning.

References

1.         Principles of pharmacogenetics - implications for the anaesthetist. Iohom, G.  Fitzgerald, D.  Cunningham, A J. British Journal of Anaesthesia.  93(3):440-50, 2004 Sep.

2.         Pharmacogenetics of anesthetic and analgesic agents. Palmer SN. Giesecke NM. Body SC. Shernan SK. Fox AA. Collard CD. Anesthesiology; 102(3):663-71, 2005 Mar.