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

Beginning of the chapterPharmacogenetics: Drug side effects

(Pharmaco Sensor)

20

SENSORS

PHARMACO SENSOR

Drug side effects

GENETICSPharmacogenetics - medication and

side effects

Drugs have the desired effect only for 60% of the populationDrugs have the desired effect only for 60% of the population>>>>>> Side effects (deadly)Side effects (deadly)>>>>>> No effectNo effect

One out of 12 hospital patients suffer from One out of 12 hospital patients suffer from severe side effectssevere side effects

One out of 250 hospital patients One out of 250 hospital patients die due to side effectsdie due to side effects

The The fifth most frequent cause of death fifth most frequent cause of death in the Western world in the Western world

Certain genes control the breakdown of drugs Certain genes control the breakdown of drugs CYP 2D6, CYP 2C9, CYP 2C19CYP 2D6, CYP 2C9, CYP 2C19

GENETICS

The drug is takenThe drug is taken

The drug is broken down by the The drug is broken down by the enzymeenzyme

The drug ends up in the urineThe drug ends up in the urine

Enzyme geneEnzyme gene

The drug The drug exhibits its exhibits its effecteffect

Pharmacogenetics

GENETICS

EFFECTIVE DOSE OF DRUG

Dru

g in

the

bloo

dD

rug

in th

e bl

ood

Time (days)Time (days)1d 2d 3d 4d 1d 2d 3d 4d

IntakeIntake

A drug is absorbed into the blood and then filtered out.A drug is absorbed into the blood and then filtered out.

It is taken daily to maintain a constant levelIt is taken daily to maintain a constant level

Pharmacogenetics

GENETICS

The drug is takenThe drug is taken

The drug is not broken The drug is not broken downdown

Enzyme geneEnzyme gene

The drug The drug exhibits its exhibits its effecteffect

The drug is not filtered out of The drug is not filtered out of the bodythe body

Warfarin exampleWarfarin example

Pharmacogenetics

GENETICS

EFFECTIVE DOSE OF DRUG

Dru

g in

the

bloo

dD

rug

in th

e bl

ood

Time (days)Time (days)1d 2d 3d 4d 1d 2d 3d 4d

IntakeIntake

Side effects

Pharmacogenetics

PHARMACOGENETICS

Various drugs and enzymes

ViagraSildenafil

break down

3A42C192E9NAT2

CODEINE

2D6

Glimepiride

2C9

Tacrine

1A2

PHARMACOGENETICS


Main metabolic pathway Main metabolic pathway of drugs through enzymesof drugs through enzymes::

PHARMACOGENETICS


ViagraSildenafil

3A42C192E9NAT2

CODEINE

2D6

Glimepiride

2C9

Tacrine

break down

PHARMACOGENETICS


ViagraSildenafil

3A42C192E9NAT2

CODEINE

Glimepiride

2C9

Tacrine

1A2

break down

PHARMACOGENETICS


The various enzyme The various enzyme activitiesactivities

PHARMACOGENETICS

The breakdown of active drugs through enzymes

ACTIVE

EXTENSIVE EXTENSIVE METABOLIZERMETABOLIZER

ACTIVE

INTERMEDIATEINTERMEDIATEMETABOLIZERMETABOLIZER

ACTIVE

POOR POOR METABOLIZERMETABOLIZER

ACTIVE

ULTRA RAPID ULTRA RAPID METABOLIZERMETABOLIZER

2% of the population




INACTIVE INACTIVE INACTIVE INACTIVE

PHARMACOGENETICS


PRO-DrugsPRO-DrugsDrugs that are activated Drugs that are activated

by enzymesby enzymes

PHARMACOGENETICS

Prodrugs – first, they must be activated

ACTIVE


ACTIVE


ACTIVE


ACTIVE


INACTIVE INACTIVE INACTIVE INACTIVE

CODEINECODEINE

EFFECT EFFECT NO EFFECTOVERDOSE

PHARMACOGENETICS


Dosage exampleDosage example

Drug which is deactivatedDrug which is deactivated

PHARMACOGENETICS

Example: drug dosage

3A42C192E9NAT2

ACTIVE

2C91A2 2D6


INACTIVE

100mg/day

Drug is inactivated through breakdown

PHARMACOGENETICS


3A42C192E9NAT2

ACTIVE

2C91A2 2D6

INACTIVE


50mg/day

100mg/dayDrug is inactivated through breakdown

PHARMACOGENETICS


3A42C192E9NAT2

ACTIVE

2C91A2 2D6

INACTIVE

0mg/day

100mg/day



PHARMACOGENETICS


3A42C192E9NAT2

ACTIVE

2C91A2

INACTIVE

200mg/day

100mg/day


2D6


PHARMACOGENETICS


Dosage exampleDosage example

PRO-Drug, drug which PRO-Drug, drug which must be activatedmust be activated

PHARMACOGENETICS


3A42C192E9NAT2

ACTIVE

2C91A2 2D6


INACTIVE

100mg/day

PRO-Drug (such as codeine)Must be activated to have an effect

PHARMACOGENETICS


3A42C192E9NAT2 2C91A2 2D6


50mg/day

100mg/day

ACTIVE

INACTIVEPRO-Drug (such as codeine)Must be activated to have an effect

50% effect!

PHARMACOGENETICS


3A42C192E9NAT2 2C91A2 2D6

0mg/day

100mg/day


ACTIVE


NO effect!

PHARMACOGENETICS


3A42C192E9NAT2 2C91A2

100mg/day


2D6

ACTIVE


200% effect! Possible overdose

PHARMACOGENETICS


Alternative break down Alternative break down pathwayspathways

PHARMACOGENETICS

Alternative break down pathways

3A42C19NAT2

DRUG

2C91A22E9

60%60%15%15%10%10% 15%15%

100% break down100% break down

break down

PHARMACOGENETICS


3A42C19NAT2

DRUG

2C91A22E9

60%60%15%15%10%10% 15%15%


break down

PHARMACOGENETICS


3A42C19NAT2

DRUG

2C91A22E9

60%60%15%15%10%10% 15%15%


break down

PHARMACOGENETICS


3A42C19NAT2

DRUG

2C91A22E9

60%60%15%15%10%10% 15%15%


break down

60%60%

PHARMACOGENETICS


3A42C19NAT2

DRUG

2C91A22E9

60%60%15%15%10%10% 15%15%


break down

PHARMACOGENETICS


Drug interactionsDrug interactions

PHARMACOGENETICS

Inducers and inhibitors

DRUG C

3A42C192E9NAT2 2D6

DRUG BDRUG A

1A2 2C9

INHIBITORINHIBITOR

INDUCERINDUCER

break down

PHARMACOGENETICS


How can all this be taken How can all this be taken into consideration?into consideration?

PHARMACOGENETICS


PHARMACOGENETICS

Pharmacogenetics results

PHARMACOGENETICS

Pharmacogenetics results

PHARMACOGENETICS

PHARMACO SENSOR

~ 260 active ingredients are genetically evaluated~ 260 active ingredients are genetically evaluated

Complex processes, such as alternative break down pathways, are taken into Complex processes, such as alternative break down pathways, are taken into

considerationconsideration

8 drugs enzymes are analyzed8 drugs enzymes are analyzed

break down rate of drug is estimatedbreak down rate of drug is estimated

Prodrug activation is taken into considerationProdrug activation is taken into consideration

Dose recommendation is providedDose recommendation is provided

End of the chapterPharmacogenetics: Drug side effects

(Pharmaco Sensor)

20

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