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20 Beginning of the chapter
Pharmacogenetics: Drug side effects (Pharmaco Sensor)
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SENSORS PHARMACO SENSOR Drug side effects
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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
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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
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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 d d d Time (days)
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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
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GENETICS Pharmacogenetics Side effects Intake Drug in the blood
EFFECTIVE DOSE OF DRUG Drug in the blood 1d d d d Time (days)
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Various drugs and enzymes
PHARMACOGENETICS Various drugs and enzymes Viagra Sildenafil Tacrine Glimepiride CODEINE NAT2 2E9 1A2 2C19 2C9 2D6 3A4 3A5 break down
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Various drugs and enzymes
PHARMACOGENETICS Various drugs and enzymes Main metabolic pathway of drugs through enzymes:
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Various drugs and enzymes
PHARMACOGENETICS Various drugs and enzymes Viagra Sildenafil Tacrine Glimepiride CODEINE NAT2 2E9 1A2 2C19 2C9 2D6 3A4 3A5 break down
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Various drugs and enzymes
PHARMACOGENETICS Various drugs and enzymes Viagra Sildenafil Tacrine Glimepiride CODEINE NAT2 2E9 1A2 2C19 2C9 2D6 3A4 3A5 break down
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Various drugs and enzymes The various enzyme activities
PHARMACOGENETICS Various drugs and enzymes The various enzyme activities
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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
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Various drugs and enzymes Drugs that are activated by enzymes
PHARMACOGENETICS Various drugs and enzymes PRO-Drugs Drugs that are activated by enzymes
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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
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Various drugs and enzymes Drug which is deactivated
PHARMACOGENETICS Various drugs and enzymes Dosage example Drug which is deactivated
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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
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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
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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
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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
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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
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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
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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!
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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!
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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
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Various drugs and enzymes Alternative break down pathways
PHARMACOGENETICS Various drugs and enzymes Alternative break down pathways
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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
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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
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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
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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
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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
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Various drugs and enzymes
PHARMACOGENETICS Various drugs and enzymes Drug interactions
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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
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How can all this be taken into consideration?
PHARMACOGENETICS Various drugs and enzymes How can all this be taken into consideration?
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Various drugs and enzymes
PHARMACOGENETICS Various drugs and enzymes
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Pharmacogenetics results
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Pharmacogenetics results
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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
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Pharmacogenetics: Drug side effects (Pharmaco Sensor)
20 End of the chapter Pharmacogenetics: Drug side effects (Pharmaco Sensor)
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