Pharmacogenomics is the study of how an individual's genetic inheritance affects their body's response to drugs. It involves studying the genetic basis for variability in drug efficacy and toxicity. The goal is to develop personalized medicine by understanding how genetic factors influence an individual's ability to metabolize and respond to drugs. Key factors that can vary between individuals include drug metabolizing enzymes, drug transporters, and drug targets. Genetic variations in these factors are associated with differences in drug efficacy or risk of adverse effects. Pharmacogenomic testing helps identify genetic polymorphisms that can predict drug response and dosing requirements.
Pharmacogenetics and pharmacogenomics is an upcoming branch in therapeutics. Various pharmacogenomic tests are currently available to aid in actual clinical practice. It has shown to have promising results in personalized medicine It is my attempt to compile the basic concepts from various books, articles, and online journals. Please feel free to comment.
Pharmacogenetics and pharmacogenomics is an upcoming branch in therapeutics. Various pharmacogenomic tests are currently available to aid in actual clinical practice. It has shown to have promising results in personalized medicine It is my attempt to compile the basic concepts from various books, articles, and online journals. Please feel free to comment.
A genome is an organism’s complete set of DNA or complete genetic makeup, The entire DNA complement. It describes the identity and the sequence of genes of an organism.
Genomics is the study of entire genomes(structure, function, evolution, mapping, and editing of genomes)
Executing the sequencing and analysis of entire human genome enables more rapid and effective identification of disease associated genes and provide drug companies with pre validated targets.
Proteomics is the systematic high-throughput separation and characterization of proteins within biological systems./ large scale study of protein and their functions.
Proteomics measures protein expression directly, not via gene expression, thus achieving better accuracy. Current work uses 2-dimensional polyacrylamide gel electrophoresis(2D- PAGE) and mass spectrometry.
New separation and characterization technologies, such as protein microarray and high throughput chromatography are being developed.
Pharmacogenomics is the branch of biochemistry in which study how an individual’s genetic inheritance affects the body response to drug. Pharmacogenomics is the intersection of genetics and pharmaceutical industry.
In this presentation a brief note is given about what is pharmacogenomics. Why different drugs work differently in different people. today pharmacogenomics, future of pharmacogenomics. also describe the future of pharmacogenomics. challenges which have to pharmacogenomics.
Role of Target Identification and Target Validation in Drug Discovery ProcessPallavi Duggal
Target identification and Validation tells about the how target is neccesary for new drug discovery and its development to reach into market for rare diseases.
Pharmacogenomics is a new trending branch which has created enormous hopes in improving diagnostic methods, treatment outcomes and preventing adverse events and therapeutic failures. In this ppt basics of pharmacogenomics and pharmacogenetics has been discussed in simplest possible way along with two case studies. Clinical applications of pharmacogenomics has also been discussed in brief.
INTRODUCTION
What is pharmacogenomics
History
Principle
So what’s new about pharmacogenomics?
single nucleotide polymorphism (SNP)?
Genes commonly involved in pharmacogenomic drug metabolism and response
The anticipated benefits of pharmacogenomics
Pharmacogenetics Research/Database Program
Some of the barriers to using pharmacogenomics
Conclusion
References
The above presentation consist of the definition of microarray, brief history, general principle of the same, the type of scanner that are used to read or to scan the microarray , type of DNA microarray and finally its various apliccation including the role of DNA microaarray in drug discovery.
Pharmacogenetics is the study of influences of a gene on therapeutic and adverse effects of drugs.
Pharmacogenetics plays an important role in drug development and drug safety.
This presentation gives the brief idea of the various guidelines carried out to study the genetic damage to cells when there is a discover of new active molecule.
A genome is an organism’s complete set of DNA or complete genetic makeup, The entire DNA complement. It describes the identity and the sequence of genes of an organism.
Genomics is the study of entire genomes(structure, function, evolution, mapping, and editing of genomes)
Executing the sequencing and analysis of entire human genome enables more rapid and effective identification of disease associated genes and provide drug companies with pre validated targets.
Proteomics is the systematic high-throughput separation and characterization of proteins within biological systems./ large scale study of protein and their functions.
Proteomics measures protein expression directly, not via gene expression, thus achieving better accuracy. Current work uses 2-dimensional polyacrylamide gel electrophoresis(2D- PAGE) and mass spectrometry.
New separation and characterization technologies, such as protein microarray and high throughput chromatography are being developed.
Pharmacogenomics is the branch of biochemistry in which study how an individual’s genetic inheritance affects the body response to drug. Pharmacogenomics is the intersection of genetics and pharmaceutical industry.
In this presentation a brief note is given about what is pharmacogenomics. Why different drugs work differently in different people. today pharmacogenomics, future of pharmacogenomics. also describe the future of pharmacogenomics. challenges which have to pharmacogenomics.
Role of Target Identification and Target Validation in Drug Discovery ProcessPallavi Duggal
Target identification and Validation tells about the how target is neccesary for new drug discovery and its development to reach into market for rare diseases.
Pharmacogenomics is a new trending branch which has created enormous hopes in improving diagnostic methods, treatment outcomes and preventing adverse events and therapeutic failures. In this ppt basics of pharmacogenomics and pharmacogenetics has been discussed in simplest possible way along with two case studies. Clinical applications of pharmacogenomics has also been discussed in brief.
INTRODUCTION
What is pharmacogenomics
History
Principle
So what’s new about pharmacogenomics?
single nucleotide polymorphism (SNP)?
Genes commonly involved in pharmacogenomic drug metabolism and response
The anticipated benefits of pharmacogenomics
Pharmacogenetics Research/Database Program
Some of the barriers to using pharmacogenomics
Conclusion
References
The above presentation consist of the definition of microarray, brief history, general principle of the same, the type of scanner that are used to read or to scan the microarray , type of DNA microarray and finally its various apliccation including the role of DNA microaarray in drug discovery.
Pharmacogenetics is the study of influences of a gene on therapeutic and adverse effects of drugs.
Pharmacogenetics plays an important role in drug development and drug safety.
This presentation gives the brief idea of the various guidelines carried out to study the genetic damage to cells when there is a discover of new active molecule.
Humans are 99% similar to each other; but it is the 1% that is the cause of concern. This relatively small difference actually how a drug will effect our body. Pharmacogenomics is the study of how genes affect a person’s response to drugs. In order to prevent any unwanted reactions it has become necessary to consider one's genome while prescribing medicine. Thus pharmacogenomics is the starting point of personalized medicine.
ARBs (Angiotensin receptor blockers) are the most widely used anti hypertensive throughout the world. A solid knowledge related to ARB will make our practice more patients friendly & benefit will be maximum.
Pharmacogenomics deals with the influence of genetic variation on drug response by co-relating gene expression or polymorphism with a drug’s efficacy or toxicity.
Genetic polymorphisms are variations in gene sequences that occur in at least 1% of the general population, resulting in multiple alleles or variants of a gene sequence.
The most commonly occurring form of genetic variability is the single nucleotide polymorphism (SNP, often called “snip”)
This Presentation is about Pharmacogenomics and Pharmacogenetics , its Working , application, History.
It also contain a little bit info related to polypharmacy and its effects.
You can also see information regarding Drug Metabolism Phase, and drug Metabolizing Enzymes like CYPs, VKORC1, TPMT
GENETIC POLYMORPHISM IN DRUG METABOLISM.pptxAmeena Kadar
Genetic Polymorphism is one of the factors that affects the Drug metabolism. Cytochrome P - 450, one of the prominent group of metabolizing enzymes. In this ppt, genetic polymorphism of cytochrome p 450 is discussed.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journey
Pharmacogenomics
1.
2.
3. What is pharmacogenomics?
Pharmacogenomics is the study of how an individual's genetic
inheritance affects the body's response to drugs.
The term ‘Pharmacogenomics’ comes from the words
‘pharmacology’ (the science of drugs) and ‘genomics’ (the study of
genes and their functions) and is thus the intersection of
pharmaceuticals and genetics.
+
Shahid Chamran university of Ahvaz
4. personalized and Pharmacogenomics
• Pharmacogenetics- is often a study of the
variations in a targeted gene, or group of
functionally related genes.
• Pharmacogenomics , on the other hand is a
much broader investigation of genetic
variations at the level of the genome
Pharmacogenomics includes Pharmacogenetics
7. INTRODUCTION TO PHARMACOGENOMICS
The goal of pharmacogenomics is to:
• understand polymorphisms of drug
metabolizing enzymes
• transporters, and/or receptors that ultimately
determine the outcome of drug therapy.
Shahid Chamran university of Ahvaz
8. INTRODUCTION TO PHARMACOGENOMICS
Differences in drug response in
patients:
• Genetic (genotype, gender, ethnic
background)
• Environment (disease, previous
treatment and the environment)
9. INTRODUCTION TO PHARMACOGENOMICS
Focus:
At the beginning: On individual differences
But Over time: Genetic differences between
populations
pharmacogenomics is used For all organisms that are
able to respond to drugs or other chemicals
Shahid Chamran university of Ahvaz
10. INTRODUCTION TO PHARMACOGENOMICS
Research in the field of pharmacogenetics is moving in two main
directions:
• 1) identify specific genes and their products that are
associated with different diseases and may be targets for new
treatments.
• 2) Identification of genes and allelic variants of genes that
may affect the response to drugs for diseases.
11. History of pharmacogenetics
First discovered of Pharmacogenetics
was over 50 years ago.
A person with a genetic polymorphism
leads to deficiency G6PD
The time needed to Treatment with
primaquine
Hemolysis
12. History of pharmacogenetics
• Pythagoras510 BC(Some people eat fava anemia)
• Fredrich Vogel Word of pharmacogenetics(at first In 1959)
• Sir Archibald Garrod The role of genetics in response to
drugs(1990)
• In 1990, the emergence and development of the field was
divided into four periods:
The first stage (1910-1850)
The second stage (1950-1910)
The third stage (1990-1950)
The fourth stage (1990 and thereafter)
13. History of pharmacogenetics
The first stage(1910-1850)
With the discovery of three findings :
The ability of the body's metabolism of foreign substances
(chemists and physiologists)
Mendelian inheritance (Gregory Mendel)
and drug receptors (Ehrlich)
Sir Archibald Garrod Said:
Errors of metabolism and chromosome in human and therefore
specific and personal biochemistry in each person is hereditary.
14. History of pharmacogenetics
The second stage (1950-1910) it seems to me, the most important
step
Archibald Garrod, William Bateson ,Lucien Cuenot genetic material has
an important role in the transfer of chemicals and chemical changes.
Marshal(1918) Blacks are more than resistant whites, against the
mustard gas
Chen & middleton Changes of ephedrine, and cocaine in the expansion
of eyes in white, black and Chinese are different.
1920s Differences in perceptions and emotions were discovered.
Synder(1932) Deficiency of taste is an inherited
Alcohol dehydrogenase and aldehyde dehydrogenase deficiency Was
discovered.
15. History of pharmacogenetics
N- acetyltransferase polymorphism Racial distribution and depends on
the latitude of countries.
Finally, double-stranded helix structure of DNA was discovered.
Polymorphism discovery in hemoglobin Sickle cell disease
the SNP of: HFE gene hemochromatosis
Apolipoprotein E=ApoE Cardiovascular and Alzheimer's disease,
Factor’s gene 5 and protrombin gene thrombosis
Methylene Tetra Hydro Folate Reductase=MTHFR) Venous
thromboembolism
Start correct and systematic pharmacogenetics.
thus
16. History of pharmacogenetics
The third stage (1990-1950) and The fourth stage (1990 and
thereafter)
• In 1956 the human chromosomes were observed.
• Chronic myelogenous Leukemia(CML) Its association with chromosomal
defects (Philadelphia chromosome)
• Advances in technology
• The inheritance pattern of responses to some of the drugs were found
during this period.
• Until 1990, about100 of properties polymorphic and monomorphic
pharmacogenetics were identified.
17. There is a great deal of variability at the DNA level
between individuals that governs many characteristics
of the person, including his or her ability to respond to
a particular drug therapy:
SNPs account for over 90% of the genetic variations
in the human genome.
deletions,
tandem repeats,
and microsatellites
Genetics and metabolism of drugs
18. Single-nucleotide polymorphisms(SNPs) effect on
Pharmacogenomics :
Single Nucleotide Polymorphism (SNP):
GAATTTAAG
GAATTCAAG
SNPs are defined as Single base-pair positions
in genomic DNA that vary among individuals
in one or several populations.
SNPs are believed to underlie susceptibility
to such common diseases as cancer, diabetes,
and heart disease and to contribute to the
traits that make individuals unique.
SNPs are used as genomic biomarkers.
Hence SNP analysis can be used to enhance
drug discovery and development.
DNA molecule 1 differs from DNA
molecule 2 at a single base-pair
location (a C/T polymorphism)
Shahid Chamran university of Ahvaz
19. Clinical trials and the creation of an SNP linkage
disequilibrium database for a fictitious drug
Shahid Chamran university of Ahvaz
20. Genetics and metabolism of drugs
Based on the response to a drug, individuals can be classified
as poor or extensive metabolizers.
Molecular genetic testing can characterize an enzyme’s gene
to demonstrate which alleles (genetic polymorphisms) are
present, and how such alleles may affect enzymatic activity.
Some of these alleles may be associated with loss or
reduction of gene function (alleles are denoted by an asterisk
(*) and a number). In general, *1 usually means a normally
functioning gene, and hence a normally functioning enzyme.
21. Different metabolizers of a drug that depend
on genetic makeup include:
Extensive Metabolizers (EM): Individuals who have two
normal genes metabolize a drug normally.
Poor Metabolizers (PM): Individuals with two non-functional
genes metabolize a drug very slowly compared to a normal
individual (EM).
Ultra-Rapid Metabolizers (UM): These individuals may have
multiple copies of active genes and may metabolize a particular
drug so fast that the drug doesn’t have any pharmacological
effect.
Intermediate Metabolizers (IM): These individuals may have
one active and one non-active allele for the same gene.
24. Drug target
There are three types of genetic variety:
Some cases which play a role in the transmission,
distribution and elimination of external factors.
Those that cause adverse drug reactions in the
body.
And genetic variation which are targets of a drug.
26. Drug target
Genetic variants in response to therapeutic
agents:
Enzymes which play a role in drug
metabolism
A drug targets proteins (transmitter and
receiver drug or drug carriers).
27. POLYMORPHISM OF ENZYMES RESPONSIBLE FOR DRUG
METABOLISM
Most drugs undergo phase I metabolism, which involves oxidation,
reduction, or hydrolysis. Such reactions transform the drug into a more
polar water-soluble metabolite.
some drugs can undergo phase II metabolism, which entails conjugation of
a polar group to the drug molecule to make it more polar.
Enzymes responsible for such transformations may show a wide variation
in enzymatic activities due to genetic polymorphisms.
The goal of pharmacogenomics is to understand such genetic
variations in order to predict the response of a particular
drug in a particular patient.
28. POLYMORPHISM OF ENZYMES RESPONSIBLE
FOR DRUG METABOLISM
The cytochrome P-450 mixed-function oxidase (CYP)
are N-acetyltransferase (NAT1 and NAT2)
thiopurine-S-methyltransferase (TPMT)
polymorphism of uridine-5 diphosphate glucuronyl
transferase (UDP-glucuronyl transferase)
29. Effect of Cytochrome P450 Enzymes on Drug Metabolism:
The cytochrome P-450 mixed-function oxidase (CYP), the most important
family of enzymes responsible for drug metabolism, comprises a large
group of heme-containing enzymes.
These enzymes are found in abundance in the liver and other organs.
The major CYP isoforms responsible for the metabolism of drugs include
CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4/CYP3A5.
30. Effect of Cytochrome P450 Enzymes on Drug Metabolism:
Cytochrome P450 enzymes are essential for the
metabolism of many medications.
The most significant enzymes are : CYP3A4 and
CYP2D6.
Shahid Chamran university of Ahvaz
31. Enzymes involved in Pharmacogenomics:
Cytochrome P450 (CYP) family of
enzymes is involved in metabolism of
several drugs.
Example: CYP2D6 enzyme
CYP3A4 enzyme
CYP2A6enzyme
CYP2B6 enzyme
CYP2C9enzyme
CYP2C19enzyme
CYP2E1 enzyme
32. An example of different CYP2D6 alleles and their
effects on enzyme function
33. Key points regarding CYP enzymes:
CYP3A4 is the predominant isoform of the CYP family
(almost 30%), and is responsible for the metabolism of
many drugs.
Genetic polymorphisms of CYP2D6, CYP2C9, and
CYP2C19 have been well studied and account for some
wide interindividual responses to various drugs.
If the enzymatic activity is lost or significantly reduced due
to a genetic polymorphism, then the individual may not be
able to metabolize a particular drug (that is typically
metabolized through that enzyme) effectively, and can suffer
from drug toxicity.
34. Other polymorphically expressed drug-metabolizing enzymes
a polymorphism of uridine-5 diphosphate glucuronyl transferase (UDP-
glucuronyl transferase) may also play a vital role in metabolism of certain
drugs (e.g. irinotecan, an anticancer drug).
This enzyme is responsible for conjugation of glucuronic acid with the drug
molecule in phase II metabolism, thus inactivating the drug.
This enzyme is mostly found in the liver, but may also be present in other
organs.
There are two main families of UDP-glucuronyl transferase: UGT1 and
UGT2.
Polymorphisms of UGT1A1 and UGT2B7 play important roles in the phase
II metabolism of certain drugs.
35. Other polymorphically expressed drug-metabolizing enzymes
N-acetyltransferase (NAT1 and NAT2) and thiopurine-S-methyltransferase
(TPMT).
The slow acetylator phenotype of the NAT1/2 polymorphism results in
isoniazid-induced peripheral neuropathy and sulfonamide-induced hyper-
sensitivity reactions
while TPMT catalyzes inactivation of various anticancer and anti-
inflammatory drugs.
36. Polymorphisms of the transporter and
receptor proteins:
Most drug responses Interaction of several
gene products that affect the pharmacokinetics
and pharmacodynamics.
Today 500 to 1200 genes of drug transporter have
been identified
The best example of a drug transporter:
multidrug-resistant transporter
and p-glycol- protine /MDR1
37. AmpliChip CYP450Using FDA-approved test
kit
• Determine the genotype of the patient
in terms of two CYPP450 enzymes: 2D6
and 2C19
• FDA approved the test on December 24,
2004. The AmpliChip CYP450 test is the
first FDA approved pharmacogenetic
test.
Pharmacogeneticstestingmethods
38. Pharmacogenetics testing methods
Technologies and methods that used in pharmacogenetics:
1. The DNA microarray
2 -pyro-sequencing
3. Mass Spectrometry
4-Fluorescence based-platform
5-RFLP and RTPCR and their types (such as PCR-5 QPCR)
39. Pharmacogenetics and clinical application
pharmacogenomics is one of the main members of
Individual therapy.
Recipients of treatment with:
o Warfarin
o Chemotherapy by Specific anticancer drugs
o Pain management with certain opioids
40. Examples of drugs where pharmacogenomics testing is useful are
listed in this Table
Shahid Chamran university of Ahvaz
41. Pharmacogenetics and clinical application
Pharmacogenetics in oncology:
Pharmacogenetics focused on the effects of genetics in cancer
treatment.
Pharmacogenetics And selection of anticancer drugs:
• Thiopurine
• Irinotecan،
• Tamoxifen
42. Thiopurine such as :
6-mercaptopurine (6-MP)
thioguanine
and azathioprine (TPMT)
Metabolized by: thiopurine-S-methyl transferase (TPMT)
Pharmacogenetics and clinical application
48. Tamoxifen (estrogen receptor-positive breast
cancer)
Tamoxifen is a prodrug
endoxifen (4-hydroxy-N-desmethyl-tomoxifer)
Tamoxifen
By CYP2D6
49. Pharmacogenetics in Cardiovascular Disease
Shahid Chamran university of Ahvaz
• Current Status of Pharmacogenetics in
Antithrombotic Drug Therapy:
• The impact of VKORC1 and CYP2C9
variants on warfarin response, established
the value of genetic variability to predict
the appropriate warfarin dose for
improving and easing the transition to a
therapeutic INR level.
50. Pharmacogenetics in Cardiovascular Disease
Pharmacogenetics and warfarin treatment
• Respond differently to warfarin dose:
CYP2C9 genetic polymorphisms
Vitamin K epoxide reductase complex (VKORC1)
Patients with CYP2C9 * 2 and CYP2C9 * 3 alleles Need
lower maintenance dose of warfarin
51. Warfarin consists of a racemic mixture of two
active enantiomers—R and S- forms
Shahid Chamran university of Ahvaz
55. Drugs used for pain management, such as:
Codeine , Dihydrocodeine, Fentanyl ,Hydrocodone
Methadone ,Morphine ,Oxycodone ,Tramadol, Tricyclic
antidepressante
• Metabolized By :
• polymorphic CYP450 enzymes such as:CYP2D6 and
CYP3A4
• And UGT2B7(uridine diphosphate glucuronyl transferase 2B7)
Pharmacogenetics in Selection of opioids
56. Shahid Chamran university of Ahvaz
• ultra-metabolizers Multiple copies of
the gene CYP2D6
• extensive-metabolizer With a single
copy of the wild type gene of CYP2D6
• intermediate metabolizers Decrease in
enzyme activity
• poor metabolizers any activity
58. The metabolism of codeine to morphine by CYP2D6
Shahid Chamran university of Ahvaz
59. The tricyclic antidepressant amitriptyline is
metabolized by CYP2C19 to the active metabolite
nortriptyline.
CYP2D6 is needed for deactivation of
nortriptyline.
Adverse drug reactions tend to be associated with
nortriptyline concentrations,
And poor metabolizers of CYP2D6 are more likely
to suffer from adverse effects due to the build-up
of nortriptyline concentrations.
Pharmacogenetics in Selection Psychoactive drugs
60. Pharmacogenetics in other miscellaneous drugs
• Organ transplant recipients receive immunosuppressants in
order to prevent organ rejection.
• These drugs are metabolized by the cytochrome P-450 family
of enzymes, including CYP3A4 and CYP3A5.
• Although polymorphisms of CYP3A4 do not alter the enzyme
activity significantly,
• polymorphisms of CYP3A5 may be clinically more significant
because enzyme activities can vary significantly between
different alleles.
61. Pharmacogenetics in other miscellaneous drugs
• Pharmacogenomics testing can be used to identify
polymorphisms of CYP3A5 to predict optimal initial dosage of
Tacrolimus.
• HLA-B*1502, which is more abundant among Asians, is
associated with severe skin rashes (including Stevens Johnson
syndrome) following treatment with carbamazepine.
• HLA-B*5701 is strongly associated with hypersensitivity
towards the anti-HIV drug abacavir.
• HLA-B*5801 is associated with hypersensitivity to allopurinol
62. Shahid Chamran university of Ahvaz
1. Preparing profiles related to sensitivity of the
pharmaceutical, food and other external factors.
2. Preparing profiles of the SNP.
3. Create profiles of diagnostic markers and
laboratory tests
4. Determination of the location of the cell and
function of proteins and metabolic pathways in
different cell lines.
Necessary action to Advancement of
pharmacogenetics in the future
63. Shahid Chamran university of Ahvaz
5. Preparing profiles of ethnic diversity and racial.
6. The appropriate design of drugs
7. Comparison profiles between the genomes of
different organisms
Necessary action to Advancement of
pharmacogenetics in the future
69. Irinotecan
CAMPTOSAR®
CRC
UGT1A1
First FDA approved pharmacogenetic test ““Third Wave Technologies, Invader
assay”” (2005), with dose optimization guidelines dependent on UGT1A1 genotype:
avoid severe (grade III/IV) neutropenia and diarrhoea for those who are at high risk,
i.e. Homozygous (and possibly heterozygous) for UGT1A1*28 and UGT1A1*1 alleles.
Warfarin
COUMADIN®
Thrombo-embolism
CYP2C9 and
VKORC1
(-1639G>A)
Improve drug efficacy and safety: avoid increased risk of bleeding to patients
homozygous or heterozygous for CYP2C9*2 or CYP2C9*3 alleles by prescribing
differentiated doses (as compared with those for CYP2C9*1 homozygous).
Pharmacogenetic test: ““Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test;
therapeutic algorithm based on genotype and clinical factors
(http://www.WarfarinDosing.org.)
Clopidogrel
(prodrug)
PLAVIX®
Thrombo-embolism
CYP2C19
Improve efficacy and safety: doses adjustment for ultrarapid metabolizers who are
carriers of CYP2C19*17/*17 genotype and for poor metabolizers due to CYP2C19*2
allele presence.
Carbamazepine
TEGRETOL®
Epilepsy
HLA-B*1502
allele
Improve drug safety: avoid serious dermatologic reactions (Stevens––Johnson
syndrome and/or toxic epidermal necrolysis).
Drug
Indication
Pharmacogenetic
biomarker Comments
Rasburicase
ELITEK®
Hyperuricemia G6PD
Improve drug safety: pre-therapy screening to avoid severe hemolytic reactions
associated with G6PD deficiency.
70. Clozapine CLOZARIL®
Schizophrenia HLA-DQB1
Improved safety: pharmacogenetic testing, in parallel with WBC monitoring, avoid
prescription to patients with high agranulocytosis risk.
Test „„PGxPredict: Clozapine””
Tretinoin VESANOID® APL PML/RARD Improve drug efficacy and safety.
Disease confirmation by t(15;17) cytogenetic marker
Valproic acid
DEPAKENE®
Seizures
UCD deficiency
Confirm disease: consider evaluation of UCD before therapy with valproate
Only informational pharmacogenetic tests in drug label
Panitumumab
VECTIBIX®
Cetuximab
ERBITUX® mCRC
K-RAS Improve efficacy: clinical benefit limited to patients with nonmutated K-RAS.
Imatinib
GLEEVEC®
GIST
C-KIT
Improve drug efficacy: clinical benefit in patients carriers of the activating C-KIT
mutation
Busulfan
MYLERAN®
CML
Philadelphia chromosome Improve drug efficacy: responders are positives for Philadelphia chromosome (BCR-
ABL)
Capecitabine
XELODA®
CRC
DPD deficiency
Improve drug safety: decreased DPD and increased level of 5fluorouracil is associated
with severe toxicity (e.g., stomatitis, diarrhoea, neutropenia and neurotoxicity).
Primaquine Malaria G6PD
deficiency
Improve drug safety: avoid acute intravascular hemolytic reactions.
Isoniazid,
Pyrazinamide
TB
NAT
Improve drug safety: dose adjustements based on NATmetabolic status, for slow
acetylators and fast acetylators to avoid severe adverse reaction of peripheral
neuropathy, or lack of efficacy, respectively.
Erlotinib
TARCEVA® NSCLC EGFR mutations
Confirm disease (at least 10% of the cells are EGFR-positive) and response to EGFR
tyrosine kinase inhibitors
Lenalidomide
REVLIMID®
Myelodysplasic syndromes
Deletion of chromosome
5q
(del[5q])
Confirm disease: indicated to treat those with transfusion dependent anemia caused
by low- or intermediate-risk of myelodysplasic syndromes associated with 5q(del[5q])