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20 Beginning of the chapter Pharmacogenetics: Drug side effects (Pharmaco Sensor) SENSORS PHARMACO SENSOR Drug side effects 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 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 GENETICS Pharmacogenetics A drug is absorbed into the blood and then filtered out. Drug in the blood It is taken daily to maintain a constant level Intake EFFECTIVE DOSE OF DRUG 1d 2d 3d Time (days) 4d 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 GENETICS Pharmacogenetics Drug in the blood Side effects Intake EFFECTIVE DOSE OF DRUG 1d 2d 3d Time (days) 4d PHARMACOGENETICS Various drugs and enzymes Tacrine Glimepiride Viagra Sildenafil CODEINE NAT2 2E9 1A2 2C19 2C9 2D6 break down 3A4 3A5 PHARMACOGENETICS Various drugs and enzymes Main metabolic pathway of drugs through enzymes: 1B1 3A5 1% 9% 2D6 16% 2C19 10% 2A6 4% 2B6 5% 2C9 12% 1A2 12% 3A4 31% PHARMACOGENETICS Various drugs and enzymes Tacrine Glimepiride Viagra Sildenafil CODEINE NAT2 2E9 1A2 2C19 2C9 2D6 break down 3A4 3A5 PHARMACOGENETICS Various drugs and enzymes Tacrine Glimepiride Viagra Sildenafil CODEINE NAT2 2E9 1A2 2C19 2C9 2D6 break down 3A4 3A5 PHARMACOGENETICS Various drugs and enzymes The various enzyme activities PHARMACOGENETICS The breakdown of active drugs through enzymes ACTIVE ACTIVE ACTIVE ACTIVE 2D6 2D6 2D6 2D6 INACTIVE INACTIVE INACTIVE INACTIVE ULTRA RAPID METABOLIZER 2% of the population EXTENSIVE INTERMEDIATE METABOLIZER METABOLIZER 77% of the population 11% of the population POOR METABOLIZER 10% of the population PHARMACOGENETICS Various drugs and enzymes PRO-Drugs Drugs that are activated by enzymes PHARMACOGENETICS Prodrugs – first, they must be activated INACTIVE INACTIVE INACTIVE INACTIVE 2D6 2D6 2D6 2D6 ACTIVE ACTIVE CODEINE ACTIVE ULTRA RAPID METABOLIZER OVERDOSE ACTIVE EXTENSIVE INTERMEDIATE METABOLIZER METABOLIZER EFFECT EFFECT POOR METABOLIZER NO EFFECT PHARMACOGENETICS Various drugs and enzymes Dosage example Drug which is deactivated PHARMACOGENETICS Example: drug dosage ACTIVE Drug is inactivated through breakdown NAT2 2E9 100mg/day 1A2 2C19 2C9 2D6 EXTENSIVE METABOLIZER INACTIVE 3A4 3A5 PHARMACOGENETICS Example: drug dosage Drug is inactivated through breakdown NAT2 2E9 ACTIVE 100mg/day 50mg/day 1A2 2C19 2C9 2D6 INTERMEDIATE METABOLIZER INACTIVE 3A4 3A5 PHARMACOGENETICS Example: drug dosage Drug is inactivated through breakdown NAT2 2E9 ACTIVE 100mg/day 0mg/day 1A2 2C19 2C9 2D6 POOR METABOLIZER INACTIVE 3A4 3A5 PHARMACOGENETICS Example: drug dosage Drug is inactivated through breakdown NAT2 2E9 ACTIVE 100mg/day 200mg/day 1A2 2C19 2C9 2D6 ULTRA RAPID METABOLIZER INACTIVE 3A4 3A5 PHARMACOGENETICS Various drugs and enzymes Dosage example PRO-Drug, drug which must be activated PHARMACOGENETICS Example: drug dosage INACTIVE PRO-Drug (such as codeine) Must be activated to have an effect NAT2 2E9 100mg/day 1A2 2C19 2C9 2D6 EXTENSIVE METABOLIZER ACTIVE 3A4 3A5 PHARMACOGENETICS Example: drug dosage INACTIVE 100mg/day PRO-Drug (such as codeine) Must be activated 50mg/day to have an effect NAT2 2E9 1A2 2C19 2C9 2D6 INTERMEDIATE METABOLIZER ACTIVE 50% effect! 3A4 3A5 PHARMACOGENETICS Example: drug dosage INACTIVE 100mg/day PRO-Drug (such as codeine) Must be activated 0mg/day to have an effect NAT2 2E9 1A2 2C19 2C9 2D6 POOR METABOLIZER ACTIVE NO effect! 3A4 3A5 PHARMACOGENETICS Example: drug dosage INACTIVE PRO-Drug (such as codeine) Must be activated to have an effect NAT2 2E9 100mg/day 1A2 2C19 2C9 2D6 3A4 ULTRA RAPID METABOLIZER ACTIVE 200% effect! Possible overdose 3A5 PHARMACOGENETICS Various drugs and enzymes Alternative break down pathways PHARMACOGENETICS Alternative break down pathways DRUG NAT2 10% 15% 2E9 1A2 60% 15% 2C19 2C9 2D6 100% break down break down 3A4 3A5 PHARMACOGENETICS Alternative break down pathways DRUG NAT2 10% 15% 2E9 1A2 60% 15% 2C19 2C9 2D6 40% break down break down 3A4 3A5 PHARMACOGENETICS Alternative break down pathways DRUG NAT2 10% 15% 2E9 1A2 60% 15% 2C19 2C9 2D6 85% break down break down 3A4 3A5 PHARMACOGENETICS Alternative break down pathways DRUG NAT2 10% 15% 2E9 1A2 60% 15% 2C19 2C9 2D6 75% break down break down 3A4 3A5 PHARMACOGENETICS Alternative break down pathways DRUG NAT2 10% 15% 2E9 1A2 60% 60% 15% 2C19 2C9 2D6 160% break down break down 3A4 3A5 PHARMACOGENETICS Various drugs and enzymes Drug interactions PHARMACOGENETICS Inducers and inhibitors DRUG A DRUG B DRUG C INDUCER NAT2 2E9 1A2 2C19 2C9 2D6 INHIBITOR break down 3A4 3A5 PHARMACOGENETICS Various drugs and enzymes How can all this be taken into consideration? PHARMACOGENETICS Various drugs and enzymes PHARMACOGENETICS Pharmacogenetics results PHARMACOGENETICS Pharmacogenetics results 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 20 End of the chapter Pharmacogenetics: Drug side effects (Pharmaco Sensor)
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