current drug prescribing based on: signs and symptoms average response consequence:some respond...
TRANSCRIPT
![Page 1: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/1.jpg)
Current Drug Prescribing
Based on: Signs and symptoms
Average response
Consequence: Some respond
others do not
some have adverse
events
![Page 2: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/2.jpg)
Pharmacogenetics /-genomics
Linking the information on the variation of human genes to variation in clinical responses to drugs
Variation in drug response
Genetic factors
Environmental & Biological factors
Drug interactions
Metabolism
Transport
Drug target
Cell
Drugs
![Page 3: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/3.jpg)
AIM: Identification of the right drug and dose for each patient (‚Individualized
Medicine‘)
![Page 4: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/4.jpg)
Hypothetical example
Kirchheiner et al. (2005)
toxicity
no response
![Page 5: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/5.jpg)
Why pharmacogenetics? - Adverse drug reactions
• Account for 5% of all hospital admissions
• Occur in 10 - 20% of hospital inpatients (USA: 2 mio cases in 1994)
• Cause of death in 0.1 % of medical inpatients (USA: 100‘000 deaths 1994)
• Among top ten causes of death in hospital inpatients
Pirmohamed et al., 1998 BMJ
![Page 6: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/6.jpg)
Why pharmacogenetics?
- Drug efficacy
Response rates of major drugs for important diseases often <50%!
Spear et al., 2001 BMJ
![Page 7: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/7.jpg)
• Aufnahme
• Verteilung
• Stoffwechsel
• Zielmolekül
• Ausscheidung
Medikamentenwirkung
Roche Facetten (2003)
Aufnahme
Aufnah
me
Ausscheidung
Metabolismus
Verteilung
Zielmolekül
![Page 8: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/8.jpg)
Beispiel 1: Cytochrom P450 2D6• Verantwortlich für den Abbau von Fremdstoffen im Körper
• Abbau von ca. 25% aller Medikamente
• Grosse Unterschiede in der Aktivität zwischen verschiedenen Menschen:
Ingelman-Sundberg (2004)
Weinshilboum (2003)
20-30 Mio Menschen haben keine CYP 2D6
Enzyme (PM)
15-20 Mio Menschen haben CYP 2D6 dupliziert (UM)
• Abbau zu langsam• Medikamentenspiegel zu hoch bei normaler Dosis• Hohes Risiko für NW• Keine Wirkung bei gewissen Prodrugs
• Abbau zu schnell• Keine Wirkung bei normaler Dosis• Zu starke Wirkung bei gewissen Prodrugs
![Page 9: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/9.jpg)
Ein Fallbeispiel• Mann, 62 Jahre
• Chronische Lymphatische Leukämie (Chemotherapie)
• Symptome: Müdigkeit, Kurzatmigkeit, Fieber, Husten
• Diagnose: Lungenentzündung (Lobärpneumonie)
• Behandlung: Antibiotika, Codein gegen den Husten
• Am 4. Spitaltag: Koma
• Morphin-Werte im Blut 20-80x höher als erwartet
• CYP2D6 Genotypisierung zeigt eine Duplikation des Gens
Gasche et al., NEJM (2004)
Abbau/ Ausscheidung
Ausscheidung
![Page 10: Current Drug Prescribing Based on: Signs and symptoms Average response Consequence:Some respond others do not some have adverse events](https://reader035.vdocument.in/reader035/viewer/2022070310/55204d6449795902118b9b3b/html5/thumbnails/10.jpg)
Beispiel 2: Thiopurin-Methyltransferase• Abbau von 6-Mercaptopurin (Leukämie-Chemotherapie)• Verschiedene Mutationen im Gen führen zu reduzierter
Enzymaktivität• Mutationsträger haben ein erhöhtes Risiko für schwere NW
(Knochenmarksdepression)
Weinshilboum (2003) Miller & McLeod (2007)
Anpassung der 6-MP-Dosis je nach Genotyp: