OVERVIEW Pharmacogenomics Single nucleotide polymorphism Importance of pharmacogenomics Examples of altered drug reponse Benefits of pharmacogenomics Pharmacogenomic drugs Ethical concerns Challenges to the growth and expansion
PHARMACOGENOMICS IT 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 NUCLEOTIDEPOLYMORPHISMS (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 Medicine It 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.
CorelationPharmacogenetics:- The study ofinherited differences or variations indrug metabolism and response.Pharmacogenomics:- The study of therole of inheritance in individualvariation 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 GENEGLUCOSE -6 -PHOSPHATE G6PDDEHYDROGENASE DEFICIENCYTHIOPURINE S-METHYL TRANSFERASE TPMTCYTOCHROME P450 ENJYME AND - CYP2D6DRUG METABOLISMWARFARIN AND COAGULATION CYP2C9 VKORC1
GLUCOSE 6-PHOSPHATE DEHYDROGENASE It is a cytosolic enzyme. Enjyme in Hexose Monophosphate Shunt It 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.
Thiopurine methyl transferase It 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 :- Azathioprine 6- Mercaptopurine 6- thioguanine
THIOPURINE METHYLTRANSFERASE DEFICIENCY Decreased methylation Decreased inactivation of 6 MP Bone marrow toxicity Anaemia, Bleeding tendency, and infection.
CYTOCHROME P2D6 There 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 Deficiency Many individuals lack functional 2D6. These subjects will be predisposed to drug toxicity caused by antidepressants or neuroleptics Other drugs include: Dexfenfluramine Perhexiline (withdrawn from the market due to neuropathy)
ETHICAL CONCERNS Many fear the implications pharmacogenomics can bring to their lives: 1. Through the development of individual pharmacogenomic profiles, an individuals 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 andExpansion Education of various healthcare providers regarding pharmacogenomics. Potentially smaller and more specialized drug markets. Resistance to genetic testing. Ethical & Legal issues. Expense.
REFERENCE One 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
Reference Eichelbaum 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