Beginning of the chapter

1. 20 Beginning of the chapter Pharmacogenetics: Drug side effects (Pharmaco Sensor)

2. SENSORS PHARMACO SENSOR Drug side effects

3. GENETICS Pharmacogenetics - medication and side effects Drugs have the desired effect only for 60% of the population >>> Side effects (deadly) >>> No effect One out of 12 hospital patients suffer from severe side effects One out of 250 hospital patients die due to side effects The fifth most frequent cause of death in the Western world Certain genes control the breakdown of drugs CYP 2D6, CYP 2C9, CYP 2C19

4. GENETICS Pharmacogenetics The drug is taken The drug exhibits its effect Enzyme gene The drug is broken down by the enzyme The drug ends up in the urine

5. GENETICS Pharmacogenetics A drug is absorbed into the blood and then filtered out. It is taken daily to maintain a constant level Intake EFFECTIVE DOSE OF DRUG Drug in the blood 1d 2d 3d 4d Time (days)

6. GENETICS Pharmacogenetics The drug is taken The drug exhibits its effect Enzyme gene The drug is not broken down Warfarin example The drug is not filtered out of the body

7. GENETICS Pharmacogenetics Side effects Intake EFFECTIVE DOSE OF DRUG Drug in the blood 1d 2d 3d 4d Time (days)

8. PHARMACOGENETICS Various drugs and enzymes Viagra Sildenafil Tacrine Glimepiride CODEINE NAT2 3A4 2C19 2E9 3A5 2D6 2C9 1A2 break down

9. PHARMACOGENETICS Various drugs and enzymes Main metabolic pathway of drugs through enzymes:

10. PHARMACOGENETICS Various drugs and enzymes Viagra Sildenafil Tacrine Glimepiride CODEINE NAT2 3A4 2C19 2E9 3A5 2D6 2C9 1A2 break down

11. PHARMACOGENETICS Various drugs and enzymes Viagra Sildenafil Tacrine Glimepiride CODEINE NAT2 3A4 2C19 2E9 3A5 2D6 2C9 1A2 break down

12. PHARMACOGENETICS Various drugs and enzymes The various enzyme activities

13. 11% of the population 10% of the population 77% of the population 2% of the population PHARMACOGENETICS The breakdown of active drugs through enzymes ACTIVE ACTIVE ACTIVE ACTIVE 2D6 2D6 2D6 2D6 INACTIVE INACTIVE INACTIVE INACTIVE ULTRA RAPID METABOLIZER EXTENSIVE METABOLIZER INTERMEDIATEMETABOLIZER POOR METABOLIZER

14. PHARMACOGENETICS Various drugs and enzymes PRO-Drugs Drugs that are activated by enzymes

15. PHARMACOGENETICS Prodrugs – first, they must be activated INACTIVE INACTIVE INACTIVE INACTIVE CODEINE 2D6 2D6 2D6 2D6 ACTIVE ACTIVE ACTIVE ACTIVE ULTRA RAPID METABOLIZER EXTENSIVE METABOLIZER INTERMEDIATEMETABOLIZER POOR METABOLIZER EFFECT NO EFFECT EFFECT OVERDOSE

16. PHARMACOGENETICS Various drugs and enzymes Dosage example Drug which is deactivated

17. PHARMACOGENETICS Example: drug dosage ACTIVE Drug is inactivated through breakdown 100mg/day NAT2 3A4 2C19 2E9 2C9 1A2 2D6 3A5 EXTENSIVE METABOLIZER INACTIVE

18. PHARMACOGENETICS Example: drug dosage ACTIVE 100mg/day Drug is inactivated through breakdown 50mg/day NAT2 3A4 2C19 2E9 2C9 1A2 2D6 3A5 INTERMEDIATEMETABOLIZER INACTIVE

19. PHARMACOGENETICS Example: drug dosage ACTIVE 100mg/day Drug is inactivated through breakdown 0mg/day NAT2 3A4 2C19 2E9 2C9 1A2 2D6 3A5 POOR METABOLIZER INACTIVE

20. PHARMACOGENETICS Example: drug dosage ACTIVE 100mg/day Drug is inactivated through breakdown 200mg/day NAT2 3A4 2C19 2E9 2C9 1A2 2D6 3A5 ULTRA RAPID METABOLIZER INACTIVE

21. PHARMACOGENETICS Various drugs and enzymes Dosage example PRO-Drug, drug which must be activated

22. PHARMACOGENETICS Example: drug dosage INACTIVE PRO-Drug (such as codeine) Must be activated to have an effect 100mg/day NAT2 3A4 2C19 2E9 2C9 1A2 2D6 3A5 EXTENSIVE METABOLIZER ACTIVE

23. PHARMACOGENETICS Example: drug dosage INACTIVE 100mg/day PRO-Drug (such as codeine) Must be activated to have an effect 50mg/day NAT2 3A5 1A2 3A4 2C9 2E9 2D6 2C19 INTERMEDIATEMETABOLIZER ACTIVE 50% effect!

24. PHARMACOGENETICS Example: drug dosage INACTIVE 100mg/day PRO-Drug (such as codeine) Must be activated to have an effect 0mg/day NAT2 3A5 1A2 3A4 2C9 2E9 2D6 2C19 POOR METABOLIZER ACTIVE NO effect!

25. PHARMACOGENETICS Example: drug dosage INACTIVE PRO-Drug (such as codeine) Must be activated to have an effect 100mg/day NAT2 3A4 2C19 2E9 2C9 1A2 2D6 3A5 ULTRA RAPID METABOLIZER ACTIVE 200% effect! Possible overdose

26. PHARMACOGENETICS Various drugs and enzymes Alternative break down pathways

27. PHARMACOGENETICS Alternative break down pathways DRUG 60% 15% 15% 10% NAT2 3A5 3A4 2C19 2E9 2C9 1A2 2D6 100% break down break down

28. PHARMACOGENETICS Alternative break down pathways DRUG 60% 15% 15% 10% NAT2 3A5 3A4 2C19 2E9 2C9 1A2 2D6 40% break down break down

29. PHARMACOGENETICS Alternative break down pathways DRUG 60% 15% 15% 10% NAT2 3A5 3A4 2C19 2E9 2C9 1A2 2D6 85% break down break down

30. PHARMACOGENETICS Alternative break down pathways DRUG 60% 15% 15% 10% NAT2 3A5 3A4 2C19 2E9 2C9 1A2 2D6 75% break down break down

31. PHARMACOGENETICS Alternative break down pathways DRUG 60% 60% 15% 15% 10% NAT2 2E9 2C9 3A5 2D6 2C19 3A4 1A2 160% break down break down

32. PHARMACOGENETICS Various drugs and enzymes Drug interactions

33. PHARMACOGENETICS Inducers and inhibitors DRUG A DRUG B DRUG C INDUCER NAT2 3A4 2C19 2E9 3A5 2D6 1A2 2C9 INHIBITOR break down

34. PHARMACOGENETICS Various drugs and enzymes How can all this be taken into consideration?

35. PHARMACOGENETICS Various drugs and enzymes

36. PHARMACOGENETICS Pharmacogenetics results

37. PHARMACOGENETICS Pharmacogenetics results

38. PHARMACOGENETICS PHARMACO SENSOR ~ 260 active ingredients are genetically evaluated Complex processes, such as alternative break down pathways, are taken into consideration 8 drugs enzymes are analyzed break down rate of drug is estimated Prodrug activation is taken into consideration Dose recommendation is provided

39. 20 End of the chapter Pharmacogenetics: Drug side effects (Pharmaco Sensor)