PHARMACOGENOMICS

By,Shabnam Relhan

M.Pharm(Biotech.)AIP

OVERVIEWPharmacogenomicsSingle nucleotide polymorphismImportance of pharmacogenomicsExamples of altered drug reponseBenefits of pharmacogenomicsPharmacogenomic drugsEthical concernsChallenges to the growth and expansion

PHARMACOGENOMICS

Pharmacology + Genomics = pharmacogenomics

PHARMACOGENOMICSIT IS THE BRANCH OF PHARMACOLOGY

WHICH DEALS WITH THE INFLUENCE OF GENETIC VARIATION ON DRUG RESPONSE BY CO-RELATING GENE EXPRESSION OR SINGLE NUCLEOTIDE POLYMORPHISM WITH A DRUG’S EFFICACY OR TOXICITY.

It is an approach to PERSONALIZED MEDICINE.

SINGLE NUCLEOTIDE POLYMORPHISMS (SNPs)A Single Nucleotide Polymorphism (SNP) are

DNA sequence variation that occurs when a single nucleotide in the genome sequence is altered.

…CTAGATACGAACTGCATC……CTAGATACGGACTGCATC…Occur in atleast 1% of the population and

make up about 90% of all human genetic variation

•Frequency: 1: 300 to 500 Nucleotides

Personalized MedicineIt refers to an approach of clinical

practice where a particular treatment is not chosen based on the ‘average pateint’ but on characteristic of an individual pateint.

Simple Definition

Corelation

Pharmacogenetics:- The study of inherited differences or variations in drug metabolism and response.

Pharmacogenomics:- The study of the role of inheritance in individual variation in drug response.

IMPORTANCE OF PHARMACOGENOMICS“ONE SIZE FITS ALL” Only work for

about60 percent of the population at the best. And the other 40 percent of the population increase their risks of adverse drug reaction because their genes do not do what is intended of them

ONE SIZE DOES NOT FIT ALL A 1998 study of hospitalized patients

published in the Journal of the American Medical Association reported that in 1994, adverse drug reactions accounted for more than 2.2 million serious cases and over 100,000 deaths, making adverse drug reactions (ADRs) one of the leading causes of hospitalization and death in the United States.

EXAMPLES OF ALTERED DRUG RESPONSE ENZYME/DISEASES GENE

GLUCOSE -6 -PHOSPHATE DEHYDROGENASE DEFICIENCY

G6PD

THIOPURINE S-METHYL TRANSFERASE

TPMT

CYTOCHROME P450 ENJYME AND -DRUG METABOLISM

CYP2D6

WARFARIN AND COAGULATION CYP2C9 VKORC1

GLUCOSE 6-PHOSPHATE DEHYDROGENASE It is a cytosolic enzyme.Enjyme in Hexose Monophosphate ShuntIt is a principal source of NADPH generation.NADPH is required to reduce the thiol

groups on the glutathione and other proteins.Glutathione prevents the Red blood cells

damage.

GLUCOSE 6- PHOHPHATE DEHYDROGENASE DEFICIENCYGSH deficiency in Red blood cells results inMembrane Fragility Haemolysis

Hemolytic

Anaemia SYMPTOMS:- Prolonged neonatal jaundice Hemolytic Anaemia.

GLUCOSE 6- PHOHPHATE DEHYDROGENASE DEFICIENCY

SOME AGENTS THAT CAUSE HEMOLYSIS IN G-6-P D DEFICIENT INDIVIDUALSPrimaquineNitrofurantoinSulfacetamideSulfanilamideSulfapyridine

EXAMPLES OF ALTERED DRUG RESPONSE

Thiopurine methyl transferaseIt is an enjyme that methylates thiopurine

compounds.The methyl donor is S- adenosyl-L-

methionine which is converted to S-adenosyl-L-homocysteine.

TPMT is best known for the role in the metabolism of thiopurine drugs such as :-

Azathioprine6- Mercaptopurine6- thioguanine

THIOPURINE METHYL TRANSFERASE DEFICIENCYDecreased methylation Decreased inactivation

of 6 MP

Bone marrow toxicity

Anaemia, Bleeding tendency,

and infection.

EXAMPLES OF ALTERED DRUG RESPONSE

CYTOCHROME P450

CYP:- It is a host of enzyme that use iron to oxidize things.

Found in liver and small intestine.

There are thousand different cytochromes Although the no. in man is only about 50

CYP ISOFORMSCYP3A4 CYP2D6CYP2C9CYP2C19

CYTOCHROME P2D6There is high expression of CYP2D6 in many

persons of Ethiopian and Saudi Arabian origin.

2D6 is not inducible, so these people have developed a different strategy to cope with the high load of toxic alkaloids in their diet .

These CYPs therefore chew up a variety of drugs, making them ineffective - many antidepressants and neuroleptics

CYTOCHROME P2D6 DeficiencyMany individuals lack functional 2D6.These subjects will be predisposed to drug

toxicity caused by antidepressants or neuroleptics

Other drugs include:DexfenfluraminePerhexiline (withdrawn from the market due

to neuropathy)

EXAMPLES OF ALTERED DRUG RESPONSE

WARFARIN•The Most Commonly Prescribed

Anticoagulant•Patients Maybe: Resistant - Need Higher Dose

to Prevent StrokesSensitive - Need Lower Dose to Prevent CNS

Bleeds

• Warfarin Is Metabolised by the Cytochrome P450, Cyp2c9

• Warfarin Metabolism Involves Vitamin K Epoxide Reductase (VKORC1).

BENEFITS OF PHARMACOGENOMICSMore Powerful MedicinesSafer Drugs The First TimeMore Accurate Methods Of Determining The Dosages.

Better Vaccines.

PHARMACOGENOMIC DRUGS

HERCEPTIN

GLEEVAC

ETHICAL CONCERNSMany fear the implications pharmacogenomics can bring to

their lives:

1.  Through the development of individual pharmacogenomic profiles, an individual's privacy and confidentiality are at risk

2.  Certain individuals (such as Health Insurance Companies or Employers) can obtain the profiles of others and use the "weak points" in their genes to discriminate (The U.S. Senate and the U.S. House of Representatives  are attempting to pass the Genetic Information Nondiscrimination Act of 2007 in hopes of protecting individuals from genetic discrimination in terms of health insurance and employment).

ETHICAL CONCERNS

3.  Since the drugs are more focused, the test groups become smaller, which can lead to rare and more fatal Adverse Drug Reactions

4.  Developing drugs beneficial to one group but dangerous to another

5.  Should physicians inform patients that due to their genetic makeup, they have a high chance of developing a disease that currently has no effective treatment?

ETHICAL CONCERNS

6.  How will the FDA regulate the development and distribution of genetic tests and associated medicines? 

7.  It will become challenging to fully inform patients on possible risks.

8.  Will these "personalized medicines" be available only to those who can afford it?

Challenges to the growth and ExpansionEducation of various healthcare providers

regarding pharmacogenomics.Potentially smaller and more specialized drug

markets.Resistance to genetic testing.Ethical & Legal issues.Expense.

REFERENCEOne size does not fit all: The promise of

pharmacogenomics A pharmacogenomics primer for the national centre for Biotecnology information(NCBI)

  Zdanowicz Martin M” Concept in Pharmacogenomics” page no-61-66

Ingelman-Sundberg et al. Polymorphic cytochrome P450 enzymes: an opportunity for individualized drug treatment Trends in Pharm Sci Aug 1999 342-9 

ReferenceEichelbaum M, Ingelman-Sundberg M,

Evans WE. “Pharmcogenomics and individualized drug therapy”. Annu Rev Med. 2006.57:119-137.

Dr D.P katare “Basics in Biotechnology”page no. 267-269

THANK YOU