Skip to main content
SpringerLink
Log in

Pharmakogenetik

Klinische Bedeutung in der Anästhesiologie

Pharmacogenetics

Clinical relevance in anesthsiology

  • Leitthema
  • Published:
Der Anaesthesist Aims and scope Submit manuscript

Zusammenfassung

Hintergrund

Die Pharmakogenetik befasst sich mit dem Einfluss unterschiedlicher genetischer Ausprägungen bei Patienten und deren Wirkung auf die Pharmakokinetik und Pharmakodynamik von Arzneimitteln. Unterschiede in der Pharmakogenetik von Patienten können auch in der Anästhesiologie zu klinisch relevanten Veränderungen der Arzneimittelwirkung führen.

Ziel der Arbeit

Der vorliegende Beitrag informiert über die klinische Bedeutung der Pharmakogenetik in der Anästhesiologie. Er will Möglichkeiten, aber auch Probleme und Grenzen der pharmakogenetischen Diagnose und Therapie aufzeigen und erläutert das dabei verfolgte Ziel der individualisierten Medizin.

Material und Methode

In der vorliegenden Arbeit werden ausführlich für die Anästhesie relevante Veränderungen der Pharmakogenetik und deren klinische Bedeutung vorgestellt. Anhand aktueller Studienergebnisse wird ein Überblick über die wichtigsten anästhesiologischen Medikamente gegeben, in deren Stoffwechsel Polymorphismen eine Rolle spielen. Hierzu gehören Opioide, Muskelrelaxanzien, volatile Anästhetika, nichtsteroidale Antiphlogistika, Benzodiazepine, Antiemetika, kardiovaskuläre Medikamente sowie Thrombozytenaggregationshemmer, Antikoagulanzien und die sogenannten neuen oralen Antikoagulanzien. Als klassisches anästhesierelevantes Beispiel der dramatischen Interaktion zwischen einem Medikament und einem mutierten Rezeptor ist die Entstehung der malignen Hyperthermie zu nennen.

Ergebnisse

Genetische Veränderungen können zu erheblichen Modifikationen der Wirksamkeit von Medikamenten führen. Genetische Veränderungen des Opioidrezeptors und des Enzyms Zytochrom-P450(CYP)2D6 können in einer fehlenden Analgesie nach der Opioidgabe resultieren. Veränderungen der Plasmacholinesteraseaktivität gehen mit der verlängerten Wirksamkeit von Muskelrelaxanzien einher. Polymorphismen im Ryanodinrezeptor können zur Entwicklung der gefürchteten MH nach Applikation volatiler Anästhetika bzw. von Succinylcholin beitragen.

Schlussfolgerung

Die vorgestellten Studienergebnisse machen deutlich, dass auch heute schon Kenntnisse zur Pharmakogenetik in der modernen Narkoseführung nicht fehlen dürfen. In der Zukunft könnte dem Arzt eine Blutentnahme ermöglichen, pharmakogenomisch relevante Marker zu identifizieren und als Entscheidungshilfe dafür heranzuziehen, welches Medikament in welcher Dosis dem Kranken zu verschreiben ist, um das geringste Risiko von Nebenwirkungen mit der höchsten Effektivität der Wirksubstanz zu erzielen.

Abstract

Background

Pharmacogenetics deals with hereditary factors which influence the pharmacodynamics and pharmacokinetics of drugs leading to individual diverse reactions. Also in anesthesiology differences in the pharmacogenetics of patients can lead to relevant alterations in the pharmacodynamics of drugs.

Aim

This article provides a summary of polymorphisms relevant to commonly used anesthetic agents and the clinical relevance in patients treated with these compounds. It describes the possibilities, the problems and limits of pharmacogenetic diagnostics and therapy and explains how this follows the target of individualized medicine.

Material and methods

This article describes in detail the alterations in pharmacodynamics and pharmakokinetics relevant for anesthesia and their clinical significance. Based on the results of current studies, an overview of the most important drugs in anesthesiology with significant polymorphisms is given. These include opioids, muscle relaxants, volatile anesthetic agents, non-steroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, antiemetics and cardiovascular drugs as well as platelet aggregation inhibitors, anticoagulants and the so-called new oral anticoagulants.

Results

Genetic alterations can lead to substantial modifications in the effectiveness of drugs. Genetic alterations of opioid receptors and the enzyme cytochrome P450 (CYP) 2D6 can result in a failure of analgesia after administration of opioids. Alterations in plasma cholinesterase activity are associated with a prolonged effectiveness of muscle relaxants. Polymorphisms in ryanodine receptors can contribute to the development of the feared MH in patients after administration of volatile anesthetics or succinylcholine.

Conclusion

The study results presented here emphasize that these days knowledge on pharmacogenetics should not be missing in modern induction of anesthesia. In the future a blood sample could enable physicians to identify pharmacologically relevant markers. And these could guide the decision on the prescription of drugs and their appropriate dose, in order to achieve the lowest risk of side effects and the highest effectiveness of the active substance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1

Literatur

  1. Bönicke R, Reif W (1953) Enzymatische Inaktivierung von Isonicotinsäurehydrazid im menschlichen und tierischen Organismus. Arch Exper Pathol Pharmakol 220:321–333

    Google Scholar 

  2. Brandom B (2006) Genetics of malignant hyperthermia. Sci World J 6:1722–1730

    Article  CAS  Google Scholar 

  3. Cichon S, Haenisch B (2009) Klinische Pharmakologie. Vorlesungsskript WS09/19. Zugegriffen: 20. Feb. 2011

  4. Denborough MA, Forster JF, Lovell RR et al (1962) Anesthetic deaths in a family. Br J Anaesth 34:395–396

    Article  PubMed  CAS  Google Scholar 

  5. Eerenberg ES, Kamphuisen PW, Sijpkens MK et al (2011) Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124:1573–1579

    Article  PubMed  CAS  Google Scholar 

  6. Efferth T (2006) Pharmako- und Toxikogenetik. In: Efferth T (Hrsg) Molekulare Pharmakolgie und Toxikologie. Springer, Berlin Heidelberg New York Tokio, S 261–283

  7. European Medicines Agency (EMEA) (2013) European public assessment report: Pradaxa. http://www.ema.europa.eu. Zugegriffen: 27. Feb. 2013

  8. Francis CW (2008) New issues in oral anticoagulants. Am Soc Hematol Educ Program 259–265

  9. Hulot JS, Bura A, Villard E et al (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108:2244–2247

    Article  PubMed  CAS  Google Scholar 

  10. Iohom G, Fitzgerald D, Cunnigham AJ (2004) Principles of pharmacogenetics – implications for the anaesthesist. Br J Anesth 93:440–450

    Article  CAS  Google Scholar 

  11. Israel E (2000) The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 162:75–80

    Article  PubMed  CAS  Google Scholar 

  12. Johnson JA, Gong L, Whirl-Carrillo M et al (2011) Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 90:625–629

    Article  PubMed  CAS  Google Scholar 

  13. Jones M, McEwan P, Morgan CL et al (2005) Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 91:472–477

    Article  PubMed  CAS  Google Scholar 

  14. Kaiser R, Sezer O, Papies A et al (2002) Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 genotypes. J Clin Oncol 12:2805–2811

    Article  Google Scholar 

  15. Kaiser R, Tremblay PB, Sezer O et al (2004) Investigation of the association between 5-HT3A receptor gene polymorphisms and efficiency of antiemetic treatment with 5-HT3 receptor antagonists. Pharmacogenetics 14:271–278

    Article  PubMed  CAS  Google Scholar 

  16. Kalow W, Gunn DR (1957) The relation between dose of succinylcholine and duration of apnea in man. J Pharmacol Exp Ther 120:203–204

    PubMed  CAS  Google Scholar 

  17. Keith A, Candiotti DJ, Birnbach DA et al (2005) The impact of pharmacogenomics on postoperative nausea and vomiting. Do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology 102:543

    Article  Google Scholar 

  18. Kest B, Sarton E, Dahan A (2000) Gender differences in opioid-mediated analgesia: animal and human studies. Anesthesiology 93:539–547

    Article  PubMed  CAS  Google Scholar 

  19. Kharasch ED, Russell M, Mautz D et al (1997) The role of cytochrome P450 3A4 in alfentanil clearance. Anesthesiology 87:36–50

    Article  PubMed  CAS  Google Scholar 

  20. Kirchheiner J, Meineke I, Steinbach N et al (2003) Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphisms in humans. Br J Clin Pharmacol 55:51–61

    Article  PubMed  CAS  Google Scholar 

  21. Kirchheiner J, Ufer M, Walter EC et al (2004) Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Pharmacogenetics 14:19–26

    Article  PubMed  CAS  Google Scholar 

  22. Korsarac B, Fox AA, Collard CD (2009) Effect of genetic factors on opioid action. Curr Opin Anaesthesiol 22:476–482

    Article  Google Scholar 

  23. Lanfear DE, Jones PG, Marsh S et al (2005) Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome. JAMA 294:1526–1533

    Article  PubMed  CAS  Google Scholar 

  24. Lazarou J, Pomeranz BH, Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279:1200–1205

    Article  PubMed  CAS  Google Scholar 

  25. Levy JH, Faraoni D, Spring JL et al (2013) Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology 118:1466–1474

    Article  PubMed  CAS  Google Scholar 

  26. Li T, Chang CY, Jin DY et al (2004) Identification of the gene for vitamin K epoxide reductase. Nature 427:541–544

    Article  PubMed  CAS  Google Scholar 

  27. Løvlie R, Daly AK, Matre GE et al (2001) Polymorphisms in CYP2D6 duplication-negative individuals with the ultrarapid metabolizer phenotype: a role for the CYP2D6*35 allele in ultrarapid metabolism? Pharmacogenetics 11:45–55

    Article  PubMed  Google Scholar 

  28. Mega JL, Close SL, Wiviott SD et al (2010) Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 376:1312–1319

    Article  PubMed  CAS  Google Scholar 

  29. Palmer SN, Giesecke NM, Body SC et al (2005) Pharmacogenetics of anesthetic and analgesic agents. Anesthesiology 102:663–671

    Article  PubMed  CAS  Google Scholar 

  30. Paré G, Eriksson N, Lehr T et al (2013) Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 127:1404–1412

    Article  PubMed  Google Scholar 

  31. Perzborn E, Roehrig S, Straub A et al (2011) The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov 10:61–75

    Article  PubMed  CAS  Google Scholar 

  32. Poulsen L, Arendt-Nielsen L, Brøsen K, Sindrup SH (1996) The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 60:636–644

    Article  PubMed  CAS  Google Scholar 

  33. Qin XP, Xie HG, Wang W et al (1999) Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects. Clin Pharmacol Ther 66:642–646

    PubMed  CAS  Google Scholar 

  34. Rodríguez-Monguió R, Otero MJ, Rovira J (2003) Assessing the economic impact of adverse drug effects. Pharmacoeconomics 21:623–650

    Article  PubMed  Google Scholar 

  35. Rost S, Fregin A, Ivaskevicius V et al (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427:537–541

    Article  PubMed  CAS  Google Scholar 

  36. Sawyer MB, Innocenti F, Das S et al (2003) A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 73:566–574

    Article  PubMed  CAS  Google Scholar 

  37. Scott SA, Sangkuhl K, Gardner EE et al (2011) Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450–2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Therapeut 90:328–332

    Article  CAS  Google Scholar 

  38. Shin J, Johnson JA (2007) Pharmacogenetics of β-blockers. Pharmacotherapy 27:874–887

    Article  PubMed  CAS  Google Scholar 

  39. Sibbing D, Koch W, Gebhard D et al (2010) Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 121:512–518

    Article  PubMed  CAS  Google Scholar 

  40. Shuldiner AR, O’Connell JR, Bliden KP et al (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302:849–858

    Article  PubMed  CAS  Google Scholar 

  41. Stamer U, Bayerer B, Stüber F (2006) Genetik, Schmerz und Analgesie. Anaesthesist 55:746–752

    Article  PubMed  CAS  Google Scholar 

  42. Streetman DS, Bertino JS Jr, Nafziger AN (2000) Phenotyping of drug metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 10:187–216

    Article  PubMed  CAS  Google Scholar 

  43. Tantry US, Bliden KP, Wei C et al (2010) First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet 3:556–566

    Article  PubMed  CAS  Google Scholar 

  44. Taubert D, Beckerath N von, Grimberg G et al (2006) Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 80:486–501

    Article  PubMed  CAS  Google Scholar 

  45. Van Geest-Daalderop JH, Hutten BA, Péquériaux NC et al (2009) Improvement in the regulation of the vitamin K antagonist acenocoumarol after a standard initial dose regimen: prospective validation of a prescription model. J Thromb Thrombolysis 27:207–214

    Article  Google Scholar 

  46. Van Schie RM, Wessels JA, Cessie S le et al (2011) Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart J 32:1909–1917

    Article  Google Scholar 

  47. Vogel F (1959) Moderne Probleme der Humangenetik. Ergeb Inn Med Kinderheilkd 12: 52–125

    Article  Google Scholar 

  48. Wallentin L, James S, Storey RF et al (2010) Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 376:1320–1328

    Article  PubMed  CAS  Google Scholar 

  49. Wang B, Wang J, Huang SQ et al (2009) Genetic polymorphism of the human cytochrome P450 2C9 gene and its clinical significance. Curr Drug Metab 10:781–834

    Article  PubMed  CAS  Google Scholar 

  50. Wiviott SD, Trenk D, Frelinger AL et al (2007) Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 116:2923–2932

    Article  PubMed  CAS  Google Scholar 

Download references

Einhaltung ethischer Richtlinien

Interessenkonflikt. E.M. Zeidler, A.E. Goetz und C. Zöllner geben an, dass kein Interessenkonflikt besteht. Das vorliegende Manuskript enthält keine Studien an Menschen oder Tieren.

Author information

Authors and Affiliations

  1. Klinik und Poliklinik für Anästhesiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland

    E.M. Zeidler, A.E. Goetz & C. Zöllner

Authors
  1. E.M. Zeidler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A.E. Goetz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Zöllner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E.M. Zeidler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zeidler, E., Goetz, A. & Zöllner, C. Pharmakogenetik. Anaesthesist 62, 874–886 (2013). https://doi.org/10.1007/s00101-013-2233-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00101-013-2233-3

Schlüsselwörter

Keywords

Search

Navigation