2005 Annual Scientific Meeting - CLICK FOR PROGRAMME

Pharmacodynamic Variability

 J. Vuyk, M.D. Ph.D., Associate Professor in Anaesthesia, Leiden University Medical Centre, Leiden, The Netherlands

j.vuyk@lumc.nl

The variability in the concentration-effect relationship between subjects is huge. To get an understanding of its magnitude, examples of the pharmacodynamic variability of midazolam, spinal bupivacaine and various opioids will be evaluated.

The origin in the pharmacodynamic variability lies in the varying response of a drug at its receptor. This response may be inherently different between subjects because of genetic factors or due to “classical” factors such as organ function, co-medication or underlying disease. [1.2]

Genetic factors may influence both the pharmacokinetics and dynamics of anaesthetic agents. Many genetic influences on opioid effects are due to changes in the pharmacokinetics. These are described as consequences of polymorphism that affect e.g. the function of membrane transporters, the bioavailability, CNS distribution and/or elimination of the opioid. Also polymorphism of enzyme systems may affect the clearance of anaesthetic agents in many ways.

Next to these pharmacogenetic changes in pharmacokinetics, pharmacogenetic changes exist that affect purely the pharmacodynamics of anaesthetic agents. Among the effector sites of the anaesthetic agents, the best studied receptor in this research area is the μ-opioid receptor. Various mutations are reported in the μ-opioid receptor related to the exonic organization of the OPRM1 gene at chromosome 6. Mutations in the OPRM1 gene result in amino-acid exchanges in the receptor protein and thereby in changes in receptor function. SNP (single nucleotide polymorphism) 118A>G results in an amino acid exchange from asparagine to aspartate at N40D mutant receptors. This mutation naturally exists in an allelic frequency of 10-19%. Carriers of this mutation need more alfentanil for postoperative pain relief, need more morphine for cancer pain relief,[3,4] exhibit a decreased miotic potency for M6G and morphine and an increased demand for M6G to produce analgesia. Lastly some suggest that the SNP 118A>G may be protective against opioid side effects. Not only has the μ-opioid receptor been the subject of pharmacogenetic studies. Single nucleotide polymorphism in the GABA-receptor system as coded on chromosome 4, have been associated with alcohol dependence, various types of epilepsy and a reduced effect of benzodiazepines.

Gender and ethnicity also are partially responsible for the PD-variability. Examples of these are the following. Men need more morphine for adequate postoperative pain relief, and morphine was noticed to displace the CO₂-response curve in contrast to men. Nalbuphine, has greater effect in women than in men. Also women have been noticed to emerge from propofol anaesthesia faster than men. [5,6] Compared to Caucasians, Northern American citizens experience less respiratory depression to morphine, and Caucasians do need more morphine for analgesia than do Africans or Asians. [7] Apart from PD-variability a varying nociception in between ethnic groups may also play a role in this.

Lastly also age and co-medication, the more classical factors regarding PK-PD variability, affect the response to anaesthetic agents. With age the propofol requirements decrease. [8] Also for remifentanil the EC₅₀ has been shown to decrease, and the blood-brain equilibration half-life to increase, with age. [9] Co medication strongly affects the pharmacodynamics of both hypnotic and analgesic agents. The interaction in between hypnotics generally is additive whereas that between hypnotics and analgesics appears to be synergistic. [10,11]

In conclusion, the pharmacodynamic variability of anaesthetic agents is huge. The main factors involved are pharmacogenetic variability as exhibited through single nucleotide polymorphism, effects of gender and ethnicity, as well as the more ”classical” factors as organ function, co-medication or underlying disease.

References

   1.   Lotsch J, Geisslinger G: Are mu-opioid receptor polymorphisms important for clinical opioid therapy? Trends in Molecular Medicine 2005; 11: 82-9

   2.   Lotsch J, Skarke C, Liefhold J, Geisslinger G: Genetic predictors of the clinical response to opioid analgesics - Clinical utility and future perspectives. Clinical Pharmacokinetics 2004; 43: 983-1013

   3.   Klepstad P, Dale O, Skorpen F, Borchgrevink PC, Kaasa S: Genetic variability and clinical efficacy of morphine. Acta Anaesthesiologica Scandinavica 2005; 49: 902-8

   4.   Klepstad P, Rakvag TT, Kaasa S, Holthe M, Dale O, Borchgrevink PC, Baar C, Vikan T, Krokan HE, Skorpen F: The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiologica Scandinavica 2004; 48: 1232-9

   5.   Gan TJ, Glass PS, Sigl J, Sebel P, Payne F, Rosow C, Embree P: Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999; 90: 1283-7

   6.   Hoymork SC, Raeder J, Grimsmo B, Steen PA: Bispectral index, serum drug concentrations and emergence associated with individually adjusted target-controlled infusions of remifentanil and propofol for laparoscopic surgery. British Journal of Anaesthesia 2003; 91: 773-80

   7.   Dahmani S, Dupont H, Mantz J, Desmonts JM, Keita H: Predictive factors of early morphine requirements in the post-anaesthesia care unit (PACU). British Journal of Anaesthesia 2001; 87: 385-9

   8.   Schnider TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB, Youngs EJ: The influence of age on propofol pharmacodynamics. Anesthesiology 1999; 90: 1502-16

   9.   Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL, Billard V, Hoke JF, Moore KH, Hermann DJ, Muir KT, Mandema JW, Shafer SL: Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997; 86: 10-23

  10.   Vuyk J, Mertens MJ, Olofsen E, Burm AG, Bovill JG: Propofol anesthesia and rational opioid selection: determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology 1997; 87: 1549-62

  11.   Vuyk J: Clinical interpretation of pharmacokinetic and pharmacodynamic propofol- opioid interactions. Acta Anaesthesiol.Belg. 2001; 52: 445-51