Pharmacogenetics&

Pharmacogenomics

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

Patient’s responseto drug

Diagnosis

Interactions with

concomitant drugs

Dose

Compliance

Genetic differences among patients

Response to Medicine

Sources of Pharmacokinetic and Pharmacodynamic Variability

Drug Specific:Dose & Schedule

Dosage formMorphometric:Body SizeBody Composition

Genetics:

Environment:Drug-drug interactions

Drug-CAM interactionsDrug-formulation interactions

Drug-food constituent interactions

Physiologic:DiseaseHepatic FunctionRenal Function

Demographic:AgeRace/EthnicitySex

Variability

Non-Responders and Patients Experiencing

Severe Toxicity

All patients with same diagnosis

Responders and Patients not Experiencing

Severe Toxicity

Definition

people respond differently to medicines due to their genetic inheritance.

Pharmacogenetics: study of genetically determined interindividual differences in response to drugs

Pharmacogenomics: use of genome based techniques in drug development

The Goals

Medicines do not have the same effect on everyone.

Some people do not respond at all, while others experience severe side effects.

Genetic factors account for some of these differences.

Recent research has suggested that 85% of patient responses to a drug are due to genetic factors.

The Goals

Pharmacogenetic determines:

How genetic make-up affects a drug effect. what side effects are likely to occur. Whether patients get the right drugs at the right dose.

scientists are trying:

to identify which genotypes respond to particular medicines.

To “personalise” medicines so that each drug has the desired effect on each person who uses it.

The Goals

Personalized Medicine: The Right Drug for the Right Patient at the Right Time

Pharmacogenetics The human genome contains 3 billion nucleotides

and the genomes of any 2 individuals vary in 3 million of them.

It is no surprise, then, that individuals have different responses to the same medicine.

Differences in our genes can affect drug absorption, distribution, metabolism and excretion.

Single Nucleotide Polymorphisms (SNPs or snips)

SNPs involve variations in single base pairs

This may not cause a change in amino acid sequence of a protein

But it may cause changes in the levels of its transcription or translation which affects response to a drug.

The aim is to identify SNPs determining which parts of the genome are relevant to drug response and to adverse reactions.

Succinylcholine Succinylcholine is used in surgery and some

patients suffer from prolonged paralysis.

Succinylcholine is broken down by an enzyme (Pseudocholinesterase).

The gene which codes for this enzyme is polymorphic.

The affected patients had a gene which coded for a different enzyme not capable of normal breakdown of acetylcholine.

Lymphoblastic Leukaemia

Mercaptopurine is used to treat lymphoblastic leukaemia in children.

It is broken down by an enzyme whose level is controlled by a single gene.

Homozygous people produce either very high or very low quantities of the enzyme.

Heterozygous people produce intermediate quantities of the enzyme.

Lymphoblastic Leukaemia

Lymphoblastic Leukaemia

Normal doses of mercaptopurine in homozygous negative patients can cause myelosuppression

The level of the enzyme can be measured using a simple blood test

this was one of the first pharmacogenetic tests in clinical use.

Alzheimer’s disease Sufferers have variations in the presence of

apolipoprotein E.

These differences predict not only the onset of the disease but also give clues for the treatment.

A drug can be given which slows progression in patients who do not have 2 copies of the gene for this protein.

Asthma bronchodilators are used for asthma but not

everyone responds in the same way.

>50% of the variance in response is due to genetic difference.

The drug that acts on bronchial smooth muscle has a target protein.

Some patients make a variant of this protein and cannot benefit from this form of treatment.

Techniques

Microarrays and Proteomics are used to identify how an individual’s genotype affects their response to a drug.

A microarray is a ‘chip’ which contains an array of DNA or RNA sequences or proteins.

It determines the effect of a drug on gene expression or to identify target genes for drug activity (i.e. to ‘design’ drugs).

Techniques

Proteomics is the study of all the proteins being expressed in a cell at a given time.

It can be used to help to identify which proteins may be good targets for drugs.

SummaryIn English

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