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

SENSORS PHARMACO SENSOR Drug side effects

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 Intake 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)

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

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

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

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

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

Various drugs and enzymes The various enzyme activities PHARMACOGENETICS Various drugs and enzymes The various enzyme activities

ACTIVE ACTIVE ACTIVE ACTIVE 2D6 2D6 2D6 2D6 INACTIVE INACTIVE INACTIVE 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 2% of the population 77% of the population 11% of the population 10% of the population

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

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

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

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

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

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

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

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

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

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

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

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

Various drugs and enzymes Alternative break down pathways PHARMACOGENETICS Various drugs and enzymes Alternative break down pathways

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

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

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

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

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

Various drugs and enzymes PHARMACOGENETICS Various drugs and enzymes Drug interactions

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

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

Various drugs and enzymes PHARMACOGENETICS Various drugs and enzymes

Pharmacogenetics results

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

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